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Trial record 1 of 1 for:    S1608
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Obinutuzumab With or Without Umbralisib, Lenalidomide, or Combination Chemotherapy in Treating Patients With Relapsed or Refractory Grade I-IIIa Follicular Lymphoma

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ClinicalTrials.gov Identifier: NCT03269669
Recruitment Status : Suspended (Other - Comparative excess risks seen in UNITY trial)
First Posted : September 1, 2017
Last Update Posted : June 22, 2022
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Study Description
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Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Grade 1 Follicular Lymphoma Grade 2 Follicular Lymphoma Grade 3a Follicular Lymphoma Recurrent Follicular Lymphoma Refractory Follicular Lymphoma Drug: Bendamustine Hydrochloride Drug: Cyclophosphamide Drug: Doxorubicin Hydrochloride Drug: Lenalidomide Biological: Obinutuzumab Drug: Prednisone Drug: Umbralisib Drug: Vincristine Sulfate Phase 2

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Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 103 participants
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
Actual Study Start Date : August 10, 2017
Estimated Primary Completion Date : December 31, 2022
Estimated Study Completion Date : December 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arms and Interventions
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Arm Intervention/treatment
Experimental: Arm I (obinutuzumab, umbralisib)
Patients 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.
 Biological: Obinutuzumab
Given IV

Drug: Umbralisib
Given PO
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 cycles in the absence of disease progression or unacceptable toxicity.
 Drug: Lenalidomide
Given PO

Biological: Obinutuzumab
Given IV
Active Comparator: Arm III (obinutuzumab, combination chemotherapy)

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 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.

 Drug: Bendamustine Hydrochloride
Given IV

Drug: Cyclophosphamide
Given IV

Drug: Doxorubicin Hydrochloride
Given IV

Biological: Obinutuzumab
Given IV

Drug: Prednisone
Given PO

Drug: Vincristine Sulfate
Given IV


Outcome Measures
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Primary Outcome Measures :
  1. Complete response (CR) [ Time Frame: Up to 6 cycles ]

Secondary Outcome Measures :
  1. Sustained complete response rate (CR30) [ Time Frame: Up to 30 months ]
    Defined by centrally read positron emission tomography (PET)/computed tomography (CT).

  2. 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 ]
    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.

  3. 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 ]
    Will be calculated using the method of Kaplan-Meier.

  4. Overall survival (OS) [ 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 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.

  5. Incidence of adverse events [ Time Frame: Up to 5 years ]
    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.

  6. 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

  7. Active lymphoma and circulating tumor DNA in plasma [ Time Frame: From baseline up to 30 months after initiation of treatment ]
    The Cox proportional hazards model will be used to assess the association and odds ratio will be calculated.

  8. m7-FLIPI 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.


Eligibility Criteria
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Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
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 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 prior treatment related toxicities (except alopecia) must have resolved to Grade 1 or less 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
  • Patients must be >= 18 years of age
  • 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
Contacts and Locations
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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


Locations
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Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Paul M Barr Southwest Oncology Group
More Information
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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT03269669    
Other Study ID Numbers: NCI-2017-00009
NCI-2017-00009 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
S1608 ( Other Identifier: SWOG )
S1608 ( Other Identifier: CTEP )
U10CA180888 ( U.S. NIH Grant/Contract )
First Posted: September 1, 2017    Key Record Dates
Last Update Posted: June 22, 2022
Last Verified: June 2022

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Lymphoma
Lymphoma, Follicular
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Lymphoma, Non-Hodgkin
Prednisone
Cyclophosphamide
Bendamustine Hydrochloride
Doxorubicin
Liposomal doxorubicin
Vincristine
 Lenalidomide
Obinutuzumab
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
Topoisomerase II Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors