Clinical Trials /

Acalabrutinib and Obinutuzumab for the Treatment of Previously Untreated Follicular Lymphoma or Other Indolent Non-Hodgkin Lymphomas

NCT04883437

Description:

This phase II trial studies the effect of acalabrutinib and obinutuzumab in treating patients with follicular lymphoma or other indolent non-Hodgkin lymphoma for which the patient has not received treatment in the past (previously untreated). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib and obinutuzumab may kill more cancer cells.

Related Conditions:
  • Follicular Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Lymphoproliferative Disorder
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib and Obinutuzumab for the Treatment of Previously Untreated Follicular Lymphoma or Other Indolent Non-Hodgkin Lymphomas
  • Official Title: An Open-Label Phase 2 Trial of Acalabrutinib Plus Obinutuzumab in Patients With Untreated, Low Tumor Burden Follicular Lymphoma and Other Indolent Non-Hodgkin Lymphomas

Clinical Trial IDs

  • ORG STUDY ID: STUDY00002247
  • SECONDARY ID: NCI-2021-00894
  • SECONDARY ID: STUDY00002247
  • SECONDARY ID: WINSHIP5186-20
  • SECONDARY ID: P30CA138292
  • NCT ID: NCT04883437

Conditions

  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Grade 3a Follicular Lymphoma
  • Indolent Non-Hodgkin Lymphoma
  • Lymphoplasmacytic Lymphoma
  • Lymphoproliferative Disorder
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (acalabrutinib, obinutuzumab)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759Treatment (acalabrutinib, obinutuzumab)

Purpose

This phase II trial studies the effect of acalabrutinib and obinutuzumab in treating patients with follicular lymphoma or other indolent non-Hodgkin lymphoma for which the patient has not received treatment in the past (previously untreated). Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Immunotherapy with obinutuzumab may induce changes in body's immune system and may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib and obinutuzumab may kill more cancer cells.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To determine if treatment acalabrutinib and obinutuzumab is effective in patients with
      untreated, low tumor burden follicular lymphoma and other indolent non-Hodgkin lymphomas
      (NHLs).

      SECONDARY OBJECTIVES:

      I. Determine the complete response (CR) rate for single agent acalabrutinib at the end of a
      single-agent run-in for patients with untreated low tumor burden follicular lymphoma (FL).

      II. Determine tolerability of acalabrutinib and obinutuzumab via assessment of
      patient-reported outcomes and conventional assessments.

      III. Assess duration of response and long-term outcomes including progression-free survival.

      IV. Assess the impact of early treatment with this regimen on health-related quality of life.

      TERTIARY/EXPLORATORY OBJECTIVES:

      I. Evaluate the impact of treatment discontinuation in patients who have achieved a complete
      response at the end of the induction phase.

      II. To assess the safety and efficacy of acalabrutinib and obinutuzumab in other subtypes of
      indolent NHL.

      OUTLINE:

      INDUCTION PHASE: Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28.
      Patients also receive obinutuzumab intravenously (IV) on days 1, 8, and 15 of cycle 3, then
      on day 1 of cycles 4-8. Treatments repeat every 28 days for up to 12 cycles in the absence of
      disease progression or unacceptable toxicity.

      FOLLOW-UP PHASE: After cycle 12, patients who are in CR are randomized to either discontinue
      acalabrutinib or to continue acalabrutinib monotherapy in the absence of disease progression
      or unacceptable toxicity. Patients with partial response (PR) or stable disease (SD) after
      cycle 12 continue acalabrutinib monotherapy in the absence of disease progression or
      unacceptable toxicity. Patients with disease progression after cycle 12 discontinue study
      treatment. Patients with disease progression at any time prior to the conclusion of cycle 12
      may continue study therapy if they are felt to be benefiting by the treating physician, but
      not past cycle 12.

      After completion of study treatment, patients are followed up at 30 days, every 12 weeks for
      1 year, then every 6 months until disease progression or next anti-lymphoma treatment.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (acalabrutinib, obinutuzumab)ExperimentalINDUCTION PHASE: Patients receive acalabrutinib PO BID on days 1-28. Patients also receive obinutuzumab IV on days 1, 8, and 15 of cycle 3, then on day 1 of cycles 4-8. Treatments repeat every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. FOLLOW-UP PHASE: After cycle 12, patients who are in CR are randomized to either discontinue acalabrutinib or to continue acalabrutinib monotherapy in the absence of disease progression or unacceptable toxicity. Patients with PR or SD after cycle 12 continue acalabrutinib monotherapy in the absence of disease progression or unacceptable toxicity. Patients with disease progression after cycle 12 discontinue study treatment. Patients with disease progression at any time prior to the conclusion of cycle 12 may continue study therapy if they are felt to be benefiting by the treating physician, but not past cycle 12.
  • Acalabrutinib
  • Obinutuzumab

Eligibility Criteria

        Inclusion Criteria:

          -  Men and women >= 18 years of age

          -  Patients will need to have one of the following clinical scenarios:

               -  Previously untreated follicular lymphoma grade 1-3a with low tumor burden by
                  Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria

               -  Previously untreated follicular lymphoma grade 1-3a with high tumor burden by
                  GELF criteria but who are unable or unwilling to receive standard front-line
                  treatment approaches

               -  Previously untreated marginal zone lymphoma, lymphoplasmacytic lymphoma, or any
                  other indolent B-cell lymphoproliferative disorder with low tumor burden by GELF
                  criteria or who are unable/unwilling to receive more intensive front-line
                  treatment

               -  Previously untreated mantle cell lymphoma who would otherwise be appropriate
                  candidates for watchful waiting OR who have symptomatic disease but are not
                  candidates for or decline standard induction approaches

          -  Patients with previously untreated low tumor burden FL (criterion above) must have
             measurable and/or assessable disease defined as at least one involved lymph node or
             extranodal disease site that measures >= 1.5cm in greatest diameter

          -  Patients who meet inclusion criteria above are eligible as long as they meet one of
             the following criteria for measurable/assessable disease:

               -  At least one involved lymph node or extranodal disease site measuring > 1.5cm in
                  greatest diameter

               -  Pathologically-confirmed bone marrow or peripheral blood involvement that can be
                  reassessed for response

               -  Pathologically confirmed splenic or extranodal involvement with at least one
                  known site of disease remaining after diagnostic biopsy that can be reassessed
                  (i.e., patients with splenic marginal zone lymphoma who complete splenectomy and
                  have no other detectable disease would not be eligible)

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0-2

          -  Woman of childbearing potential (WOCBP) and men enrolled on this protocol must agree
             to use adequate contraception (hormonal or barrier method of birth control;
             abstinence) prior to study entry for the duration of study participation, and for at
             least 2 days after the last dose of acalabrutinib or 18 months after the last dose of
             obinutuzumab, whichever is longer. Should a woman become pregnant or suspect she is
             pregnant while she or her partner is participating in this study, she should inform
             her treating physician immediately

          -  Women of childbearing potential must have a negative serum or urine pregnancy test
             prior to starting therapy

          -  Willing and able to participate in all required evaluations and procedures in this
             study protocol

          -  Ability to understand the purpose and risks of the study and provide signed and dated
             informed consent and authorization to use protected health information Ability to
             understand the purpose and risks of the study and provide signed and dated informed
             consent and authorization to use protected health information

        Exclusion Criteria:

          -  The presence or history of histologically transformed or co-existing high-grade or
             aggressive non-Hodgkin lymphoma

          -  Confirmed active or prior central nervous system disease

          -  Prior receipt of lymphoma-directed therapy or prior antibody-based therapy (except for
             anti-microbial therapy for infection-associated marginal zone lymphoma such as
             hepatitis C or H pylori)

               -  A short course of steroids is permitted for patients aside from those in the low
                  tumor burden FL cohort. This course may be no more than 14 days and steroids must
                  be discontinued (or tapered to =< 10mg prednisone or equivalent) no later than 3
                  days after initiation of study treatment. Patients in the low tumor burden FL
                  cohort may not receive corticosteroids as an anti-lymphoma therapy at any time
                  before starting treatment

          -  Prior malignancy (or any other malignancy requiring active treatment), except for
             adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer,
             or other cancer from which the subject has been disease free for >= 2 years or which
             will not limit survival to < 5 years

          -  Clinically significant cardiovascular disease such as symptomatic ventricular
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             screening, or any class 3 or 4 cardiac disease as defined by the New York Heart
             Association Functional Classification. Note: Subjects with controlled, asymptomatic
             atrial fibrillation can enroll on study if deemed appropriate by the investigator

          -  Has difficulty with or is unable to swallow oral medication, or has significant
             gastrointestinal disease that would limit absorption of oral medication

          -  Known history of human immunodeficiency (HIV) or any active significant infection
             (e.g., bacterial, viral, or fungal) within 14 days of cycle 1. Patients with
             uncomplicated viral or bacterial infections that are being managed with oral
             antibiotics and/or supportive care alone are eligible

          -  Known history of hypersensitivity or anaphylaxis to study drug(s) including active
             product or excipient components

          -  Active bleeding or history of bleeding diathesis (e.g., hemophilia or von Willebrand
             disease)

          -  Uncontrolled AIHA (autoimmune hemolytic anemia) or ITP (idiopathic thrombocytopenic
             purpura)

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

          -  Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer

          -  Requires or receiving anticoagulation with warfarin or equivalent vitamin K
             antagonists

          -  Requires treatment with proton pump inhibitors (e.g, omeprazole, esomeprazole,
             lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving
             proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible
             for enrollment to this study

          -  History of significant cerebrovascular disease/event, including stroke or intracranial
             hemorrhage, within 6 months before the first dose of study drug. Patients with a
             transient ischemic attack which has resolved and for which there are no ongoing
             symptoms are eligible

          -  Major surgical procedure within 28 days of first dose of study drug (not including a
             diagnostic procedure to make the lymphoma diagnosis). 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

          -  Hepatitis B or C serologic status: subjects who are hepatitis B core antibody
             (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need
             to have a negative polymerase chain reaction (PCR) and must be willing to undergo
             deoxyribonucleic acid (DNA) PCR testing during the study to be eligible. Those who are
             HBsAg positive or hepatitis B PCR positive will be excluded. Subjects who are
             hepatitis C antibody positive will need to have a negative PCR result to be eligible
             and have completed appropriate anti-viral treatment. Those who are hepatitis C PCR
             positive will be excluded. Anti-viral therapy for patients with hepatitis-C associated
             marginal zone lymphoma will not be considered a prior anti-lymphoma treatment

          -  Absolute neutrophil count (ANC) < 1,000/mcL

          -  Platelet count < 50,000/mcL (Unless felt to be related to underlying disease)

          -  Total bilirubin >= 1.5 x the upper limit of normal (ULN). Isolated bilirubin > 1.5 x
             ULN is permitted if the direct proportion is < 35%

          -  Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) > 2.5 x ULN

          -  Creatinine clearance =< 40 mL/min/1.73m^2

          -  Breastfeeding or pregnant

          -  Concurrent participation in another therapeutic clinical trial
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR) rate
Time Frame:Up to start of cycle 6 (each cycle = 28 days)
Safety Issue:
Description:Complete response rate will be calculated, and a 95% confidence interval will be estimated using the Clopper-Pearson method.

Secondary Outcome Measures

Measure:Overall response rate
Time Frame:Up to 3 years
Safety Issue:
Description:Overall response rate will be calculated, and a 95% confidence interval will be estimated using the Clopper-Pearson method.
Measure:CR rate for acalabrutinib monotherapy at end of single-agent run-in
Time Frame:Up to 3 years
Safety Issue:
Description:Will be calculated, and a 95% confidence interval will be estimated using the Clopper-Pearson method.
Measure:2-year progression free survival (PFS)
Time Frame:From first dose to documented disease progression, or death from any cause, whichever occurs first, assessed at 2 years
Safety Issue:
Description:PFS will be estimated using Kaplan-Meier methodology. Approximate 95% confidence intervals (CIs) for median PFS will be computed using the Brookmeyer and Crowley method.
Measure:Overall survival (OS)
Time Frame:From first dose to death from any cause, assessed up to 3 years
Safety Issue:
Description:Duration of OS will be estimated using Kaplan-Meier methodology. Approximate 95% CIs for median OS will computed using the Brookmeyer and Crowley method.
Measure:Duration of response (DOR)
Time Frame:From the first tumor assessment supports the response to the time of confirmed disease progression or death due to any cause, whichever occurs first, assessed up to 3 years
Safety Issue:
Description:DOR will be estimated using Kaplan-Meier method. Approximate 95% CIs for median DOR will be computed using the Brookmeyer and Crowley method.
Measure:Time to next anti-lymphoma treatment
Time Frame:From the end of induction visit up to and including the date of initiation of next treatment for any reason, assessed up to 3 years
Safety Issue:
Description:Time to next anti-lymphoma treatment is defined as the time from the end of induction visit up to and including the date of initiation of next treatment for any reason. This includes any chemotherapy, antibody therapy, oral therapy, and radiation therapy. Time to next anti-lymphoma treatment will be estimated using Kaplan-Meier methodology. Approximate 95% CIs for median time to next anti-lymphoma treatment will be computed using the Brookmeyer and Crowley method
Measure:Quality of life (QOL) assessments
Time Frame:Up to 3 years
Safety Issue:
Description:QOL measures from the Functional Assessment of Cancer Therapy General questionnaire obtained during treatment will be compared to the baseline values obtained at the screening visit using paired t-tests, McNemar's tests, or their nonparametric equivalents, where appropriate.
Measure:Patient-reported adverse events.
Time Frame:Up to 3 years
Safety Issue:
Description:Categorical Patient Reported Outcomes (PRO)-CTCAE variables will be summarized using frequencies and percentages, and numeric PRO-CTCAE variables will be summarized using mean, median, standard deviation, interquartile range (IQR), and range.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Last Updated

May 12, 2021