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Ibrutinib With or Without Bortezomib and Dexamethasone in Treating Patients With Relapsed or Refractory Immunoglobulin Light Chain Amyloidosis

Primary Purpose

Amyloidosis, Immunoglobulin Light Chain Deposition

Status

Withdrawn

Phase

Phase 2

Locations

Study Type

Interventional

Intervention

Bortezomib

Dexamethasone

Ibrutinib

Laboratory Biomarker Analysis

About this trial

This is an interventional treatment trial for Amyloidosis

Eligibility Criteria

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

Criteria:

Measurable disease of AL amyloidosis as defined by at least ONE of the following:
- Serum monoclonal protein >= 1.0 by protein electrophoresis
- > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis
- Free light chains (abnormal absolute value, ratio and the dFLC > 5 mg/dL)

Inclusion Criteria:

Histological diagnosis of AL amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens; the type must have been confirmed unequivocally
Must have had one prior line of systemic therapy for AL; Note: patients who do not achieve at least a PR to frontline therapy in 3 months may be eligible after discussion with study chair
Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2
Absolute neutrophil count (ANC) >= 1000/mm^3
Platelet count >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement independent of transfusion support in either situation
Hemoglobin >= 8.0 g/dL
Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome or of non-hepatic origin
Aspartate transaminase (AST) =< 3 x upper limit of normal (ULN)
Alanine aminotransferase (ALT) =< 3 x ULN
Creatinine =< 3 mg/dL and creatinine clearance (CrCL) >= 25 ml/min
Negative serum pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only
Ability to complete questionnaire(s) by themselves or with assistance
Ability to provide written informed consent
Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study)
Willing to provide bone marrow and blood samples for correlative research purposes

Exclusion Criteria:

Any of the following:
- Pregnant persons
- Nursing persons
- Persons of childbearing potential who are unwilling to employ adequate contraception; Note: persons of childbearing potential and persons able to father a child who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials; subjects must agree to not donate sperm during and after the study; for persons of childbearing potential, these restrictions apply for 1 month after the last dose of study drug; for persons able to father a child, these restrictions apply for 3 months after the last dose of study drug
Concomitant high dose corticosteroids (concurrent use of corticosteroids) while on single agent ibrutinib; EXCEPTION: patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than amyloid, (i.e., adrenal insufficiency, rheumatoid arthritis, etc)
Active malignancy =< 3 years prior to registration; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer
Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens
Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection
Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk
Receiving any other investigational agent which would be considered as a treatment for AL amyloidosis
Vaccinated with live, attenuated vaccines =< 4 weeks prior to registration
Clinically overt multiple myeloma (i.e. original hypercalcemia, renal failure, anemia, bone lesions [CRAB] criteria); Note: extent of marrow plasmacytosis is not prohibitive
Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction =< 6 months prior to registration, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification
NT-ProBNP > 8,500 pg/mL
Use of strong and moderate CYP3A inhibitors and inducers =< 7 days prior to registration
Anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon); Note: use of low molecular weight heparin (or any anticoagulation agent) is allowed provided there is no history of bleeding (minor or major) =< 12 months prior to registration; the treating physician should discuss the case with the study chair
History of stroke or intracranial hemorrhage =< 6 months prior to registration
Known central nervous system metastasis
Major surgery or a wound that has not fully healed =< 4 weeks prior to registration
Surgery or invasive procedure requiring sutures or staples for closure =< 7 days prior to registration
Minor procedures (such as a central line placement, needle biopsy, thoracentesis, or paracentesis) =< 3 days prior to registration

Sites / Locations

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (ibrutinib, bortezomib, dexamethasone)

Arm Description

Patients receive ibrutinib PO QD on days 1-28. After 3 courses, patients who achieve partial response repeat treatment every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients who do not achieve partial response after 3 courses continue receiving ibrutinib PO QD on days 1-28. Beginning at course 4, patients who do not achieve partial response also receive bortezomib SC and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity.

Outcomes

Primary Outcome Measures

Overall hematologic response rate during the first 6 courses for patients treated with ibrutinib, bortezomib, and dexamethasone

Will include a confirmed stringent complete response, amyloid complete response, very good partial response, and partial response. Confirmation will be defined as a response that is maintained on two consecutive evaluations at least 2 weeks apart. Progression will be defined as either hematologic or organ progression. The proportion of successes will be estimated by the number of successes divided by the total number of evaluable patients. Confidence intervals for the true success proportion will be calculated according to the approach of Duffy and Santner.

Secondary Outcome Measures

Incidence of adverse events

The maximum grade for each type of adverse event will be recorded for each patient, and frequency tables will be reviewed to determine patterns. Additionally, the relationship of the adverse event(s) to the study treatment will be taken into consideration. Adverse events will be summarized separately for single agent Ibrutinib and combination therapy.

Organ response rate

Will be estimated by the total number of patients who have an organ response divided by the total number of evaluable patients who had involvement in that organ at baseline. Exact binomial 95% confidence intervals for the true organ Up to response rate will be calculated.

Overall hematologic response rate for single agent ibrutinib

Will be estimated by the total number of patients who achieve a partial response, very good partial response, stringent complete response, or amyloid complete response while receiving single agent ibrutinib divided by the total number of evaluable patients. Exact binomial 95% confidence intervals for the true overall hematologic response rate will be calculated.

Progression-free survival

Will be estimated using the method of Kaplan-Meier.

Full Information

NCT ID

NCT03130348

First Posted

April 21, 2017

Last Updated

February 28, 2018

Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

1. Study Identification

Unique Protocol Identification Number

NCT03130348

Brief Title

Ibrutinib With or Without Bortezomib and Dexamethasone in Treating Patients With Relapsed or Refractory Immunoglobulin Light Chain Amyloidosis

Official Title

Phase II Study of Ibrutinib With or Without Bortezomib and Dexamethasone for the Treatment of Patients With Relapsed/Refractory Immunoglobulin Light Chain Amyloidosis

Study Type

Interventional

2. Study Status

Record Verification Date

February 2018

Overall Recruitment Status

Withdrawn

Why Stopped

Study was dropped at site before participation

Study Start Date

March 15, 2018 (Anticipated)

Primary Completion Date

April 2022 (Anticipated)

Study Completion Date

April 2022 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Mayo Clinic

Collaborators

National Cancer Institute (NCI)

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

This phase II trial studies how well ibrutinib with or without bortezomib and dexamethasone works in treating patients with immunoglobulin light chain amyloidosis that has come back after a period of improvement or that does not respond to treatment. Ibrutinib and bortezomib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as dexamethasone, 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. Giving ibrutinib with or without bortezomib and dexamethasone may work better in treating patients with relapsed or refractory immunoglobulin light chain amyloidosis.

Detailed Description

PRIMARY OBJECTIVES: I. To evaluate the overall hematologic response rate (stringent complete response [sCR] + amyloid complete response [ACR]+ very good partial response [VGPR] + partial response [PR]) during the first 6 cycles for ibrutinib with bortezomib and dexamethasone added for lack of response in patients with amyloid light chain (AL). SECONDARY OBJECTIVES: I. To evaluate overall hematologic response rate (sCR+ACR+VGPR+PR) of single agent ibrutinib in patients with AL. II. To evaluate overall hematologic response rate (sCR+ACR+VGPR+PR) to ibrutinib + bortezomib and dexamethasone (Vd) in subjects with progressive disease after initial response to single agent ibrutinib. III. To describe the toxicities associated with ibrutinib, alone and in combination with Vd, in patients with AL. IV. To determine the organ response in AL patients treated with ibrutinib alone and in combination with Vd. V. To determine 3 year progression free survival of AL patients on the study. TERTIARY OBJECTIVES: I. To characterize health related quality of life of patients. II. To determine the caregiver and patient disease burden. III. To determine the correlation between cardiac biomarkers and hematologic response to therapy. IV. To evaluate the effect of ibrutinib on AL microenvironment. V. To characterize BTK expression in neoplastic plasma cells. VI. To evaluate the characterization of CD38 expression on neoplastic plasma cells. OUTLINE: Patients receive ibrutinib orally (PO) daily (QD) on days 1-28. After 3 courses, patients who achieve partial response repeat treatment every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. Patients who do not achieve partial response after 3 courses continue receiving ibrutinib PO QD on days 1-28. Beginning at course 4, patients who do not achieve partial response also receive bortezomib subcutaneously (SC) and dexamethasone PO on days 1, 8, and 15. Treatment repeats every 28 days for up to 18 courses in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, and then every 6 months for 2 years.

6. Conditions and Keywords

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

Amyloidosis, Immunoglobulin Light Chain Deposition

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

0 (Actual)

8. Arms, Groups, and Interventions

Arm Title

Treatment (ibrutinib, bortezomib, dexamethasone)

Arm Type

Experimental

Arm Description

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

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, Baycuten, Baycuten N, Cortidexason, Cortisumman, Decacort, Decadrol, Decadron, 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, Dexamethasonum, Dexamonozon, Dexapos, Dexinoral, Dexone, Dinormon, Fluorodelta, Fortecortin, Gammacorten, Hexadecadrol, Hexadrol, Lokalison-F, Loverine, Methylfluorprednisolone, Millicorten, Mymethasone, Orgadrone, Spersadex, Visumetazone

Intervention Description

Given PO

Intervention Type

Drug

Intervention Name(s)

Ibrutinib

Other Intervention Name(s)

BTK Inhibitor PCI-32765, CRA-032765, Imbruvica, PCI-32765

Intervention Description

Given PO

Intervention Type

Other

Intervention Name(s)

Laboratory Biomarker Analysis

Intervention Description

Correlative studies

Primary Outcome Measure Information:

Title

Overall hematologic response rate during the first 6 courses for patients treated with ibrutinib, bortezomib, and dexamethasone

Description

Time Frame

Up to 6 months

Secondary Outcome Measure Information:

Title

Incidence of adverse events

Description

Time Frame

Up to 3 years

Title

Organ response rate

Description

Time Frame

Up to 3 years

Title

Overall hematologic response rate for single agent ibrutinib

Description

Time Frame

Up to 6 months

Title

Progression-free survival

Description

Will be estimated using the method of Kaplan-Meier.

Time Frame

From registration to the earliest date of documentation of disease progression (on single agent or combination therapy) or death due to any cause, assessed up to 3 years

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Criteria: Measurable disease of AL amyloidosis as defined by at least ONE of the following: Serum monoclonal protein >= 1.0 by protein electrophoresis > 200 mg of monoclonal protein in the urine on 24 hour electrophoresis Free light chains (abnormal absolute value, ratio and the dFLC > 5 mg/dL) Inclusion Criteria: Histological diagnosis of AL amyloidosis as based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens; the type must have been confirmed unequivocally Must have had one prior line of systemic therapy for AL; Note: patients who do not achieve at least a PR to frontline therapy in 3 months may be eligible after discussion with study chair Eastern Cooperative Oncology Group (ECOG) performance status (PS) 0, 1 or 2 Absolute neutrophil count (ANC) >= 1000/mm^3 Platelet count >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement independent of transfusion support in either situation Hemoglobin >= 8.0 g/dL Total bilirubin =< 1.5 x upper limit of normal (ULN) unless due to Gilbert's syndrome or of non-hepatic origin Aspartate transaminase (AST) =< 3 x upper limit of normal (ULN) Alanine aminotransferase (ALT) =< 3 x ULN Creatinine =< 3 mg/dL and creatinine clearance (CrCL) >= 25 ml/min Negative serum pregnancy test done =< 7 days prior to registration, for persons of childbearing potential only Ability to complete questionnaire(s) by themselves or with assistance Ability to provide written informed consent Willing to return to enrolling institution for follow-up (during the Active Monitoring Phase of the study) Willing to provide bone marrow and blood samples for correlative research purposes Exclusion Criteria: Any of the following: Pregnant persons Nursing persons Persons of childbearing potential who are unwilling to employ adequate contraception; Note: persons of childbearing potential and persons able to father a child who are sexually active must be practicing a highly effective method of birth control during and after the study consistent with local regulations regarding the use of birth control methods for subjects participating in clinical trials; subjects must agree to not donate sperm during and after the study; for persons of childbearing potential, these restrictions apply for 1 month after the last dose of study drug; for persons able to father a child, these restrictions apply for 3 months after the last dose of study drug Concomitant high dose corticosteroids (concurrent use of corticosteroids) while on single agent ibrutinib; EXCEPTION: patients may be on chronic steroids (maximum dose 20 mg/day prednisone equivalent) if they are being given for disorders other than amyloid, (i.e., adrenal insufficiency, rheumatoid arthritis, etc) Active malignancy =< 3 years prior to registration; EXCEPTIONS: Non-melanotic skin cancer or carcinoma-in-situ of the cervix; Note: if there is a history of prior malignancy, they must not be receiving other specific treatment for their cancer Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens Known history of human immunodeficiency virus (HIV) or active hepatitis C virus or active hepatitis B virus infection or any uncontrolled active systemic infection Any life-threatening illness, medical condition, or organ system dysfunction which, in the investigator's opinion, could compromise the subject's safety, interfere with the absorption or metabolism of ibrutinib capsules, or put the study outcomes at undue risk Receiving any other investigational agent which would be considered as a treatment for AL amyloidosis Vaccinated with live, attenuated vaccines =< 4 weeks prior to registration Clinically overt multiple myeloma (i.e. original hypercalcemia, renal failure, anemia, bone lesions [CRAB] criteria); Note: extent of marrow plasmacytosis is not prohibitive Clinically significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction =< 6 months prior to registration, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by the New York Heart Association Functional Classification NT-ProBNP > 8,500 pg/mL Use of strong and moderate CYP3A inhibitors and inducers =< 7 days prior to registration Anticoagulation with warfarin or equivalent vitamin K antagonists (e.g., phenprocoumon); Note: use of low molecular weight heparin (or any anticoagulation agent) is allowed provided there is no history of bleeding (minor or major) =< 12 months prior to registration; the treating physician should discuss the case with the study chair History of stroke or intracranial hemorrhage =< 6 months prior to registration Known central nervous system metastasis Major surgery or a wound that has not fully healed =< 4 weeks prior to registration Surgery or invasive procedure requiring sutures or staples for closure =< 7 days prior to registration Minor procedures (such as a central line placement, needle biopsy, thoracentesis, or paracentesis) =< 3 days prior to registration

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Taimur Sher

Organizational Affiliation

Mayo Clinic

Official's Role

Principal Investigator

12. IPD Sharing Statement

Learn more about this trial

Ibrutinib With or Without Bortezomib and Dexamethasone in Treating Patients With Relapsed or Refractory Immunoglobulin Light Chain Amyloidosis

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