Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

PRIMARY OBJECTIVES:

I. To compare the complete response rate at 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, vincristine sulfate, and prednisone [CHOP] or 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 at 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: 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 courses 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 courses 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 hydrochloride IV on day 1, vincristine sulfate IV
on day 1, and prednisone PO on days 1-5. Treatment with obinutuzumab repeats every 21 or 28
days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Treatment with combination chemotherapy repeats every 21 days for 6 courses 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 courses
(bendamustine and obinutuzumab, respectively) in the absence of disease progression or
unacceptable toxicity.

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

Inclusion Criteria:

- Patients must have follicular lymphoma (grade I, II or IIIa) confirmed at initial
diagnosis and at relapse with identifiable fludeoxyglucose F-18 (FDG) avid disease on
PET/CT; patients that have involvement with large cell lymphoma are not eligible

- Patients must not have clinical evidence of central nervous system involvement by
lymphoma since the proposed treatment strategies are not designed to address central
nervous system (CNS) involvement adequately; if performed, any laboratory or
radiographic tests performed to assess CNS involvement must be negative

- Patients must have a whole body or limited whole body PET/CT scan performed within 42
days prior to registration

- Patients must have bone marrow biopsy performed within 42 days prior to registration

- All disease must be assessed and documented on the S1608 FDG-PET/CT assessment form

- Patients must have either failed to achieve a complete remission, or must have
relapsed within 2 years after completing CHOP or bendamustine-containing
chemoimmunotherapy (including an anti-CD20 monoclonal antibody), as measured from the
last dose of CHOP or bendamustine; relapsed patients must not have received any
intervening chemotherapy; patients must have received only 1 course of chemotherapy,
containing at least 3 cycles of CHOP or bendamustine; (note that no minimum dose of
bendamustine is required); patients who received any anti-CD20 antibody therapy prior
to CHOP or bendamustine are eligible; patients who additionally received any
maintenance anti-CD-20 antibody therapy or consolidative radioimmunotherapy within 2
years of the last dose of the CHOP or bendamustine therapy are eligible; involved
field or involved site radiation is not considered a line of therapy; examples of
eligible prior treatment regimens (note this list is not all inclusive):

- 1st line rituximab treatment followed years later by bendamustine rituximab x 4
cycles

- Bendamustine rituximab x 4 cycles

- 1st line rituximab treatment, 2nd line ibritumomab tiuxetan, followed by
bendamustine bortezomib rituximab x 6 cycles followed by rituximab maintenance

- Bendamustine obinutuzumab x 3 cycles

- CHOP rituximab x 6 cycles followed by rituximab maintenance

- For all forms of systemic therapy, patients must have completed therapy at least 21
days prior to registration; patients must have completed any radioimmunotherapy at
least 84 days prior to registration; patients must have recovered from all treatment
related toxicities from these therapies prior to registration

- Patients must not have any prior treatment with any PI3K inhibitor, or lenalidomide

- Patients must have tissue specimens collected prior to registration; patients must be
offered participation in biobanking of residual specimens; with patient consent,
residuals from the mandatory submission will be banked for future research

- All patients must have a Zubrod performance status of 0, 1 or 2

- Absolute neutrophil count (ANC) >= 1,500/mcL within 28 days prior to registration

- Platelets >= 75,000/mcL within 28 days prior to registration

- Patients must have adequate renal function as documented by a calculated creatinine
clearance >= 60 mL/min, within 28 days prior to registration

- Total bilirubin =< 1.5 x institutional upper limit of normal (IULN) (=< 5 x IULN if
secondary to lymphoma, Gilbert's syndrome, or medication related [e.g., indinavir,
tenofovir, atazanavir]) within 28 days prior to registration

- Direct bilirubin =< 1.5 x IULN (=< 5 x IULN if secondary to lymphoma) within 28 days
prior to registration

- Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (=<
5 x IULN secondary to lymphoma) within 28 days prior to registration

- Patients must have an echocardiogram (ECHO) or multigated acquisition (MUGA) scan
within 42 days prior to registration with a cardiac ejection fraction >= 45%

- Patients with hepatitis B virus infection must have undetectable hepatitis B virus
(HBV) on suppressive therapy and no evidence of HBV-related hepatic damage; patients
with hepatitis C virus infection are eligible if complete eradication therapy has been
successfully completed, and there is no detectable hepatitis C virus (HVC) or related
hepatic damage; patients with known human immunodeficiency virus (HIV) infection are
eligible if they meet all of the following criteria in addition to the other protocol
eligibility criteria:

- Patient must have no history of acquired immune deficiency syndrome
(AIDS)-related complications, other than a history of low CD4+ T-cell count (<
200/mm^3) prior to initiation of combination antiretroviral therapy; on study
CD4+ T-cell count may not be informative due to leukemia and should not be used
as an exclusion criterion if low

- Patient must be healthy on the basis of HIV disease with high likelihood of near
normal life span were it not for the leukemia

- Patient must have serum HIV viral load of < 200 copies/mm^3

- Patient must be on combination antiretroviral therapy with minimal
pharmacokinetic interactions with study therapy and minimal overlapping clinical
toxicity with protocol therapy; (recommend a regimen of the integrase inhibitor
dolutegravir combined with either disoproxil fumarate/emtricitabine or
dolutegravir combined with tenofovir alafenamide/emtricitabine)

- Protease inhibitors and once daily formulations containing cobicistat are NOT
allowed due to potential pharmacokinetic interactions with leukemia therapy

- Stavudine and zidovudine (AZT) are NOT allowed because of overlapping toxicity
with protocol therapy

- Patients must be able and willing to receive prophylaxis with daily aspirin, low
molecular weight heparin, factor X inhibitors or warfarin if randomized to
lenalidomide; patients must also be willing to receive pneumocystis jirovecii
prophylaxis with sulfamethoxazole/trimethoprim, dapsone, atovaquone or inhaled
pentamidine, in the event that they are randomized to TGR-1202; patients unable or
unwilling to take any listed prophylaxis are NOT eligible

- Patients must be able to discontinue CYP2C9 substrates with a narrow therapeutic index
(e.g. warfarin, phenytoin), if randomized to TGR-1202; patients must discontinue such
agents at least 1 week or 5 half-lives prior to beginning protocol therapy (whichever
is longer)

- No second prior malignancy is allowed except for adequately treated basal (or squamous
cell) skin cancer, in situ cervical cancer or other cancer for which the patient has
been disease free for three years

- Patients must have a complete history and physical examination within 28 days prior to
registration

- Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy
test with a sensitivity of at least 25 mIU/mL within 10-14 days and again within 24
hours prior to starting cycle 1 of lenalidomide; further, they must either commit to
complete abstinence (true abstinence is acceptable when this is in line with the
preferred and usual lifestyle of the subject; periodic abstinence [e.g., calendar,
ovulation, symptothermal or post ovulation methods] and withdrawal are not acceptable
methods of contraception) 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 28 days before starting lenalidomide; while taking
lenalidomide, during dose interruptions, and for at least 28 days after the last dose
of lenalidomide; FCBP must also agree to ongoing pregnancy testing; men must agree to
use a latex condom during sexual contact with a FCBP, even if they have had a
successful vasectomy; a FCBP is a female who: 1) has achieve menarche at some point;
2) has not undergone a hysterectomy or bilateral oophorectomy; or 3) has not been
naturally postmenopausal (amenorrhea following cancer therapy does not rule out
childbearing potential) for at least 24 consecutive months (i.e., has had menses at
any time in the preceding 24 consecutive months); all patients must be counseled by a
trained counselor every 28 days about pregnancy precautions and risks of fetal
exposure; NOTE: patients not randomized to receive lenalidomide will not be required
to undergo serial pregnancy testing or lenalidomide counseling after registration

- Patients must have lactate dehydrogenase (LDH) and beta-2-microglobulin collected
within 28 days prior to registration

- Patients must be informed of the investigational nature of this study and must sign
and give written informed consent in accordance with institutional and federal
guidelines

- As a part of the OPEN registration process the treating institution's identity is
provided in order to ensure that the current (within 365 days) date of institutional
review board approval for this study has been entered in the system