Research study of Ibrutinib in Combination with Venetoclax in patients with Mantle Cell Lymphoma

Phase 1

• Conditions: Mantle Cell Lymphoma; MedDRA version: 20.0Level: PTClassification code 10061275Term: Mantle cell lymphomaSystem Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps); Therapeutic area: Diseases [C] - Cancer [C04]

• Registration Number: EUCTR2017-000129-12-NL
• Lead Sponsor: Pharmacyclics LLC

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Study Start: 2018-01-16
• Last Update Posted: 29 July 2024

Recruitment & Eligibility

• Status: ot Recruiting
• Sex: All
• Target Recruitment: 362

Inclusion Criteria

For SRI and Randomization Phase
Disease-Related
• Pathologically confirmed MCL (in tumor tissue), with documentation of either overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed by cytogenetics, fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
• At least 1 measurable site of disease on cross-sectional imaging that is =2.0 cm in the longest diameter and measurable in 2 perpendicular dimensions per CT
• At least 1, but no more than 5, prior treatment regimens for MCL including at least 1 prior rituximab/anti-CD20 containing regimen
• Failure to achieve at least partial response (PR) with, or documented disease progression after, the most recent treatment regimen
• Subjects must have adequate fresh or paraffin embedded tissue.
Laboratory
• Adequate hematologic function
• Adequate hepatic and renal function
Demographic
• Men and women = 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of =2

For Treatment-naive Open-label Arm:
1. Pathologically confirmed treatment-naive MCL (tumor tissue), with documentation of either
overexpression of cyclin D1 in association with other relevant markers (eg, CD19, CD20,
PAX5, CD5) or evidence of t(11;14), as assessed by cytogenetics, fluorescent in situ
hybridization (FISH), or polymerase chain reaction (PCR)
• A report from the local laboratory is acceptable if available; however, it must be reviewed
and approved by the central pathology laboratory to verify the above criteria prior to
enrollment
• If the report from the local laboratory is not available, a tumor block or slides must be sent
to the central pathology laboratory for confirmation of the MCL diagnosis prior to
enrollment.
2. Men and women =18 years of age, with a TP53 mutation
3. At least 1 measurable site of disease that is =2.0 cm in the longest diameter and measurable in
2 perpendicular dimensions per CT
4. Subjects must have adequate fresh or paraffin-embedded tissue
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of = 2
6. Adequate hematologic function independent of transfusion and growth factor support for at
least 7 days prior to first dose, with the exception of pegylated G-CSF (pegfilgrastim) and
darbepoeitin which require at least 14 days prior to the first dose defined as:
• Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L)
• Platelet count >50,000 cells/mm3 (50 x 109/L)
• Hemoglobin >8.0 g/dL
7. Adequate hepatic and renal function defined as:
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) =3.0 x upper limit of
normal (ULN)
• Estimated Creatinine Clearance (CrCl) =30 mL/min (Cockcroft-Gault)
• Bilirubin =1.5 x ULN (unless bilirubin rise is due to Gilbert’s syndrome or of non-hepatic
origin)
8. Prothrombin time (PT) or International normal ratio (INR) <1.5 x upper limit of normal
(ULN) and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless
abnormalities are unrelated to coagulopathy or bleeding disorder). When treated with warfarin
or other vitamin K antagonists, then INR =3.0
9. Male and female subjects of reproductive potential who agree to use both a highly effectivemethod of birth control (eg, implants, injectables, combined oral contraceptives, some
intrauterine devices [IUDs], complete abstinence5, or sterilized partner) and a barrier method
(eg, condoms, cervical ring, sponge, etc) during the period of th

Exclusion Criteria

For SRI and Randomization Phase
Disease-Related
• History or current evidence of central nervous system lymphoma
Concurrent Conditions
• Concurrent enrollment in another therapeutic investigational study or prior therapy with ibrutinib or other BTK inhibitors
• Prior treatment with venetoclax or other BCL2 inhibitors
• Anticancer therapy including chemotherapy, radiotherapy, small molecule and investigational agents =21 days prior to receiving the first dose of study drug
• Treatment with any of the following within 7 days prior to the first dose of study drug:
o moderate or strong cytochrome P450 3A (CYP3A) inhibitors
o moderate or strong CYP3A inducers

For Treatment-naive Open-label Arm:
1. Blastoid variant of MCL
2. History or current evidence of central nervous system lymphoma
3. Concurrent enrollment in another therapeutic investigational study or prior therapy, including
ibrutinib or other BTK inhibitors
4. Prior treatment with venetoclax or other BCL2 inhibitors
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. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug
7. Clinically significant infection requiring IV systemic treatment that was completed =14 days
before the first dose of study drug
8. Any uncontrolled active systemic infection
9. Known bleeding disorders (eg, von Willebrand’s disease or hemophilia)
10. History of stroke or intracranial hemorrhage within 6 months prior to enrollment
11. Known history of human immunodeficiency virus (HIV) or active with hepatitis C virus
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B core antibody, or
hepatitis C antibody must have a negative polymerase chain reaction (PCR) result before
enrollment. Those who are hepatitis B surface antigen (HBsAg) or PCR positive will be
excluded.
12. Major surgery within 4 weeks of the first dose of study drug.
13. 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
14. 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
15. 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
16. Treatment with any of the following within 7 days prior to the first dose of study drug:
• Moderate or strong cytochrome P450 3A (CYP3A) inhibitors
• Moderate or strong CYP3A inducers
17. Administration or consumption of any of the following within 3 days prior to the first dose
of study drug:
• grapefruit or grapefruit products
• Seville oranges (including marmalade containing Seville oranges)
• star fruit
18. Known allergy to xanth

Study & Design

• Study Type: Interventional clinical trial of medicinal product
• Study Design: Not specified