Preliminary Safety and Efficacy of the Combination of Brentuximab Vedotin and Ipilimumab in Relapsed / Refractory Hodgkin Lymphoma: A Trial of the ECOG-ACRIN Cancer Research Group (E4412)

Background: Despite advances in chemotherapy, R/R HL remains a significant clinical problem with over 1,000 primarily young lives lost annually.  HL is a unique tumor in which a small number of malignant Hodgkin Reed-Sternberg (HRS) cells propagate an immunosuppressive microenvironment that augments HRS growth and survival.  We hypothesized that immune checkpoint inhibitor therapy could activate the tumor immune microenvironment, while the CD30 expressing HRS cells could be targeted by brentuximab vedotin (BV), thereby overcoming tumor cell resistance and deepening clinical responses. E4412 is a phase 1 ECOG-ACRIN sponsored study of the combination of BV and the checkpoint inhibitors ipilimumab (IPI) and nivolumab (NIVO) in patients with relapsed/refractory (R/R) Hodgkin lymphoma (HL).  Here we report the data on the patients treated with BV + IPI, the first cohort of the study.  

Methods:  Patients with biopsy proven R/R HL were treated with BV 1.8mg/kg and two escalating doses of IPI:  1 mg/kg or 3mg/kg. After safety was determined an expanded cohort was treated with BV 1.8mg/kg IV and IPI 3mg/kg IV.  The schedule consisted of BV administered every 21 days for 16 cycles and IPI every 21 days x 4 doses and thereafter every 3 months for up to a year.  Dose limiting toxicity (DLT) was defined for purposes of dose escalation within the first cycle of therapy.  Patients are followed for toxicity up to 30 days beyond their last treatment. 

Results:  As of 7/2015 19 of 23 planned patients have been treated with BV + IPI.  We report the data on the full dose escalation population (13 patients:  Dose level 1 (6), Dose level 2 (7)).  The median age was 33 years (range: 20-49).  Seven patients were male.  Patients were heavily pretreated with a median of 4 prior therapies (2-13). Four patients had prior treatment with BV; 8 patients had prior SCT (7 autologous, 1 allogeneic). 

Safety: Overall the regimen of BV + IPI was extremely well tolerated with no DLTs noted during dose escalation.  Toxicities considered at least possibly related to drug during any cycle of treatment are shown according to grade in Table 1. The most common treatment related adverse events were: diarrhea, rash, and peripheral sensory neuropathy.   Other AEs of interest included: alopecia, transaminitis, and uveitis.  Grade 3 and 4 treatment related adverse events (AEs) included: Dose level  1: one grade 3 infusion reaction, which led to a  protocol amendment  to include premedication, no further grade 3 infusion reactions were noted; Dose level  2: one each: grade 3 rash, vomiting, and peripheral sensory neuropathy, and one grade 4 thrombocytopenia in patient with pre-existing thrombocytopenia.   

Response: For the 12 evaluable patients, the overall response (ORR) for the combination of BV + IPI was 67% with a complete response (CR) rate of 42% (5 of 12 patients).  An additional 2 patients had stable disease (SD) giving a clinical benefit rate of 83%.  Three of 5 of the CRs occurred at dose level 1 (1mg dose of IPI).  The median progression free survival (PFS) is 0.74 years with a median follow-up of 0.66 years.  

Conclusion:  In this first reported study of the combination of checkpoint inhibitor and ADC, toxicity was low, primarily grades 1 and 2.  In a heavily pretreated patient population, 33% of whom had had prior BV and 67% of whom were s/p ASCT, the ORR of 67% and CR rate of 42% suggests a potential deepening of response compared to monotherapy.    More than half of these CRs occurred at 1mg of IPI suggesting that in combination with ADC, low doses of immune stimulation may be highly active.  Optimization of this combination strategy is planned with ongoing accrual to cohorts receiving BV + NIVO, and BV + IPI + NIVO.  Data will be updated to include the full BV + IPI cohort by the time of the annual meeting.  

Table 1: Common and Immune Toxicities

Toxicity Type	Dose Level 1 (n=6)				Dose Level 2 (n=7)
	Grade				Grade
	1,2	3	4	5	1,2	3	4	5
	(n)	(n)	(n)	(n)	(n)	(n)	(n)	(n)
Fatigue	5	-	-	-	3	-	-	-
Fever	1	-	-	-	3	-	-	-
Pain	2	-	-	-	3	-	-	-
Alopecia	2	-	-	-	1	-	-	-
Pruritus	1	-	-	-	2	-	-	-
Rash maculo-papular	4	-	-	-	2	1	-	-
Diarrhea	4	-	-	-	4	-	-	-
Dyspepsia	2	-	-	-	1	-	-	-
Nausea	6	-	-	-	4	-	-	-
Vomiting	3	-	-	-	2	1	-	-
Papulopustular rash	1	-	-	-	1	-	-	-
Alanine aminotransferase increased	3	-	-	-	3	-	-	-
Aspartate aminotransferase increased	3	-	-	-	2	-	-	-
Platelet count decreased	-	-	-	-	-	-	1	-
Anorexia	3	-	-	-	-	-	-	-
Headache	2	-	-	-	2	-	-	-
Peripheral sensory neuropathy	5	-	-	-	4	1	-	-
Dry eye	2	-	-	-	-	-	-	-
Uveitis	1	-	-	-	-	-	-	-
Cough	2	-	-	-	1	-	-	-