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Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

Primary Purpose

Refractory Follicular Lymphoma, Relapsed Follicular Lymphoma

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Ibrutinib
Venetoclax
Sponsored by
Georgetown University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Refractory Follicular Lymphoma focused on measuring Ibrutinib, Venetoclax, Follicular, Refractory, Relapsed, Lymphoma

Eligibility Criteria

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

Inclusion Criteria:

  1. Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa which requires therapy defined by at least one of the following:

    • Constitutional symptoms
    • Cytopenias
  2. High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic splenomegaly, organ compression or compromise, ascites, pleural effusion)Must have received at least two prior systemic therapies
  3. All risk by FLIPI 0-5 factors (Appendix I)
  4. Measurable disease Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable. Any tumor mass > 1.5 cm is acceptable.

    Lesions that are considered non-measurable include the following:

    • Bone lesions (lesions if present should be noted)
    • Ascites
    • Pleural/pericardial effusion
    • Lymphangitis cutis/pulmonis
    • Bone marrow (involvement by lymphoma should be noted)
  5. Adequate hematologic function independent of transfusion and growth factor support for at least 3 weeks prior to screening unless attributable to disease. Defined as:

    • Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L). ANC > 500 cells/mm3 is permissible if due to disease.
    • Platelet count >50,000 cells/mm3 (50 x 109/L) unless attributable to disease. Platelet count > 20,000 cells/mm3 is permissible if due to disease.
    • Hemoglobin >8.0 g/dL.
  6. Adequate hepatic and renal function defined as:

    • Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 5 is permissible if due to disease.
    • Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) Bilirubin ≤3 x ULN is permissible if due to disease.
    • Estimated Creatinine Clearance ≥50 ml/min (Cockcroft-Gault based on actual weight)
  7. Prothrombin time (PT)/International normalized ratio (INR) <1.5 x ULN and PTT (aPTT) <1.5 x ULN.
  8. Men and women ≥ 18 years of age.
  9. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II)
  10. Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
  11. Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug

Exclusion Criteria:

  1. Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or equal 21 days prior to first administration of study treatment
  2. Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (BCL-2) inhibitor.
  3. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or venetoclax.
  4. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome.
  5. History of other malignancies, except:

    • Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
    • Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease.
    • Adequately treated carcinoma in situ without evidence of disease.
  6. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration [>14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug.
  7. Undergone an allogeneic stem cell transplant within the past 1 year.
  8. Current or history of graft versus host disease
  9. Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug.
  10. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
  11. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade ≤1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia.
  12. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia.
  13. History of stroke or intracranial hemorrhage within 6 months prior to enrollment.
  14. Known HIV infection
  15. Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV).

    • Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, must have a negative polymerase chain reaction (PCR) result for the respective disease before enrollment. Those who are PCR positive will be excluded.

  16. Any uncontrolled active systemic infection.
  17. Major surgery within 4 weeks of first dose of study drug.
  18. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk.
  19. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization.
  20. Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction.
  21. Concomitant use of warfarin or other Vitamin K antagonists.
  22. Requires treatment with a strong cytochrome P450 CYP3A4/5 inhibitor. (Appendix V)
  23. Richter's transformation confirmed by biopsy.
  24. Malabsorption syndrome or other condition precluding enteral route of administration.
  25. Known Central nervous system (CNS) involvement by lymphoma
  26. Erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome
  27. Lactating or pregnant.
  28. Unwilling or unable to participate in all required study evaluations and procedures.
  29. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations).
  30. Currently active, clinically significant hepatic impairment (greater than or equal moderate hepatic impairment according to the Child Pugh classification (see Appendix IX)

Sites / Locations

  • Georgetown Lombardi Comprehensive Cancer Center
  • John Theurer Cancer Center at Hackensack University Medical Center
  • Seattle Cancer Care Alliance

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Phase I - Dose Level 0

Phase I - Dose Level 1

Phase I - Dose Level 2

Phase I - Dose Level 3

Phase II Dose

Arm Description

Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long.

Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long.

Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg Each medication is taken daily. Treatment cycles are 28 days long.

Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg Each medication is taken daily. Treatment cycles are 28 days long.

The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion.

Outcomes

Primary Outcome Measures

Recommended Phase 2 dose
The maximum tolerated dose of Ibrutinib and Venetoclax
Response Rate
Response rate seen in the combination versus 30% response rate for current individual therapies for this group of patients

Secondary Outcome Measures

Pharmacokinetics of Ibrutinib
Steady-state plasma concentrations of ibrutinib
Pharmacokinetics of Venetoclax
Steady-state plasma concentrations of venetoclax
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Toxicity (attribute and grade) will be summarized for each dose level for all patients who receive at least one dose of study treatment

Full Information

First Posted
November 2, 2016
Last Updated
January 17, 2023
Sponsor
Georgetown University
Collaborators
AbbVie, Pharmacyclics LLC., Hackensack Meridian Health
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1. Study Identification

Unique Protocol Identification Number
NCT02956382
Brief Title
Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma
Official Title
Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma
Study Type
Interventional

2. Study Status

Record Verification Date
January 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
March 1, 2017 (Actual)
Primary Completion Date
November 2023 (Anticipated)
Study Completion Date
November 2024 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Georgetown University
Collaborators
AbbVie, Pharmacyclics LLC., Hackensack Meridian Health

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 is a phase I/II study in which patients will be enrolled in a standard 3+3 design. Once the maximum tolerated dose (MTD) is determined amongst patients with relapsed or refractory grade 1-3a follicular lymphoma, there will be a 17-patient phase II study.
Detailed Description
In vitro studies of ibrutinib and venetoclax have noted significant cytotoxicity and synergy in mantle cell lymphoma and chronic lymphocytic leukemia cell lines.Data have demonstrated synergy between the two agents in various other B-cell Non-Hodgkin Lymphoma (NHL) cell lines. The investigators theorize that the combination of ibrutinib and venetoclax will provide dual, yet unique, targeted inhibition for patients with follicular lymphoma, resulting in both significant efficacy and less nonspecific toxicity.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Refractory Follicular Lymphoma, Relapsed Follicular Lymphoma
Keywords
Ibrutinib, Venetoclax, Follicular, Refractory, Relapsed, Lymphoma

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
Non-Randomized
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Phase I - Dose Level 0
Arm Type
Experimental
Arm Description
Ibrutinib (capsule) - 420mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long.
Arm Title
Phase I - Dose Level 1
Arm Type
Experimental
Arm Description
Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 400mg Each medication is taken daily. Treatment cycles are 28 days long.
Arm Title
Phase I - Dose Level 2
Arm Type
Experimental
Arm Description
Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 600mg Each medication is taken daily. Treatment cycles are 28 days long.
Arm Title
Phase I - Dose Level 3
Arm Type
Experimental
Arm Description
Ibrutinib (capsule) - 560mg Venetoclax (tablet) - 800mg Each medication is taken daily. Treatment cycles are 28 days long.
Arm Title
Phase II Dose
Arm Type
Experimental
Arm Description
The Phase II dose will be the maximum tolerated dose as determined in the Phase I portion.
Intervention Type
Drug
Intervention Name(s)
Ibrutinib
Other Intervention Name(s)
PCI-32765
Intervention Description
Ibrutinib is dispensed as a capsule.
Intervention Type
Drug
Intervention Name(s)
Venetoclax
Other Intervention Name(s)
ABT-199
Intervention Description
Venetoclax is dispensed as a tablet.
Primary Outcome Measure Information:
Title
Recommended Phase 2 dose
Description
The maximum tolerated dose of Ibrutinib and Venetoclax
Time Frame
18 months
Title
Response Rate
Description
Response rate seen in the combination versus 30% response rate for current individual therapies for this group of patients
Time Frame
36 months
Secondary Outcome Measure Information:
Title
Pharmacokinetics of Ibrutinib
Description
Steady-state plasma concentrations of ibrutinib
Time Frame
18 months
Title
Pharmacokinetics of Venetoclax
Description
Steady-state plasma concentrations of venetoclax
Time Frame
18 months
Title
Number of participants with treatment-related adverse events as assessed by CTCAE v4.03
Description
Toxicity (attribute and grade) will be summarized for each dose level for all patients who receive at least one dose of study treatment
Time Frame
36 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Relapsed or refractory, histologically confirmed follicular lymphoma, grade I, II, or IIIa which requires therapy defined by at least one of the following: Constitutional symptoms Cytopenias High tumor burden (single mass > 7 cm, three masses > 3 cm, symptomatic splenomegaly, organ compression or compromise, ascites, pleural effusion)Must have received at least two prior systemic therapies All risk by FLIPI 0-5 factors (Appendix I) Measurable disease Measurable disease must be present either on physical examination or imaging studies; non-measurable disease alone is not acceptable. Any tumor mass > 1.5 cm is acceptable. Lesions that are considered non-measurable include the following: Bone lesions (lesions if present should be noted) Ascites Pleural/pericardial effusion Lymphangitis cutis/pulmonis Bone marrow (involvement by lymphoma should be noted) Adequate hematologic function independent of transfusion and growth factor support for at least 3 weeks prior to screening unless attributable to disease. Defined as: Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L). ANC > 500 cells/mm3 is permissible if due to disease. Platelet count >50,000 cells/mm3 (50 x 109/L) unless attributable to disease. Platelet count > 20,000 cells/mm3 is permissible if due to disease. Hemoglobin >8.0 g/dL. Adequate hepatic and renal function defined as: Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 2.5 x upper limit of normal (ULN) Serum aspartate transaminase (AST) or alanine transaminase (ALT) ≤ 5 is permissible if due to disease. Bilirubin ≤1.5 x ULN (unless bilirubin rise is due to Gilbert's syndrome or of non-hepatic origin) Bilirubin ≤3 x ULN is permissible if due to disease. Estimated Creatinine Clearance ≥50 ml/min (Cockcroft-Gault based on actual weight) Prothrombin time (PT)/International normalized ratio (INR) <1.5 x ULN and PTT (aPTT) <1.5 x ULN. Men and women ≥ 18 years of age. Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2. (Appendix II) Female subjects who are of non-reproductive potential (i.e., post-menopausal by history - no menses for ≥1 year; OR history of hysterectomy; OR history of bilateral tubal ligation; OR history of bilateral oophorectomy). Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry. Male and female subjects who agree to use highly effective methods of birth control (e.g., condoms, implants, injectables, combined oral contraceptives, some intrauterine devices (IUDs), sexual abstinence, or sterilized partner) during the period of therapy and for 30 days after the last dose of study drug Exclusion Criteria: Chemotherapy, monoclonal antibody, or small molecule kinase inhibitor less than or equal 21 days prior to first administration of study treatment Prior exposure to a Bruton's tyrosine kinase (BTK) or B-cell lymphoma 2 (BCL-2) inhibitor. History of allergic reactions attributed to compounds of similar chemical or biologic composition to ibrutinib or venetoclax. Known allergy to xanthine oxidase inhibitors and/or rasburicase for subjects at risk for tumor lysis syndrome. History of other malignancies, except: Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician. Adequately treated non-melanoma skin cancer or lentigo maligna without evidence of disease. Adequately treated carcinoma in situ without evidence of disease. Concurrent systemic immunosuppressant therapy (e.g., cyclosporine A, tacrolimus, etc., or chronic administration [>14 days] of > 20 mg/day of prednisone) within 28 days of the first dose of study drug. Undergone an allogeneic stem cell transplant within the past 1 year. Current or history of graft versus host disease Vaccinated with live, attenuated vaccines within 4 weeks of first dose of study drug. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug. Unresolved toxicities from prior anti-cancer therapy, defined as having not resolved to Common Terminology Criteria for Adverse Event (CTCAE, version 4.03), grade ≤1, or to the levels dictated in the inclusion/exclusion criteria with the exception of alopecia. Known bleeding disorders (e.g., von Willebrand's disease) or hemophilia. History of stroke or intracranial hemorrhage within 6 months prior to enrollment. Known HIV infection Active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). • Subjects who are positive for hepatitis B core antibody, hepatitis B surface antigen, hepatitis C antibody, must have a negative polymerase chain reaction (PCR) result for the respective disease before enrollment. Those who are PCR positive will be excluded. Any uncontrolled active systemic infection. Major surgery within 4 weeks of first dose of study drug. Any life-threatening illness, medical condition, or organ system dysfunction that, in the investigator's opinion, could compromise the subject's safety or put the study outcomes at undue risk. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, unstable angina, or acute coronary syndrome within 6 months prior to randomization. Unable to swallow capsules or tablets or malabsorption syndrome, disease significantly affecting gastrointestinal function, or resection of the stomach or small bowel, symptomatic inflammatory bowel disease or ulcerative colitis, or partial or complete bowel obstruction. Concomitant use of warfarin or other Vitamin K antagonists. Requires treatment with a strong cytochrome P450 CYP3A4/5 inhibitor. (Appendix V) Richter's transformation confirmed by biopsy. Malabsorption syndrome or other condition precluding enteral route of administration. Known Central nervous system (CNS) involvement by lymphoma Erythema multiforme, toxic epidermal necrolysis, or Stevens-Johnson syndrome Lactating or pregnant. Unwilling or unable to participate in all required study evaluations and procedures. Unable to understand the purpose and risks of the study and to provide a signed and dated informed consent form (ICF) and authorization to use protected health information (in accordance with national and local subject privacy regulations). Currently active, clinically significant hepatic impairment (greater than or equal moderate hepatic impairment according to the Child Pugh classification (see Appendix IX)
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Chaitra Ujjani, MD
Organizational Affiliation
Seattle Cancer Care Alliance
Official's Role
Study Chair
Facility Information:
Facility Name
Georgetown Lombardi Comprehensive Cancer Center
City
Washington
State/Province
District of Columbia
ZIP/Postal Code
20007
Country
United States
Facility Name
John Theurer Cancer Center at Hackensack University Medical Center
City
Hackensack
State/Province
New Jersey
ZIP/Postal Code
07601
Country
United States
Facility Name
Seattle Cancer Care Alliance
City
Seattle
State/Province
Washington
ZIP/Postal Code
98109
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Ibrutinib and Venetoclax in Relapsed and Refractory Follicular Lymphoma

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