Clinical Trials /

Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma

NCT04783415

Description:

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.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib, Umbralisib, and Ublituximab for the Treatment of Previously Untreated Mantle Cell Lymphoma
  • Official Title: 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)

Clinical Trial IDs

  • ORG STUDY ID: 20459
  • SECONDARY ID: NCI-2021-00498
  • SECONDARY ID: 20459
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT04783415

Conditions

  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (ublituximab, acalabrutinib, umbralisib)
UblituximabLFB-R603, TG-1101, TG-20, TGTX-1101Treatment (ublituximab, acalabrutinib, umbralisib)
Umbralisib2-((1S)-1-(4-Amino-3-(3-fluoro-4-(1-methylethoxy)phenyl)-1H-pyrazolo(3,4-d)pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one, RP-5264, RP5264, TGR-1202Treatment (ublituximab, acalabrutinib, umbralisib)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (ublituximab, acalabrutinib, umbralisib)ExperimentalPatients 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.
  • Acalabrutinib
  • Ublituximab
  • Umbralisib

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

          -  Without bone marrow involvement: Platelets >= 75,000/mm^3

               -  NOTE: Platelet transfusions are not permitted within 7 days of platelet
                  assessment unless cytopenia is secondary to disease involvement

          -  With bone marrow involvement: Platelets >= 30,000/mm^3

               -  NOTE: Platelet transfusions are not permitted within 7 days of platelet
                  assessment unless cytopenia is secondary to disease involvement

          -  Total bilirubin =< 1.5 X upper limit of normal (ULN) or =< 3X ULN for Gilbert's
             disease

          -  Aspartate aminotransferase (AST) =< 2.5 x ULN

          -  Alanine aminotransferase (ALT) =< 2.5 x ULN

          -  Creatinine clearance of >= 30 mL/min per 24 hour urine test or the Cockcroft-Gault
             formula

          -  If not receiving anticoagulants: International normalized ratio (INR) OR prothrombin
             (PT) =< 1.5 x ULN. If on anticoagulant therapy: PT must be within therapeutic range of
             intended use of anticoagulants

          -  If not receiving anticoagulants: Activated partial thromboplastin time (aPTT) =< 1.5 x
             ULN. If on anticoagulant therapy: aPTT must be within therapeutic range of intended
             use of anticoagulants

          -  Left ventricular ejection fraction (LVEF) >= 40%

          -  Women of childbearing potential (WOCBP): negative serum pregnancy test

          -  Agreement by females and males of childbearing potential to use an highly effective
             method of birth control or abstain from heterosexual activity for the course of the
             study through at least 2 days after the last dose of acalabrutinib for females, and at
             least 4 months after the last dose of ublituximab or umbralisib, whichever comes
             later, for both men and women

               -  Childbearing potential defined as not being surgically sterilized (men and women)
                  or have not been free from menses for > 1 year (women only)

        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

          -  Malabsorption syndrome, disease significantly affecting gastrointestinal function, or
             resection of the stomach or small bowel that is likely to affect absorption,
             symptomatic inflammatory bowel disease, partial or complete bowel obstruction, or
             gastric restrictions and bariatric surgery, such as gastric bypass

          -  Presence of a gastrointestinal ulcer diagnosed by endoscopy within 3 months before
             screening

          -  Known bleeding disorders (e.g., von Willebrand's disease or hemophilia)

          -  History of significant cerebrovascular disease/event, including stroke, myocardial
             infarction or intracranial hemorrhage, within 6 months prior to start of protocol
             therapy

          -  Known active central nervous system (CNS) involvement by lymphoma, including
             leptomeningeal involvement

          -  Clinically significant cardiovascular disease such as symptomatic arrhythmias,
             congestive heart failure, or myocardial infarction within 6 months of screening, or
             any class III or IV cardiac disease as defined by the New York Heart Association
             Functional Classification. Note: Subjects with controlled, asymptomatic atrial
             fibrillation can enroll on study

          -  Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 6
             months)

          -  History of or current progressive multifocal leukoencephalopathy (PML)

          -  Inability to swallow and retain an oral medication

          -  Clinically significant uncontrolled illness, including active infection requiring
             antibiotics

          -  Live virus vaccines within 4 weeks of start of protocol therapy or planned
             administration of live virus vaccines during ublituximab therapy

          -  Evidence of chronic active hepatitis B (HBV, not including patients with prior
             hepatitis B vaccination; or positive serum Hepatitis B antibody) or chronic active
             hepatitis C infection (HCV), or active cytomegalovirus (CMV). If hepatitis B virus
             core (HBc) antibody is positive, the subject must be evaluated for the presence of HBV
             deoxyribonucleic acid (DNA) by polymerase chain reaction (PCR). If HCV antibody is
             positive, the subject must be evaluated for the presence of HCV RNA by PCR. If the
             subject is CMV IgG or CMV IgM positive, the subject must be evaluated for the presence
             of CMV DNA by PCR. Subjects with positive HBc antibody and negative HBV DNA by PCR are
             eligible. Subjects with positive HCV antibody and negative HCV RNA by PCR are
             eligible. Subjects who are CMV IgG or CMV IgM positive but who are CMV DNA negative by
             PCR are eligible. Patients with a prior known history of hepatitis B and those with a
             positive anti-HBc with negative hepatitis B surface antigen (HBsAg) at screening must
             be able to receive antiviral agents effective against hepatitis B

          -  Known history of human immunodeficiency virus (HIV) infection

          -  Females only: Pregnant or breastfeeding

          -  Any other condition that would, in the Investigator's judgment, contraindicate the
             patient's participation in the clinical study due to safety concerns with clinical
             study procedures

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR)
Time Frame:up to 24 weeks
Safety Issue:
Description:Defined as the proportion of response-evaluable participants that achieve a CR at the end of induction therapy. CR rate after Induction therapy will be estimated by the proportion of response-evaluable patients achieving CR after Induction therapy, along with the 95% exact binomial confidence interval.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:Up to 2 years
Safety Issue:
Description:Defined as the proportion of response-evaluable participants that achieve a best response of either CR or partial response (PR) during protocol therapy. ORR rate after Induction therapy will be estimated by the proportion of response-evaluable patients achieving ORR after Induction therapy, along with the 95% exact binomial confidence interval.
Measure:Progression-free survival (PFS)
Time Frame:From start of protocol treatment to time of disease relapse/progression, start of non-protocol anti-lymphoma therapy, or death due to any cause, whichever occurs earlier, assessed up to 2 years
Safety Issue:
Description:PFS will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation. Median PFS will be estimated when available. Observed toxicities of Induction therapy and Maintenance therapy will be summarized by type, severity, and attribution.
Measure:Overall survival (OS)
Time Frame:From start of protocol treatment to time of death due to any cause, assessed up to 2 years
Safety Issue:
Description:OS will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error; 95% confidence interval will be constructed based on log-log transformation. Median OS will be estimated when available. Observed toxicities of Induction therapy and Maintenance therapy will be summarized by type, severity, and attribution.
Measure:Duration of response (DOR)
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Toxicity of ublituximab regimen
Time Frame:Up to 2 years
Safety Issue:
Description:Toxicity and adverse events will be recorded using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) 5.0 scale. Observed toxicities will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by NCI CTCAE v5.0 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:City of Hope Medical Center

Last Updated

March 5, 2021