Clinical Trials /

Acalabrutinib, Lenalidomide, and Rituximab for the Treatment of CD20 Positive Stage III-IV, Grade 1-3a Follicular Lymphoma

NCT04404088

Description:

This phase II trial studies how well acalabrutinib, lenalidomide, and rituximab work in treating patients with CD20 positive stage III-IV, grade 1-3a follicular lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib, lenalidomide, and rituximab may help to control the disease.

Related Conditions:
  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Grade 3 Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Acalabrutinib, Lenalidomide, and Rituximab for the Treatment of CD20 Positive Stage III-IV, Grade 1-3a Follicular Lymphoma
  • Official Title: A Phase II Study of Acalabrutinib, Lenalidomide, and Rituximab (aR2) in Patients With Previously Untreated Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 2020-0034
  • SECONDARY ID: NCI-2020-01922
  • SECONDARY ID: 2020-0034
  • SECONDARY ID: P30CA016672
  • NCT ID: NCT04404088

Conditions

  • Ann Arbor Stage III Grade 1 Follicular Lymphoma
  • Ann Arbor Stage III Grade 2 Follicular Lymphoma
  • Ann Arbor Stage III Grade 3 Follicular Lymphoma
  • Ann Arbor Stage IV Grade 1 Follicular Lymphoma
  • Ann Arbor Stage IV Grade 2 Follicular Lymphoma
  • Ann Arbor Stage IV Grade 3 Follicular Lymphoma
  • Grade 3a Follicular Lymphoma

Interventions

DrugSynonymsArms
AcalabrutinibACP-196, Bruton Tyrosine Kinase Inhibitor ACP-196, CalquenceTreatment (acalabrutinib, lenalidomide, rituximab)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (acalabrutinib, lenalidomide, rituximab)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaTreatment (acalabrutinib, lenalidomide, rituximab)

Purpose

This phase II trial studies how well acalabrutinib, lenalidomide, and rituximab work in treating patients with CD20 positive stage III-IV, grade 1-3a follicular lymphoma. Acalabrutinib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as lenalidomide, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Rituximab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. Giving acalabrutinib, lenalidomide, and rituximab may help to control the disease.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the efficacy of acalabrutinib combined with rituximab and lenalidomide in
      patients with previously untreated follicular lymphoma (FL) (determined by complete remission
      [CR] rate by the end of treatment).

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of acalabrutinib combined with rituximab and lenalidomide in
      subjects with FL as assessed by objective response rate (ORR) at the end of treatment,
      duration of response (DOR), progression rate within 24 months from treatment initiation
      (progression-free survival [PFS] 24), PFS and overall survival (OS).

      II. To evaluate the safety and tolerability of acalabrutinib combined with rituximab and
      lenalidomide in previously untreated subjects with FL.

      EXPLORATORY OBJECTIVE:

      I. To determine the pharmacodynamic effects and investigate biomarkers of response and
      resistance of the 3-drug combination.

      OUTLINE:

      Patients receive acalabrutinib orally (PO) twice daily (BID) on days 1-28. Beginning cycle 2,
      patients receive lenalidomide PO once daily (QD) on days 1-21 and rituximab intravenously
      (IV) on days 1, 8, 15, and 22 of cycle 2 and day 1 of subsequent cycles. Treatment repeats
      every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up every 3 months for 1 year and
      then every 6 months for 2 years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (acalabrutinib, lenalidomide, rituximab)ExperimentalPatients receive acalabrutinib PO BID on days 1-28. Beginning cycle 2, patients receive lenalidomide PO QD on days 1-21 and rituximab IV on days 1, 8, 15, and 22 of cycle 2 and day 1 of subsequent cycles. Treatment repeats every 28 days for 13 cycles in the absence of disease progression or unacceptable toxicity.
  • Acalabrutinib
  • Lenalidomide
  • Rituximab

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically confirmed CD20 positive (+) follicular lymphoma, grade 1, 2, or 3a

          -  Have had no prior systemic treatment for lymphoma

          -  Bi-dimensionally measurable disease, with at least one mass lesion >= 2 cm in longest
             diameter by computed tomography (CT), positron emission tomography (PET)/CT, and/or
             magnetic resonance imaging (MRI)

          -  Meeting Groupe d'Etude des Lymphomes Folliculaires (GELF) criteria for initiation of
             treatment

          -  Stage III or IV disease

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Absolute neutrophil count (ANC) >= 1,000/mm^3, independent of growth factor support
             (within 28 days prior to signing informed consent)

          -  Platelet counts >= 100,000/mm^3 or >= 50,000/mm^3 if bone marrow involvement with
             lymphoma, independent of transfusion support in either situation (within 28 days prior
             to signing informed consent)

          -  Hemoglobin > 8 g/dL, independent of transfusion support (within 28 days prior to
             signing informed consent)

          -  Serum aspartate transaminase (AST) or alanine transaminase (ALT) < 2 x upper limit of
             normal (ULN) (within 28 days prior to signing informed consent)

          -  Creatinine clearance > 30 ml/min calculated by modified Cockcroft-Gault formula
             (within 28 days prior to signing informed consent)

          -  Bilirubin < 1.5 x ULN unless bilirubin is due to Gilbert's syndrome, documented liver
             involvement with lymphoma, or of non-hepatic origin, in which case bilirubin should
             not exceed 3 g/dL (within 28 days prior to signing informed consent)

          -  Prothrombin time (PT)/international normalized ratio (INR) < 1.5 x ULN and partial
             thromboplastin time (PTT) < 1.5 x ULN (within 28 days prior to signing informed
             consent)

          -  Must be able to adhere to the study visit schedule and other protocol requirements

          -  Women of childbearing potential and men who are sexually active must be practicing a
             highly effective method of birth control during and after the study (females of
             childbearing potential: must either completely abstain from heterosexual sexual
             conduct or must use 2 methods of reliable contraception, 1 highly effective
             [intrauterine device, birth control pills, hormonal patches, injections, vaginal
             rings, or implants] and at least 1 additional method [condom, diaphragm, cervical cap]
             of birth control). Reliable contraceptive methods must be started at least 4 weeks
             before lenalidomide, and continued for at least 4 weeks after last dose of
             lenalidomide. Males who are sexually active must be practicing complete abstinence or
             agree to a condom during sexual contact with a pregnant female or female of child
             bearing potential. Men must agree to not donate sperm during and after the study. For
             females, these restrictions apply at least 4 weeks before study treatment, during the
             period of therapy and for 1 month after the last dose of study drug. For males, these
             restrictions apply during the period of therapy and for 3 months after the last dose
             of study drug

          -  Women of childbearing potential must have a negative serum (beta-human chorionic
             gonadotropin [beta-hCG]) pregnancy test at screening. Women who are pregnant or
             breastfeeding are ineligible for this study

               -  Females of reproductive potential must adhere to the scheduled pregnancy testing
                  as required in the Revlimid Risk Evaluation and Mitigation Strategies (REMS)
                  program

          -  Sign (or their legally-acceptable representatives must sign) an informed consent
             document indicating that they understand the purpose of and procedures required for
             the study, including biomarkers, and are willing to participate in the study

          -  All study participants must be registered into the mandatory Revlimid REMS program,
             and be willing and able to comply with the requirements of the REMS program

        Exclusion Criteria:

          -  Known active central nervous system lymphoma or leptomeningeal disease, except
             subjects with a history of central nervous system lymphoma treated and in remission >
             6 months

          -  Evidence of diffuse large B-cell transformation

          -  Grade 3b FL

          -  Any prior history of other malignancy besides FL or marginal zone lymphoma, unless the
             patient has been free of disease for >= 5 years and felt to be at low risk for
             recurrence by the treating physician, except:

               -  Adequately treated non-melanoma skin cancer or lentigo maligna without evidence
                  of disease

               -  Adequately treated cervical carcinoma in situ without evidence of disease

          -  Any life-threatening illness, medical condition, or organ system dysfunction which, in
             the investigator's opinion, could compromise the subject's safety, interfere with the
             absorption or metabolism of acalabrutinib or lenalidomide capsules, or put the study
             outcomes at undue risk

          -  Known history of human immunodeficiency virus (HIV), or active hepatitis C Virus, or
             active hepatitis B Virus infection, or any uncontrolled active significant infection,
             including suspected or confirmed John Cunningham (JC) virus infection

               -  Patients with inactive hepatitis B infection must adhere to hepatitis B
                  reactivation prophylaxis unless contraindicated. Hepatitis B or C serologic
                  status: subjects who are hepatitis B core antibody (anti-HBc) positive and who
                  are surface antigen negative will need to have a negative polymerase chain
                  reaction (PCR). Those who are hepatitis B surface antigen (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. Those who are hepatitis C PCR
                  positive will be excluded. Subjects with a history of Hepatitis C who received
                  antiviral treatment are eligible as long as PCR is negative

          -  Concurrent systemic immunosuppressant therapy (e.g., cyclosporine, tacrolimus, etc.,
             or chronic administration glucocorticoid equivalent of > 10 mg/day of prednisone)
             within 28 days of the first dose of study drug

          -  Known anaphylaxis or immunoglobulin (Ig) E-mediated hypersensitivity to murine
             proteins or to any component of acalabrutinib, lenalidomide and/or rituximab

          -  Requires anticoagulation with warfarin or equivalent vitamin K antagonists (e.g.,
             phenprocoumon). If patients have been on warfarin or equivalent vitamin K antagonists
             in the past, they will not be eligible if administered within 30 days of the first
             dose of study drug

          -  Requires chronic treatment with strong CYP3A inhibitors, for a list of strong CYP3A
             inhibitors. If patients have been on a strong CYP3A inhibitor in the past, they will
             not be eligible if the CYP3A inhibitor was administered within 7 days of the first
             dose of study drug

          -  Requires chronic treatment with strong CYP3A inducers, for a list of strong CYP3A
             inducers. If patients have been on a strong CYP3A inducer in the past, they will not
             be eligible if the CYP3A inducer was administered within 7 days of the first dose of
             study drug

          -  Clinically significant cardiovascular disease such as uncontrolled or symptomatic
             arrhythmias, congestive heart failure, or myocardial infarction within 6 months of
             screening, or any class 3 (moderate) or class 4 (severe) cardiac disease as defined by
             the New York Heart Association functional classification. Subjects with controlled,
             asymptomatic atrial fibrillation during screening can enroll on study

          -  Significant screening electrocardiogram (ECG) abnormalities including left bundle
             branch block, 2nd degree atrioventricular (AV) block, type II AV block, or 3rd degree
             block

          -  Active bleeding or known bleeding diathesis (e.g., von Willebrand's disease) or
             hemophilia

          -  History of stroke or intracranial hemorrhage within 6 months prior to study entry

          -  Vaccinated with live, attenuated vaccines within 4 weeks of study entry

          -  Lactating or pregnant subjects

          -  Administration of any investigational agent within 28 days of first dose of study drug

          -  Patients who have undergone major surgery within 28 days or minor surgery within 3
             days of first dose of study drug

          -  Patients taking corticosteroids during the last 4 weeks, unless administered at a dose
             equivalent to < 10 mg/day prednisone (over these 4 weeks)

          -  Life expectancy < 6 months

          -  Neuropathy > grade 1

          -  Prior exposure to lenalidomide or to a BCR inhibitor, independently from indication

          -  Patient who require treatment with proton pump inhibitors (e.g., omeprazole,
             esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole), and are
             unable to switch to H2-receptor antagonists

          -  Patients who have difficulty with or are unable to swallow oral medication, or have
             disease significantly affecting gastrointestinal function that would limit absorption
             of oral medication

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

          -  Known history of deep vein thrombosis or pulmonary embolism

          -  Known history of Stevens-Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN) or
             drug rash with eosinophilia and systemic symptoms (DRESS)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete remission rate
Time Frame:(Up to end of treatment; 1 year)
Safety Issue:
Description:Will be based on Cheson, Lugano classification 2014. The number and percentage of subjects with a complete remission at the end of treatment will be tabulated.

Secondary Outcome Measures

Measure:Overall response rate (complete response + partial response)
Time Frame:(At the end of treatment ; 1 year )
Safety Issue:
Description:Will be based on Cheson, Lugano classification 2014. The number and percentage of subjects with an overall response rate will be tabulated. The best overall response rate will be recorded.
Measure:Duration of response
Time Frame:From the time by which measurement criteria for complete response or partial response, whichever is recorded first, is met until death or the first date by which progressive disease is documented, assessed up to 3 years
Safety Issue:
Description:Will be based on Cheson, Lugano classification 2014. Cox proportional hazards models will be used to assess the effects of patient prognostic factors on duration of response. Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval.
Measure:Progression-free survival within 24 months from treatment initiation
Time Frame:From the treatment start date (cycle 1, day 1) until the firstdate of objectively documented progressive disease or date of death from any cause, assessed up to 24 months
Safety Issue:
Description:Will be estimated by the Kaplan-Meier method. Corresponding 95% confidence intervals will be summarized. Cox proportional hazards models will be used to assess the effects of patient prognostic factors on progression-free survival.
Measure:Progression-free survival
Time Frame:From the date of cycle 1, day 1 to the date of first documented progression, transformation to diffuse large B-cell lymphoma, initiation of new anti-lymphoma treatment, or death, assessed up to 3 years
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Cox proportional hazards models will be used to assess the effects of patient prognostic factors on progression-free survival.
Measure:Overall survival
Time Frame:From the date of cycle 1, day 1 to the date of death regardless of cause, assessed up to 3 years
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Cox proportional hazards models will be used to assess the effects of patient prognostic factors on overall survival.
Measure:Frequency, severity, and relatedness of treatment-emergent adverse events (AEs)
Time Frame:Up to 3 years
Safety Issue:
Description:Adverse experiences will be graded and recorded throughout the study and during the follow-up period according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5. Safety summaries will include tabulations in the form of tables and listings. The frequency (number and percentage) of treatment-emergent AEs will be reported. Additional AE summaries will include AE frequency by AE severity and by relationship to study drug. Clinically significant abnormal laboratory values will be summarized.
Measure:Frequency of treatment-emergent AEs requiring study drug discontinuation or dose reduction
Time Frame:Up to 3 years
Safety Issue:
Description:Adverse experiences will be graded and recorded throughout the study and during the follow-up period according to NCI CTCAE version 5. Safety summaries will include tabulations in the form of tables and listings. The frequency (number and percentage) of treatment-emergent AEs will be reported. Additional AE summaries will include AE frequency by AE severity and by relationship to study drug. Clinically significant abnormal laboratory values will be summarized.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:M.D. Anderson Cancer Center

Last Updated

May 21, 2020