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

  • STATUS
    Recruiting
  • End date
    Apr 1, 2023
  • participants needed
    24
  • sponsor
    Joseph Tuscano
Updated on 27 January 2021

Summary

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.

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).

Details
Condition Recurrent Chronic Lymphocytic Leukemia, Recurrent Mantle Cell Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Chronic Lymphocytic Leukemia, Refractory Mantle Cell Lymphoma, Refractory Small Lymphocytic Lymphoma, Recurrent Follicular Lymphoma, Recurrent Lymphoplasmacytic Lymphoma, Recurrent Marginal Zone Lymphoma, Refractory Hairy Cell Leukemia, Refractory Follicular Lymphoma, Refractory Lymphoplasmacytic Lymphoma, Refractory Marginal Zone Lymphoma, Recurrent Hairy Cell Leukemia, Chronic Lymphocytic Leukemia Refractory, chronic lymphocytic leukemia, relapsed, Indolent B-Cell Non-Hodgkin Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Mucosa-Associated Lymphoid Tissue Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Mucosa-Associated Lymphoid Tissue Lymphoma, Indolent B-Cell Non-Hodgkin Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Mucosa-Associated Lymphoid Tissue Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Mucosa-Associated Lymphoid Tissue Lymphoma, Indolent B-Cell Non-Hodgkin Lymphoma, Recurrent B-Cell Non-Hodgkin Lymphoma, Recurrent Mucosa-Associated Lymphoid Tissue Lymphoma, Refractory B-Cell Non-Hodgkin Lymphoma, Refractory Mucosa-Associated Lymphoid Tissue Lymphoma
Treatment Obinutuzumab, Lenalidomide, Oral Azacitidine
Clinical Study IdentifierNCT04578600
SponsorJoseph Tuscano
Last Modified on27 January 2021

Eligibility

Yes No Not Sure

Inclusion Criteria

Is your age greater than or equal to 18 yrs?
Gender: Male or Female
Do you have any of these conditions: Refractory Mantle Cell Lymphoma or Recurrent Small Lymphocytic Lymphoma or Indolent B-Cell Non-Hodgkin Lymphoma or Recurrent Follicular Lymphoma or Re...?
Do you have any of these conditions: Recurrent Mantle Cell Lymphoma or Refractory Lymphoplasmacytic Lymphoma or Refractory Small Lymphocytic Lymphoma or Recurrent Hairy Cell Leukemia or R...?
Do you have any of these conditions: Refractory Mantle Cell Lymphoma or Refractory B-Cell Non-Hodgkin Lymphoma or Chronic Lymphocytic Leukemia Refractory or Recurrent Hairy Cell Leukemia ...?
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
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