Grade 3a Follicular Lymphoma, Recurrent Follicular Lymphoma, Recurrent Grade 1 Follicular Lymphoma, Recurrent Grade 2 Follicular Lymphoma, Recurrent Grade 3 Follicular Lymphoma, Recurrent Marginal Zone Lymphoma, Recurrent Small Lymphocytic Lymphoma, Refractory Follicular Lymphoma, Refractory Marginal Zone Lymphoma, Refractory Small Lymphocytic Lymphoma
Conditions
Brief summary
This phase I/II trial studies the side effects and best dose of lenalidomide when given together with obinutuzumab and how well this combination works in treating patients with low-grade non-Hodgkin lymphoma (NHL) that has returned after a period of improvement (relapsed). Biological therapies, such as lenalidomide, may attack specific cancer cells and stop them from growing or kill them. Obinutuzumab is a form of targeted therapy because it attaches itself to specific molecules (receptors) on the surface of cancer cells, known as CD20 receptors. When obinutuzumab attaches to CD20 receptors, the signals that tell the cells to grow are blocked and the cancer cell may be marked for destruction by the body's immune system. Giving lenalidomide and obinutuzumab together may work better in treating NHL.
Detailed description
PRIMARY OBJECTIVES: I. To determine the maximum tolerated dose of lenalidomide plus obinutuzumab in relapsed/refractory indolent lymphoma. (Phase I) II. To evaluate the safety of lenalidomide in combination with obinutuzumab in patients with relapsed/refractory indolent lymphoma. (Phase II) III. To determine the overall response rate (ORR) of the combination in patients with relapsed/refractory indolent lymphoma. (Phase II) SECONDARY OBJECTIVES: I. To determine the complete response rate, time to progression (TTP), and progression free survival in patients with indolent lymphoma following treatment with obinutuzumab + lenalidomide. II. To evaluate changes in immune effector cells and the tumor microenvironment following treatment with obinutuzumab + lenalidomide. OUTLINE: This is a phase I, dose-escalation study of lenalidomide followed by a phase II study. Patients receive lenalidomide orally (PO) once daily (QD) on days 2-22 and obinutuzumab intravenously (IV) over 4-5 hours on days 1, 2, 8, 15, and 22 of cycle 1 and on day 1 of each subsequent cycle. Treatment repeats every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. Patients not experiencing progression and who in the opinion of treating physician are deriving benefit from combination treatment may continue lenalidomide for an additional 6 cycles (up to cycle 12) and obinutuzumab on day 1 every 2 months for up to 2 years in the absence of disease progression or unacceptable toxicity. After completion of study treatment, patients are followed up every 3 months for 1 year, every 6 months for 1 year, and then yearly thereafter.
Interventions
OTHERLaboratory Biomarker Analysis
Correlative studies
DRUGLenalidomide
Given PO
BIOLOGICALObinutuzumab
Given IV
Sponsors
National Cancer Institute (NCI)
M.D. Anderson Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* A diagnosis of small lymphocytic lymphoma, follicular lymphoma (grades 1-3a), or marginal zone lymphoma * Evidence of progression or lack of response following at least 1 prior treatment for indolent lymphoma * Able and willing to provide written informed consent and to comply with the study protocol * Must have at least 1 node greater than 1.5 cm in short axis diameter * Adequate hematologic function (unless abnormalities are related to NHL), defined as follows: * Hemoglobin \>= 9.0 g/dL * Absolute neutrophil count (ANC) \>= 1.5 x 10\^9/L; ANC \< 1.5 x 10\^9/L if cytopenia is due to extensive bone marrow involvement of disease as determined by the treating physician * Platelet count (PLT) \>= 75 x 10\^9/L; PLT count less than 100 x 10\^9/L if cytopenia is due to extensive bone marrow involvement of disease as determined by the treating physician * For men who are not surgically sterile, agreement to use a barrier method of contraception for \>= 3 months after the last obinutuzumab dose; in addition, male patients must agree to request that their partners use an additional method of contraception, such as oral contraceptives, intrauterine device, barrier method of contraception, or spermicidal jelly * For women of reproductive potential who are not surgically sterile, agreement to use two adequate methods of contraception, such as oral contraceptives, intrauterine device, or barrier method of contraception in conjunction with spermicidal jelly for \>= 12 months after the last obinutuzumab dose * Females of childbearing potential (FCBP) must have a negative serum pregnancy test with a sensitivity of at least 50 mIU/mL within 10-14 days prior to and again within 24 hours of prescribing lenalidomide and must either commit to continued abstinence from heterosexual intercourse or begin TWO acceptable methods of birth control, one highly effective method and one additional effective method AT THE SAME TIME, at least 4 weeks before she starts taking lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to use a latex condom during sexual contact with a female of child bearing potential even if they have had a successful vasectomy * A female of childbearing potential is a sexually mature woman who: 1) has not undergone a hysterectomy or bilateral oophorectomy; or 2) has not been naturally postmenopausal for at least 24 consecutive months (i.e., has had menses at any time in the preceding 24 consecutive months) * All study participants must be registered into the mandatory Revlimid Risk Evaluation and Mitigation Strategy (REMS) program, and be willing and able to comply with the requirements of Revlimid REMS program * For patients with bulky disease (tumors \> 5 cm); must be able to take aspirin (81 mg or 325 mg) daily as prophylactic anticoagulation (patients intolerant to acetylsalicylic acid \[ASA\] may use warfarin or low molecular weight heparin) * 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 (patients intolerant to ASA may use warfarin or low molecular weight heparin)
Exclusion criteria
* Evidence ongoing transformation into aggressive NHL * History of severe allergic or anaphylactic reactions to monoclonal antibody therapy * Known hypersensitivity to thalidomide or lenalidomide * Regular treatment with corticosteroids during the 4 weeks prior to the start of cycle 1, unless administered for indications other than NHL at a dose equivalent to =\< 30 mg/day prednisone * History of prior malignancy within the last 5 years, with the exception of curatively treated basal or squamous cell carcinoma of the skin and low-grade in situ carcinoma of the cervix * Evidence or history of significant, uncontrolled concomitant diseases that could affect compliance with the protocol or interpretation of results, including significant cardiovascular disease (such as New York Heart Association class III or IV cardiac disease, severe arrhythmia, myocardial infarction within the previous 6 months, unstable arrhythmias, or unstable angina) or pulmonary disease (including obstructive pulmonary disease and history of bronchospasm) * Known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds) or any major episode of infection requiring treatment with IV antibiotics or hospitalization (relating to the completion of the course of antibiotics, except if for tumor fever) within 4 weeks prior to the start of cycle 1; patients with suspected active or latent tuberculosis (latent tuberculosis needs to be confirmed by positive interferon-gamma release assay) * Vaccination with live vaccines within 28 days prior to start of treatment * Any of the following abnormal laboratory values (unless any of these abnormalities are due to underlying lymphoma) * Creatinine \> 1.5 times the upper limit of normal (ULN) (unless creatinine clearance normal), or calculated creatinine clearance \< 40 mL/min (using Cockcroft-Gault formula) * Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) \> 2.5 x ULN * Total bilirubin \> 1.5 x ULN (or \> 3 x ULN for patients with documented Gilbert syndrome) * Any history of hepatitis B infection * Positive test results for hepatitis C (hepatitis C virus \[HCV\] antibody serology testing); patients positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV ribonucleic acid (RNA) * Known history of human immunodeficiency virus (HIV) seropositive status * Positive test results for human T-lymphotropic 1 (HTLV 1) virus; HTLV testing is required in patients from endemic countries (Japan, countries in the Caribbean basin, South America, Central America, Sub Saharan Africa, and Melanesia) * Pregnant or lactating * Eastern Cooperative Oncology Group (ECOG) performance status greater than 2 * Participation in another clinical trial with drug intervention within 21 days prior to start of cycle 1 and during the study * Patients with small lymphocytic lymphoma (SLL)/chronic lymphocytic leukemia (CLL) are excluded during the phase I portion of the study
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Tolerated Dose of Lenalidomide When Given With Obinutuzumab Defined as the Highest Dose Level Have Been Treated With Less Than 2 Instances of Dose Limiting Toxicity DLT. | 28 days after 168 days (6 courses) | To determine the maximum tolerated dose of lenalidomide plus obinutuzumab in relapsed/refractory indolent lymphoma the 3 by 3 method was used. (Phase I) Doses of Lenalidomide to be used are 10mg, 15mg, 20mg in Phase 1. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Overall Survival, Time to Progression, and Progression Free Survival (Phase II) | up to 4 years | The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test. |
Countries
United States
Participant flow
Recruitment details
Patients were enrolled into an investigator initiated, open-label, phase 1/2 trial at a single institution, MD Anderson Cancer Center, Houston, TX, US.
Participants by arm
| Arm | Count |
|---|---|
| Phase I Dose Level 10mg Lenolidomide + 1000mg Obinutuzimab Patients with relapsed or refractory WHO Grade 1 to 3A follicular lymphoma | 3 |
| Phase I Dose Level 15mg Lenolidomide + 1000mg Obinutuzimab Patients with relapsed or refractory WHO Grade 1 to 3A follicular lymphoma | 3 |
| Phase I Dose Level 20mg Lenolidomide + 1000mg Obinutuzimab Patients with relapsed or refractory WHO Grade 1 to 3A follicular lymphoma | 3 |
| Ph. II: Expansion Len 20 mg Plus Obin 1000 mg Participants with relapsed or refractory WHO Grade 1 to 3A follicular lymphoma, marginal zone lymphoma and small lymphocytic lymphoma | 57 |
| Total | 66 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 |
|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 0 | 3 |
| Overall Study | Death | 0 | 0 | 0 | 6 |
| Overall Study | Insurance Expired | 0 | 0 | 0 | 1 |
| Overall Study | Progression | 2 | 1 | 1 | 13 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 6 |
Baseline characteristics
| Characteristic | Phase I Dose Level 10mg Lenolidomide + 1000mg Obinutuzimab | Phase I Dose Level 15mg Lenolidomide + 1000mg Obinutuzimab | Phase I Dose Level 20mg Lenolidomide + 1000mg Obinutuzimab | Ph. II: Expansion Len 20 mg Plus Obin 1000 mg | Total |
|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 0 Participants | 2 Participants | 3 Participants | 25 Participants | 30 Participants |
| Age, Categorical Between 18 and 65 years | 3 Participants | 1 Participants | 0 Participants | 32 Participants | 36 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 7 Participants | 7 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 3 Participants | 3 Participants | 3 Participants | 50 Participants | 59 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants | 0 Participants | 1 Participants | 3 Participants | 4 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 2 Participants | 3 Participants | 2 Participants | 54 Participants | 61 Participants |
| Region of Enrollment United States | 3 Participants | 3 Participants | 3 Participants | 57 Participants | 66 Participants |
| Sex: Female, Male Female | 1 Participants | 0 Participants | 1 Participants | 28 Participants | 30 Participants |
| Sex: Female, Male Male | 2 Participants | 3 Participants | 2 Participants | 29 Participants | 36 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk |
|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 3 | 1 / 3 | 0 / 3 | 6 / 57 |
| other Total, other adverse events | 3 / 3 | 3 / 3 | 3 / 3 | 57 / 57 |
| serious Total, serious adverse events | 1 / 3 | 3 / 3 | 1 / 3 | 34 / 57 |
Outcome results
Primary
Maximum Tolerated Dose of Lenalidomide When Given With Obinutuzumab Defined as the Highest Dose Level Have Been Treated With Less Than 2 Instances of Dose Limiting Toxicity DLT.
To determine the maximum tolerated dose of lenalidomide plus obinutuzumab in relapsed/refractory indolent lymphoma the 3 by 3 method was used. (Phase I) Doses of Lenalidomide to be used are 10mg, 15mg, 20mg in Phase 1.
Time frame: 28 days after 168 days (6 courses)
Population: Phase II was not assessed.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| All Participants | Maximum Tolerated Dose of Lenalidomide When Given With Obinutuzumab Defined as the Highest Dose Level Have Been Treated With Less Than 2 Instances of Dose Limiting Toxicity DLT. | 20 mg |
Secondary
Overall Survival, Time to Progression, and Progression Free Survival (Phase II)
The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.The distribution of time-to-event endpoints will be estimated using the method of Kaplan and Meier. Comparison of time-to-event endpoints by important subgroups will be made using the log-rank test.
Time frame: up to 4 years
Population: Phase I was not assessed for this outcome.
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| All Participants | Overall Survival, Time to Progression, and Progression Free Survival (Phase II) | PFS | 44.2 months |
| All Participants | Overall Survival, Time to Progression, and Progression Free Survival (Phase II) | OS | NA months |
| All Participants | Overall Survival, Time to Progression, and Progression Free Survival (Phase II) | TTP | 44.2 months |