Nivolumab and Combination Chemotherapy in Treating Patients with Untreated Stage III-IV Classical Hodgkin Lymphoma
This phase I trial studies the best dose and side effects of nivolumab and combination chemotherapy in treating patients with untreated stage III-IV classical 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. Drugs used in combination chemotherapy, such as doxorubicin hydrochloride, bleomycin sulfate, vinblastine, and dacarbazine (ABVD) work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nivolumab and more than one drug (combination chemotherapy) may kill more tumor cells and work better at treating Hodgkin lymphoma.
Inclusion Criteria
- COHORT A OVERVIEW: patients age less than 60 with untreated stage III or IV classical Hodgkin lymphoma will be eligible for cohort A; in phase I, patients may enroll onto cohort A if they have a baseline IPS >= 3 OR if their PET scan after 2 cycles of ABVD is positive (Deauville 4 or 5); enrollment onto phase I has now ceased and enrollment will begin for phase II; in phase II, patients less than 60 years of age with stage III or IV HL are eligible; Memorial Sloan Kettering (MSK) patients may enroll anytime within the first 2 cycles of ABVD; non-MSK patients must enroll after positive PET-2 scan
- COHORT B OVERVIEW: patients 60 or older with untreated classical Hodgkin lymphoma (regardless of stage) will be eligible for cohort B
- Histologic diagnosis of classical Hodgkin lymphoma
- Fludeoxyglucose F-18 (FDG)-avid disease by FDG-PET/computed tomography (CT) * Non-MSK patients ONLY: PET-2 positive disease (Cohort A only)
- Ann Arbor stage III or IV disease (Cohort A only)
- Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotropin [HCG]) within 2 weeks prior to the start of study drug; women who undergo fertility preservation within 2 weeks of beginning chemotherapy are expected to have false-positive pregnancy tests and therefore testing may be waived for these patients * WOCBP must agree to follow instructions for method(s) of contraception from the time of enrollment for the duration of treatment with study drug plus 5 half-lives of study drug plus 30 days (duration of ovulatory cycle) for a total of 23 weeks post treatment completion * Reliable methods of birth control include a double barrier method, oral contraceptive, implant, dermal contraception, long-term injectable contraceptive, intrauterine device, tubal ligation or total abstinence during the study * Women must not be breastfeeding
- Men who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception (i.e. use of a condom during intercourse) for the duration of treatment with study drug plus 5 half-lives of study drug plus 90 days (duration of sperm turnover) for a total of 31 weeks posttreatment completion
- Age >= 18
- Serum creatinine =< 1.5 x upper limit of normal (ULN) or creatinine clearance (CrCl) >= 40 mL/min (measured using the Cockcroft-Gault formula)
- Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 3 x ULN (5 x ULN for those with lymphoma involvement of the liver)
- Total bilirubin =< 1.5 x ULN (except subjects with Gilbert syndrome, who can have total bilirubin < 3.0 mg/dL)
Exclusion Criteria
- Subjects with active brain metastases or leptomeningeal metastases
- Subjects with nodular lymphocyte-predominant HL
- Any serious or uncontrolled medical disorder that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the subject to receive protocol therapy, or interfere with the interpretation of study results
- Prior malignancy active within the previous 3 years except for locally curable cancers that have been apparently cured, such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast
- Subjects with active, known or suspected autoimmune disease; subjects with vitiligo, 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 are permitted to enroll
- Subjects with a condition requiring systemic treatment with systemic corticosteroids (equivalent of > 10 mg/day of prednisone); patients may receive steroid therapy if steroids are tapered down to 10 mg or less by 4 weeks after initiating A(B)VD to control lymphoma-related symptoms
- Any of the following cardiovascular conditions or values within 6 months before the first dose of study drug: * A left-ventricular ejection fraction < 50% * Myocardial infarction within 2 years of randomization * New York Heart Association (NYHA) class III or IV heart failure
- Evidence of current uncontrolled cardiovascular conditions, including cardiac arrhythmias, congestive heart failure (CHF), angina, or electrocardiographic evidence of acute ischemia or active conduction system abnormalities
- Any positive test for hepatitis B virus or hepatitis C virus indicating acute infection
- Known history of testing positive for human immunodeficiency virus (HIV) or known acquired immunodeficiency syndrome (AIDS)
- History of severe hypersensitivity reaction to any monoclonal antibody
- Adjusted diffusion capacity of the lung for carbon monoxide (DLCO) < 60% (if unadjusted DLCO is >= 60% then there is no need to calculate adjusted)
Additional locations may be listed on ClinicalTrials.gov for NCT03033914.
See trial information on ClinicalTrials.gov for a list of participating sites.
PRIMARY OBJECTIVES:
I. Establish the safety of adding nivolumab to doxorubicin hydrochloride (Adriamycin), vinblastine, dacarbazine (AVD) during cycles 3 through 6 for international prognostic score (IPS) 3-7 or positron emission tomography (PET)-2 positive patients. (Cohort A: high risk advanced stage Hodgkin lymphoma; Phase I)
II. Establish the safety of adding nivolumab to AVD during cycles 1 through 6 for older patients with Hodgkin lymphoma. (Cohort B: older Hodgkin lymphoma patients; Phase I)
III. Determine the 2-year PFS for PET-2 positive advanced stage Hodgkin lymphoma (HL) patients receiving ABVD for 2 cycles followed by AVD plus nivolumab for 4 cycles. (Cohort A: high risk advanced stage Hodgkin lymphoma; Phase II)
IV. Determine the 2-year progression free survival (PFS) for older HL patients treated with 6 cycles of nivolumab plus AVD. (Cohort B: older Hodgkin lymphoma patients; Phase II)
SECONDARY OBJECTIVES:
I. Evaluate the toxicity profile of anti-PD-1 therapy combined with AVD chemotherapy. (Cohort A: high risk advanced stage Hodgkin lymphoma)
II. Assess 2-year PFS for PET-2 negative patients enrolled on study receiving standard of care therapy. (Cohort A: high risk advanced stage Hodgkin lymphoma)
III. Assess 2-year overall survival (OS) for all patients enrolled. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IV. Identify biomarkers that predict which patients are more likely to benefit from nivolumab. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IVa. Assess cell populations within the Hodgkin lymphoma (HL) tumor microenvironment (by immunohistochemical staining) on baseline biopsies. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IVb. Assess major histocompatibility complex (MHC) class I/II and beta-2-microglobulin expression (by immunohistochemical staining) on Hodgkin lymphoma Reed-Sternberg cells. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IVc. Assess serum cytokine/chemokine levels, including thymus and activation-regulated chemokine (TARC), IL-6, IL-10, at baseline and throughout treatment. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IVd. Assess 9p24.1 chromosome alterations by fluorescent in situ hybridization (FISH) on baseline tumor biopsies. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IVe. Evaluate gene expression profiling of microdissected Reed-Sternberg (RS)-cells from baseline biopsies. (Cohort A: high risk advanced stage Hodgkin lymphoma)
IVf. Quantification and molecular profiling of tumor specific cell free dexoxyribonucleic acid (cfDNA) collected at baseline, after 2 cycles (+ 14 days) of ABVD, after 6 cycles (+ 14 days) of AVD (+/-nivolumab), and 3 (+/- 1 month) 6 (+/- 1 month) and 12 (+/- 1 month), months following completion of treatment. (Cohort A: high risk advanced stage Hodgkin lymphoma)
V. Evaluate the toxicity profile of anti-PD-1 therapy combined with AVD chemotherapy. (Cohort B: older Hodgkin lymphoma patients)
VI. Assess 2-year OS. (Cohort B: older Hodgkin lymphoma patients)
VII. Evaluate the impact of baseline geriatric assessment on treatment toxicity. (Cohort B: older Hodgkin lymphoma patients)
VIII. Identify biomarkers that predict which patients are more likely to benefit from nivolumab. (Cohort B: older Hodgkin lymphoma patients)
VIIIa. Assess cell populations within the HL tumor microenvironment (by immunohistochemical staining) on baseline biopsies. (Cohort B: older Hodgkin lymphoma patients)
VIIIb. Assess MHC class I/II and beta-2-microglobulin expression (by immunohistochemical staining) on Hodgkin lymphoma Reed-Sternberg cells. (Cohort B: older Hodgkin lymphoma patients)
VIIIc. Assess serum cytokine/chemokine levels, including TARC, IL-6, IL-10, at baseline and throughout treatment. (Cohort B: older Hodgkin lymphoma patients)
VIIId. Assess 9p24.1 chromosome alterations by fluorescent in situ hybridization (FISH) on baseline tumor biopsies. (Cohort B: older Hodgkin lymphoma patients)
VIIIe. Evaluate gene expression profiling of microdissected RS-cells from baseline biopsies. (Cohort B: older Hodgkin lymphoma patients)
VIIIf. Quantification and molecular profiling of tumor specific cell free DNA (cfDNA) collected at baseline, after 2 cycles (+ 14 days) of ABVD, after 6 cycles (+ 14 days) of AVD (+/-nivolumab), and 3 (+/- 1 month), 6 (+/- 1 month), and 12 (+/- 1 month) months following completion of treatment. (Cohort B: older Hodgkin lymphoma patients)
OUTLINE: Patients are assigned to 1 of 2 cohorts.
COHORT A (HIGH RISK ADVANCED STAGE HODGKIN LYMPHOMA)
DOSE LEVEL 1: Patients receive ABVD intravenously (IV) alone on days 1 and 15 for up to 5 cycles. Patients then receive nivolumab IV over 30 minutes and AVD IV on days 1 and 15 for 1 cycle, and nivolumab IV over 60 minutes alone on days 1 and 15 for 3 cycles.
DOSE LEVEL 2 (only if a dose limiting toxicity [DLT] is observed on dose level 1): Patients receive ABVD IV alone on days 1 and 15 for up to 4 cycles. Patients then receive nivolumab IV over 30 minutes and AVD IV on days 1 and 15 for 2 cycles, and nivolumab IV over 30 minutes alone on days 1 and 15 for 2 cycles.
DOSE LEVEL 3: Patients receive ABVD IV alone on days 1 and 15 for up to 2 cycles. Patients then receive nivolumab IV over 60 minutes and AVD IV on days 1 and 15 for 4 cycles.
COHORT B (OLDER HODGKIN LYMPHOMA PATIENTS)
DOSE LEVEL 1: Patients receive AVD alone IV on days 1 and 15 for up to 4 cycles. Patients then receive nivolumab IV over 30 minutes and AVD IV on days 1 and 15 for 2 cycles, and nivolumab IV over 30 minutes alone on days 1 and 15 for 4 cycles.
DOSE LEVEL 2 (only if a DLT is observed on dose level 1): Patients receive AVD IV alone on days 1 and 15 for up to 2 cycles. Patients then receive nivolumab IV over 30 minutes and AVD IV on days 1 and 15 for 4 cycles, and nivolumab IV over 30 minutes alone on days 1 and 15 for 2 cycles.
DOSE LEVEL 3: Patients receive nivolumab IV over 30 minutes and AVD IV on days 1 and 15 for 6 cycles.
In all cohorts, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.
After completion of study treatment, patients are followed up at 3 months, 6 months, and then every 6 months for up to 2 years.
Trial PhasePhase I/II
Trial Typetreatment
Lead OrganizationMemorial Sloan Kettering Cancer Center
Principal InvestigatorAlison J. Moskowitz
- Primary ID16-1536
- Secondary IDsNCI-2017-00334
- ClinicalTrials.gov IDNCT03033914