Clinical Trials /

Nivolumab and Brentuximab Vedotin After Stem Cell Transplant in Treating Patients With Relapsed or Refractory High-Risk Classical Hodgkin Lymphoma

NCT03057795

Description:

This phase II trial studies how well nivolumab and brentuximab vedotin work after stem cell transplant in treating patients with high-risk classical Hodgkin lymphoma that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as nivolumab and brentuximab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Related Conditions:
  • Classical Hodgkin Lymphoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Nivolumab and Brentuximab Vedotin After Stem Cell Transplant in Treating Patients With Relapsed or Refractory High-Risk Classical Hodgkin Lymphoma
  • Official Title: A Phase 2 Study of Nivolumab and Brentuximab Vedotin Consolidation After Autologous Stem Cell Transplantation in Patients With High-Risk Classical Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: 16378
  • SECONDARY ID: NCI-2017-00222
  • SECONDARY ID: 16378
  • SECONDARY ID: P30CA033572
  • NCT ID: NCT03057795

Conditions

  • Classic Hodgkin Lymphoma
  • Hematopoietic Cell Transplant Recipient
  • Recurrent Hodgkin Lymphoma
  • Refractory Hodgkin Lymphoma

Interventions

DrugSynonymsArms
BrentuximabAnti-CD30 Monoclonal Antibody, CAC-10, CAC10, Monoclonal Antibody SGN-30, SGN-30, SGN30Treatment (brentuximab vedotin, nivolumab)
Brentuximab VedotinADC SGN-35, Adcetris, Anti-CD30 Antibody-Drug Conjugate SGN-35, Anti-CD30 Monoclonal Antibody-MMAE SGN-35, Anti-CD30 Monoclonal Antibody-Monomethylauristatin E SGN-35, cAC10-vcMMAE, SGN-35Treatment (brentuximab vedotin, nivolumab)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoTreatment (brentuximab vedotin, nivolumab)

Purpose

This phase II trial studies how well nivolumab and brentuximab vedotin work after stem cell transplant in treating patients with high-risk classical Hodgkin lymphoma that has come back or does not respond to treatment. Immunotherapy with monoclonal antibodies, such as nivolumab and brentuximab, may help the body?s immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread.

Detailed Description

      PRIMARY OBJECTIVES:

      I. Assess the efficacy of nivolumab plus brentuximab vedotin consolidation after autologous
      stem cell transplantation (ASCT) in participants with relapsed/refractory Hodgkin lymphoma
      (HL), as assessed by 18-month progression-free survival (PFS).

      SECONDARY OBJECTIVES:

      I. Estimate the overall survival (OS), the cumulative incidence of relapse/progression, the
      cumulative incidence of non-relapse mortality (TRM) in participants with relapsed/ refractory
      HL who receive nivolumab plus brentuximab vedotin consolidation after ASCT.

      II. Estimate the overall response rate to nivolumab plus brentuximab vedotin therapy in
      participants with measurable disease after ASCT.

      III. Establish the safety and tolerability of nivolumab plus brentuximab vedotin when used as
      consolidation after ASCT in participants with relapsed/ refractory HL.

      TERTIARY OBJECTIVES:

      I. Evaluate the Lymphoma Response to Immunomodulatory therapy Criteria (LYRIC) definition of
      indeterminate response to guide the management of patients regarding treatment past
      progressive disease.

      II. Explore the impact of nivolumab plus brentuximab vedotin therapy on immune reconstitution
      after ASCT.

      III. Explore the prognostic impact of and temporal dynamics of minimal residual disease (MRD)
      in the peripheral blood as assessed by the next-generation sequencing-based ClonoSEQ
      platform.

      IV. Explore the prognostic impact of 9p24.1 abnormalities in tumor tissue assessed by
      fluorescence in situ hybridization (FISH) on outcomes after ASCT and nivolumab plus
      brentuximab vedotin post-ASCT consolidation therapy.

      V. Explore the relationship between immune cells and Hodgkin and Reed/Sternberg (HRS) in
      tumor samples by 6-color quantitative spatial image analysis using the Vectra system, and
      correlate with outcome after ASCT and nivolumab plus brentuximab vedotin post-ASCT
      consolidation therapy.

      VI. Explore whether genetic alterations (e.g. gene expression profiles or genetic mutations)
      in HL tumor samples are associated with outcome after ASCT and nivolumab plus brentuximab
      vedotin post-ASCT consolidation therapy.

      OUTLINE:

      Beginning 30-60 days post-ASCT, patients receive brentuximab vedotin intravenously (IV) over
      30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up
      to 8 courses in the absence of disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 and 100 days, at 3, 6,
      12, and 18 months from start of treatment, and then biannually thereafter.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (brentuximab vedotin, nivolumab)ExperimentalBeginning 30-60 days post-ASCT, patients receive brentuximab vedotin IV over 30 minutes and nivolumab IV over 60 minutes on day 1. Treatment repeats every 21 days for up to 8 courses in the absence of disease progression or unacceptable toxicity.
  • Brentuximab
  • Brentuximab Vedotin
  • Nivolumab

Eligibility Criteria

        Inclusion Criteria:

          -  Documented informed consent

          -  Agreement to allow the use of archival tissue from pre-ASCT tumor biopsies

               -  If unavailable, exceptions may be granted with study principal investigator (PI)
                  approval

          -  Eastern Cooperative Oncology Group (ECOG) performance status =< 2

          -  Histologically confirmed diagnosis of classical Hodgkin lymphoma (excluding nodular
             lymphocyte predominant Hodgkin lymphoma) according to the World Health Organization
             (WHO) classification, with hematopathology review at the participating institution

          -  Have high-risk relapsed or refractory Hodgkin lymphoma (HL), defined as at least one
             of the following:

               -  Primary refractory disease to front-line therapy

               -  Relapse within 1 year of completing front-line therapy

               -  Extranodal involvement at the time of pre-ASCT relapse

               -  B symptoms at pre-ASCT relapse

               -  More than one type of pre-ASCT salvage therapy required

          -  Planning to receive or have received autologous stem cell transplantation (ACST) per
             institutional standards as part of standard of care

               -  Pre-ASCT participants may consent but will not be eligible to begin treatment
                  until after ASCT, and will have to fulfill all inclusion and exclusion criteria
                  before starting protocol

               -  All participants must initiate day 1 of protocol therapy within 30-60 days post
                  stem cell reinfusion; study PI can grant exception for a patient to start as late
                  as 75 days post stem cell reinfusion with a reasonable justification for a delay
                  (e.g. recovery from post -ASCT toxicity) and this will not be a protocol
                  deviation, nor require an exception to be filled

          -  Recovery from ASCT toxicity as defined as outpatient status, able to drink, eat
             normally, and do not need intravenous hydration prior to day 1 of therapy

          -  Achieved at least stable disease to salvage treatment determined by positron emission
             tomography (PET)/computed tomography (CT) using 2014 Lugano Classification prior to
             ASCT

          -  Brentuximab vedotin naive OR had at least stable disease by Lugano Classification to
             prior brentuximab vedotin treatment

          -  Absolute neutrophil count (ANC) >= 1000/mm^3

          -  Platelets >= 50,000/mm^3

          -  Hemoglobin >= 8 g/dL

          -  Total bilirubin =< 1.5 x upper limit of normal (ULN) or 3 x ULN for Gilbert's disease

          -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x ULN

          -  Creatinine clearance >= 40 mL/min per 24 hour urine collection or the Cockcroft-Gault
             formula

          -  Forced expiratory volume in one second (FEV1) and carbon monoxide diffusion capacity
             (DLCO) (adjusted for hemoglobin [Hb]) >= 50% adjusted

          -  Women of childbearing potential (WOCBP) only: Negative urine or serum pregnancy test
             (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin
             [HCG])

               -  If the urine test is positive or cannot be confirmed as negative, a serum
                  pregnancy test will be required

          -  Woman of childbearing potential (WOCBP): use two effective methods of contraception
             (hormonal or barrier method) or be surgically sterile, or abstain from heterosexual
             activity for the course of the study through 7 months post last dose of nivolumab

               -  WOCBP defined as not being surgically sterilized or have not been free from
                  menses for > 1 year

               -  Male: use two effective methods of contraception (barrier method) or abstain from
                  heterosexual activity with the first dose of study therapy through 7 months post
                  last dose of nivolumab

        Exclusion Criteria:

          -  Post-ASCT anti-lymphoma or investigational therapy; immediate post-ASCT consolidative
             radiation therapy is allowed as long as it occurs prior to initiation of study
             therapy; baseline imaging and pulmonary function tests (PFTs) must be performed after
             completion of radiation

          -  Previous allogeneic transplant

          -  Total carmustine (BCNU) dose of > 600 mg/m^2 with prior treatments including
             transplant conditioning regimen

          -  Live vaccine within 30 days prior to day 1 of protocol therapy (e.g. measles, mumps,
             rubella, varicella, yellow fever, rabies, Bacillus Calmette?Guerin [BCG], oral polio
             vaccine, and oral typhoid)

          -  Refractory to prior brentuximab vedotin (i.e. progression while on treatment)

          -  Refractory to prior anti-PD-1/PD-L1 agent

          -  History of prior >= grade 3 hypersensitivity to either brentuximab vedotin or
             nivolumab

          -  History of another primary malignancy that has not been in remission for at least 3
             years; exceptions include:

               -  Basal cell carcinoma of the skin or

               -  Squamous cell carcinoma of the skin that has undergone potentially curative
                  therapy or

               -  In situ cervical cancer

          -  Known active central nervous system (CNS) involvement by lymphoma, including
             parenchymal and/or lymphomatous meningitis

          -  History of progressive multifocal leukoencephalopathy (PML)

          -  Grade >= 2 peripheral neuropathy at the present time

          -  Prior diagnosis of inherited or acquired immunodeficiency

          -  Condition requiring systemic treatment with either corticosteroids (> 10 mg daily
             prednisone or equivalent) or other immunosuppressive medications within 14 days of
             study drug administration; exceptions are:

               -  Inhaled or topical steroids and

               -  Adrenal replacement doses > 10 mg daily prednisone equivalents in the absence of
                  active autoimmune disease

          -  Uncontrolled illness including ongoing or active infection

          -  History of or active pneumonitis or interstitial lung disease:

               -  For history of pneumonitis to be an exclusion, patient had to have required
                  supplemental oxygen or corticosteroid treatment; radiographic changes alone are
                  not an exclusion

          -  An active, known or suspected autoimmune disease; the following are exceptions:

               -  Vitiligo

               -  Hemolytic anemia associated with the lymphoma (history of or at the present time)

               -  Type I diabetes mellitus

               -  Residual hypothyroidism due to autoimmune condition only requiring hormone
                  replacement

               -  Psoriasis not requiring systemic treatment, or

               -  Conditions not expected to recur in the absence of an external trigger

          -  Active or known history (standard pre-ASCT assessments) of:

               -  Hepatitis B or C infection

               -  Human immunodeficiency virus (HIV)

               -  Acquired immunodeficiency syndrome (AIDS)

          -  Women who are pregnant or lactating

          -  History of a cerebral vascular event (stroke or transient ischemic attack), unstable
             angina, myocardial infarction, or cardiac symptoms consistent with New York Heart
             Association Class III-IV within 6 months prior to day 1 of protocol therapy

          -  History or current evidence of any condition, therapy, or laboratory abnormality that
             might confound the results of the trial, interfere with the subject's participation
             for the full duration of the trial, or is not in the best interest of the subject to
             participate, in the opinion of the treating investigator

          -  Prospective participants who, in the opinion of the investigator, may not be able to
             comply with all study procedures (including compliance issues related to
             feasibility/logistics)
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression-free survival
Time Frame:From the first dose of study treatment to the first observation of disease relapse/progression or death from any cause, whichever occurs first, assessed at 18 months
Safety Issue:
Description:Progression-free survival will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error. When there is no censoring in progression-free survival prior to 18 months after the first dose of study treatment, the observed 18-month progression-free survival will be compared to the baseline of 65% by one-sided exact test of binomial proportion. In case of censoring in progression-free survival prior to 18 months after the first dose of study treatment, the Kaplan-Meier estimate for 18-month progression-free survival along with the Greenwood standard error estimator will be used for the testing of null hypothesis at 65%.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:From the first dose of study treatment to death from any cause, assessed up to 18 months
Safety Issue:
Description:Overall survival will be estimated using the product-limit method of Kaplan and Meier along with the Greenwood estimator of standard error.
Measure:Cumulative incidence of relapse/progression defined as the time from the first dose of study treatment to disease relapse/progression
Time Frame:Up to 18 months
Safety Issue:
Description:Cumulative incidence of relapse/progression as well as its confidence intervals will be estimated using competing risk methodology, treating the other event as a competing risk.
Measure:Cumulative incidence of non-relapse mortality defined as the time from the first dose of study treatment to non-disease related death
Time Frame:Up to 18 months
Safety Issue:
Description:Cumulative incidence of non-relapse mortality as well as its confidence intervals will be estimated using competing risk methodology, treating the other event as a competing risk.
Measure:Overall response rate
Time Frame:Up to 18 months
Safety Issue:
Description:Overall response rate will be estimated by the proportion of patients achieving either complete response or partial response among participants with measurable disease after autologous stem cell transplantation, along with the exact binomial confidence interval.
Measure:Incidence of toxicities evaluated according to National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03
Time Frame:Up to 18 months
Safety Issue:
Description:Observed toxicities will be summarized by type (organ affected or laboratory determination such as absolute neutrophil count), severity (by National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03 and nadir or maximum values for lab measures), date of onset, duration, reversibility, and attribution.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:City of Hope Medical Center

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