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A Trial Comparing Chemotherapy Versus Novel Immune Checkpoint Inhibitor (Pembrolizumab) Plus Chemotherapy in Treating Relapsed/Refractory Classical Hodgkin Lymphoma

Primary Purpose

Recurrent Classic Hodgkin Lymphoma, Refractory Classic Hodgkin Lymphoma

Status
Withdrawn
Phase
Phase 3
Locations
Study Type
Interventional
Intervention
Autologous Hematopoietic Stem Cell Transplantation
Bendamustine
Brentuximab Vedotin
Carboplatin
Computed Tomography
Etoposide
Gemcitabine
Ifosfamide
Pegylated Liposomal Doxorubicin Hydrochloride
Pembrolizumab
Positron Emission Tomography
Radiation Therapy
Transplant Conditioning
Vinorelbine
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Recurrent Classic Hodgkin Lymphoma

Eligibility Criteria

5 Years - 75 Years (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria: Patient must be >= 5 years of age and =< 75 years of age Patient must have relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after frontline (first line of chemotherapy) as evidenced by Fludeoxyglucose F-18 (FDG) avid on PET scan. If regimen is adjusted based on PET2 results or toxicity during frontline therapy, this will only be considered one line of therapy. Prior checkpoint inhibitor is completed > 6 months prior to randomization Patients >= 18 years of age must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. Pediatric patients (16-17 years of age) must have a Karnofsky performance level >= 50%. Pediatric patients (5-15 years of age) must have a Lansky performance level >= 50 Patient must be deemed fit for high dose chemo and autologous stem cell transplant Patient must have the ability to understand and the willingness to sign a written informed consent document. Pediatric patients (< 18 years of age) and patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible. Child assent must be obtained as appropriate in accordance with institutional guidelines Absolute neutrophil count (ANC) >= 1000/mcL (must be obtained =< 7 days prior to randomization) If disease includes marrow involvement or hypersplenism, please reference the below revised requirement: ANC >= 500/mcL Platelets >= 75,000/mcL (must be obtained =< 7 days prior to randomization) If disease includes marrow involvement or hypersplenism, please reference the below revised requirement: Platelets >= 25,000/mcL Total bilirubin =< 2x institutional upper limit of normal (ULN) (must be obtained =< 7 days prior to randomization) Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN for age (must be obtained =< 7 days prior to randomization) Glomerular filtration rate (GFR) >= 50 mL/min/1.73m^2 73m^2 for patients >= 18 years of age (must be obtained =< 7 days prior to randomization) Pediatric patients (< 18 years old) must have a creatinine clearance OR radioisotope GFR >= 70 mL/min/1.73 m^2 OR serum creatinine below the maximum based on age/gender as follows (derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention [CDC]): Age: 5 to < 6 years; Maximum Serum Creatinine (mg/dL): Male (0.8); Female (0.8) Age: 6 to 10 years; Maximum Serum Creatinine (mg/dL): Male (1.0); Female (1.0) Age: 10 to 13 years; Maximum Serum Creatinine (mg/dL): Male (1.2); Female (1.2) Age: 13 to < 16 years; Maximum Serum Creatinine (mg/dL): Male (1.5); Female (1.4) Age: >= 16 years; Maximum Serum Creatinine (mg/dL): Male (1.7); Female (1.4) Patient must have a left ventricular ejection fraction (LVEF) >= 50%, as measured by echocardiogram, multi-gated acquisition (MUGA) scan, or functional cardiac imaging scan (or a shortening fraction of >= 27% for patients < 18 years of age only) Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients >= 18 years of age with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Exclusion Criteria: Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Patients of childbearing potential and/or sexually active patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Additionally, patients of childbearing potential must continue contraception measures for 4 months after the last dose of pembrolizumab, 6 months after the last dose of vinorelbine and for 3 months after the last dose of bendamustine. Male patients must continue contraception measures for 6 months after the last dose of ifosfamide and for 3 months after the last dose of vinorelbine. Patients must also not breastfeed while on study treatment and for 4 months after the last dose of Pembrolizumab and 9 days after the last dose of vinorelbine Patient must not have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or have current pneumonitis/interstitial lung disease Patient must not have the following symptomatic autoimmune disorders: rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, Sjögren's syndrome, or autoimmune vasculitis (e.g., Wegener's Granulomatosis), or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone). Patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study. Replacement doses of steroids for patients with adrenal insufficiency are allowed. Additionally, patients must not have an autoimmune disease that is felt by the treating physician to have the potential to be exacerbated by checkpoint inhibition

Sites / Locations

    Arms of the Study

    Arm 1

    Arm 2

    Arm Type

    Active Comparator

    Experimental

    Arm Label

    Arm A (chemotherapy regimen, HDT-ASCT)

    Arm B (chemotherapy regimens+pembrolizumab, HD-ASCT)

    Arm Description

    SALVAGE THERAPY: Patients receive 1 of 3 chemotherapy regimens as clinically indicated: 1) ifosfamide IV, carboplatin IV, and etoposide IV; 2) gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin IV; or 3) brentuximab vedotin IV and bendamustine IV. Patients then undergo a PET/CT scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve SD or PD come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo RT as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated.

    SALVAGE THERAPY: Patients receive pembrolizumab IV plus 1 of 3 chemotherapy regimens specified in Arm A as clinically indicated. Patients then undergo a PET scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve SD or PD come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo RT as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated.

    Outcomes

    Primary Outcome Measures

    Event free survival (EFS)
    Events include: failure to achieve partial remission (PR) or complete remission (CR) to salvage chemotherapy, failure to achieve a CR post high dose chemotherapy and autologous stem cell transplant (HDT-ASCT), progression, receipt of unplanned radiation or brentuximab vedotin maintenance, or death. Patients who have not experienced any of these events will be censored at the date they are last known to be progression free. Kaplan-Meier method will be used to estimate EFS, including medians and confidence intervals. Comparison of EFS between treatment arms will be conducted based on intent-to-treat principle using a one-sided stratified log-rank test with the stratification factors.
    Lugano-based response
    Will be assessed using positron emission tomography/computed tomography (PET/CT) scan with Deauville score. Will assess the diagnostic performance of baseline metabolic tumor volume (TMTV) in predicting response (CR+PR vs no response) at pre-transplant/post-salvage, overall and by study arm. Diagnostic performance of baseline TMTV will be assessed using area under the receiver operator characteristic curve (ROC AUC) analysis, where the reference standard is pre-transplant/post-salvage response (CR/PR).

    Secondary Outcome Measures

    Percentage change in TMTV (delta TMTV)
    Similar methods will be used as the primary imaging aim to assess the diagnostic performance of delta TMTV in predicting pre-transplant/post-salvage response (CR+PR vs no response). Delta TMTV will be defined as the percent change from baseline to pre-transplant/post-salvage [(post-salvage/pre-transplant - baseline)/baseline X 100].
    Baseline TMTV and delta TMTV
    Will assess baseline TMTV and delta TMTV in predicting EFS/overall survival (OS) for each arm separately and overall. The association between TMTV and EFS will be analyzed through a Cox regression model. TMTV will be analyzed individually as its absolute value and the percent change from baseline. We will also test if there is a difference by arm by including an interaction term in the model between TMTV and arm. The Kaplan-Meier method will be used to estimate EFS, including median survival times and confidence intervals. In addition to examining the TMTV, we will also analyze standard uptake value maximum (SUVmax) and total lesion glycolysis (TLG) with the same methods. The OS outcome will be analyzed in a similar manner.

    Full Information

    First Posted
    February 2, 2023
    Last Updated
    August 30, 2023
    Sponsor
    National Cancer Institute (NCI)
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    1. Study Identification

    Unique Protocol Identification Number
    NCT05711628
    Brief Title
    A Trial Comparing Chemotherapy Versus Novel Immune Checkpoint Inhibitor (Pembrolizumab) Plus Chemotherapy in Treating Relapsed/Refractory Classical Hodgkin Lymphoma
    Official Title
    Randomized Phase III Trial of Chemotherapy vs. Pembrolizumab Plus Chemotherapy for Relapsed/Refractory Classical Hodgkin Lymphoma
    Study Type
    Interventional

    2. Study Status

    Record Verification Date
    August 2023
    Overall Recruitment Status
    Withdrawn
    Why Stopped
    Other - Protocol moved to Withdrawn
    Study Start Date
    August 10, 2023 (Anticipated)
    Primary Completion Date
    June 30, 2028 (Anticipated)
    Study Completion Date
    June 30, 2028 (Anticipated)

    3. Sponsor/Collaborators

    Responsible Party, by Official Title
    Sponsor
    Name of the Sponsor
    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
    No

    5. Study Description

    Brief Summary
    This phase III trial compares chemotherapy versus an immune checkpoint inhibitor drug called pembrolizumab plus chemotherapy in treating patients with classical Hodgkin lymphoma that has come back (relapsed) or that does not respond to treatment (refractory). The usual approach for patients with classical Hodgkin lymphoma is treatment with standard chemotherapy, including drugs that are Food and Drug Administration (FDA)-approved. If this treatment puts a patient into remission, high dose chemotherapy and stem cell transplant may be used to increase the likelihood of a cure. Hodgkin lymphoma is capable of inhibiting the immune system from killing it. Pembrolizumab is a checkpoint inhibitor that may be able to stop this inhibition, allowing the immune system to attack the lymphoma.
    Detailed Description
    PRIMARY OBJECTIVE: I. To assess the 2-year event free survival (EFS) of patients treated with pembrolizumab added to chemotherapy versus chemotherapy alone, in patients with relapsed/refractory (R/R) classical Hodgkin's lymphoma (cHL) who are intended to receive salvage therapy followed by high dose chemotherapy and autologous stem cell transplant (HDT-ASCT). PRIMARY IMAGING OBJECTIVE: I. To assess the diagnostic performance of baseline total metabolic tumor volume (TMTV) in predicting response (complete remission [CR] + partial remission [PR] versus [vs] no response) at pre-transplant/post-salvage for each arm separately and overall. SECONDARY OBJECTIVES: I. To assess the 2-year progression free survival (PFS) and overall survival (OS) in the transplanted population. II. To assess the complete remission (CR) rate to salvage therapy. III. To assess the CR rate post HDT-ASCT. IV. To assess the post HDT-ASCT partial remission (PR) to CR conversion rate. SECONDARY IMAGING OBJECTIVES: I. To assess the % change in TMTV (delta TMTV) from baseline to pre-transplant/post-salvage in predicting response (CR+PR vs no response) at pre-transplant/post-salvage for each arm separately and overall. II. To assess baseline TMTV and delta TMTV in predicting EFS/OS for each arm separately and overall. OUTLINE: Patients are randomized to 1 of 2 arms. ARM A: SALVAGE THERAPY: Patients receive 1 of 3 chemotherapy regimens as clinically indicated: 1) ifosfamide intravenously (IV), carboplatin IV, and etoposide IV; 2) gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin IV; or 3) brentuximab vedotin IV and bendamustine IV. Patients then undergo a positron emission tomography (PET)/computed tomography (CT) scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve stable disease (SD) or progressive disease (PD) come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo radiation therapy (RT) as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated. ARM B: SALVAGE THERAPY: Patients receive pembrolizumab IV plus 1 of 3 chemotherapy regimens specified in Arm A as clinically indicated. Patients then undergo a PET scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve SD or PD come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo RT as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated. All patients undergo CT scans during follow-up.

    6. Conditions and Keywords

    Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
    Recurrent Classic Hodgkin Lymphoma, Refractory Classic Hodgkin Lymphoma

    7. Study Design

    Primary Purpose
    Treatment
    Study Phase
    Phase 3
    Interventional Study Model
    Parallel Assignment
    Masking
    None (Open Label)
    Allocation
    Randomized
    Enrollment
    0 (Actual)

    8. Arms, Groups, and Interventions

    Arm Title
    Arm A (chemotherapy regimen, HDT-ASCT)
    Arm Type
    Active Comparator
    Arm Description
    SALVAGE THERAPY: Patients receive 1 of 3 chemotherapy regimens as clinically indicated: 1) ifosfamide IV, carboplatin IV, and etoposide IV; 2) gemcitabine IV, vinorelbine IV, and pegylated liposomal doxorubicin IV; or 3) brentuximab vedotin IV and bendamustine IV. Patients then undergo a PET/CT scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve SD or PD come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo RT as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated.
    Arm Title
    Arm B (chemotherapy regimens+pembrolizumab, HD-ASCT)
    Arm Type
    Experimental
    Arm Description
    SALVAGE THERAPY: Patients receive pembrolizumab IV plus 1 of 3 chemotherapy regimens specified in Arm A as clinically indicated. Patients then undergo a PET scan. Patients who achieve a CR or PR proceed to HDT-ASCT. Patients who achieve SD or PD come off study treatment. HDT-ASCT: Patients undergo ASCT. Patients may also receive a standard preparative chemotherapy regimen as clinically indicated. Patients who achieve PR prior to ASCT may also undergo RT as clinically indicated. Patients who went into ASCT with PR also undergo a PET/CT scan 30 days post-transplant. MAINTENANCE THERAPY: Patients may receive brentuximab vedotin IV as clinically indicated.
    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
    Undergo ASCT
    Intervention Type
    Drug
    Intervention Name(s)
    Bendamustine
    Other Intervention Name(s)
    SDX-105
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Brentuximab Vedotin
    Other Intervention Name(s)
    ADC SGN-35, Adcetris, Anti-CD30 Antibody-Drug Conjugate SGN-35, Anti-CD30 Monoclonal Antibody-MMAE SGN-35, Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35, cAC10-vcMMAE, SGN-35
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Carboplatin
    Other Intervention Name(s)
    Blastocarb, Carboplat, Carboplatin Hexal, Carboplatino, Carboplatinum, Carbosin, Carbosol, Carbotec, CBDCA, Displata, Ercar, JM-8, Nealorin, Novoplatinum, Paraplatin, Paraplatin AQ, Paraplatine, Platinwas, Ribocarbo
    Intervention Description
    Given IV
    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 PET/CT and CT
    Intervention Type
    Drug
    Intervention Name(s)
    Etoposide
    Other Intervention Name(s)
    Demethyl Epipodophyllotoxin Ethylidine Glucoside, EPEG, Lastet, Toposar, Vepesid, VP 16, VP 16-213, VP-16, VP-16-213, VP16
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Gemcitabine
    Other Intervention Name(s)
    dFdC, dFdCyd, Difluorodeoxycytidine
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Ifosfamide
    Other Intervention Name(s)
    Asta Z 4942, Asta Z-4942, Cyfos, Holoxan, Holoxane, Ifex, IFO, IFO-Cell, Ifolem, Ifomida, Ifomide, Ifosfamidum, Ifoxan, IFX, Iphosphamid, Iphosphamide, Iso-Endoxan, Isoendoxan, Isophosphamide, Mitoxana, MJF 9325, MJF-9325, Naxamide, Seromida, Tronoxal, Z 4942, Z-4942
    Intervention Description
    Given IV
    Intervention Type
    Drug
    Intervention Name(s)
    Pegylated Liposomal Doxorubicin Hydrochloride
    Other Intervention Name(s)
    ATI-0918, Caelyx, Dox-SL, Doxil, Doxilen, Doxorubicin HCl Liposomal, Doxorubicin HCl Liposome, Doxorubicin Hydrochloride Liposome, Duomeisu, Evacet, LipoDox, Lipodox 50, Liposomal Adriamycin, Liposomal Doxorubicin Hydrochloride, Liposomal-Encapsulated Doxorubicin, Pegylated Doxorubicin HCl Liposome, S-Liposomal Doxorubicin, Stealth Liposomal Doxorubicin, TLC D-99
    Intervention Description
    Given IV
    Intervention Type
    Biological
    Intervention Name(s)
    Pembrolizumab
    Other Intervention Name(s)
    BCD-201, Keytruda, Lambrolizumab, MK-3475, Pembrolizumab Biosimilar BCD-201, SCH 900475
    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
    Radiation
    Intervention Name(s)
    Radiation Therapy
    Other Intervention Name(s)
    Cancer Radiotherapy, Energy Type, ENERGY_TYPE, Irradiate, Irradiated, Irradiation, Radiation, Radiation Therapy, NOS, Radiotherapeutics, Radiotherapy, RT, Therapy, Radiation
    Intervention Description
    Undergo RT
    Intervention Type
    Other
    Intervention Name(s)
    Transplant Conditioning
    Other Intervention Name(s)
    conditioning regimen
    Intervention Description
    Receive standard preparative chemotherapy regimen
    Intervention Type
    Drug
    Intervention Name(s)
    Vinorelbine
    Other Intervention Name(s)
    Dihydroxydeoxynorvinkaleukoblastine
    Intervention Description
    Given IV
    Primary Outcome Measure Information:
    Title
    Event free survival (EFS)
    Description
    Events include: failure to achieve partial remission (PR) or complete remission (CR) to salvage chemotherapy, failure to achieve a CR post high dose chemotherapy and autologous stem cell transplant (HDT-ASCT), progression, receipt of unplanned radiation or brentuximab vedotin maintenance, or death. Patients who have not experienced any of these events will be censored at the date they are last known to be progression free. Kaplan-Meier method will be used to estimate EFS, including medians and confidence intervals. Comparison of EFS between treatment arms will be conducted based on intent-to-treat principle using a one-sided stratified log-rank test with the stratification factors.
    Time Frame
    Time from randomization to the earlier of events listed in description field, assessed up to 15 years
    Title
    Lugano-based response
    Description
    Will be assessed using positron emission tomography/computed tomography (PET/CT) scan with Deauville score. Will assess the diagnostic performance of baseline metabolic tumor volume (TMTV) in predicting response (CR+PR vs no response) at pre-transplant/post-salvage, overall and by study arm. Diagnostic performance of baseline TMTV will be assessed using area under the receiver operator characteristic curve (ROC AUC) analysis, where the reference standard is pre-transplant/post-salvage response (CR/PR).
    Time Frame
    Pre-transplant/post-salvage therapy
    Secondary Outcome Measure Information:
    Title
    Percentage change in TMTV (delta TMTV)
    Description
    Similar methods will be used as the primary imaging aim to assess the diagnostic performance of delta TMTV in predicting pre-transplant/post-salvage response (CR+PR vs no response). Delta TMTV will be defined as the percent change from baseline to pre-transplant/post-salvage [(post-salvage/pre-transplant - baseline)/baseline X 100].
    Time Frame
    Baseline to pre-transplant/post-salvage therapy
    Title
    Baseline TMTV and delta TMTV
    Description
    Will assess baseline TMTV and delta TMTV in predicting EFS/overall survival (OS) for each arm separately and overall. The association between TMTV and EFS will be analyzed through a Cox regression model. TMTV will be analyzed individually as its absolute value and the percent change from baseline. We will also test if there is a difference by arm by including an interaction term in the model between TMTV and arm. The Kaplan-Meier method will be used to estimate EFS, including median survival times and confidence intervals. In addition to examining the TMTV, we will also analyze standard uptake value maximum (SUVmax) and total lesion glycolysis (TLG) with the same methods. The OS outcome will be analyzed in a similar manner.
    Time Frame
    Baseline and pre-transplant/post-salvage therapy

    10. Eligibility

    Sex
    All
    Minimum Age & Unit of Time
    5 Years
    Maximum Age & Unit of Time
    75 Years
    Accepts Healthy Volunteers
    No
    Eligibility Criteria
    Inclusion Criteria: Patient must be >= 5 years of age and =< 75 years of age Patient must have relapsed/refractory classical Hodgkin lymphoma (R/R cHL) after frontline (first line of chemotherapy) as evidenced by Fludeoxyglucose F-18 (FDG) avid on PET scan. If regimen is adjusted based on PET2 results or toxicity during frontline therapy, this will only be considered one line of therapy. Prior checkpoint inhibitor is completed > 6 months prior to randomization Patients >= 18 years of age must have an Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-2. Pediatric patients (16-17 years of age) must have a Karnofsky performance level >= 50%. Pediatric patients (5-15 years of age) must have a Lansky performance level >= 50 Patient must be deemed fit for high dose chemo and autologous stem cell transplant Patient must have the ability to understand and the willingness to sign a written informed consent document. Pediatric patients (< 18 years of age) and patients with impaired decision-making capacity (IDMC) who have a legally authorized representative (LAR) or caregiver and/or family member available will also be considered eligible. Child assent must be obtained as appropriate in accordance with institutional guidelines Absolute neutrophil count (ANC) >= 1000/mcL (must be obtained =< 7 days prior to randomization) If disease includes marrow involvement or hypersplenism, please reference the below revised requirement: ANC >= 500/mcL Platelets >= 75,000/mcL (must be obtained =< 7 days prior to randomization) If disease includes marrow involvement or hypersplenism, please reference the below revised requirement: Platelets >= 25,000/mcL Total bilirubin =< 2x institutional upper limit of normal (ULN) (must be obtained =< 7 days prior to randomization) Aspartate aminotransferase (AST)(serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT)(serum glutamate pyruvate transaminase [SGPT]) =< 3.0 x institutional ULN for age (must be obtained =< 7 days prior to randomization) Glomerular filtration rate (GFR) >= 50 mL/min/1.73m^2 73m^2 for patients >= 18 years of age (must be obtained =< 7 days prior to randomization) Pediatric patients (< 18 years old) must have a creatinine clearance OR radioisotope GFR >= 70 mL/min/1.73 m^2 OR serum creatinine below the maximum based on age/gender as follows (derived from the Schwartz formula for estimating GFR utilizing child length and stature data published by the Centers for Disease Control and Prevention [CDC]): Age: 5 to < 6 years; Maximum Serum Creatinine (mg/dL): Male (0.8); Female (0.8) Age: 6 to 10 years; Maximum Serum Creatinine (mg/dL): Male (1.0); Female (1.0) Age: 10 to 13 years; Maximum Serum Creatinine (mg/dL): Male (1.2); Female (1.2) Age: 13 to < 16 years; Maximum Serum Creatinine (mg/dL): Male (1.5); Female (1.4) Age: >= 16 years; Maximum Serum Creatinine (mg/dL): Male (1.7); Female (1.4) Patient must have a left ventricular ejection fraction (LVEF) >= 50%, as measured by echocardiogram, multi-gated acquisition (MUGA) scan, or functional cardiac imaging scan (or a shortening fraction of >= 27% for patients < 18 years of age only) Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months of randomization are eligible for this trial For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. For patients with HCV infection who are currently on treatment, they are eligible if they have an undetectable HCV viral load Patients with treated brain metastases are eligible if follow-up brain imaging after central nervous system (CNS)-directed therapy shows no evidence of progression Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial Patients >= 18 years of age with known history or current symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of cardiac function using the New York Heart Association Functional Classification. To be eligible for this trial, patients should be class 2B or better Exclusion Criteria: Patient must not be pregnant or breast-feeding due to the potential harm to an unborn fetus and possible risk for adverse events in nursing infants with the treatment regimens being used. All patients of childbearing potential must have a blood test or urine study within 14 days prior to randomization to rule out pregnancy. A patient of childbearing potential is defined as anyone, regardless of sexual orientation or whether they have undergone tubal ligation, who meets the following criteria: 1) has achieved menarche at some point, 2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) Patients of childbearing potential and/or sexually active patients must not expect to conceive or father children by using an accepted and effective method(s) of contraception or by abstaining from sexual intercourse for the duration of their participation in the study. Additionally, patients of childbearing potential must continue contraception measures for 4 months after the last dose of pembrolizumab, 6 months after the last dose of vinorelbine and for 3 months after the last dose of bendamustine. Male patients must continue contraception measures for 6 months after the last dose of ifosfamide and for 3 months after the last dose of vinorelbine. Patients must also not breastfeed while on study treatment and for 4 months after the last dose of Pembrolizumab and 9 days after the last dose of vinorelbine Patient must not have a history of (non-infectious) pneumonitis/interstitial lung disease that required steroids or have current pneumonitis/interstitial lung disease Patient must not have the following symptomatic autoimmune disorders: rheumatoid arthritis, systemic progressive sclerosis (scleroderma), systemic lupus erythematosus, Sjögren's syndrome, or autoimmune vasculitis (e.g., Wegener's Granulomatosis), or conditions of immunosuppression that require current ongoing treatment with systemic corticosteroids (or other systemic immunosuppressants), including oral steroids (i.e., prednisone, dexamethasone). Patients who discontinue use of these classes of medication for at least 2 weeks prior to randomization eligible if, in the judgment of the treating physician investigator, the patient is not likely to require resumption of treatment with these classes of drugs during the study. Replacement doses of steroids for patients with adrenal insufficiency are allowed. Additionally, patients must not have an autoimmune disease that is felt by the treating physician to have the potential to be exacerbated by checkpoint inhibition
    Overall Study Officials:
    First Name & Middle Initial & Last Name & Degree
    Vaishalee P Kenkre
    Organizational Affiliation
    ECOG-ACRIN Cancer Research Group
    Official's Role
    Principal Investigator

    12. IPD Sharing Statement

    Plan to Share IPD
    Yes
    IPD Sharing Plan Description
    NCI is committed to sharing data in accordance with NIH policy. For more details on how clinical trial data is shared, access the link to the NIH data sharing policy page.
    IPD Sharing URL
    https://grants.nih.gov/policy/sharing.htm

    Learn more about this trial

    A Trial Comparing Chemotherapy Versus Novel Immune Checkpoint Inhibitor (Pembrolizumab) Plus Chemotherapy in Treating Relapsed/Refractory Classical Hodgkin Lymphoma

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