nivolumab + brentuximab vedotin

Author: Julia Dobke, erstellt am: 2018/05/02, Last modification: 2018/05/02

Title Risk-based, response-adapted, Phase II open-label trial of nivolumab + brentuximab vedotin (N + Bv) for children, adolescents, and young adults with relapsed/refractory (R/R) CD30+ classic Hodgkin lymphoma (cHL) after failure of first-line therapy, followed by brentuximab + bendamustine (Bv + B) for participants with a suboptimal response.
Disease relapsed/refractory (R/R) CD30 + classic Hodgkin lymphoma (cHL)
Type Phase 2 trial
Problem / Objectives

R1 (Low Risk) Cohort: To describe event-free survival (EFS) rate at 3 years, as assessed by blinded independent central review (BICR).
R2 (Standard Risk) Cohort: To describe the complete metabolic response (CMR) rate prior to
HDCT/ASCT by BICR, using Lugano 2014 response criteria

Therapy / Study arms

Eligible participants will receive treatment with brentuximab vedotin at 1.8mg/kg IV as a 30 minute infusion on Day 1 of every 21-day cycle.
For Cycle 1 only, nivolumab will be administered alone on Day 8 of Cycle 1. Nivolumab injection at 3 mg/kg is to be administered as an IV infusion over 30 minutes.
For Cycle 2 and beyond, nivolumab should be administered at least 30 minutes after the completion of brentuximab vedotin infusion.
After 4 cycles of N+Bv, R1 (or R2) cohort with tumor assessment of PMR/NMR will receive augment therapy with Bv+B, with objective to achieve CMR prior to IFRT (or HDCT/ASCT). Eligible participants will receive brentuximab vedotin (1.8 mg/kg) on Day 1 and bendamustine (90 mg/m2) on Days 1 and 2 of a 21-day cycle, respectively.

Inclusion Criteria
  • Signed Written Informed Consent
  • Participants must have measurable disease, documented by pathological and radiographic criteria
  • Performance Level: Karnofsky >=50 for participants > 16 years of age or Lansky >=50 for participants >=16 years of age
  • Evaluable tumor tissue (archived or new biopsy) must be provided for biomarker analysis as formalin-fixed paraffin-embedded (FFPE) tumor block or a minimum of 20 slides
  • Males and Females, ages 5 to 30 years, inclusive
  • Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study treatment
  • Women must not be breastfeeding
  • WOCBP must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drugs to undergo approximately 5 half-lives. WOCBP receiving nivolumab should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo approximately 5 half-lives) after the last dose. WOCBP must have
  • a negative serum or urine beta human chorionic gonadotropin pregnancy test result within 7 days prior to the first dose of brentuximab vedotin.
  • Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drugs to undergo approximately 5 half-lives. Males receiving nivolumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo approximately 5 half-lives) after the last dose of investigational drug.
  • Adequate bone marrow function
  • Creatinine clearance or radioisotope GFR  70 ml/min/1.73 m2
  • Adequate hepatic function
  • Prior Anti-tumor Therapy: a) Participants must have received first-line anti-cancer therapy that failed; b) Participants must have fully recovered from the acute toxic effects of all prior anti-cancer chemotherapy prior to signing consent; c) Myelosuppressive chemotherapy: At least 14 days after the last dose of myelosuppressive
  • chemotherapy; d) Hematopoietic growth factors: At least 14 days after the last dose of a long-acting growth
  • factor (eg, Neulasta) or 7 days for short-acting growth factor. For agents that have known AEs occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the BMS Medical Monitor; e) Biologic (anti-neoplastic agent): At least 7 days after the last dose of a biologic agent. For agents that have known AEs occurring beyond 7 days after administration, this period must be extended beyond the time during which AEs are known to occur. The duration of this interval must be discussed with the BMS Medical Monitor; f) Monoclonal antibodies: At least 3 half-lives of the antibody after the last dose of a monoclonal antibody; g) Bleomycin: At least 28 days must have elapsed since the most recent dose of bleomycin, to allow adequate time to detect evidence of bleomycin-related pulmonary toxicity.
Exclusion Criteria
  • Medical Conditions: a) Participants with an immunodeficiency that existed prior to diagnosis, such as primary
  • immunodeficiency syndromes, organ transplant recipients, and participants on current systemic mmunosuppressive agents are not eligible; b) Active cerebral/meningeal disease related to the underlying malignancy; c) History of progressive multifocal leukoencephalopathy (PML) d) Pre-existing neuropathy of >=Grade 2; e) Any active Grade 3 or higher (per Common Terminology Criteria for Adverse Events [CTCAE] version 4) viral, bacterial or fungal infection prior to the first dose of brentuximab vedotin; routine antimicrobial prophylaxis is permitted; f) Participants with an active, known or suspected autoimmune disease. Participants with type I diabetes mellitus, hypothyroidism only requiring hormone replacement, skin disorders (such as vitiligo, psoriasis, or alopecia) not requiring systemic treatment, or conditions not expected to recur in the absence of an external trigger are permitted to enroll; g) Other serious underlying medical condition that, in the opinion of the investigator, would impair the ability to receive or tolerate the planned treatment and follow-up
  • h) 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; i) Known history of positive test for human immunodeficiency virus (HIV) or known
  • acquired immunodeficiency syndrome (AIDS). NOTE: Testing for HIV must be performed at sites where mandated locally.
  • Prior/Concomitant Therapy: a) Participants who received more than one line of anti-cancer therapy or are treatment naive are not eligible; b) Previously received an allogeneic and/or autologous SCT for HL c) Participants who have received a prior solid organ transplantation are not eligible; d) Participants with a condition requiring systemic treatment with either corticosteroids (> 10 mg daily prednisone equivalent) or other immunosuppressive medications within 14 days of first dose of study medication. Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of active autoimmune disease; e) Prior exposure to anti-PD1, anti-PDL1, anti-PD-L2, anti-CD137 or anti- CTLA-4
  • antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways; f) Prior radiation therapy within 3 weeks, or chest radiation  12 weeks prior to first dose of study drug(s); g) Any concurrent anti-neoplastic therapy (ie, chemotherapy, hormonal therapy, immunotherapy, extensive, non-palliative radiation therapy, or standard or investigational agents for treatment of cHL); h) Prior exposure to bendamustine.
  • Any positive test for hepatitis B or C virus indicating acute or chronic infection, and/or detectable virus
  • History of allergy or hypersensitivity to study drug components
  • Participants with serious or uncontrolled medical disorders that, in the opinion of the investigator, may increase the risk associated with study participation or study drug administration, impair the ability of the participant to receive protocol therapy, or interfere with the interpretation of study results.
  • Participants who are compulsorily detained for treatment of either a psychiatric or physical (eg, infectious disease) illness.
Recruitment Approximately 100 participants are planned to be enrolled, with approximately 80 treated (R1 cohort 40, R2 cohort 40)
Status Start 2017
EudraCT 2016-002347-41
Entry Study Register ClinicalTrials.gov: NCTNCT02927769
National Cancer Institute: Protocol ID clinical.trials@bms.com
Principal Investigator Bristol-Myers Squibb
Weitere Informationen Sponsor: BRISTOL-MYERS SQUIBB RESEARCH & DEVELOPMENT Avenue de Finlande 4
B-1420 Braine-l’Alleud, Belgium