Clinical Trials /

Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma

NCT03907488

Description:

This randomized phase III trial compares immunotherapy drugs (nivolumab or brentuximab vedotin) when given with combination chemotherapy in treating patients with newly diagnosed stage III or IV classic Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin, vinblastine, and dacarbazine, 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. The addition of nivolumab or brentuximab vedotin to combination chemotherapy may shrink the cancer or extend the time without disease symptoms coming back.

Related Conditions:
  • Classical Hodgkin Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 3

Trial Eligibility

Document

Title

  • Brief Title: Immunotherapy (Nivolumab or Brentuximab Vedotin) Plus Combination Chemotherapy in Treating Patients With Newly Diagnosed Stage III-IV Classic Hodgkin Lymphoma
  • Official Title: A Phase III, Randomized Study of Nivolumab (Opdivo) Plus AVD or Brentuximab Vedotin (Adcetris) Plus AVD in Patients (Age >/= 12 Years) With Newly Diagnosed Advanced Stage Classical Hodgkin Lymphoma

Clinical Trial IDs

  • ORG STUDY ID: NCI-2019-01960
  • SECONDARY ID: NCI-2019-01960
  • SECONDARY ID: S1826
  • SECONDARY ID: S1826
  • SECONDARY ID: U10CA180888
  • NCT ID: NCT03907488

Conditions

  • Ann Arbor Stage III Hodgkin Lymphoma
  • Ann Arbor Stage III Lymphocyte-Depleted Classic Hodgkin Lymphoma
  • Ann Arbor Stage III Mixed Cellularity Classic Hodgkin Lymphoma
  • Ann Arbor Stage III Nodular Sclerosis Classic Hodgkin Lymphoma
  • Ann Arbor Stage IIIA Hodgkin Lymphoma
  • Ann Arbor Stage IIIB Hodgkin Lymphoma
  • Ann Arbor Stage IV Hodgkin Lymphoma
  • Ann Arbor Stage IV Lymphocyte-Depleted Classic Hodgkin Lymphoma
  • Ann Arbor Stage IV Mixed Cellularity Classic Hodgkin Lymphoma
  • Ann Arbor Stage IV Nodular Sclerosis Classic Hodgkin Lymphoma
  • Ann Arbor Stage IVA Hodgkin Lymphoma
  • Ann Arbor Stage IVB Hodgkin Lymphoma
  • Classic Hodgkin Lymphoma
  • Lymphocyte-Rich Classic Hodgkin Lymphoma

Interventions

DrugSynonymsArms
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-35Arm II (chemotherapy, brentuximab vedotin, radiation)
Dacarbazine4-(Dimethyltriazeno)imidazole-5-carboxamide, 5-(Dimethyltriazeno)imidazole-4-carboxamide, Asercit, Biocarbazine, Dacarbazina, Dacarbazina Almirall, Dacarbazine - DTIC, Dacatic, Dakarbazin, Deticene, Detimedac, DIC, Dimethyl (triazeno) imidazolecarboxamide, Dimethyl Triazeno Imidazol Carboxamide, Dimethyl Triazeno Imidazole Carboxamide, dimethyl-triazeno-imidazole carboxamide, Dimethyl-triazeno-imidazole-carboximide, DTIC, DTIC-Dome, Fauldetic, Imidazole carboxamide, Imidazole Carboxamide Dimethyltriazeno, WR-139007Arm I (chemotherapy, nivolumab, radiation)
DoxorubicinAdriablastin, Hydroxydaunomycin, Hydroxyl Daunorubicin, HydroxyldaunorubicinArm I (chemotherapy, nivolumab, radiation)
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 I (chemotherapy, nivolumab, radiation)
FilgrastimG-CSF, Neupogen, r-metHuG-CSF, Recombinant Methionyl Human Granulocyte Colony Stimulating Factor, rG-CSF, TevagrastimArm I (chemotherapy, nivolumab, radiation)
NivolumabBMS-936558, MDX-1106, NIVO, ONO-4538, OpdivoArm I (chemotherapy, nivolumab, radiation)
PegfilgrastimFilgrastim SD-01, filgrastim-SD/01, Fulphila, HSP-130, Jinyouli, Neulasta, Neulastim, Pegfilgrastim Biosimilar HSP-130, Pegfilgrastim Biosimilar Pegcyte, Pegfilgrastim-jmdb, SD-01, SD-01 sustained duration G-CSFArm I (chemotherapy, nivolumab, radiation)
VinblastineVincaleucoblastine, VLBArm I (chemotherapy, nivolumab, radiation)
Vinblastine Sulfate29060 LE, 29060-LE, Exal, Velban, Velbe, Velsar, VINCALEUKOBLASTINEArm I (chemotherapy, nivolumab, radiation)

Purpose

This randomized phase III trial compares immunotherapy drugs (nivolumab or brentuximab vedotin) when given with combination chemotherapy in treating patients with newly diagnosed stage III or IV classic Hodgkin lymphoma. Immunotherapy with monoclonal antibodies, such as nivolumab, may help the body's immune system attack the cancer, and may interfere with the ability of tumor cells to grow and spread. Brentuximab vedotin is a monoclonal antibody, brentuximab, linked to a toxic agent called vedotin. Brentuximab attaches to cancer cells in a targeted way and delivers vedotin to kill them. Drugs used in chemotherapy, such as doxorubicin, vinblastine, and dacarbazine, 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. The addition of nivolumab or brentuximab vedotin to combination chemotherapy may shrink the cancer or extend the time without disease symptoms coming back.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To compare the progression-free survival (PFS) in patients with newly diagnosed advanced
      stage classical Hodgkin lymphoma randomized to N-AVD (nivolumab, doxorubicin hydrochloride
      [doxorubicin], vinblastine sulfate [vinblastine], dacarbazine) versus that obtained with
      BV-AVD (brentuximab vedotin, doxorubicin, vinblastine, dacarbazine).

      SECONDARY OBJECTIVES:

      I. To compare overall survival (OS) in patients randomized to N-AVD versus BV-AVD.

      II. To compare event-free survival (EFS) in patients randomized to N-AVD versus BV-AVD.

      III. To compare the metabolic complete response (CR) rate at the end of treatment in patients
      randomized to N-AVD versus BV-AVD.

      IV. To compare the physician-reported treatment-related adverse event rates between arms
      stratified by age groups.

      V. To compare patient-reported symptoms using selected Patient Reported Outcome Common
      Toxicity Criteria for Adverse Events (PRO-CTCAE) items between arms stratified by age groups.

      VI. To compare the safety and tolerability of N-AVD versus that of BV-AVD.

      QUALITY OF LIFE OBJECTIVES:

      I. To compare between arms patient-reported fatigue, neuropathy and health-related quality of
      life over time (baseline, beginning of cycle 3, 4-8 weeks after completion of treatment, and
      1 and 3 years after randomization) using the Patient Reported Outcomes Measurement
      Information System (PROMIS)-Fatigue, the Functional Assessment of Cancer Therapy/Gynecologic
      Oncology Group-Neurotoxicity (FACT/GOG-Ntx), and the PROMIS Global, respectively.

      BANKING OBJECTIVES:

      I. To bank specimens for future correlative studies. II. To bank positron emission tomography
      (PET)-computed tomography (CT) images for future correlative studies.

      OUTLINE: Patients are randomized to 1 of 2 arms.

      ARM I: Patients receive doxorubicin hydrochloride intravenously (IV), vinblastine sulfate IV,
      dacarbazine IV, and nivolumab IV over 30 minutes on days 1 and 15. Patients may receive
      pegfilgrastim subcutaneously (SC) on days 2 and 16, or filgrastim SC or IV on days 5-10 and
      20-25 for adults or days 4-9 for pediatric patients. Treatment repeats every 28 days for 6
      cycles in the absence of disease progression or unacceptable toxicity. After completion of
      cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at
      the discretion of the treating physician.

      ARM II: Patients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine
      IV, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Patients may receive
      pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 5-10 and 20-25 for adults
      or days 4-9 for pediatric patients. Treatment repeats every 28 days for 6 cycles in the
      absence of disease progression or unacceptable toxicity. After completion of cycle 6,
      patients may receive radiation therapy 5 days per week for approximately 4 weeks at the
      discretion of the treating physician.

      After completion of study treatment and prior to disease progression, patients are followed
      up every 3 months for the first year, every 6 months for years 2 and 3, then annually until
      10 years after registration. Patients are followed up at the time of progression and then
      annually until 10 years after registration. Patients who receive radiation therapy are
      followed up at 8-12 weeks after completion of radiation therapy.
    

Trial Arms

NameTypeDescriptionInterventions
Arm I (chemotherapy, nivolumab, radiation)ExperimentalPatients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine IV, and nivolumab IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 5-10 and 20-25 for adults or days 4-9 for pediatric patients. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician.
  • Dacarbazine
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Filgrastim
  • Nivolumab
  • Pegfilgrastim
  • Vinblastine
  • Vinblastine Sulfate
Arm II (chemotherapy, brentuximab vedotin, radiation)ExperimentalPatients receive doxorubicin hydrochloride IV, vinblastine sulfate IV, dacarbazine IV, and brentuximab vedotin IV over 30 minutes on days 1 and 15. Patients may receive pegfilgrastim SC on days 2 and 16, or filgrastim SC or IV on days 5-10 and 20-25 for adults or days 4-9 for pediatric patients. Treatment repeats every 28 days for 6 cycles in the absence of disease progression or unacceptable toxicity. After completion of cycle 6, patients may receive radiation therapy 5 days per week for approximately 4 weeks at the discretion of the treating physician.
  • Brentuximab Vedotin
  • Dacarbazine
  • Doxorubicin
  • Doxorubicin Hydrochloride
  • Filgrastim
  • Pegfilgrastim
  • Vinblastine
  • Vinblastine Sulfate

Eligibility Criteria

        Inclusion Criteria:

          -  All patients must have histologically confirmed newly diagnosed, previously untreated
             stage III or IV classical Hodgkin lymphoma (nodular sclerosing, mixed cellularity,
             lymphocyte-rich, or lymphocyte-depleted, or not otherwise specified [NOS]). Nodular
             lymphocyte predominant Hodgkin lymphoma is not eligible.

          -  Patients must have bidimensionally measurable disease (at least one lesion with
             longest diameter >= 1.5 cm) documented on the Lymphoma Baseline Tumor Assessment Form
             in Rave.

          -  Patients must have a whole body or limited whole body PET-CT scan performed within 42
             days prior to registration. (A contrast-enhanced [diagnostic] CT, magnetic resonance
             imaging [MRI] or MRI-PET is acceptable in event that PET-CT is contraindicated,
             however the same modality must be utilized through the trial.) NOTE: All images from
             PET-CT, CT, MRI or MR-PET scans performed as standard of care to assess disease
             (within 42 days prior to registration) must be submitted and associated radiology
             reports must be submitted.

          -  Patients must not have received any prior chemotherapy, radiation, or antibody-based
             treatment for classical Hodgkin lymphoma. Steroid pre-treatment is permitted.

          -  Patients must not have had prior solid organ transplant.

          -  Patients must not have had prior allogeneic stem cell transplantation.

          -  Patients must not have received a live vaccine within 30 days prior to planned day 1
             of protocol therapy (e.g. measles, mumps, rubella, varicella, yellow fever, rabies,
             Bacillus Calmette-Guerin [BCG], oral polio vaccine, and oral typhoid).

          -  At registration, investigator must declare intent-to-treat with residual PET radiation
             therapy (residual PET RT- RPRT) to be administered after patient completes 6 cycles of
             therapy if, after end of treatment, the patient meets criteria specified for receiving
             RT). Patients will be stratified by investigator's intent-to-treat with residual PET
             RT.

               -  All patients enrolled by Children's Oncology Group (COG) investigators will be
                  considered intent-to-treat with residual PET RT.

          -  Patients must have a performance status corresponding to Zubrod scores of 0, 1 or 2.
             Use Lansky for patients =< 17 years of age. *The conversion of the Lansky to Eastern
             Cooperative Oncology Group (ECOG) scales is intended for National Cancer Institute
             (NCI) reporting purposes only.

          -  Adults (age 18 or older): Creatinine clearance >= 30 mL/min, as estimated by the
             Cockcroft and Gault formula. The creatinine value used in the calculation must have
             been obtained within 28 days prior to registration. Estimated creatinine clearance is
             based on actual body weight.

        Pediatric Patients (age 12-17), the following must have been obtained within 14 days prior
        to registration:

          -  Measured or calculated creatinine clearance or radioisotope glomerular filtration rate
             (GFR) >= 70 ml/min/1.73 m^2, or

          -  Serum creatinine =< 1.5 x institutional upper limit of normal (IULN), or a serum
             creatinine (SCr) based on age/gender as follows:

               -  Age < 13 maximum serum creatinine: Male 1.2 mg/dL; Female 1.2 mg/dL

               -  Age 13 to < 16 maximum serum creatinine: Male 1.5 mg/dL; Female 1.4 mg/dL

               -  Age 16-17 maximum serum creatinine: Male 1.7 mg/dL; Female 1.4 mg/dL

                    -  Total bilirubin =< 2 x IULN (must be documented within 28 days prior to
                       registration for adults [age 18 or older]; must be documented within 14 days
                       prior to registration for pediatric patients [age 12-17]).

          -  Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile
             duct syndrome

               -  Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x IULN
                  (must be documented within 28 days prior to registration for adults [age 18 or
                  older]; must be documented within 14 days prior to registration for pediatric
                  patients [age 12-17]).

          -  Unless due to Gilbert's disease, lymphomatous involvement of liver or vanishing bile
             duct syndrome

               -  Patients must have an echocardiogram (ECHO), multigated acquisition (MUGA), or
                  functional cardiac imaging scan with a left ventricular ejection (LVEF) fraction
                  >= 50% or a shortening fraction of >= 27%.

          -  For adults (age 18 or older), the ECHO or MUGA be performed within 42 days prior to
             registration.

          -  For pediatric patients (age 12-17), the ECHO, MUGA, or functional cardiac imaging scan
             must be performed within 14 days prior to registration.

               -  Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral
                  therapy with undetectable or unquantifiable viral load within 6 months prior to
                  registration are eligible for this trial.

               -  Patients must not have known active hepatitis B (HBV) or hepatitis C virus (HCV)
                  at date of registration. Patients with previously treated HBV or HCV that have an
                  undetectable viral load and no residual hepatic impairment are eligible.

               -  Patients must not have any known central nervous system lymphoma.

               -  Patients must not have a history of or active interstitial pneumonitis or
                  interstitial lung disease.

               -  Patients must not have had a diagnosis of inherited or acquired immunodeficiency.

               -  Patients must not have any known uncontrolled intercurrent illness including, but
                  not limited to symptomatic congestive heart failure, unstable angina pectoris,
                  hemodynamically unstable cardiac arrhythmia, or psychiatric illness/social
                  situations that would limit compliance with study requirements.

               -  Patients must not have a condition requiring systemic treatment with either
                  corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive
                  medications within 14 days prior to registration. Inhaled or topical steroids,
                  and adrenal replacement doses > 10 mg daily prednisone equivalents are permitted
                  in the absence of active autoimmune disease. Steroid use for the control of
                  Hodgkin lymphoma symptoms is allowable, but must be discontinued prior to cycle
                  1, day 1.

               -  Patients with peripheral neuropathy must have < grade 2 at date of registration.

               -  Patients must not have active autoimmune disease that has required systemic
                  treatment in past 2 years (i.e., with use of disease modifying agents,
                  immunosuppressive drugs, or corticosteroids with doses higher than prednisone 10
                  mg or equivalent). Autoimmune diseases include but are not limited to autoimmune
                  hepatitis, inflammatory bowel disease (including ulcerative colitis and Crohn's
                  disease), as well as symptomatic disease (e.g.: rheumatoid arthritis, systemic
                  progressive sclerosis [scleroderma], systemic lupus erythematosus, autoimmune
                  vasculitis [e.g., Wegener's granulomatosis]); central nervous system (CNS) or
                  motor neuropathy considered of autoimmune origin (e.g., Guillain-Barre syndrome
                  and myasthenia gravis, multiple sclerosis or glomerulonephritis). Vitiligo,
                  alopecia, hypothyroidism on stable doses of thyroid replacement therapy,
                  psoriasis not requiring systemic therapy within the past 2 years are permitted.

               -  No second prior malignancy is allowed except for adequately treated basal (or
                  squamous cell) skin cancer, any in situ cancer or other cancer for which the
                  patient has been disease free for two years.

               -  Females of childbearing potential must not be pregnant or nursing, and have a
                  negative pregnancy test within 28 days prior to registration. Women/men of
                  reproductive potential must have agreed to use an effective contraceptive method
                  while receiving study drug and for women until 6 months after receiving the last
                  dose of study drug or, for men, until 7 months after receiving the last dose of
                  study drug. A woman is considered to be of "reproductive potential" if she has
                  had menses at any time in the preceding 12 consecutive months. In addition to
                  routine contraceptive methods, "effective contraception" also includes
                  heterosexual celibacy and surgery intended to prevent pregnancy (or with a
                  side-effect of pregnancy prevention) defined as a hysterectomy, bilateral
                  oophorectomy or bilateral tubal ligation. However, if at any point a previously
                  celibate patient chooses to become heterosexually active during the time period
                  for use of contraceptive measures outlined in the protocol, he/she is responsible
                  for beginning contraceptive measures.

               -  Patients must have sufficient diagnostic tissue specimens collected prior to
                  registration.

               -  Patients must be offered participation in banking for planned translational
                  medicine and future research. With patient consent, any residuals from the
                  mandatory tissue submission will also be banked for future research.

               -  Patients who can complete patient-reported outcome instruments in English,
                  Spanish, or French must complete the PROMIS Fatigue, the FACT/GOG-Ntx, and the
                  PROMIS Global prior to registration and must agree to complete these instruments
                  and the PRO-CTCAE or Pediatric PRO-CTCAE at the scheduled on-study assessment
                  timepoints.

               -  Patients must be informed of the investigational nature of this study and all
                  patients and/or their parents or legal guardians (for patients < 18 years of age)
                  must sign and give written informed consent and assent (where appropriate) in
                  accordance with institutional and federal guidelines.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:12 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From date of registration to date of first observation of progressive disease according to the 2014 Lugano classification, or death due to any cause, assessed at 2 years
Safety Issue:
Description:Will test the null hypothesis (HR=1) for PFS using stratified log-rank test with a one-sided alpha of 0.021. The analysis will be based on modified intent-to-treat and will include all eligible patients as randomized regardless of treatment received. The one-sided alpha of .021 will control of the overall type-one error of the study (including the 2 interim superiority analyses) to be less than .025.

Secondary Outcome Measures

Measure:Overall survival
Time Frame:2 years
Safety Issue:
Description:
Measure:Event-free survival (EFS)
Time Frame:From date of registration to date of first occurrence of EFS event, assessed at 2 years
Safety Issue:
Description:Will be estimated using Kaplan-Meier method and compared between treatment arms using cox regression model.
Measure:Metabolic complete response rate
Time Frame:Up to 10 years
Safety Issue:
Description:Defined using 2014 Lugano classification.
Measure:Incidence of adverse events
Time Frame:Up to 10 years
Safety Issue:
Description:Toxicity will be evaluated using Common Terminology Criteria of Adverse Events (CTCAE) version 5 items. Treatment-related toxicities between arms will be compared using Fisher's exact test stratified by age groups. Targeted patient-reported toxicities also will be collected at each time point using the Patient Reported Outcome (PRO)-CTCAE for patients 18 years and older and from youth 12-17 years, using the Pediatric (Ped) PRO-CTCAE.

Details

Phase:Phase 3
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

Last Updated

February 12, 2020