Phase 3 Study of Ibrutinib in Combination with Venetoclax in Subjects with Mantle Cell Lymphoma

Phase 3

Recruiting

• Conditions: Mantle Cell lymphoma; Non-Hodgkin lymphoma; 10025320

• Registration Number: NL-OMON52949
• Lead Sponsor: Pharmacyclics

Brief Summary

Not available

Detailed Description

Not available

Study Timeline

• Last Update Posted: 15 April 2024

Recruitment & Eligibility

• Status: Recruiting
• Sex: Not specified
• Target Recruitment: 18

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 co

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:
• moderate or strong cytochrome P450 3A (CYP3A) inhibitors
• 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. Admini

Study & Design

• Study Type: Interventional
• Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
<p>Randomization Phase:<br /><br>To evaluate whether the combination of ibrutinib and venetoclax will result in<br /><br>prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed<br /><br>or refractory MCL.<br /><br><br /><br>Treatment-naive Open-label Arm Primary Endpoint<br /><br>The primary efficacy endpoint of the treatment-naive open-label arm is the<br /><br>complete response (CR) rate based on the best overall response according to the<br /><br>Revised Response Criteria for Malignant Lymphoma<br /><br>(Cheson 2014) - every 3 months for the first year starting with week 13; every<br /><br>4 months during the second and third years, and every 6 months thereafter until<br /><br>PD </p><br>