PRIMARY OBJECTIVES:
I. To evaluate the efficacy of a combination of venetoclax and acalabrutinib, in patients
with previously treated relapsed/refractory mantle cell lymphoma (MCL).
SECONDARY OBJECTIVES:
I. To evaluate the efficacy of this combination regimen in previously treated subjects with
relapsed/refractory MCL with overall response rate (ORR), duration of response (DOR), event
free survival (EFS), progression free survival (PFS), and overall survival (OS).
II. To evaluate the safety and tolerability of venetoclax and acalabrutinib in previously
treated subjects with relapsed/refractory MCL.
CORRELATIVE/TRANSLATIONAL COMPONENT OBJECTIVES:
I. Sequential peripheral blood (PB)/plasma/tissue fine needle aspirate will be stored.
II. Clonal evolution with targeted sequencing (seq) and/or whole exome sequencing (WES) in
sequential samples.
III. Pattern of mutation changes with Bruton tyrosine kinase inhibitor (BTKi) or with
venetoclax resistance.
IV. Response predictors - mutations, cytokine-chemokines, clonal evolution (CE).
V. Minimal residual disease (MRD) assay using circulating tumor deoxyribonucleic acid (ctDNA)
analysis, flow cytometry at various time points from peripheral blood (PB)/ bone marrow (BM).
VI. Sequential immunologic studies with cytokines/chemokines, T cell numbers, and
immunoglobulins (Ig).
VII. Tissue microenvironmental studies with simultaneous assessment of PB, BM and lymph nodes
for gene expression profiling (GEP), single cell seq, ribonucleic acid (RNA) seq and clonal
heterogeneity and the impact of acalabrutinib - venetoclax (A-V) treatment.
OUTLINE: This is a dose escalation study of venetoclax.
Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Starting cycle 2
day 1, patients also receive venetoclax PO daily. Cycles repeat every 28 days in the absence
of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up within 30 days, then every 4
months for 2 years, then every 6 months for the next 2 years, and then annually thereafter.
Inclusion Criteria:
- Confirmed diagnosis of previously treated relapsed/refractory patients MCL with CD5+,
CD23-, CD20+ and chromosome translocation t(11;14), (q13;q32) and/or overexpress
cyclin D1 in tissue biopsy (blastoid/pleomorphic morphology, complex karyotype is
acceptable).
- Disease had relapsed after or been refractory to >= 1 prior therapy for MCL and now
requires further treatment.
- Understand and voluntarily sign an Institutional Review Board (IRB) approved informed
consent form (ICF).
- Bi-dimensional measurable disease using the Cheson criteria (measurable disease by
computed tomography [CT] scan defined as at least 1 lesion that measures >= 1.5 cm in
single dimension). Gastrointestinal (GI), bone marrow or spleen only patients are
allowable.
- Eastern Cooperative Oncology Group (ECOG) performance status of 2 or less.
- Absolute neutrophil count (ANC) > 1,000/mm^3 independent of growth factor support.
- Platelet count >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involved with
lymphoma, independent of transfusion support in either situation.
- Creatinine (Cr) =< 2 or Cr clearance >= 30 mL/min.
- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) < 3 x upper limit
of normal (ULN).
- Serum bilirubin < 1.5 mg/dl, unless due to Gilbert's syndrome, documented liver
involvement with lymphoma, or of non-hepatic origin.
- Prothrombin time (PT)/international normalized ratio (INR) =< 1.5 x ULN and partial
thromboplastin time (PTT) =< 1.5 x ULN.
- Disease free of prior malignancies other than MCL with exception of currently treated
basal cell, squamous cell carcinoma of the skin, carcinoma "in situ" of the cervix or
breast, or other malignancies in remission (including prostate cancer patients in
remission from radiation therapy, surgery or brachytherapy), not actively being
treated with life expectancy of > 3 years. Principal investigator (PI) can use
clinical judgement in the best interest of patients.
- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test and willing to use highly effective methods of birth control. A female of
childbearing potential is a sexually mature woman who:
- Has not undergone a hysterectomy or bilateral oophorectomy; or
- Has not been naturally postmenopausal for at least 24 consecutive months (i.e.,
has had menses at any time in the preceding 24 consecutive months).
Exclusion Criteria:
- Any serious medical condition including but not limited to, uncontrolled hypertension,
uncontrolled diabetes mellitus, active/symptomatic coronary artery disease, chronic
obstructive pulmonary disease, renal failure, active hemorrhage, or psychiatric
illness that, in the investigator's opinion places the patient at unacceptable risk
and would prevent the subject from signing the ICF.
- Pregnant or breast-feeding females.
- Known human immunodeficiency virus (HIV) infection.
- Uncontrolled autoimmune hemolytic anemia (AIHA) or idiopathic thrombocytopenic purpura
(ITP).
- Patients with active hepatitis B infection (not including patients with prior
hepatitis B vaccination; or positive serum hepatitis B antibody). Known hepatitis C
infection is allowed as long as there is no active disease and is cleared by
gastrointestinal (GI) consultation.
- Central nervous system (CNS) disease with serious significance.
- Malabsorption syndrome, disease significantly affecting GI function, or resection of
the stomach or small bowel or ulcerative colitis, symptomatic inflammatory bowel
disease, or partial or complete bowel obstruction, or any other GI condition that
could interfere with the absorption and metabolism of acalabrutinib or venetoclax.
- Major surgery or a wound that has not fully healed within 4 weeks of initiation of
therapy.
- Known bleeding diathesis (e.g., von Willebrand's disease) or hemophilia.
- History of stroke or intracranial hemorrhage within 6 months prior to study entry.
- Requires anticoagulation with warfarin or equivalent vitamin K antagonist.
- Vaccinated with live, attenuated vaccines within 4 weeks of study entry.
- Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,
or chronic administration of > 10 mg/day of prednisone or equivalent) within 28 days
of the first dose of study drug.
- Requires treatment with strong CYP3A inhibitors or inducers or strong CYP1A2
inhibitors.
- Refractory to prior ibrutinib or BTK mutation or previous exposure to ibrutinib.
- Patients with New York Heart Association (NYHA) class III and IV heart failure,
myocardial infarction in the preceding 6 months, and significant conduction
abnormalities, including but not limited to left bundle branch block, 2nd degree
atrioventricular (AV) block type II, 3rd degree block, sick sinus syndrome,
ventricular tachycardia, symptomatic bradycardia (heart rate < 50 beats per minute
[bpm]), hypotension, light headedness and syncope, persistent and uncontrolled atrial
fibrillation.
- Recent placement of a stent (within last 12 months) and by recommendation of their
cardiologist need to stay on anticoagulants such as warfarin or equivalent vitamin K
antagonist or anti-platelet agents.
- Exclude patients with active ongoing infections requiring intravenous (IV)
antimicrobials.
- Requires treatment with proton-pump inhibitors (e.g., omeprazole, esomeprazole,
lansoprazole, dexlansoprazole, rabeprazole or pantoprazole). Subjects receiving
proton-pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
for enrollment to this study.
