Clinical Trials /

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

NCT03269669

Description:

This randomized 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 or does not respond to treatment. 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. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, 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.

Related Conditions:
  • Follicular Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma
  • Official Title: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2017-00009
  • SECONDARY ID: NCI-2017-00009
  • SECONDARY ID: S1608
  • SECONDARY ID: S1608
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03269669

Conditions

  • Grade 1 Follicular Lymphoma
  • Grade 2 Follicular Lymphoma
  • Grade 3a Follicular Lymphoma
  • Recurrent Follicular Lymphoma
  • Refractory Follicular Lymphoma

Interventions

DrugSynonymsArms
BendamustineSDX-105Arm III (obinutuzumab, combination chemotherapy)
Cyclophosphamide(-)-Cyclophosphamide, 2H-1,3,2-Oxazaphosphorine, 2-[bis(2-chloroethyl)amino]tetrahydro-, 2-oxide, monohydrate, Carloxan, Ciclofosfamida, Ciclofosfamide, Cicloxal, Clafen, Claphene, CP monohydrate, CTX, CYCLO-cell, Cycloblastin, Cycloblastine, Cyclophospham, Cyclophosphamid monohydrate, Cyclophosphamide Monohydrate, Cyclophosphamidum, Cyclophosphan, Cyclophosphane, Cyclophosphanum, Cyclostin, Cyclostine, Cytophosphan, Cytophosphane, Cytoxan, Fosfaseron, Genoxal, Genuxal, Ledoxina, Mitoxan, Neosar, Revimmune, Syklofosfamid, WR- 138719Arm III (obinutuzumab, combination chemotherapy)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinArm III (obinutuzumab, combination chemotherapy)
Doxorubicin Hydrochloride5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin HCl, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, RubexArm III (obinutuzumab, combination chemotherapy)
LenalidomideCC-5013, CC5013, CDC 501, RevlimidArm II (obinutuzumab, lenalidomide)
ObinutuzumabAnti-CD20 Monoclonal Antibody R7159, GA-101, GA101, Gazyva, huMAB(CD20), R7159, RO 5072759, RO-5072759, RO5072759Arm I (obinutuzumab, umbralisib)
Prednisone.delta.1-Cortisone, 1, 2-Dehydrocortisone, Adasone, Cortancyl, Dacortin, DeCortin, Decortisyl, Decorton, Delta 1-Cortisone, Delta-Dome, Deltacortene, Deltacortisone, Deltadehydrocortisone, Deltasone, Deltison, Deltra, Econosone, Lisacort, Meprosona-F, Metacortandracin, Meticorten, Ofisolona, Orasone, Panafcort, Panasol-S, Paracort, Perrigo Prednisone, PRED, Predicor, Predicorten, Prednicen-M, Prednicort, Prednidib, Prednilonga, Predniment, Prednisone Intensol, Prednisonum, Prednitone, Promifen, Rayos, Servisone, SK-PrednisoneArm III (obinutuzumab, combination chemotherapy)
Umbralisib2-((1S)-1-(4-Amino-3-(3-fluoro-4-(1-methylethoxy)phenyl)-1H-pyrazolo(3,4-d)pyrimidin-1-yl)ethyl)-6-fluoro-3-(3-fluorophenyl)-4H-1-benzopyran-4-one, RP-5264, RP5264, TGR-1202Arm I (obinutuzumab, umbralisib)
VincristineLEUROCRISTINE, VCR, VincrystineArm III (obinutuzumab, combination chemotherapy)
Vincristine SulfateKyocristine, Leurocristine sulfate, Leurocristine, sulfate, Oncovin, Vincasar, Vincosid, Vincrex, Vincristine, sulfateArm III (obinutuzumab, combination chemotherapy)

Purpose

This randomized 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 or does not respond to treatment. 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. Drugs used in chemotherapy, such as cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, 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.

Detailed Description

      PRIMARY OBJECTIVE:

      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 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 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 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.

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

Trial Arms

NameTypeDescriptionInterventions
Arm I (obinutuzumab, umbralisib)ExperimentalPatients receive obinutuzumab IV on day 1 and umbralisib 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.
  • Obinutuzumab
  • Umbralisib
Arm II (obinutuzumab, lenalidomide)ExperimentalPatients receive obinutuzumab IV on day 1 and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 cycles in the absence of disease progression or unacceptable toxicity.
  • Lenalidomide
  • Obinutuzumab
Arm III (obinutuzumab, combination chemotherapy)Active ComparatorPRIOR 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 cycles in the absence of disease progression or unacceptable toxicity. Treatment with combination chemotherapy repeats every 21 days for up to 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 1 hour 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.
  • Bendamustine
  • Cyclophosphamide
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Obinutuzumab
  • Prednisone
  • Vincristine
  • Vincristine Sulfate

Eligibility Criteria

        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

          -  The intent is to enroll patients with FL relapsed within 2 years of completing their
             first course of chemotherapy (CHOP or bendamustine based therapy) + anti-CD20 therapy.
             Patient is still eligible if he/she received radiation therapy or anti-CD20 therapy
             prior to chemoimmunotherapy or if maintenance anti-CD20 therapy was administered after
             chemoimmunotherapy

               -  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 Oncology Patient Enrollment Network (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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR)
Time Frame:Up to 6 courses
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Sustained complete response rate (CR30)
Time Frame:Up to 30 months
Safety Issue:
Description:Defined by centrally read positron emission tomography (PET)/computed tomography (CT).
Measure:Progression-free survival (PFS)
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
Safety Issue:
Description: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 45 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 +/- 15% with 95% confidence.
Measure:Duration of response (CR, partial response [PR])
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
Safety Issue:
Description:Will be calculated using the method of Kaplan-Meier.
Measure:Overall survival (OS)
Time Frame:Up to 5 years
Safety Issue:
Description: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 45 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 +/- 15% with 95% confidence.
Measure:Incidence of adverse events
Time Frame:Up to 5 years
Safety Issue:
Description: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 +/- 15% with 95% confidence.
Measure:Non-invasive genotyping and circulating tumor deoxyribonucleic acid (DNA) assessment
Time Frame:Up to 5 years
Safety Issue:
Description: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
Measure:Active lymphoma and circulating tumor DNA in plasma
Time Frame:From baseline up to 30 months after initiation of treatment
Safety Issue:
Description:The Cox proportional hazards model will be used to assess the association and odds ratio will be calculated.
Measure:m7-FLIPI model validation
Time Frame:Up to 5 years
Safety Issue:
Description:The Cox proportional hazards model will be used to assess the association of the m7-FLIPI with to PFS.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 7, 2020