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Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis

Primary Purpose

AL Amyloidosis

Status
Not yet recruiting
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Autologous Hematopoietic Stem Cell Transplantation
Biopsy
Biospecimen Collection
Bone Marrow Aspiration
Bone Marrow Biopsy
Bortezomib
Computed Tomography
Cyclophosphamide
Daratumumab and Hyaluronidase-fihj
Dexamethasone
Echocardiography
Magnetic Resonance Imaging
Melphalan
Positron Emission Tomography
Stem Cell Isolation
Survey Administration
Sponsored by
SWOG Cancer Research Network
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for AL Amyloidosis

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: STEP 1: Participants must have systemic AL amyloidosis which is biopsy proven and includes histologically-confirmed by positive Congo red stain with green birefringence on polarized light microscopy, OR characteristic appearance by electron microscopy AND confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or immunofluorescence). If there is question regarding diagnosis, consult study chairs prior to registration STEP 1: Participants must have measurable disease within 28 days prior to treatment if initiated prior to registration or within 28 days of registration as defined by at least one of the following: Positive monoclonal serum immunofixation electrophoresis Positive monoclonal urine immunofixation electrophoresis Monoclonal plasma cells in bone marrow In addition, participants must also have a difference between the involved and uninvolved free light chain (dFLC) >= 2 mg/dL STEP 1: Participants may receive up to one cycle (or 28 days) of therapy prior to enrollment. If a patient receives >= 75% of 1 cycle of protocol identical Dara-VCD, this will be considered 1 cycle of protocol induction. Any patient who receives less than 75% of 1 cycle of Dara-VCD or non-protocol therapy will still be eligible but will be treated per protocol. If protocol identical therapy is initiated prior to enrollment, this treatment is not continued but rather treatment is dictated per protocol STEP 1: Participants may be receiving chronic corticosteroids if they are being given for disorders other than AL amyloidosis or myeloma STEP 1: Participant must be >= 18 years old STEP 1: Participant must have Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0, 1, or 2 (PS = 3 may be allowed if secondary to neuropathy) STEP 1: Participant must have a complete medical history and physical exam within 28 DAYS prior to registration STEP 1: Participants must be willing to undergo high dose chemotherapy and autologous stem cell transplantation if they are randomized to the arm receiving high dose chemotherapy and autologous stem cell transplantation STEP 1: Participants must be eligible to receive high dose chemotherapy with melphalan at a dose of 200 mg/m^2 or 140 mg/m^2 (200 mg/m^2 is highly encouraged but not mandated). Transplant eligibility criteria are included in the general eligibility criteria listed below: Participant must have a supine systolic blood pressure (BP) >= 90 mmHg (at registration step-1, this may by supported by midodrine Participant must have non-severe cardiac AL (meeting all the below criteria) as defined by: N-terminal proB-type natriuretic peptide (NT proBNP) < 5000 (if no NTproBNP, brain natriuretic peptide [BNP] must be available and < 400) Troponin T (TnT) < 0.06. If not available, one of the following two criteria must be met: High sensitivity troponin (hsTnT) T < 75 or troponin I < 0.1ng/dL New York Heart Association (NYHA) I or II Cardiac ejection fraction (EF) >= 40% STEP 1: Hemoglobin >= 8.0 g/dL (> 5 mmol/L); red blood cell transfusion allowed up to 7 day prior to registration (within 28 days prior to registration) (NOTE: Growth factor support granulocyte colony-stimulating factor [G-CSF] is permitted per institutional guidelines) STEP 1: Leukocytes >= 2 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 1: Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 1: Platelets >= 50 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 1: Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration) STEP 1: Direct bilirubin =< 2.0 mg/dL (within 28 days prior to registration) STEP 1: Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3x upper limit of normal (ULN) (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 1: Alkaline phosphatase =< 750 U/L (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 1: Participants must have a serum creatinine =< the institutional (I)ULN OR measured OR calculated creatinine clearance >= 30 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 28 days prior to registration STEP 1: If peripheral neuropathy is present at diagnosis, participants must be grade 2 (moderate symptoms; limiting instrumental activity of daily living [ADL]) or less STEP 1: Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2 or better STEP 1: Participants must not be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR STEP 1: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated STEP 1: Participants must not have concurrent multiple myeloma as defined by the presence of lytic bone disease, plasmacytomas, >= 60% plasma cells in the bone marrow, or hypercalcemia. Participants will not be excluded solely based on the presence of plasma cells > 10% in the bone marrow unless the plasma cell percentage exceeds >60% STEP 1: Participants must not have known allergies to any of the study drugs STEP 1: Participants must not have had a major surgery within 14 days prior to registration and be fully recovered from surgery completed within 14 days prior to registration STEP 1: Participants must not have a known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal STEP 1: Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration STEP 1: Participants must not have either moderate or severe persistent asthma within the past 2 years), or currently have uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study) STEP 1: Participants must not have uncontrolled diabetes within 28 days prior to registration STEP 1: Participants must not have uncontrolled blood pressure and hypertension within 14 days prior to registration. Participants must have a supine systolic BP of >= 90 mmHg STEP 1: Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen STEP 1: Participants must not have received vaccination with live attenuated vaccines within 28 days prior to Registration to Step 1 STEP 1: Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment STEP 1: Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen STEP 1: Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the Southwestern Oncology group (SWOG) Specimen Tracking System STEP 1: Participants must agree to have blood, bone marrow core biopsy and aspirate, and fat pad biopsy specimens submitted for minimal residual disease assessment and future exploratory studies STEP 1: Participants who can complete PRO, QOL, PRO-CTCAE questionnaires, etc. forms in English, Spanish and French must participate in the patient-reported outcomes and quality of life STEP 2: Participants must have met all eligibility criteria for Step-1 registration STEP 2: Participants must have achieved at least a partial response STEP 2: Participants must continue receiving at least one of study drugs (bortezomib, cyclophosphamide, or daratumumab and hyaluronidase-fihj) if another study drug (daratumumab and hyaluronidase-fihj, cyclophosphamide, or bortezomib) has been discontinued due to adverse events. Note: daratumumab and hyaluronidase-fihj cannot be permanently discontinued STEP 2: Participants must have completed induction therapy STEP 2: Participants must be registered to Step 2 within 42 days of cycle 3, day 28 of induction therapy STEP 2: Participants must plan to initiate their assigned consolidation therapy within 8 weeks after randomization STEP 2: Participants must not have experienced a MOD-PFS event STEP 2: Participants must have ECOG performance score (PS) of 0, 1, or 2 (PS = 3 may be allowed if secondary to neuropathy) STEP 2: Participant must have a complete medical history and physical exam within 28 days prior to registration STEP 2: Participants must be willing to undergo high dose chemotherapy and autologous stem cell transplantation if they are randomized to the arm receiving high dose chemotherapy and autologous stem cell transplantation STEP 2: Participants randomized to Arm 2 must be willing and able to return to a participating treatment center for their assigned treatment after transplant. Note that participants need not to have a direct relationship with the transplant center in order to register STEP 2: Participants must be eligible to receive high dose chemotherapy with melphalan at a dose of 200 mg/m^2 or 140 mg/m^2 (200 mg/m^2 is highly encouraged but not mandated). Transplant eligibility criteria are included in the general eligibility criteria listed below: Patient must have a supine systolic BP >= 90 mmHg (at registration step-1, this may not by supported by midodrine) Patient must have non-severe cardiac AL as defined by: NT proBNP <5000 (if no NTproBNP, BNP must be available and < 400 pg/mL) (within 14 days prior to registration step-2) TnT < 0.06. If not available, one of the following two criteria must be met (within 14 days prior to registration step-2) hsTnT <75 or troponin I < 0.1ng/dL NYHA I or II (within 14 days prior to registration step-2) Cardiac EF >= 40% (within 14 days prior to registration step-2) STEP 2: Hemoglobin > 8.0 g/dL (> 5 mmol/L); red blood cell transfusion allowed up to 7 days prior to registration (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Leukocytes >= 2 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Platelets >= 50 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Total bilirubin =< 1.5 times the institutional ULN unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration) STEP 2: Direct bilirubin =< 2.0 mg/dL (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 2: AST/ALT =< 3x upper limit of normal (ULN) (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 2: Alkaline phosphatase =< 750 U/L (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 2: Participants must have a serum creatinine =< the IULN OR calculated creatinine clearance ≥ 30 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration STEP 2: Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment STEP 2: Participants randomized to the ASCT arm must be able to have at least 2.0 x 10^6 CD34 cells/kg collected STEP 2: Participants who can complete PRO, QOL, PRO-CTCAE questionnaires, etc. forms in English, Spanish and French must participate in the patient-reported outcomes and quality of life STEP 3: Participants must have met all eligibility criteria for Step-1 and Step-2 registration STEP 3: Participants must not have had daratumumab and hyaluronidase-fihj permanently discontinued during induction or consolidation STEP 3: Participants must have completed induction and consolidation therapy STEP 3: Participants must be registered to Step 3 within the following time frames: If randomized to Arm 1 Dara-VCD consolidation: within 28 days of completion of 3 cycles of consolidation therapy If randomized to Arm 2 high dose chemotherapy and autologous stem cell transplantation: within 180 days following initiation of stem cell transplantation STEP 3: Participants must not have experienced a MOD-PFS event STEP 3: Participants must have ECOG performance score (PS) of 0, 1, or 2 (PS = 3 is allowed if secondary to neuropathy) STEP 3: Participants must have a complete medical history and physical exam within 28 DAYS prior to registration STEP 3: Hemoglobin > 8.0 g/dL (> 5 mmol/L); red blood cell transfusion allowed up to 7 days prior to registration (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Leukocytes >= 2 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Platelets >= 50 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration) STEP 3: Direct bilirubin =< 2.0 mg/dL (within 28 days prior to registration) STEP 3: AST/ALT =< 3x upper limit of normal (ULN) (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 3: Alkaline phosphatase =< 750 U/L (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 3: Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm 3

    Arm 4

    Arm Type

    Active Comparator

    Experimental

    Experimental

    Experimental

    Arm Label

    Consolidation Arm I (Chemotherapy)

    Consolidation Arm II (Chemotherapy, ASCT)

    Induction (Chemotherapy)

    Maintenance (daratumumab and hyaluronidase-fihj)

    Arm Description

    Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1 and 15 as well as bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within14-28 days post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression.

    Patients undergo collection of peripheral blood stem cells. Patients receive melphalan IV for 1 cycle and then 2 days later receive the stem cell transplant IV in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within 60-90 days post initiation of stem cell transplant. Patients undergo blood and urine sample collection at screening, during treatment, and the end of treatment and during follow up or at progression.

    Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1, 8, 15 and 22 for 2 cycles and then days 1 and 15 for cycle 3. Patients receive bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI or PET-CT and fat pad aspiration at screening. Patients undergo echocardiography at screening, the completion of induction, and at progression. Patients undergo bone marrow aspiration and biopsy at screening, post induction treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression.

    Patients receive maintenance daratumumab and hyaluronidase-fihj SC over 3-5 minutes on day 1 of each cycle. Cycles repeat every 28 days for up 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening, 12 months post consolidation treatment and at progression. Patients undergo bone marrow aspiration and biopsy 12 months post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, during treatment, 12 months post consolidation treatment and during follow up or at progression.

    Outcomes

    Primary Outcome Measures

    Major organ deterioration progression-free survival (PFS)
    Will be performed using a stratified log-rank test for comparison between study arms. The analyses will be stratified according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 versus [vs.] 2-3), hematological response following 2 cycles of daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) induction (partial response [PR] or worse vs. very good partial response [VGPR] or better), and presence of t(11;14) by interphase fluorescence in situ hybridization [iFISH] (yes vs. no). All eligible participants will be considered in analyses of the primary endpoint, according to their assigned arm at randomization.

    Secondary Outcome Measures

    Overall survival
    Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. [VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Hematologic PFS
    Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Cardiac and renal organ response rates
    Progression will be defined based on objective evidence of worsening of organ dysfunction due to AL amyloid. Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Measurable residual disease (MRD) negativity rate
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Best overall hematologic response
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Overall hematologic response rate
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Rate of complete response
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Rate of very good complete response or better
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time to next treatment
    Will be analyzed using the cumulative incidence competing risks method.
    Change in patient reported health quality of life (QOL)
    Will use the PROMIS-29+2 (version 2.1) to compare the physical function between participants in the ASCT vs. non-ASCT arm.
    Incidence of adverse events
    Participant-reported toxicity will be examined using Patient Reported Outcome-Common Terminology Criteria for Adverse Events.

    Full Information

    First Posted
    August 11, 2023
    Last Updated
    August 28, 2023
    Sponsor
    SWOG Cancer Research Network
    Collaborators
    National Cancer Institute (NCI)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT06022939
    Brief Title
    Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis
    Official Title
    A Phase III, Randomized Study of Daratumumab, Cyclophosphamide, Bortezomib and Dexamethasone (Dara-VCD) Induction Followed by Autologous Stem Cell Transplant or Dara-VCD Consolidation and Daratumumab Maintenance in Patients With Newly Diagnosed AL Amyloidosis
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Not yet recruiting
    Study Start Date
    October 31, 2023 (Anticipated)
    Primary Completion Date
    July 29, 2030 (Anticipated)
    Study Completion Date
    October 29, 2030 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    SWOG Cancer Research Network
    Collaborators
    National Cancer Institute (NCI)

    4. Oversight

    Studies a U.S. FDA-regulated Drug Product
    Yes
    Studies a U.S. FDA-regulated Device Product
    No
    Data Monitoring Committee
    Yes

    5. Study Description

    Brief Summary
    This phase III trial compares the effect of adding a stem cell transplant with melphalan after completing chemotherapy with daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) versus chemotherapy with Dara-VCD alone for treating patients with newly diagnosed amyloid light chain (AL) amyloidosis. Melphalan is a chemotherapy given prior to a stem cell transplant. Giving chemotherapy before a peripheral blood stem cell transplant helps kill cancer cells in the body and helps make room in the patient's bone marrow for new blood-forming cells (stem cells) to grow. The stem cells are then returned to the patients to replace the blood forming cells that were destroyed by the chemotherapy. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and cancer cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill cancer cells. Chemotherapy drugs, such as cyclophosphamide and bortezomib, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Dexamethasone is in a class of medications called corticosteroids. It is used to lower the body's immune response to help stop the growth of cancer cells. Giving a stem cell transplant with melphalan after Dara-VCD may kill more cancer cells in patients with newly diagnosed AL amyloidosis.
    Detailed Description
    PRIMARY OBJECTIVE: I. To compare major organ deterioration progression-free survival between participants randomized to the autologous stem cell transplant (ASCT) and non-ASCT arms of this study. SECONDARY OBJECTIVES: I. To compare overall survival (OS) between participants randomized to the ASCT and non-ASCT arms of this study. II. To compare rates of cardiac and renal organ responses between participants randomized to the ASCT and non-ASCT arms of this study. III. To compare rates of cardiac and renal organ progression between participants randomized to the ASCT and non-ASCT arms of the study. IV. To compare the frequency and severity of toxicities between participants randomized to the ASCT and non-ASCT arms of this study. V. To compare minimal residual disease (MRD) negativity rates between participants randomized to the ASCT and non-ACST arms of this study. ADDITIONAL OBJECTIVES: I. To compare the best overall hematologic response rates between participants randomized to the ASCT and non-ASCT arms of this study. II. To compare rates of hematologic complete response (CR) and very good partial response, following completion of consolidation therapy between participants randomized to the ASCT and non-ASCT arms of this study, post-consolidation. III. To compare hematologic progression-free survival between participants randomized to the ASCT and non-ASCT arms of this study. IV. To compare time to next treatment between participants randomized to the ASCT and non-ASCT arms of the study. V. To evaluate utilization of delayed ASCT in participants randomized to the non-ASCT arm of the study. TRANSLATIONAL MEDICINE PRIMARY OBJECTIVES: I. To compare MRD negativity rates from bone marrow aspirates via next generation flow cytometry (NGF) between the ASCT and non-ASCT arms of this study post-consolidation. II. To bank specimens for future use. TRANSLATIONAL MEDICINE EXPLORATORY OBJECTIVES: I. To evaluate MRD negativity rates at post-induction, and compare MRD negativity rates at 12 months post-consolidation from bone marrow aspirates via NGF between participants randomized to the ASCT and non-ASCT arms of this study. II. To investigate the association of achieving MRD negativity at any point (post-induction, post-consolidation, or 12 months post-consolidation) via NGF from bone marrow aspirates with major organ deterioration-progression free survival (MOD-PFS). III. To investigate the association of achieving sustained MRD negativity (MRD negative at two consecutive measurements -- post-induction, post-consolidation, and 12 months post-consolidation) via NGF from bone marrow aspirates with MOD-PFS. QUALITY OF LIFE (QOL) PRIMARY OBJECTIVE: I. To compare patient-reported physical function following consolidation treatment between participants randomized to the ASCT and non-ASCT arms using the Patient Reported Outcomes Measurement Information System (PROMIS)-29+2 Profile version (v) 2.1 physical function sub-scale. QOL SECONDARY OBJECTIVES: I. To compare patient-reported fatigue following consolidation treatment between participants randomized to the ASCT and non-ASCT arms using the PROMIS-29 fatigue subscale. II. To compare longitudinal changes in physical function using the PROMS-29+2 between participants randomized to the ASCT and non-ASCT arms. QOL EXPLORATORY OBJECTIVES: I. To assess baseline symptom burden in AL amyloidosis patients prior to induction therapy using the PROMIS-29+2. II. To compare mean scores of symptom scales using the PROMIS-29+2 following consolidation treatment, and at 6 months and 12 months from step 3 registration between treatment arms. III. To compare mean scores of functional scales using the PROMIS-29+2, following consolidation treatment, and at 6 months and 12 months from step 3 registration between treatment arms. IV. To explore whether longitudinal changes in symptoms, functioning, and overall heath related quality of life (HRQoL) as assessed by the PROMIS-29 +2 (version 2.1) differ according to treatment group and, separately, according to baseline cardiac or renal involvement using interaction tests between participants randomized to the ASCT and non-ASCT arms. V. To compare health utility indices using the PROMIS preference score (PROPr) between patients randomized to the ASCT and non-ASCT arms. PATIENT REPORTED OUTCOME (PRO)-COMMON TERMINOLOGY CRITERIA FOR ADVERSE EVENTS (CTCAE) PRIMARY OBJECTIVE: I. To compare patient reported symptoms regarding treatment emergent adverse events of interest using the Patient Reported Outcome CTCAE (PRO-CTCAE) Measurement System between patients randomized to the ASCT and non-ASCT arms of this study. OUTLINE: INDUCTION: Patients receive daratumumab and hyaluronidase-fihj subcutaneously (SC) over 3-5 minutes on days 1, 8, 15 and 22 for 2 cycles and then days 1 and 15 for cycle 3. Patients receive bortezomib SC over 3-5 minutes, cyclophosphamide orally (PO) or intravenously (IV), and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo computed tomography (CT), magnetic resonance imaging (MRI) or positron emission tomography (PET)-CT and fat pad aspiration at screening. Patients undergo echocardiography at screening, the completion of induction, and at progression. Patients undergo bone marrow aspiration and biopsy at screening, post induction treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression. CONSOLIDATION: Patients who achieve an overall response of partial response or better after 3 cycles of Dara-VCD are randomized to 1 of 2 arms. ARM I: Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1 and 15 as well as bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within14-28 days post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression. ARM II: Patients undergo collection of peripheral blood stem cells. Patients receive melphalan IV for 1 cycle and then 2 days later receive the stem cell transplant IV in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within 60-90 days post initiation of stem cell transplant. Patients undergo blood and urine sample collection at screening, during treatment, and the end of treatment and during follow up or at progression. MAINTENANCE: Patients receive maintenance daratumumab and hyaluronidase-fihj SC over 3-5 minutes on day 1 of each cycle. Cycles repeat every 28 days for up 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening, 12 months post consolidation treatment and at progression. Patients undergo bone marrow aspiration and biopsy 12 months post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, during treatment, 12 months post consolidation treatment and during follow up or at progression. After completion of study treatment, patients are followed up every 3 or 6 months up to 4 years after registration.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    AL Amyloidosis

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Sequential Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    338 (Anticipated)

    8. Arms, Groups, and Interventions

    Arm Title
    Consolidation Arm I (Chemotherapy)
    Arm Type
    Active Comparator
    Arm Description
    Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1 and 15 as well as bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within14-28 days post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression.
    Arm Title
    Consolidation Arm II (Chemotherapy, ASCT)
    Arm Type
    Experimental
    Arm Description
    Patients undergo collection of peripheral blood stem cells. Patients receive melphalan IV for 1 cycle and then 2 days later receive the stem cell transplant IV in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening and at progression. Patients undergo bone marrow aspiration and biopsy within 60-90 days post initiation of stem cell transplant. Patients undergo blood and urine sample collection at screening, during treatment, and the end of treatment and during follow up or at progression.
    Arm Title
    Induction (Chemotherapy)
    Arm Type
    Experimental
    Arm Description
    Patients receive daratumumab and hyaluronidase-fihj SC over 3-5 minutes on days 1, 8, 15 and 22 for 2 cycles and then days 1 and 15 for cycle 3. Patients receive bortezomib SC over 3-5 minutes, cyclophosphamide PO or IV, and dexamethasone PO or IV on days 1, 8, 15 and 22 of each cycle. Cycles repeat every 28 days for up to 3 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo CT, MRI or PET-CT and fat pad aspiration at screening. Patients undergo echocardiography at screening, the completion of induction, and at progression. Patients undergo bone marrow aspiration and biopsy at screening, post induction treatment and at progression. Patients undergo blood and urine sample collection at screening, at the start of each cycle, and the end of treatment and during follow up or at progression.
    Arm Title
    Maintenance (daratumumab and hyaluronidase-fihj)
    Arm Type
    Experimental
    Arm Description
    Patients receive maintenance daratumumab and hyaluronidase-fihj SC over 3-5 minutes on day 1 of each cycle. Cycles repeat every 28 days for up 18 cycles in the absence of disease progression or unacceptable toxicity. Patients undergo echocardiography at screening, 12 months post consolidation treatment and at progression. Patients undergo bone marrow aspiration and biopsy 12 months post consolidation treatment and at progression. Patients undergo blood and urine sample collection at screening, during treatment, 12 months post consolidation treatment and during follow up or at progression.
    Intervention Type
    Procedure
    Intervention Name(s)
    Autologous Hematopoietic Stem Cell Transplantation
    Other Intervention Name(s)
    AHSCT, Autologous, Autologous Hematopoietic Cell Transplantation, Autologous Stem Cell Transplant, Autologous Stem Cell Transplantation, Stem Cell Transplantation, Autologous
    Intervention Description
    Given IV
    Intervention Type
    Procedure
    Intervention Name(s)
    Biopsy
    Other Intervention Name(s)
    BIOPSY_TYPE, Bx
    Intervention Description
    Undergo fat pad biopsy
    Intervention Type
    Procedure
    Intervention Name(s)
    Biospecimen Collection
    Other Intervention Name(s)
    Biological Sample Collection, Biospecimen Collected, Specimen Collection
    Intervention Description
    Undergo blood and urine specimen collection
    Intervention Type
    Procedure
    Intervention Name(s)
    Bone Marrow Aspiration
    Intervention Description
    Undergo bone marrow aspiration
    Intervention Type
    Procedure
    Intervention Name(s)
    Bone Marrow Biopsy
    Other Intervention Name(s)
    Biopsy of Bone Marrow, Biopsy, Bone Marrow
    Intervention Description
    Undergo bone marrow biopsy
    Intervention Type
    Drug
    Intervention Name(s)
    Bortezomib
    Other Intervention Name(s)
    [(1R)-3-Methyl-1-[[(2S)-1-oxo-3-phenyl-2-[(pyrazinylcarbonyl)amino]propyl]amino]butyl]boronic Acid, LDP 341, MLN341, PS-341, PS341, Velcade
    Intervention Description
    Given SC
    Intervention Type
    Procedure
    Intervention Name(s)
    Computed Tomography
    Other Intervention Name(s)
    CAT, CAT Scan, Computed Axial Tomography, Computerized Axial Tomography, Computerized axial tomography (procedure), Computerized Tomography, CT, CT Scan, tomography
    Intervention Description
    Undergo CT scan
    Intervention Type
    Drug
    Intervention Name(s)
    Cyclophosphamide
    Other Intervention Name(s)
    (-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719
    Intervention Description
    Given PO or IV
    Intervention Type
    Drug
    Intervention Name(s)
    Daratumumab and Hyaluronidase-fihj
    Other Intervention Name(s)
    DARA Co-formulated with rHuPH20, DARA/rHuPH20, Daratumumab + rHuPH20, Daratumumab with rHuPH20, Daratumumab-rHuPH20, Daratumumab/Hyaluronidase-fihj, Daratumumab/rHuPH20 Co-formulation, Darzalex Faspro, Darzalex/rHuPH20, HuMax-CD38-rHuPH20, Recombinant Human Hyaluronidase Mixed with Daratumumab
    Intervention Description
    Given SC
    Intervention Type
    Drug
    Intervention Name(s)
    Dexamethasone
    Other Intervention Name(s)
    Aacidexam, Adexone, Aknichthol Dexa, Alba-Dex, Alin, Alin Depot, Alin Oftalmico, Amplidermis, Anemul mono, Auricularum, Auxiloson, Baycadron, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, Decadron DP, Decalix, Decameth, Decasone R.p., Dectancyl, Dekacort, Deltafluorene, Deronil, Desamethasone, Desameton, Dexa-Mamallet, Dexa-Rhinosan, Dexa-Scheroson, Dexa-sine, Dexacortal, Dexacortin, Dexafarma, Dexafluorene, Dexalocal, Dexamecortin, Dexameth, Dexamethasone Intensol, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Dxevo, Fluorodelta, Fortecortin, Gammacorten, Hemady, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, TaperDex, Visumetazone, ZoDex
    Intervention Description
    Given PO or IV
    Intervention Type
    Procedure
    Intervention Name(s)
    Echocardiography
    Other Intervention Name(s)
    EC
    Intervention Description
    Undergo echocardiography
    Intervention Type
    Procedure
    Intervention Name(s)
    Magnetic Resonance Imaging
    Other Intervention Name(s)
    Magnetic Resonance, Magnetic resonance imaging (procedure), Magnetic Resonance Imaging Scan, Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance, MR, MR Imaging, MRI, MRI Scan, NMR Imaging, NMRI, Nuclear Magnetic Resonance Imaging
    Intervention Description
    Undergo MRI
    Intervention Type
    Drug
    Intervention Name(s)
    Melphalan
    Other Intervention Name(s)
    Alanine Nitrogen Mustard, CB-3025, L-PAM, L-Phenylalanine Mustard, L-Sarcolysin, L-Sarcolysin Phenylalanine mustard, L-Sarcolysine, Melphalanum, Phenylalanine Mustard, Phenylalanine Nitrogen Mustard, Sarcoclorin, Sarkolysin, WR-19813
    Intervention Description
    Given IV
    Intervention Type
    Procedure
    Intervention Name(s)
    Positron Emission Tomography
    Other Intervention Name(s)
    Medical Imaging, Positron Emission Tomography, PET, PET Scan, Positron emission tomography (procedure), Positron Emission Tomography Scan, Positron-Emission Tomography, proton magnetic resonance spectroscopic imaging, PT
    Intervention Description
    Undergo PET-CT
    Intervention Type
    Procedure
    Intervention Name(s)
    Stem Cell Isolation
    Other Intervention Name(s)
    Isolation, Stem Cell, Stem Cell Collection, Stem Cell Recovery
    Intervention Description
    Undergo stem cell collection
    Intervention Type
    Other
    Intervention Name(s)
    Survey Administration
    Intervention Description
    Ancillary study
    Primary Outcome Measure Information:
    Title
    Major organ deterioration progression-free survival (PFS)
    Description
    Will be performed using a stratified log-rank test for comparison between study arms. The analyses will be stratified according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 versus [vs.] 2-3), hematological response following 2 cycles of daratumumab, cyclophosphamide, bortezomib and dexamethasone (Dara-VCD) induction (partial response [PR] or worse vs. very good partial response [VGPR] or better), and presence of t(11;14) by interphase fluorescence in situ hybridization [iFISH] (yes vs. no). All eligible participants will be considered in analyses of the primary endpoint, according to their assigned arm at randomization.
    Time Frame
    From date of randomization (Step 2 registration) to date of first documentation of hematologic progression, cardiac organ progression, renal organ progression, or death due to any cause, assessed up to 4 years
    Secondary Outcome Measure Information:
    Title
    Overall survival
    Description
    Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. [VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    From randomization to date of death due to any cause, assessed up to 4 years
    Title
    Hematologic PFS
    Description
    Will be performed using a stratified log-rank test for comparison between arms, with stratification according to Mayo 2012 Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    From randomization (Step 2 registration) to date of first documentation of hematologic progression, or death due to any cause, assessed up to 4 years
    Title
    Cardiac and renal organ response rates
    Description
    Progression will be defined based on objective evidence of worsening of organ dysfunction due to AL amyloid. Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    Up to 4 years
    Title
    Measurable residual disease (MRD) negativity rate
    Description
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    From baseline to off treatment follow-up (prior to progression) or 12 months post consolidation
    Title
    Best overall hematologic response
    Description
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    From date of initial registration (Step 1) and date of randomization (Step 2 registration) to date of first documentation of hematologic PR, VGPR, or CR, assessed up to 4 years
    Title
    Overall hematologic response rate
    Description
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    From date of initial registration (Step 1) and date of randomization (Step 2 registration) to date of first documentation of hematologic PR, VGPR, or CR, assessed up to 4 years
    Title
    Rate of complete response
    Description
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    Up to 4 years
    Title
    Rate of very good complete response or better
    Description
    Will be evaluated with a Cochran-Mantel-Haenszel test accounting for stratification according to Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    Up to 4 years
    Title
    Time to next treatment
    Description
    Will be analyzed using the cumulative incidence competing risks method.
    Time Frame
    From date of initial registration (Step 1) to date of initiation of next line of therapy, assessed up to 4 years
    Title
    Change in patient reported health quality of life (QOL)
    Description
    Will use the PROMIS-29+2 (version 2.1) to compare the physical function between participants in the ASCT vs. non-ASCT arm.
    Time Frame
    From baseline to post-maintenance, approximately 24 months
    Title
    Incidence of adverse events
    Description
    Participant-reported toxicity will be examined using Patient Reported Outcome-Common Terminology Criteria for Adverse Events.
    Time Frame
    Up to the end of maintenance therapy, approximately 24 months
    Other Pre-specified Outcome Measures:
    Title
    Bone marrow Next Generation Flow based MRD negativity rates
    Description
    Comparisons of MRD negativity rates between arms will be made using a stratified Cochran-Mantel-Haenszel test, with analyses stratified according to European modification of the Mayo Prognostic Staging System for Light Chain Amyloidosis (Stage 1 vs. 2-3a), hematological response following 2 cycles of Dara-VCD induction (PR or worse vs. VGPR or better), and presence of t(11;14) by iFISH (yes vs. no).
    Time Frame
    At the end of consolidation, approximately 6 months
    Title
    Change in physical function as assessed by the Patient-Reported Outcomes Measurement Information System (PROMIS)-29+2 physical function domain
    Description
    Analysis will be conducted using multiple linear regression analysis, adjusting for the clinical study-specified stratification factors (which are also anticipated to influence QOL endpoints), and the baseline score as covariates.
    Time Frame
    From baseline to post-consolidation, approximately 6 months
    Title
    Change in PROMIS-29 fatigue domain score
    Description
    Analysis will be conducted using linear regression, adjusting for the clinical study-specified stratification factors and the baseline PROMIS-29 fatigue domain score as covariates. Additionally, will conduct longitudinal modeling of the physical function domain score over time (through 12 months from registration Step 3). For longitudinal modeling, linear mixed models will be used.
    Time Frame
    From baseline to post-consolidation, approximately 6 months

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    18 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: STEP 1: Participants must have systemic AL amyloidosis which is biopsy proven and includes histologically-confirmed by positive Congo red stain with green birefringence on polarized light microscopy, OR characteristic appearance by electron microscopy AND confirmatory AL amyloid typing (mass spectrometry-based proteomic analysis or immunofluorescence). If there is question regarding diagnosis, consult study chairs prior to registration STEP 1: Participants must have measurable disease within 28 days prior to treatment if initiated prior to registration or within 28 days of registration as defined by at least one of the following: Positive monoclonal serum immunofixation electrophoresis Positive monoclonal urine immunofixation electrophoresis Monoclonal plasma cells in bone marrow In addition, participants must also have a difference between the involved and uninvolved free light chain (dFLC) >= 2 mg/dL STEP 1: Participants may receive up to one cycle (or 28 days) of therapy prior to enrollment. If a patient receives >= 75% of 1 cycle of protocol identical Dara-VCD, this will be considered 1 cycle of protocol induction. Any patient who receives less than 75% of 1 cycle of Dara-VCD or non-protocol therapy will still be eligible but will be treated per protocol. If protocol identical therapy is initiated prior to enrollment, this treatment is not continued but rather treatment is dictated per protocol STEP 1: Participants may be receiving chronic corticosteroids if they are being given for disorders other than AL amyloidosis or myeloma STEP 1: Participant must be >= 18 years old STEP 1: Participant must have Eastern Cooperative Oncology Group (ECOG) performance score (PS) of 0, 1, or 2 (PS = 3 may be allowed if secondary to neuropathy) STEP 1: Participant must have a complete medical history and physical exam within 28 DAYS prior to registration STEP 1: Participants must be willing to undergo high dose chemotherapy and autologous stem cell transplantation if they are randomized to the arm receiving high dose chemotherapy and autologous stem cell transplantation STEP 1: Participants must be eligible to receive high dose chemotherapy with melphalan at a dose of 200 mg/m^2 or 140 mg/m^2 (200 mg/m^2 is highly encouraged but not mandated). Transplant eligibility criteria are included in the general eligibility criteria listed below: Participant must have a supine systolic blood pressure (BP) >= 90 mmHg (at registration step-1, this may by supported by midodrine Participant must have non-severe cardiac AL (meeting all the below criteria) as defined by: N-terminal proB-type natriuretic peptide (NT proBNP) < 5000 (if no NTproBNP, brain natriuretic peptide [BNP] must be available and < 400) Troponin T (TnT) < 0.06. If not available, one of the following two criteria must be met: High sensitivity troponin (hsTnT) T < 75 or troponin I < 0.1ng/dL New York Heart Association (NYHA) I or II Cardiac ejection fraction (EF) >= 40% STEP 1: Hemoglobin >= 8.0 g/dL (> 5 mmol/L); red blood cell transfusion allowed up to 7 day prior to registration (within 28 days prior to registration) (NOTE: Growth factor support granulocyte colony-stimulating factor [G-CSF] is permitted per institutional guidelines) STEP 1: Leukocytes >= 2 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 1: Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 1: Platelets >= 50 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 1: Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration) STEP 1: Direct bilirubin =< 2.0 mg/dL (within 28 days prior to registration) STEP 1: Aspartate aminotransferase (AST)/ alanine aminotransferase (ALT) =< 3x upper limit of normal (ULN) (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 1: Alkaline phosphatase =< 750 U/L (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 1: Participants must have a serum creatinine =< the institutional (I)ULN OR measured OR calculated creatinine clearance >= 30 mL/min using the following Cockcroft-Gault formula. This specimen must have been drawn and processed within 28 days prior to registration STEP 1: If peripheral neuropathy is present at diagnosis, participants must be grade 2 (moderate symptoms; limiting instrumental activity of daily living [ADL]) or less STEP 1: Participants must have adequate cardiac function. Participants with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, must have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, participants must be class 2 or better STEP 1: Participants must not be seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (i.e., subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) deoxyribonucleic acid (DNA) levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR STEP 1: Participants with a history of hepatitis C virus (HCV) infection must have been treated and cured. Participants currently being treated for HCV infection must have undetectable HCV viral load test on the most recent test results obtained within 6 months prior to registration, if indicated STEP 1: Participants must not have concurrent multiple myeloma as defined by the presence of lytic bone disease, plasmacytomas, >= 60% plasma cells in the bone marrow, or hypercalcemia. Participants will not be excluded solely based on the presence of plasma cells > 10% in the bone marrow unless the plasma cell percentage exceeds >60% STEP 1: Participants must not have known allergies to any of the study drugs STEP 1: Participants must not have had a major surgery within 14 days prior to registration and be fully recovered from surgery completed within 14 days prior to registration STEP 1: Participants must not have a known chronic obstructive pulmonary disease with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal STEP 1: Participants with known human immunodeficiency virus (HIV)-infection must be on effective anti-retroviral therapy at registration and have undetectable viral load test on the most recent test results obtained within 6 months prior to registration STEP 1: Participants must not have either moderate or severe persistent asthma within the past 2 years), or currently have uncontrolled asthma of any classification. (Note that subjects who currently have controlled intermittent asthma or controlled mild persistent asthma are allowed in the study) STEP 1: Participants must not have uncontrolled diabetes within 28 days prior to registration STEP 1: Participants must not have uncontrolled blood pressure and hypertension within 14 days prior to registration. Participants must have a supine systolic BP of >= 90 mmHg STEP 1: Participants must not have a prior or concurrent malignancy whose natural history or treatment (in the opinion of the treating physician) has the potential to interfere with the safety or efficacy assessment of the investigational regimen STEP 1: Participants must not have received vaccination with live attenuated vaccines within 28 days prior to Registration to Step 1 STEP 1: Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment STEP 1: Participants must not be pregnant or nursing (nursing includes breast milk fed to an infant by any means, including from the breast, milk expressed by hand, or pumped). Individuals who are of reproductive potential must have agreed to use an effective contraceptive method with details provided as a part of the consent process. A person who has had menses at any time in the preceding 12 consecutive months or who has semen likely to contain sperm is considered to be of "reproductive potential." In addition to routine contraceptive methods, "effective contraception" also includes refraining from sexual activity that might result in pregnancy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) including hysterectomy, bilateral oophorectomy, bilateral tubal ligation/occlusion, and vasectomy with testing showing no sperm in the semen STEP 1: Participants must be offered the opportunity to participate in specimen banking. With participant consent, specimens must be collected and submitted via the Southwestern Oncology group (SWOG) Specimen Tracking System STEP 1: Participants must agree to have blood, bone marrow core biopsy and aspirate, and fat pad biopsy specimens submitted for minimal residual disease assessment and future exploratory studies STEP 1: Participants who can complete PRO, QOL, PRO-CTCAE questionnaires, etc. forms in English, Spanish and French must participate in the patient-reported outcomes and quality of life STEP 2: Participants must have met all eligibility criteria for Step-1 registration STEP 2: Participants must have achieved at least a partial response STEP 2: Participants must continue receiving at least one of study drugs (bortezomib, cyclophosphamide, or daratumumab and hyaluronidase-fihj) if another study drug (daratumumab and hyaluronidase-fihj, cyclophosphamide, or bortezomib) has been discontinued due to adverse events. Note: daratumumab and hyaluronidase-fihj cannot be permanently discontinued STEP 2: Participants must have completed induction therapy STEP 2: Participants must be registered to Step 2 within 42 days of cycle 3, day 28 of induction therapy STEP 2: Participants must plan to initiate their assigned consolidation therapy within 8 weeks after randomization STEP 2: Participants must not have experienced a MOD-PFS event STEP 2: Participants must have ECOG performance score (PS) of 0, 1, or 2 (PS = 3 may be allowed if secondary to neuropathy) STEP 2: Participant must have a complete medical history and physical exam within 28 days prior to registration STEP 2: Participants must be willing to undergo high dose chemotherapy and autologous stem cell transplantation if they are randomized to the arm receiving high dose chemotherapy and autologous stem cell transplantation STEP 2: Participants randomized to Arm 2 must be willing and able to return to a participating treatment center for their assigned treatment after transplant. Note that participants need not to have a direct relationship with the transplant center in order to register STEP 2: Participants must be eligible to receive high dose chemotherapy with melphalan at a dose of 200 mg/m^2 or 140 mg/m^2 (200 mg/m^2 is highly encouraged but not mandated). Transplant eligibility criteria are included in the general eligibility criteria listed below: Patient must have a supine systolic BP >= 90 mmHg (at registration step-1, this may not by supported by midodrine) Patient must have non-severe cardiac AL as defined by: NT proBNP <5000 (if no NTproBNP, BNP must be available and < 400 pg/mL) (within 14 days prior to registration step-2) TnT < 0.06. If not available, one of the following two criteria must be met (within 14 days prior to registration step-2) hsTnT <75 or troponin I < 0.1ng/dL NYHA I or II (within 14 days prior to registration step-2) Cardiac EF >= 40% (within 14 days prior to registration step-2) STEP 2: Hemoglobin > 8.0 g/dL (> 5 mmol/L); red blood cell transfusion allowed up to 7 days prior to registration (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Leukocytes >= 2 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Platelets >= 50 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 2: Total bilirubin =< 1.5 times the institutional ULN unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration) STEP 2: Direct bilirubin =< 2.0 mg/dL (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 2: AST/ALT =< 3x upper limit of normal (ULN) (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 2: Alkaline phosphatase =< 750 U/L (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 2: Participants must have a serum creatinine =< the IULN OR calculated creatinine clearance ≥ 30 mL/min using the following Cockcroft-Gault Formula. This specimen must have been drawn and processed within 28 days prior to registration STEP 2: Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment STEP 2: Participants randomized to the ASCT arm must be able to have at least 2.0 x 10^6 CD34 cells/kg collected STEP 2: Participants who can complete PRO, QOL, PRO-CTCAE questionnaires, etc. forms in English, Spanish and French must participate in the patient-reported outcomes and quality of life STEP 3: Participants must have met all eligibility criteria for Step-1 and Step-2 registration STEP 3: Participants must not have had daratumumab and hyaluronidase-fihj permanently discontinued during induction or consolidation STEP 3: Participants must have completed induction and consolidation therapy STEP 3: Participants must be registered to Step 3 within the following time frames: If randomized to Arm 1 Dara-VCD consolidation: within 28 days of completion of 3 cycles of consolidation therapy If randomized to Arm 2 high dose chemotherapy and autologous stem cell transplantation: within 180 days following initiation of stem cell transplantation STEP 3: Participants must not have experienced a MOD-PFS event STEP 3: Participants must have ECOG performance score (PS) of 0, 1, or 2 (PS = 3 is allowed if secondary to neuropathy) STEP 3: Participants must have a complete medical history and physical exam within 28 DAYS prior to registration STEP 3: Hemoglobin > 8.0 g/dL (> 5 mmol/L); red blood cell transfusion allowed up to 7 days prior to registration (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Leukocytes >= 2 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Absolute neutrophil count >= 1.0 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Platelets >= 50 x 10^3/uL (within 28 days prior to registration) (NOTE: Growth factor support [G-CSF] is permitted per institutional guidelines) STEP 3: Total bilirubin =< 1.5 times the institutional upper limit of normal (ULN) unless history of Gilbert's disease. Participants with history of Gilbert's disease must have total bilirubin =< 5 x institutional ULN (within 28 days prior to registration) STEP 3: Direct bilirubin =< 2.0 mg/dL (within 28 days prior to registration) STEP 3: AST/ALT =< 3x upper limit of normal (ULN) (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 3: Alkaline phosphatase =< 750 U/L (except if secondary to hepatic involvement) (within 28 days prior to registration) STEP 3: Participants must not have uncontrolled infection at the discretion of the enrolling physician and to be discussed with the study chair if the participant is on active anti-infectious therapy. Any patient on active anti-microbial therapy for chronic infectious issues should be discussed with the study chair prior to enrollment Participants must be informed of the investigational nature of this study and must sign and give informed consent in accordance with institutional and federal guidelines. For participants with impaired decision-making capabilities, legally authorized representatives may sign and give informed consent on behalf of study participants in accordance with applicable federal, local, and Central Institutional Review Board (CIRB) regulations
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Patrick A Hagen
    Organizational Affiliation
    SWOG Cancer Research Network
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Learn more about this trial

    Comparing Dara-VCD Chemotherapy Plus Stem Cell Transplant to Dara-VCD Chemotherapy Alone for People Who Have Newly Diagnosed AL Amyloidosis

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