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Obinutuzumab With or Without PI3K-delta Inhibitor TGR-1202, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

This study is currently recruiting participants.
Verified November 2017 by National Cancer Institute (NCI)
Sponsor:
ClinicalTrials.gov Identifier:
NCT03269669
First Posted: September 1, 2017
Last Update Posted: November 20, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
Information provided by (Responsible Party):
National Cancer Institute (NCI)
  Purpose
This randomized phase II trial studies how well obinutuzumab with or without PI3K-delta inhibitor TGR-1202, lenalidomide, or combination chemotherapy work in treating patients with grade I-IIIa follicular lymphoma that has come back or does not respond to treatment. Monoclonal antibodies, such as obinutuzumab, may interfere with the ability of cancer cells to grow and spread. PI3K-delta inhibitor TGR-1202 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, and prednisone, 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 PI3K-delta inhibitor TGR-1202, lenalidomide, or combination chemotherapy will work better in treating patients with grade I-IIIa follicular lymphoma.

Condition Intervention Phase
Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade 3a Follicular Lymphoma Recurrent Follicular Lymphoma Refractory Follicular Lymphoma Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Other: Laboratory Biomarker Analysis Drug: Lenalidomide Biological: Obinutuzumab Drug: PI3K-delta Inhibitor TGR-1202 Drug: Prednisone Drug: Vincristine Sulfate Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Randomized Phase II Trial in Early Relapsing or Refractory Follicular Lymphoma

Resource links provided by NLM:


Further study details as provided by National Cancer Institute (NCI):

Primary Outcome Measures:
  • Complete response (CR) [ Time Frame: Up to 6 courses ]
    Will be assessed.


Secondary Outcome Measures:
  • Duration of response (complete response, partial response) [ Time Frame: Up to 5 years ]
    Will be calculated using the method of Kaplan-Meier.

  • Incidence of adverse events assessed by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0 [ Time Frame: Up to 5 years ]
    Toxicity rates can be estimated to within at least ± 15% with 95% confidence.

  • M7-LIPI model validation [ Time Frame: Up to 5 years ]
    The Cox proportional hazards model will be used to assess the association of the m7-FLIPI with to PFS.

  • Non-invasive genotyping and circulating tumor deoxyribonucleic acid (DNA) assessment [ Time Frame: Up to 5 years ]
    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.

  • Overall survival [ Time Frame: Up to 5 years ]
    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, overall survival (OS) at a particular time point, and the 30-month sustained response rate can be estimated to within at least ± 15% with 95% confidence

  • Progression-free survival [ 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 ]
    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 (PFS) at a particular time point, and the 30-month sustained response rate can be estimated to within at least ± 15% with 95% confidence


Estimated Enrollment: 150
Actual Study Start Date: August 10, 2017
Estimated Study Completion Date: December 31, 2022
Estimated Primary Completion Date: December 31, 2022 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: Arm I (obinutuzumab, PI3K-delta inhibitor TGR-1202)
Patients receive obinutuzumab IV on day 1 and PI3K-delta inhibitor TGR-1202 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.
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759
Drug: PI3K-delta Inhibitor TGR-1202
Given PO
Other Names:
  • RP5264
  • TGR-1202
Experimental: Arm II (obinutuzumab, lenalidomide)
Patients receive obinutuzumab IV on day 1 and lenalidomide PO on days 1-21. Treatment repeats every 28 days for up to 12 courses in the absence of disease progression or unacceptable toxicity.
Other: Laboratory Biomarker Analysis
Correlative studies
Drug: Lenalidomide
Given PO
Other Names:
  • CC-5013
  • CC5013
  • CDC 501
  • Revlimid
Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759
Active Comparator: Treatment (obinutuzumab, combination chemotherapy)
Patients receive obinutuzumab IV on day 1, cyclophosphamide IV over 15 minutes 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 up to 6 courses in the absence of disease progression or unacceptable toxicity.
Drug: Cyclophosphamide
Given IV
Other Names:
  • (-)-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
  • Cyclophosphamidum
  • Cyclophosphan
  • Cyclophosphane
  • Cyclophosphanum
  • Cyclostin
  • Cyclostine
  • Cytophosphan
  • Cytophosphane
  • Cytoxan
  • Fosfaseron
  • Genoxal
  • Genuxal
  • Ledoxina
  • Mitoxan
  • Neosar
  • Revimmune
  • Syklofosfamid
  • WR- 138719
Drug: Doxorubicin Hydrochloride
Given IV
Other Names:
  • 5,12-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
  • Doxorubin
  • Farmiblastina
  • FI 106
  • FI-106
  • hydroxydaunorubicin
  • Rubex
Other: Laboratory Biomarker Analysis
Correlative studies
Biological: Obinutuzumab
Given IV
Other Names:
  • Anti-CD20 Monoclonal Antibody R7159
  • GA-101
  • GA101
  • Gazyva
  • huMAB(CD20)
  • R7159
  • RO 5072759
Drug: Prednisone
Given PO
Other Names:
  • .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
  • PRED
  • Predicor
  • Predicorten
  • Prednicen-M
  • Prednicort
  • Prednidib
  • Prednilonga
  • Predniment
  • Prednisonum
  • Prednitone
  • Promifen
  • Servisone
  • SK-Prednisone
Drug: Vincristine Sulfate
Given IV
Other Names:
  • Kyocristine
  • Leurocristine Sulfate
  • Leurocristine, sulfate
  • Oncovin
  • Vincasar
  • Vincosid
  • Vincrex
  • Vincristine, sulfate

Detailed Description:

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 + PI3K-delta inhibitor TGR-1202 [TGR-1202] or obinutuzumab + lenalidomide) with obinutuzumab + cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone (CHOP) in patients with early relapsing or refractory follicular lymphoma.

SECONDARY OBJECTIVES:

I. To validate the prognostic association of fthe 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 (integrated biomarker), 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 PI3K-delta inhibitor TGR-1202 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 to 12 courses in the absence of disease progression or unacceptable toxicity.

ARM III: Patients receive obinutuzumab IV on day 1, cyclophosphamide IV over 15 minutes 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 up to 6 courses 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.

  Eligibility

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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; if performed, any laboratory or radiographic tests performed to assess central nervous system (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 first line bendamustine-containing chemoimmunotherapy (including an anti-CD20 monoclonal antibody), as measured from the last dose of bendamustine; relapsed patients mustnot have received any intervening chemotherapy; patients must have received at least 3 cycles of bendamustine as first line therapy; (Note that no minimum dose of bendamustine is required); patients who additionally received any maintenance anti-CD-20 antibody based therapy or consolidative radioimmunotherapy within 2 years of the last dose of the bendamustine therapy are eligible; involved field or involved site radiation is not considered a line of therapy; patients who previously received anthracycline based therapy are excluded; examples of eligible 1st line treatment regimens (note this list is not all inclusive):

    • Bendamustine rituximab x 4 cycles
    • Bendamustine bortezomib rituximab x 6 cycles followed by rituximab maintenance
    • Bendamustine obinutuzumab x 3 cycles
  • 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 blood and tissue specimens collected prior to registration and submitted for translational medicine; Note that patients without adequate diagnostic specimens will not be eligible; 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
  • Platelets >= 750/mcL
  • 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])
  • Direct bilirubin =< 1.5 x IULN (=< 5 x IULN if secondary to lymphoma)
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x IULN (=< 5 x IULN secondary to lymphoma)
  • 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:

    • Patient must have no history of acquired immune deficiency syndrome (AIDS)-related complications, other than a history of low CD4+ T-cell count (< 200/mm3) 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
    • 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
  • No 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
  • Patients must have the following components of Follicular Lymphoma International Prognostic Index (FLIPI) available from diagnosis, and collected again at time of registration:

    • Age
    • Lactate dehydrogenase (LDH)
    • Number of nodal groups involved
    • Serum or plasma hemoglobin
    • Ann Arbor stage Additionally, patients must have beta-2-microglobulin collected at time of 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 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

Exclusion Criteria:

  • 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)
  Contacts and Locations
Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03269669


  Show 169 Study Locations
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
Principal Investigator: Paul Barr Southwest Oncology Group
  More Information

Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03269669     History of Changes
Other Study ID Numbers: NCI-2017-00009
NCI-2017-00009 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1608
S1608 ( Other Identifier: SWOG )
S1608 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Submitted: August 30, 2017
First Posted: September 1, 2017
Last Update Posted: November 20, 2017
Last Verified: November 2017

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Lymphoma
Lymphoma, Follicular
Lymphoma, Non-Hodgkin
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Cyclophosphamide
Thalidomide
Rituximab
Liposomal doxorubicin
Lenalidomide
Obinutuzumab
Doxorubicin
Prednisone
Vincristine
Cortisone acetate
Cortisone
Immunosuppressive Agents
Immunologic Factors
Physiological Effects of Drugs
Antirheumatic Agents
Antineoplastic Agents, Alkylating
Alkylating Agents
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Myeloablative Agonists
Antibiotics, Antineoplastic