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.

Conditions

Eligibility

Eligible Ages
Over 12 Years
Eligible Genders
All
Accepts Healthy Volunteers
No

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.

Study Design

Phase
Phase 3
Study Type
Interventional
Allocation
Randomized
Intervention Model
Parallel Assignment
Primary Purpose
Treatment
Masking
None (Open Label)

Arm Groups

ArmDescriptionAssigned Intervention
Experimental
Arm I (chemotherapy, nivolumab, radiation)
Patients 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.
  • Drug: Dacarbazine
    Given IV
    Other names:
    • 4-(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-139007
  • Drug: Doxorubicin
    Given IV
    Other names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • 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
    • Doxorubicin.HCl
    • Doxorubin
    • Farmiblastina
    • FI 106
    • FI-106
    • hydroxydaunorubicin
    • Rubex
  • Biological: Filgrastim
    Given SC or IV
    Other names:
    • G-CSF
    • Neupogen
    • r-metHuG-CSF
    • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    • rG-CSF
    • Tevagrastim
  • Biological: Nivolumab
    Given IV
    Other names:
    • BMS-936558
    • MDX-1106
    • NIVO
    • ONO-4538
    • Opdivo
  • Biological: Pegfilgrastim
    Given SC
    Other names:
    • Filgrastim 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-CSF
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other names:
    • Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Radiation: Radiation Therapy
    Receive radiation therapy
    Other names:
    • Cancer Radiotherapy
    • Irradiate
    • irradiated
    • irradiation
    • RADIATION
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Drug: Vinblastine
    Given IV
    Other names:
    • Vincaleucoblastine
    • VLB
  • Drug: Vinblastine Sulfate
    Given IV
    Other names:
    • 29060 LE
    • 29060-LE
    • Exal
    • Velban
    • Velbe
    • Velsar
    • VINCALEUKOBLASTINE
Experimental
Arm II (chemotherapy, brentuximab vedotin, radiation)
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.
  • Drug: Brentuximab Vedotin
    Given IV
    Other names:
    • ADC 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-35
  • Drug: Dacarbazine
    Given IV
    Other names:
    • 4-(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-139007
  • Drug: Doxorubicin
    Given IV
    Other names:
    • Adriablastin
    • Hydroxydaunomycin
    • Hydroxyl Daunorubicin
    • Hydroxyldaunorubicin
  • 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
    • Doxorubicin.HCl
    • Doxorubin
    • Farmiblastina
    • FI 106
    • FI-106
    • hydroxydaunorubicin
    • Rubex
  • Biological: Filgrastim
    Given SC or IV
    Other names:
    • G-CSF
    • Neupogen
    • r-metHuG-CSF
    • Recombinant Methionyl Human Granulocyte Colony Stimulating Factor
    • rG-CSF
    • Tevagrastim
  • Biological: Pegfilgrastim
    Given SC
    Other names:
    • Filgrastim 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-CSF
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other names:
    • Quality of Life Assessment
  • Other: Questionnaire Administration
    Ancillary studies
  • Radiation: Radiation Therapy
    Receive radiation therapy
    Other names:
    • Cancer Radiotherapy
    • Irradiate
    • irradiated
    • irradiation
    • RADIATION
    • Radiation Therapy, NOS
    • Radiotherapeutics
    • Radiotherapy
    • RT
    • Therapy, Radiation
  • Drug: Vinblastine
    Given IV
    Other names:
    • Vincaleucoblastine
    • VLB
  • Drug: Vinblastine Sulfate
    Given IV
    Other names:
    • 29060 LE
    • 29060-LE
    • Exal
    • Velban
    • Velbe
    • Velsar
    • VINCALEUKOBLASTINE

Recruiting Locations

University of Texas Health Science Center at San Antonio
San Antonio, Texas 78229
Contact:
Site Public Contact
210-450-3800
phoresearchoffice@uthscsa.edu

More Details

Status
Recruiting
Sponsor
National Cancer Institute (NCI)

Study Contact

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.

Notice

Study information shown on this site is derived from ClinicalTrials.gov (a public registry operated by the National Institutes of Health). The listing of studies provided is not certain to be all studies for which you might be eligible. Furthermore, study eligibility requirements can be difficult to understand and may change over time, so it is wise to speak with your medical care provider and individual research study teams when making decisions related to participation.