This phase II trial studies how well obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy work in treating patients with grade I-IIIa follicular lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Immunotherapy with obinutuzumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Umbralisib may stop the growth of cancer cells by blocking some of the enzymes needed for cell growth. Biological therapies, such as lenalidomide, use substances made from living organisms that may stimulate or suppress the immune system in different ways and stop cancer cells from growing. Chemotherapy drugs, such as cyclophosphamide, doxorubicin, vincristine, prednisone, and bendamustine, 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. It is not yet known whether giving obinutuzumab with or without umbralisib, lenalidomide, or combination chemotherapy will work better in treating patients with grade I-IIIa follicular lymphoma.
PRIMARY OBJECTIVE: I. To compare the complete response rate up to 6 cycles after randomization as defined by centrally read positron emission tomography (PET)/computed tomography (CT) (integral biomarker) of 2 targeted therapeutic regimens (obinutuzumab + umbralisib \[TGR-1202\] or obinutuzumab + lenalidomide) with obinutuzumab + chemotherapy (cyclophosphamide, doxorubicin hydrochloride \[doxorubicin\], vincristine sulfate \[vincristine\], and prednisone \[CHOP\] or bendamustine hydrochloride \[bendamustine\]) in patients with early relapsing or refractory follicular lymphoma. SECONDARY OBJECTIVES: I. To validate the prognostic association of the m7-FLIPI model, demonstrating that the population of follicular lymphoma patients who respond poorly to chemoimmunotherapy are enriched for having a high-risk m7-FLIPI score, and that the score is associated with progression-free survival (integrated biomarker). (Primary translational medicine) II. To estimate the 30-month sustained complete response rate (CR30) defined by centrally read PET/CT with each of the regimens in this early relapsing or refractory follicular lymphoma population. III. To estimate best response up to 12 cycles of therapy, progression free survival, duration of response and overall survival with each of the combinations in early relapsing or refractory follicular lymphoma. IV. To evaluate the adverse effects of each of the regimens in early relapsing or refractory follicular lymphoma. V. To evaluate the predictive performance of non-invasive genotyping (m7-FLIPI in circulating tumor deoxyribonucleic acid \[DNA\]) of plasma at study entry relative to standard tumor genotyping (m7-FLIPI) of formalin-fixed paraffin-embedded tumor tissue. VI. To evaluate the association between the detection of active lymphoma by PET-CT and the detection of circulating tumor DNA in plasma at baseline, after 6 and 12 cycles, and at 30 months after initiation of study therapy. OUTLINE: Patients are randomized to 1 of 3 arms. ARM I (CLOSED TO ACCRUAL): Patients receive obinutuzumab intravenously (IV) on day 1 and umbralisib orally (PO) daily on days 1-28. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. ARM II: Patients receive obinutuzumab IV on day 1 and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up 12 cycles in the absence of disease progression or unacceptable toxicity. ARM III: PRIOR BENDAMUSTINE-BASED CHEMOTHERAPY: Patients receive obinutuzumab IV on day 1, cyclophosphamide IV on day 1, doxorubicin IV on day 1, vincristine IV on day 1, and prednisone PO on days 1-5. Treatment with obinutuzumab repeats every 21 or 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity. Treatment with combination chemotherapy repeats every 21 days for 6 cycles in the absence of disease progression or unacceptable toxicity. PRIOR CHOP CHEMOTHERAPY: Patients receive obinutuzumab IV on day 1 and bendamustine IV over 60 minutes on days 1 and 2. Treatment repeats every 28 days for up to 6 or 12 cycles (bendamustine and obinutuzumab, respectively) in the absence of disease progression or unacceptable toxicity. Patients in all arms undergo biopsy and echocardiogram (ECHO) or multigated acquisition scan (MUGA) during screening, and PET/CT scans and collection of blood throughout the trial. After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 3 years.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
73
Given IV
Undergo biopsy
Undergo collection of blood
Undergo PET/CT scans
Given IV
Given IV
Undergo ECHO
Given PO
Undergo MUGA
Given IV
Undergo PET/CT scans
Given PO
Given PO
Given IV
Alaska Breast Care and Surgery LLC
Anchorage, Alaska, United States
Alaska Oncology and Hematology LLC
Anchorage, Alaska, United States
Alaska Women's Cancer Care
Anchorage, Alaska, United States
Anchorage Oncology Centre
Anchorage, Alaska, United States
Katmai Oncology Group
Anchorage, Alaska, United States
Complete response (CR)
Time frame: Up to 6 cycles
Sustained complete response rate (CR30)
Defined by centrally read positron emission tomography (PET)/computed tomography (CT).
Time frame: Up to 30 months
Progression-free survival (PFS)
Will be calculated using the method of Kaplan-Meier. 95% confidence for the survival estimates will be constructed using the method of Brookmeyer-Crowley. With 31 eligible patients in each arm, progression free survival at a particular time point, and the 30-month sustained response rate can be estimated to within at least +/- 18% with 95% confidence.
Time frame: From date of registration to date of first observation of progressive disease, or death due to any cause, assessed up to 5 years
Duration of response (CR, partial response [PR])
Will be calculated using the method of Kaplan-Meier.
Time frame: From date of first documentation of response to treatment (CR, PR) to date of first documentation of progression, or death due to any cause, assessed up to 5 years
Overall survival (OS)
Will be calculated using the method of Kaplan-Meier. 95% confidence for the survival estimates will be constructed using the method of Brookmeyer-Crowley. With 31 eligible patients in each arm, OS at a particular time point, and the 30-month sustained response rate can be estimated to within at least +/- 18% with 95% confidence.
Time frame: Up to 5 years
Incidence of adverse events
Assessed by National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 4.0 (version 5.0 will be utilized for serious adverse events reporting only). Toxicity rates can be estimated to within at least +/- 18% with 95% confidence.
Time frame: Up to 5 years
Non-invasive genotyping and circulating tumor deoxyribonucleic acid (DNA) assessment
Sensitivity, specificity, positive predictive value, negative predictive value, and kappa coefficient will be used to evaluate the concordance. Will evaluate the association of detection of active lymphoma by positron emission tomography-computed tomography and the detection of circulating tumor DNA in plasma at baseline, after 6 and 12 cycles, and at 30 months after initiation of study therapy. Chi-square test will be used to evaluate the association and odds ratio will be calculated
Time frame: Up to 5 years
Active lymphoma and circulating tumor DNA in plasma
The Cox proportional hazards model will be used to assess the association and odds ratio will be calculated.
Time frame: From baseline up to 30 months after initiation of treatment
m7-FLIPI model validation
The Cox proportional hazards model will be used to assess the association of the m7-FLIPI with to PFS.
Time frame: Up to 5 years
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