PRIMARY OBJECTIVE:
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 OBJECTIVE:
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 the last dose of protocol therapy \[following last dose of study drug or radiation therapy, whichever is later\], 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 6-10 and 21-25. 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. Patients also undergo peripheral blood specimen collection and CT, PET/CT and/or magnetic resonance imaging (MRI) on study.
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 6-10 and 21-25. 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. Patients also undergo peripheral blood specimen collection and CT, PET/CT and MRI on study.
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.
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, MRI or MR-PET is
acceptable in event that PET-CT is contra-indicated, however if it is later possible
to administer a PET-CT, then PET-CT is strongly preferred for the interim scan (after
cycle 2) (if performed) and the EOT assessment. Otherwise, if PET-CT is not
subsequently possible, then the same modality as baseline must be used throughout 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 be >= 12 years of age.
- 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 pediatric patients (< 18 years of age) will be considered intent-to-treat
with Residual PET RT at time of registration.
- 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 all patients, the ECHO, MUGA, or
functional cardiac imaging scan must be performed within 42 days prior to
registration.
- Patients with known human immunodeficiency virus (HIV) infection must be
receiving anti-retroviral therapy and have an undetectable or unquantifiable
viral load at their most recent viral load test within 6 months prior to
registration.
- 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 within 6 months prior to registration 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 one formalin-fixed paraffin embedded (FFPE) diagnostic tumor
block or at least 1 diagnostic, 4-5 micron, hematoxylin and eosin (H&E) slide
collected prior to registration and available for submission.
- 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. Patients who do not complete PRO instruments
prior to registration but are otherwise eligible will remain eligible for the
primary analysis and other secondary analyses.
- Patients who can complete Patient-Reported Outcome instruments in English,
Spanish, or French must also agree to complete the PROMIS Fatigue, the
FACT/GOG-Ntx, the PROMIS Global, and the PRO-CTCAE (or Pediatric [Ped] 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 informed consent and assent (where appropriate) in accordance
with institutional and federal guidelines. For participants with impaired
decision-making capabilities, legally authorized representatives may sign and
give informed consent on behalf of study participants in accordance with
applicable federal, local, and Central Institutional Review Board Initiative
(CIRB) regulations.
- Note: 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.
