Clinical Trials /

CC-486, Lenalidomide, and Obinutuzumab for the Treatment of Recurrent or Refractory CD20 Positive B-cell Lymphoma

NCT04578600

Description:

This phase I/Ib trial investigates the side effects of CC-486 and how well it works in combination with lenalidomide and obinutuzumab in treating patients with CD20 positive B-cell lymphoma that has come back (recurrent) or has not responded to treatment (refractory). Chemotherapy drugs, such as CC-486, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide is a drug that alters the immune system and may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may reduce or prevent the growth of cancer cells. Obinutuzumab is a type of antibody therapy that targets and attaches to the CD20 proteins found on follicular lymphoma cells as well as some healthy blood cells. Once attached to the CD20 protein the obinutuzumab is thought to work in different ways, including by helping the immune system destroy the cancer cells and by destroying the cancer cells directly. Giving CC-486 with lenalidomide and obinutuzumab may improve response rates, quality, and duration, and minimize adverse events in patients with B-cell lymphoma.

Related Conditions:
  • B-Cell Non-Hodgkin Lymphoma
  • Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma
  • Extranodal Marginal Zone Lymphoma of Mucosa-Associated Lymphoid Tissue
  • Follicular Lymphoma
  • Hairy Cell Leukemia
  • Lymphoplasmacytic Lymphoma
  • Mantle Cell Lymphoma
  • Marginal Zone Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: CC-486, Lenalidomide, and Obinutuzumab for the Treatment of Recurrent or Refractory CD20 Positive B-cell Lymphoma
  • Official Title: A Phase I/IB Pilot Study of CC-486 Combined With Lenalidomide and Obinutuzumab for Relapsed/Refractory Indolent B-Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 1548998
  • SECONDARY ID: NCI-2020-05946
  • SECONDARY ID: UCDCC#282
  • SECONDARY ID: P30CA093373
  • NCT ID: NCT04578600

Conditions

  • Indolent B-Cell Non-Hodgkin Lymphoma
  • Recurrent B-Cell Non-Hodgkin Lymphoma
  • Recurrent Chronic Lymphocytic Leukemia
  • Recurrent Mucosa-Associated Lymphoid Tissue Lymphoma
  • Recurrent Follicular Lymphoma
  • Recurrent Hairy Cell Leukemia
  • Recurrent Lymphoplasmacytic Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Chronic Lymphocytic Leukemia
  • Refractory Mucosa-Associated Lymphoid Tissue Lymphoma
  • Refractory Follicular Lymphoma
  • Refractory Hairy Cell Leukemia
  • Refractory Lymphoplasmacytic Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Refractory Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
LenalidomideCC-5013, CC5013, CDC 501, RevlimidTreatment (lenalidomide, oral azacitidine, obinutuzumab)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759Treatment (lenalidomide, oral azacitidine, obinutuzumab)
Oral AzacitidineCC-486Treatment (lenalidomide, oral azacitidine, obinutuzumab)

Purpose

This phase I/Ib trial investigates the side effects of CC-486 and how well it works in combination with lenalidomide and obinutuzumab in treating patients with CD20 positive B-cell lymphoma that has come back (recurrent) or has not responded to treatment (refractory). Chemotherapy drugs, such as CC-486, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Lenalidomide is a drug that alters the immune system and may also interfere with the development of tiny blood vessels that help support tumor growth. Therefore, in theory, it may reduce or prevent the growth of cancer cells. Obinutuzumab is a type of antibody therapy that targets and attaches to the CD20 proteins found on follicular lymphoma cells as well as some healthy blood cells. Once attached to the CD20 protein the obinutuzumab is thought to work in different ways, including by helping the immune system destroy the cancer cells and by destroying the cancer cells directly. Giving CC-486 with lenalidomide and obinutuzumab may improve response rates, quality, and duration, and minimize adverse events in patients with B-cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVE:

      To assess the safety and toxicity of oral azacitidine (CC-486) in combination with
      lenalidomide and obinutuzumab.

      SECONDARY OBJECTIVES:

      I. To evaluate the efficacy of CC-486 in combination with lenalidomide and obinutuzumab in
      subjects with relapsed/refractory indolent B-cell lymphoma as assessed by:

      Ia. Overall response rate: complete response (CR) + partial response (PR) per 2016 Lugano
      criteria and Lymphoma Response to Immunomodulatory Therapy Criteria (LYRIC) criteria.

      Ib. Duration of response (DOR): will be calculated from time of initial response assessment
      demonstrating at least PR until disease response assessment that demonstrates progressive
      disease.

      Ic. Time to response (TTR): calculated as time from registration to first disease response
      assessment that demonstrates at least PR.

      Id. Progression-free survival (PFS): Patients are considered a failure for this endpoint if
      they die or if they relapse/progress or receive additional anti-lymphoma therapy.

      Ie. Determine the recommended phase 2 dose (RP2D).
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (lenalidomide, oral azacitidine, obinutuzumab)ExperimentalPatients receive azacitidine PO QD on days 1-21, obinutuzumab IV over on days 8, 15, 22, and 29, and lenalidomide PO QD on days 8-28 of cycle 1. Treatment continues for 35 days in the absence of disease progression or unacceptable toxicity. Patients then receive azacitidine PO QD on days 1-21, obinutuzumab IV over on day 1, and lenalidomide PO QD on days 1-21. Cycles repeats every 28 days in the absence of disease progression, unacceptable toxicity, or until stem cell transplant. Patients who achieve SD, PR, or CR do not proceed to stem cell transplant may continue treatment for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Lenalidomide
  • Obinutuzumab
  • Oral Azacitidine

Eligibility Criteria

        Inclusion Criteria:

          -  Previously treated, histologically confirmed CD20+ B cell lymphoma which includes
             mantle cell lymphoma, follicular lymphoma, chronic lymphocytic leukemia/small
             lymphocytic lymphoma, hairy cell leukemia, marginal zone lymphoma, mucosa-associated
             lymphoid tissue (MALT) lymphoma, and lymphoplasmacytic lymphoma. Fine needle aspirates
             are not acceptable

          -  Ability to understand and willingness to sign an informed consent form

          -  Ability to adhere to the study visit schedule and other protocol requirements

          -  Eastern Cooperative Oncology Group (ECOG) performance status score of 0 or 1, or
             Karnofsky performance status (KPS) performance status of 60% or greater

          -  Life expectancy >= 3 months

          -  Leukocytes >= 3,000/uL

          -  Absolute neutrophil count >= 1,000/uL

          -  Platelets >= 50,000/uL

          -  Total bilirubin: =< 2.0 x institutional upper limit of normal (ULN)

          -  Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase
             [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT])
             =< 2.5 x institutional ULN

          -  Serum creatinine

               -  =< 2.0 x ULN, OR

               -  Calculated creatinine clearance >= 30 ml/min/1.73 M^2 by the modified Cockcroft
                  and Gault Formula, OR

               -  Creatinine clearance >= 30 mL/min obtained from a 24-hour urine collection

          -  At least one measurable lesion according to International workshop lymphoma response
             criteria. There must be measurable lymphadenopathy to follow with serial exam and/or
             imaging

          -  All previous cancer therapy, including radiation, hormonal therapy and surgery, must
             have been discontinued at least 4 weeks prior to treatment in this study

          -  Submission of original biopsy for review and verification by participating center
             hematopathologist

          -  Disease free of prior malignancies for >= 3 years with exception of currently treated
             basal cell, squamous cell carcinoma of the skin, or carcinoma "in situ" of the cervix
             or breast

          -  All study participants must be registered into the mandatory Revlimid Risk Evaluation
             and Mitigation Strategies (REMS) program, and be willing and able to comply with the
             requirements of the REMS program

          -  Females of reproductive potential must adhere to the scheduled pregnancy testing as
             required in the Revlimid REMS program

          -  Able to take aspirin (81 or 325 mg) daily as prophylactic anticoagulation. (Subjects
             intolerant to acetylsalicylic acid [ASA] may use low molecular weight heparin)

          -  Must be able to swallow study drugs

          -  Human immunodeficiency virus (HIV) infected patients are eligible provided they meet
             all the other eligibility criteria of the study in addition to the following:

               -  No history of acquired immunodeficiency syndrome (AIDS)-defining conditions other
                  than lymphoma or history of CD4+ T-cells below 200/mm^3 prior to beginning
                  combination antiretroviral therapy (cART)

               -  After HIV diagnosis and during treatment with cART, patients should have
                  maintained CD4+ T-cells >= 350/mm^3 prior to lymphoma diagnosis. Patents who
                  never immune reconstituted to a stable level above 350/mm^3 are not eligible

               -  At time of study entry CD4+ T-cells must have recovered from prior lymphoma
                  therapy to >= 250/mm^3

               -  At the time of study entry the HIV viral load must be undetectable by standard
                  laboratory assay

               -  During prior lymphoma therapy, patients must not have experienced documented
                  infections attributed to the HIV+ status

               -  No history of non-adherence to cART and willing to adhere to cART while on study

               -  Antiretroviral drugs with overlapping or similar toxicity profiles as study
                  agents not allowed:

                    -  Efavirenz not allowed due to potential central nervous system (CNS) toxicity

                    -  Stavudine not allowed due to potential neuropathic effects

                    -  Zidovudine not allowed due to myelosuppressive effects

               -  Patients must be willing to be followed at a minimum of approximately every 3
                  months by physician expert in HIV disease management

        Exclusion Criteria:

          -  Any serious medical condition, laboratory abnormality, or psychiatric illness that
             would prevent the subject from signing the informed consent form

          -  Any condition, including the presence of laboratory abnormalities, which places the
             subject at unacceptable risk if he/she were to participate in the study or confounds
             the ability to interpret data from the study

          -  Use of any other experimental drug or therapy within 28 days of baseline

          -  Known hypersensitivity to lenalidomide, thalidomide, obinutuzumab, or mannitol

          -  A history of erythema nodosum if characterized by a desquamating rash while taking
             thalidomide or similar drugs

          -  Any prior use of obinutuzumab or CC-486

          -  Concurrent use of other anti-cancer agents or treatments

          -  Known active hepatitis B or C. Patients on suppressive therapy with a negative viral
             load and no evidence of hepatic damage are eligible

          -  Uncontrolled systemic fungal, bacterial or viral infection (defined as ongoing
             signs/symptoms related to the infection without improvement despite appropriate
             antibiotics, antiviral therapy and/or other treatment)

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

          -  Active autoimmune disease that has required systemic treatment in the past 2 years
             (i.e. with use of disease modifying agents, corticosteroids or immunosuppressive
             drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid
             replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a
             form of systemic treatment. A history of hemolytic anemia associated with the lymphoma
             does not exclude a patient from the study

          -  Pregnant or breast feeding females. (Lactating females must agree not to breast feed
             while taking azacitidine)

          -  For CC-486: History of inflammatory bowel disease (e.g., Crohn's disease, ulcerative
             colitis), celiac disease (i.e., sprue), prior gastrectomy or upper bowel removal, or
             any other gastrointestinal disorder or defect that would interfere with the
             absorption, distribution, metabolism or excretion of the study drug (CC-486) and/or
             predispose the subject to an increased risk of gastrointestinal toxicity

          -  Abnormal coagulation parameters (prothrombin time [PT] > 15 seconds, partial
             thromboplastin time [PTT] > 40 seconds, and/or international normalized ratio [INR] >
             1.5)

          -  Significant active cardiac disease within the previous 6 months including:

               -  New York Heart Association (NYHA) class 4 congestive heart failure (CHF)

               -  Unstable angina

               -  Myocardial infarction
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events (AEs)
Time Frame:Up to 30 days post-last dose
Safety Issue:
Description:Safety summaries will include tabulations in the form of tables and listings. The frequency (number and percentage) of treatment-emergent AEs will be reported. The frequency of treatment-emergent AEs requiring discontinuation of study drug or dose reductions will be reported. Additional AE summaries will include AE frequency by AE severity and by relationship to study drug. Toxicity data by type and severity will be summarized by frequency tables. Per-treated analysis will be performed to include any patient who received the treatment regardless of the eligibility nor the duration or dose of the treatment received.

Secondary Outcome Measures

Measure:Complete response rate
Time Frame:At 48 weeks
Safety Issue:
Description:Response will be assessed based on Cheson, Lugano classification 2016. The number and percentage of subjects with a complete response at 120 weeks will be tabulated.
Measure:Overall response rate (ORR) (complete response + partial response)
Time Frame:Up to 2 years
Safety Issue:
Description:Will be assessed by the investigator based on Cheson, Lugano classification 2016. The number and percentage of subjects with an ORR will be tabulated. The best ORR 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 2 years
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Measure:Time to response
Time Frame:From registration to first disease response assessment that demonstrates at least partial response, assessed up to 2 years
Safety Issue:
Description:Comparison by important subgroups will be made using the log-rank test. Will be estimated using the product-limit method of Kaplan and Meier.
Measure:Progression-free survival
Time Frame:From the date of first dose (cycle 1, day 1) to the date of first documented progression or death, assessed up to 2 years.
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Measure:Recommended phase 2 dose
Time Frame:Up to 35 days
Safety Issue:
Description:The maximum tolerated dose (MTD) will be defined as the highest dose of CC-486 tested in which fewer than 33% of patients experience a dose-limiting toxicity and at least 6 patients have been treated at that dose. The MTD will be the recommended phase 2 dose, provided that other safety considerations are acceptable.
Measure:Time to next treatment
Time Frame:From the end of cycle 24 (each cycle is 28 days) to the date of first documented new anti-lymphoma treatment, assessed up to 2 years.
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Measure:Event-free survival
Time Frame:From the date of first dose (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 2 years.
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.
Measure:Overall survival
Time Frame:From the date of first dose (cycle 1, day 1) to the date of death regardless of cause, assessed up to years.
Safety Issue:
Description:Kaplan-Meier methodology will be used to estimate event-free curves, median, and 95% confidence interval. Comparison by important subgroups will be made using the log-rank test.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Joseph Tuscano

Last Updated

October 1, 2020