A Phase II Study of BTK Inhibitor Acalabrutinib and PI3Kδ Inhibitor Umbralisib in Combination With Ublituximab (AU2) in Patients With Previously Untreated Mantle Cell Lymphoma (MCL)
Overview
- Phase
- Phase 2
- Intervention
- Acalabrutinib
- Conditions
- Mantle Cell Lymphoma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 12
- Locations
- 1
- Primary Endpoint
- Complete Response (CR) Rate After Induction (Six Cycles)
- Status
- Active, not recruiting
- Last Updated
- last year
Overview
Brief Summary
This phase II trial studies the effects of acalabrutinib, umbralisib, and ublituximab in treating previously untreated mantle cell lymphoma. Acalabrutinib and umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Ublituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib and umbralisib with ublituximab may work better in treating mantle cell lymphoma.
Detailed Description
PRIMARY OBJECTIVE: I. Evaluate the anti-tumor activity of acalabrutinib, umbralisib and ublituximab (AU2) regimen as induction therapy in patients with treatment-naïve mantle cell lymphoma (MCL), as assessed by the complete response (CR) rate. SECONDARY OBJECTIVES: I. Evaluate the overall response rate (ORR) to AU2 in treatment-naive MCL. II. Evaluate the progression-free survival (PFS), overall survival (OS) and duration of response (DOR) in patients with treatment-naïve MCL who received AU2. III. Evaluate the safety and tolerability of AU2 in patients with treatment-naive MCL. EXPLORATORY OBJECTIVES: I. Examine the T-cell populations and functionality in patients treated with AU2. II. Explore the predictive value of minimal residual disease (MRD) in MCL. III. Explore the mechanisms of resistance to AU2 therapy. OUTLINE: INDUCTION: Patients receive ublituximab intravenously (IV) over 90 minutes-4 hours on days 1, 8, and 15 of cycle 1 and days 1 of cycles 2-6. Patients also receive acalabrutinib orally (PO) twice daily (BID) and umbralisib PO once daily (QD) on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ublituximab IV on day 1 on cycles 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30. Patients also receive acalabrutinib Po BID and umbralisib PO QD on day 1-28. Treatment repeats every 28 days for 24 cycles in the absence of disease progression of unacceptable toxicity. After completion of study treatment, patients are followed up for 30 days and then every 6 months for 2 years.
Investigators
Eligibility Criteria
Inclusion Criteria
- •Documented informed consent of the participant and/or legally authorized representative
- •Assent, when appropriate, will be obtained per institutional guidelines
- •Histologically confirmed mantle cell lymphoma with documentation of monoclonal CD20+ B cells that have a chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1
- •Age \>= 65 years; or \>= 50 years and deemed ineligible for aggressive induction therapy or autologous stem cell transplant by the investigator, or unwilling to undergo aggressive induction; or \>= 18 years with documented del(17p), or TP53 mutation, or complex karyotype (CK) by cytogenetics and/or fluorescence in situ hybridization (FISH) studies
- •Requiring treatment for MCL, and for which no prior systemic anticancer therapies have been received (local radiotherapy not exceeding a total dose of 20 Gy at least 2 weeks prior the first dose of study therapy is allowed)
- •Measurable disease by computed tomography (CT) or positron emission tomography (PET)/CT scan with one or more sites of disease \>= 1.5 cm in longest dimension (including splenomegaly), or bone marrow involvement with or without malignant lymphocytosis
- •Without bone marrow involvement: Absolute neutrophil count (ANC) \>= 1000/mm\^3
- •NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
- •With bone marrow involvement: ANC \>= 500/mm\^3
- •NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
Exclusion Criteria
- •Chronic use of corticosteroids \>= 20 mg/day (short-term use of steroids \< 14 days is allowed)
- •Major surgical procedure within 28 days of start of protocol therapy. Note: If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug
- •Known history of hypersensitivity or anaphylaxis to study drug(s) including active product or excipient components
- •Concurrent participation in another therapeutic clinical trial
- •Subjects for whom the goal of therapy is tumor debulking before stem cell transplant
- •History of prior malignancy. Exceptions include malignancy treated with curative intent and no known active disease present for \>= 2 years prior to initiation of protocol therapy; adequately treated non-melanoma skin cancer or lentigo maligna (melanoma in situ) without evidence of disease; adequately treated in situ carcinomas (e.g., cervical, esophageal, etc.) without evidence of disease; asymptomatic prostate cancer managed with "watch and wait" strategy
- •Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic purpura)
- •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
- •Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
- •Requires or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
Arms & Interventions
Treatment (ublituximab, acalabrutinib, umbralisib)
Patients receive ublituximab IV over 90 minutes-4 hours on days 1, 8, and 15 of cycle 1 and days 1 of cycles 2-6. Patients also receive acalabrutinib PO BID and umbralisib PO QD on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ublituximab IV on day 1 on cycles 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30. Patients also receive acalabrutinib Po BID and umbralisib PO QD on day 1-28. Treatment repeats every 28 days for 24 cycles in the absence of disease progression of unacceptable toxicity.
Intervention: Acalabrutinib
Treatment (ublituximab, acalabrutinib, umbralisib)
Patients receive ublituximab IV over 90 minutes-4 hours on days 1, 8, and 15 of cycle 1 and days 1 of cycles 2-6. Patients also receive acalabrutinib PO BID and umbralisib PO QD on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ublituximab IV on day 1 on cycles 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30. Patients also receive acalabrutinib Po BID and umbralisib PO QD on day 1-28. Treatment repeats every 28 days for 24 cycles in the absence of disease progression of unacceptable toxicity.
Intervention: Ublituximab
Treatment (ublituximab, acalabrutinib, umbralisib)
Patients receive ublituximab IV over 90 minutes-4 hours on days 1, 8, and 15 of cycle 1 and days 1 of cycles 2-6. Patients also receive acalabrutinib PO BID and umbralisib PO QD on days 1-28. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive ublituximab IV on day 1 on cycles 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30. Patients also receive acalabrutinib Po BID and umbralisib PO QD on day 1-28. Treatment repeats every 28 days for 24 cycles in the absence of disease progression of unacceptable toxicity.
Intervention: Umbralisib
Outcomes
Primary Outcomes
Complete Response (CR) Rate After Induction (Six Cycles)
Time Frame: Participants were assessed at the end of the induction therapy (24 weeks post-baseline). The induction therapy included six 28-day cycles of the study treatment.
Defined as the proportion of response-evaluable participants that achieve a CR at the end of the induction therapy. CR rate after the induction therapy was estimated by the proportion of response-evaluable patients achieving CR after the induction therapy, along with the 95% exact binomial confidence interval.
Secondary Outcomes
- Overall Response Rate (ORR)(Participants were followed up to 24 months after the end of protocol therapy.)