Clinical Trials /

Polatuzumab Vedotin, Venetoclax, and Rituximab and Hyaluronidase Human for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma

NCT04659044

Description:

This phase II trial studies the effect of polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Polatuzumab vedotin is a monoclonal antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79B positive cancer cells in a targeted way and delivers vedotin to kill them. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cell growth. Rituximab hyaluronidase is a combination of rituximab and hyaluronidase. Rituximab binds to a molecule called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Hyaluronidase allows rituximab to be given by injection under the skin. Giving rituximab and hyaluronidase by injection under the skin is faster than giving rituximab alone by infusion into the blood. Giving polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human may work better than standard therapy in treating patients with mantle cell lymphoma.

Related Conditions:
  • Mantle Cell Lymphoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Polatuzumab Vedotin, Venetoclax, and Rituximab and Hyaluronidase Human for the Treatment of Relapsed or Refractory Mantle Cell Lymphoma
  • Official Title: A Phase 2 Trial of the Combination of Polatuzumab Vedotin, Venetoclax and Rituximab and Hyaluronidase Human for Relapsed and Refractory Mantle Cell Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: ACCRU-LY-1806
  • SECONDARY ID: NCI-2020-08188
  • SECONDARY ID: ACCRU-LY-1806
  • SECONDARY ID: P30CA015083
  • NCT ID: NCT04659044

Conditions

  • Recurrent B-Cell Non-Hodgkin Lymphoma
  • Recurrent Grade 1 Follicular Lymphoma
  • Recurrent Grade 2 Follicular Lymphoma
  • Recurrent Grade 3a Follicular Lymphoma
  • Recurrent Mantle Cell Lymphoma
  • Recurrent Marginal Zone Lymphoma
  • Recurrent Small Lymphocytic Lymphoma
  • Refractory B-Cell Non-Hodgkin Lymphoma
  • Refractory Grade 1 Follicular Lymphoma
  • Refractory Grade 2 Follicular Lymphoma
  • Refractory Grade 3a Follicular Lymphoma
  • Refractory Mantle Cell Lymphoma
  • Refractory Marginal Zone Lymphoma
  • Refractory Small Lymphocytic Lymphoma

Interventions

DrugSynonymsArms
Polatuzumab VedotinADC DCDS4501A, Antibody-Drug Conjugate DCDS4501A, DCDS4501A, FCU 2711, polatuzumab vedotin-piiq, Polivy, RG7596, Ro 5541077-000Treatment (rituximab, polatuzumab vedotin, venetoclax)
RituximabABP 798, BI 695500, C2B8 Monoclonal Antibody, Chimeric Anti-CD20 Antibody, CT-P10, IDEC-102, IDEC-C2B8, IDEC-C2B8 Monoclonal Antibody, MabThera, Monoclonal Antibody IDEC-C2B8, PF-05280586, Rituxan, Rituximab ABBS, Rituximab Biosimilar ABP 798, Rituximab Biosimilar BI 695500, Rituximab Biosimilar CT-P10, Rituximab Biosimilar GB241, Rituximab Biosimilar IBI301, Rituximab Biosimilar JHL1101, Rituximab Biosimilar PF-05280586, Rituximab Biosimilar RTXM83, Rituximab Biosimilar SAIT101, rituximab biosimilar TQB2303, rituximab-abbs, RTXM83, TruximaTreatment (rituximab, polatuzumab vedotin, venetoclax)
Rituximab and Hyaluronidase HumanRituxan Hycela, Rituximab Plus Hyaluronidase, Rituximab/Hyaluronidase, Rituximab/Hyaluronidase HumanTreatment (rituximab, polatuzumab vedotin, venetoclax)
VenetoclaxABT-0199, ABT-199, ABT199, GDC-0199, RG7601, Venclexta, VenclyxtoTreatment (rituximab, polatuzumab vedotin, venetoclax)

Purpose

This phase II trial studies the effect of polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human in treating patients with mantle cell lymphoma that has come back (relapsed) or does not respond to treatment (refractory). Polatuzumab vedotin is a monoclonal antibody, polatuzumab, linked to a toxic agent called vedotin. Polatuzumab attaches to CD79B positive cancer cells in a targeted way and delivers vedotin to kill them. Venetoclax may stop the growth of cancer cells by blocking Bcl-2, a protein needed for cell growth. Rituximab hyaluronidase is a combination of rituximab and hyaluronidase. Rituximab binds to a molecule called CD20, which is found on B cells (a type of white blood cell) and some types of cancer cells. This may help the immune system kill cancer cells. Hyaluronidase allows rituximab to be given by injection under the skin. Giving rituximab and hyaluronidase by injection under the skin is faster than giving rituximab alone by infusion into the blood. Giving polatuzumab vedotin, venetoclax, and rituximab and hyaluronidase human may work better than standard therapy in treating patients with mantle cell lymphoma.

Detailed Description

      PRIMARY OBJECTIVE:

      I. To evaluate the end of induction (EOI) complete response rate (CR) for treatment with the
      regimen of rituximab and hyaluronidase human + polatuzumab vedotin + venetoclax (RSC + Pola +
      Ven) in relapsed/refractory mantle cell lymphoma (MCL).

      SECONDARY OBJECTIVES:

      I. To evaluate the EOI overall response rate (ORR) for the combination of RSC + Pola + Ven in
      relapsed/refractory MCL.

      II. To evaluate the best response (CR, partial response [PR]) in patients who continue on to
      maintenance therapy and evaluate the improvement in the depth of response.

      III. To evaluate the progression free survival (PFS) and overall survival (OS) for the
      combination of RSC + Pola + Ven) in relapsed/ refractory MCL.

      IV. To compare the ORR, CR, PFS, and OS in ibrutinib refractory compared to ibrutinib naive
      patients.

      V. To evaluate regimen-related toxicity for patients treated with RSC + Pola + Ven.

      CORRELATIVE RESEARCH OBJECTIVES:

      I. To evaluate changes in minimal residual disease (MRD) status in both responding and
      non-responding patients at EOI and end of maintenance and compared to baseline as well as
      correlate MRD status with PFS and OS.

      II. To evaluate changes in systemic immune profiles and T cell activation induced by
      treatment with RituxSC (RSC) + Pola + Ven.

      III. To evaluate the prognostic importance of high risk cytogenetic alterations, and other
      risk stratification scores in patients with relapsed/refractory MCL receiving RituxSC + Pola
      + Ven.

      OUTLINE:

      INDUCTION: Patients receive rituximab intravenously (IV) on day 1 of cycle 1 and rituximab
      and hyaluronidase human subcutaneously (SC) over 5 minutes on day 1 of cycles 2-6. Patients
      also receive polatuzumab vedotin IV over 30-90 minutes on day 1 and venetoclax orally (PO)
      daily on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of
      disease progression or unacceptable toxicity.

      MAINTENANCE: Patients receive venetoclax PO daily and rituximab and hyaluronidase human SC
      over 5 minutes every 60 days for up to 1 year in the absence of disease progression or
      unacceptable toxicity.

      After completion of study treatment, patients are followed up every 90 days for up to 5
      years.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (rituximab, polatuzumab vedotin, venetoclax)ExperimentalINDUCTION: Patients receive rituximab IV on day 1 of cycle 1 and rituximab and hyaluronidase human SC over 5 minutes on day 1 of cycles 2-6. Patients also receive polatuzumab vedotin IV over 30-90 minutes on day 1 and venetoclax PO daily on days 1-21. Treatment repeats every 21 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity. MAINTENANCE: Patients receive venetoclax PO daily and rituximab and hyaluronidase human SC over 5 minutes every 60 days for up to 1 year in the absence of disease progression or unacceptable toxicity.
  • Polatuzumab Vedotin
  • Rituximab
  • Rituximab and Hyaluronidase Human
  • Venetoclax

Eligibility Criteria

        Inclusion Criteria:

          -  Pathologically confirmed relapsed or primary refractory mantle cell lymphoma with
             concurrent or prior tissue sample immunohistochemistry (IHC) positive for cyclin D1 or
             that is positive for fluorescence in situ hybridization (FISH) or cytogenetics for
             t(11;14)

               -  NOTE: Safety Portion only: MCL or indolent B cell non-Hodgkin lymphoma (NHL)
                  (follicular lymphoma [FL] [grades I-IIIa] marginal zone lymphoma [MZL]), or,
                  small lymphocytic lymphoma (SLL) stratified as low risk for tumor lysis syndrome
                  (TLS), relapsed or progressed after at least two lines of therapy (or one BTK
                  inhibitor containing line of therapy). No limit to prior lines of therapy

               -  NOTE: Expansion Portion only: MCL relapsed or progressed after at least two lines
                  of therapy or one BTK inhibitor line of therapy. Prior autologous stem cell
                  transplant (AutoSCT) is allowed. No limit to number of prior therapies. May have
                  received prior BTK inhibitor therapy

          -  Measurable disease as defined with at least one lesion measuring >= 1 x 1.5 cm

          -  Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2

          -  Absolute neutrophil count (ANC) >= 1000/mm^3 (obtained =< 14 days prior to
             registration)

          -  Platelet count >= 75,000/mm^3 (obtained =< 14 days prior to registration)

          -  Hemoglobin >= 9.0 g/dL (obtained =< 14 days prior to registration)

          -  International normalized ratio =< 1.5 x upper limit of normal (ULN) for patients not
             receiving therapeutic anticoagulation (obtained =< 14 days prior to registration)

          -  Partial thromboplastin time (PTT) or activated PTT (aPTT) =< 1.5 x ULN (obtained =< 14
             days prior to registration)

          -  Calculated creatinine (Cr) clearance >= 45 ml/min using the modified Cockcroft-Gault
             formula (obtained =< 14 days prior to registration)

          -  Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) =< 2.5 x ULN
             (obtained =< 14 days prior to registration)

          -  Total bilirubin < 1.5 x ULN (or =< 3 x ULN for patients with documented Gilbert
             syndrome) (obtained =< 14 days prior to registration)

          -  Negative serum pregnancy test done =< 7 days prior to registration, for women of
             childbearing potential only

          -  Able to provide informed written consent, and ability to comply with study related
             procedures

          -  Willing to return to enrolling institution for follow-up (during the Active Monitoring
             Phase of the study)

          -  Willing to provide tissue samples for mandatory correlative research

          -  For women of childbearing potential: agreement to remain abstinent (refrain from
             heterosexual intercourse) or use a contraceptive method with a failure rate of < 1%
             per year during the treatment period and for at least 30 days after the last dose of
             venetoclax or 18 months after the last dose of rituximab and hyaluronidase human,
             whichever is longer. For men: agreement to remain abstinent (refrain from heterosexual
             intercourse) or use contraceptive measures, and agreement to refrain from donating
             sperm, as defined below:

               -  With female partners of childbearing potential, men must remain abstinent or use
                  a condom plus an additional contraceptive method that together result in a
                  failure rate of < 1% per year during the treatment period and for at least 6
                  months after the last dose. Men must refrain from donating sperm during this same
                  period.

               -  With pregnant female partners, men must remain abstinent or use a condom during
                  the treatment period and for at least 6 months after the last dose to avoid
                  exposing the embryo

        Exclusion Criteria:

          -  Any of the following because this study involves an investigational agent whose
             genotoxic, mutagenic and teratogenic effects on the developing fetus and newborn are
             unknown:

               -  Pregnant women

               -  Nursing women

               -  Men or women of childbearing potential who are unwilling to employ adequate
                  contraception

          -  Co-morbid systemic illnesses or other severe concurrent disease which, in the judgment
             of the investigator, would make the patient inappropriate for entry into this study or
             interfere significantly with the proper assessment of safety and toxicity of the
             prescribed regimens

          -  Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac
             arrhythmia, or psychiatric illness/social situations that would limit compliance with
             study requirements

          -  Receiving any other investigational or chemotherapeutic agent which would be
             considered as a treatment for the primary neoplasm

          -  Known CD20-negative status at relapse or progression

          -  Prior allogeneic SCT

          -  Completion of autologous SCT =< 100 days prior to registration

          -  Radioimmunoconjugate =< 12 weeks prior to registration

          -  Monoclonal antibody or antibody-drug conjugate (ADC) therapy within 5 half-lives or 4
             weeks prior to registration, whichever is longer

          -  Radiotherapy, chemotherapy, hormonal therapy, or targeted small-molecule therapy
             within 2 weeks prior to registration (with the exception of ibrutinib to prevent tumor
             flare, patients taking ibrutinib who are progressing must discontinue ibrutinib 2
             half-lives or 2 days prior to initiating protocol therapy)

          -  Clinically significant toxicity (other than alopecia) from prior therapy that has not
             resolved to grade =< 2 (per National Cancer Institute [NCI] Common Terminology
             Criteria for Adverse Events [CTCAE] version [v]5.0) prior to registration

          -  Current grade > 1 peripheral neuropathy

          -  Any history of central nervous system (CNS) lymphoma or leptomeningeal infiltration

          -  Treatment with systemic corticosteroids > 20 mg/day prednisone or equivalent Patients
             who are receiving corticosteroids =< 20 mg/day, prednisone or equivalent, for
             non-lymphoma treatment reasons must be documented to be on a stable dose for at >= 4
             weeks prior to registration. If corticosteroid treatment is urgently required for
             lymphoma symptom control prior to the start of study treatment, up to 100 mg/day of
             prednisone or equivalent can be given for a maximum of 5 days, but all tumor
             assessments must be completed prior to start of corticosteroid treatment

          -  History of severe allergic or anaphylactic reaction or known sensitivity to humanized
             or murine monoclonal antibodies rituximab, polatuzumab vedotin, and venetoclax

          -  Active bacterial, viral, fungal, or other infection

          -  Requirement for warfarin treatment (because of potential drug-drug interactions [DDIs]
             that may increase the exposure of warfarin)

          -  Treatment with the following agents =< 7 days prior to registration

               -  Strong and moderate CYP3A inhibitors such as fluconazole, ketoconazole, and
                  clarithromycin

               -  Strong and moderate CYP3A inducers such as rifampin and carbamazepine. If taking
                  proton pump inhibitors willing to avoid co-administration and stagger venetoclax
                  dosing

          -  Consumption of grapefruit, grapefruit products, Seville oranges (including marmalade
             that contains Seville oranges), or star fruit =< 3 days prior to registration

          -  Clinically significant history of liver disease, including viral or other hepatitis,
             current alcohol abuse, or cirrhosis

          -  Active hepatitis B or hepatitis C infection. Patients who have been successfully
             treated and cleared their virus as evidenced a negative hepatitis (Hep) B or Hep C
             polymerase chain reaction (PCR) are eligible

          -  Known history of human immunodeficiency virus (HIV) positive status or known infection
             with human T-cell leukemia virus 1. For patients with unknown HIV status, HIV testing
             will be performed at screening if required by local regulations

          -  History of PML (progressive multifocal leukoencephalopathy)

          -  Vaccination with a live virus vaccine =< 28 days prior to registration

          -  History of other malignancy that could affect compliance with the protocol or
             interpretation of results, with the exception of the following: curatively treated
             carcinoma in situ of the cervix, good-prognosis ductal carcinoma in situ of the
             breast, basal- or squamous-cell skin cancer, stage I melanoma, or low-grade,
             early-stage localized prostate cancer

          -  Any previously treated malignancy that has been in remission without treatment for =<
             3 years prior to registration

          -  Evidence of any significant, uncontrolled concomitant disease that could affect
             compliance with the protocol or interpretation of results, including significant
             cardiovascular disease (such as New York Heart Association class III or IV cardiac
             disease, myocardial infarction within the previous 6 months, unstable arrhythmia, or
             unstable angina) or significant pulmonary disease (such as obstructive pulmonary
             disease or history of bronchospasm)

          -  Major surgical procedure other than for diagnosis =< 28 days prior to day 1 of cycle
             1, or anticipation of a major surgical procedure during the course of the study

          -  Inability or unwillingness to swallow pills

          -  History of malabsorption syndrome or other condition that would interfere with enteral
             absorption

          -  History of inflammatory bowel disease (e.g., Crohn's disease or ulcerative colitis) or
             active bowel inflammation (e.g., diverticulitis)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Complete response (CR) rate
Time Frame:At Study Completion, up to 5 years from registration
Safety Issue:
Description:Objective status of CR measured by positron emission tomography (PET)-computed tomography (CT) scans according to Lugano 2014.

Secondary Outcome Measures

Measure:Overall response rate (ORR)
Time Frame:At Study Completion, up to 5 years from registration
Safety Issue:
Description:The ORR at the end of induction will be estimated by the total number of patients who achieve a complete response (CR) or partial response (PR) by PET-CT scans according to Lugano 2014 divided by the total number of evaluable patients. The ORR between ibrutinib-naive and ibrutinib-pretreated patients will be compared using Fisher's exact test.
Measure:Best response rate to maintenance therapy
Time Frame:At Study Completion, up to 5 years from registration
Safety Issue:
Description:CR, PR, and stable disease (SD) rates for patients who continue to maintenance will be estimated by number of patients who continue on maintenance therapy and achieve CR, PR or SD, respectively, at the end of maintenance divided by the total number of evaluable patients who continue to maintenance.
Measure:Progression free survival (PFS)
Time Frame:From registration to the earliest date of documentation of disease progression by CT or PET/CT or death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of PFS will be estimated using the method of Kaplan-Meier. The PFS between ibrutinib-naive and ibrutinib-pretreated patients will be compared using log-rank test.
Measure:Overall survival (OS)
Time Frame:From registration to death due to any cause, assessed up to 5 years
Safety Issue:
Description:The distribution of OS will be estimated using the method of Kaplan-Meier. The OS between ibrutinib-naive and ibrutinib-pretreated patients will be compared using log-rank test.
Measure:Incidence of adverse events (AEs)
Time Frame:Up to 5 years
Safety Issue:
Description:All AEs occurring on or after first study treatment will be summarized by National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 grade.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Academic and Community Cancer Research United

Last Updated

February 10, 2021