Phase 1 Study of Adct-301 (Camidanlumab Tesirine), a Novel Pyrrolobenzodiazepine-Based Antibody Drug Conjugate, in Relapsed/Refractory Classical Hodgkin Lymphoma
Authors: Hamadani Mehdi , Collins Graham P. , Samaniego Felipe , Spira Alexander I , Davies Andrew , Radford John , Caimi Paolo , Menne Tobias , Boni Joseph , Cruz Hans , Feingold Jay , He Shui , Wuerthner Jens , Horwitz Steven M. 
Published: October 2019

Abstract
Introduction: CD25 is expressed on the cell surface of many lymphomas, including classical Hodgkin lymphoma (cHL) and non-Hodgkin lymphoma. ADCT-301 (camidanlumab tesirine [Cami-T]) is an antibody drug conjugate comprising a human monoclonal antibody against CD25 conjugated to a potent pyrrolobenzodiazepine dimer (PBD) toxin. We report here a first-in-human clinical trial of Cami-T, focusing on patients (pts) with relapsed/refractory (R/R) cHL treated in dose-escalation and subtype-specific dose-expansion cohorts.
Methods: This was a Phase 1, open-label, dose-escalation and dose-expansion multicenter study in pts with R/R cHL. The objectives of the study were to assess the safety and tolerability, determine the recommended dose(s) for expansion, and evaluate pharmacokinetics and pharmacodynamics. The clinical activity of Cami-T was measured by overall response rate (ORR; per 2014 Lugano Classification), duration of response (DoR), progression-free survival (PFS), and overall survival. Pts received Cami-T intravenously every 3 weeks (Q3W; 1 Cycle). Dose escalation was performed according to a continual reassessment method.
Results: As of June 15, 2018, 60 pts with cHL have been enrolled. Baseline characteristics include median age: 38.5 years (range 19-80); median number of prior therapies: 5 (range 2-15). Cami-T doses ranged from 5 to 300 µg/kg (median number of cycles: 3 [range 1-15], with a median treatment duration of 43 days [range 1-354]). Treatment-emergent adverse events (TEAEs) were reported in 57/60 (95%) pts; most common TEAEs (≥20%) were fatigue (25, 41.7%), maculopapular rash (20, 33.3%), increased gamma-glutamyltransferase (GGT; 18, 30%), pyrexia (18, 30%); increased alanine aminotransferase (ALT; 14, 23.3%), dyspnea (13, 21.7%), nausea (13, 21.7%), increased aspartate aminotransferase (AST; 12, 20.0%), increased blood alkaline phosphatase (ALP; 12, 20.0%), and cough (12, 20.0%). As part of immune-related AEs, there were 2 (3.3%) cases of Guillain-Barré syndrome (1 each at dose 45 and 60 µg/kg) and 1 (1.7%) case of thyroiditis. Also, there were 16 (26.7%) cases of peripheral edema or effusion, which are AEs thought to be associated with PBDs. Grade ≥3 TEAEs occurred in 37/60 (61.7%) pts; the most common Grade ≥3 TEAEs (≥5% of pts) were liver function abnormalities (increased GGT [16.7%], ALT [10.0%] AST [5.0%], and ALP [5.0%]), maculopapular rash (13.3%), anemia (8.3%), and decreased platelet count (5.0%). TEAEs leading to treatment discontinuation occurred in 17/60 (28.3%) pts. Most pts (72%) tolerated at least 3 cycles before an AE leading to a dose reduction/delay occurred.
Exposure to the conjugated antibody was dose-related and at a ≥45 µg/kg dose was sustainable throughout the dosage interval at a mean concentration of 0.0826 µg/mL (coefficient of variation [CV] 49.9%) and mean minimum concentration of 0.0092 µg/mL (CV=81.7%; n=25).
The maximum tolerated dose was not reached; however, the recommended dose for expansion was identified as 45 µg/kg Q3W. Response data for 55 evaluable pts with cHL are shown in the Table. The ORR was 69.1% (38/55 pts) and the complete response (CR) rate was 43.6% (24/55 pts).
In the 45 µg/kg dose group (dose escalation + expansion), the ORR was 80.8% (21/26 pts) and the CR rate was 50% (13/26 pts) (Table). ORRs by prior treatment were 80.8% (21/26) in pts who previously received brentuximab vedotin (BV), 80.0% (12/15) in those who previously received both a checkpoint inhibitor (CHPi) and BV, 81.8% (9/11) in those who had a prior hematopoietic cell transplant (HCT), and 85.7% (6/7) in those who had a prior CHPi, BV, and HCT. Median DoR and PFS were 7.7 and 6.7 months, respectively (Figure).
Conclusions: In pts with R/R cHL, therapy with Cami-T provided impressive ORRs and CR rates in a heavily pretreated pt population. A 45 µg/kg dose of Cami-T was identified as having optimal activity with an acceptable safety profile. Enrollment of pts with HL is now complete and initial response data for all pts with HL will be available later this year. This data supports further investigation in a planned Phase 2 study.
Study sponsored by ADC Therapeutics. http://clinicaltrials.gov/show/NCT02432235.

Disclosures
Hamadani: Celgene Corporation: Consultancy; Cellerant: Consultancy; Janssen: Consultancy; ADC Therapeutics: Research Funding; Ostuka: Research Funding; MedImmune: Consultancy, Research Funding; Merck: Research Funding; Takeda: Research Funding; Sanofi Genzyme: Research Funding, Speakers Bureau. Collins:BMS: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; MSD: Consultancy, Honoraria; Takeda: Consultancy, Honoraria, Speakers Bureau; Celgene Corporation: Research Funding; Amgen: Research Funding; Gilead: Consultancy, Honoraria, Speakers Bureau; Roche: Consultancy, Honoraria, Speakers Bureau; Celleron: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria. Samaniego:ADC Therapeutics: Research Funding. Spira:AstraZeneca: Consultancy; AbbVie: Consultancy; BMS: Consultancy; Roche: Consultancy; ADC Therapeutics: Research Funding. Davies:GSK: Research Funding; Janssen: Consultancy, Honoraria; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Acerta Pharma: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; F. Hoffman-La Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; ADC Therapeutics: Research Funding; Pfizer: Research Funding; Gilead: Honoraria, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Kite: Consultancy. Radford:ADC Therapeutics: Consultancy, Research Funding; Celgene: Research Funding; Pfizer: Research Funding; Takeda: Consultancy, Research Funding, Speakers Bureau; Seattle Genetics: Consultancy, Speakers Bureau; AstraZeneca: Equity Ownership; Novartis: Consultancy, Speakers Bureau; GlaxoSmithKline: Equity Ownership; BMS: Consultancy, Speakers Bureau. Caimi:Celgene: Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; ADC Therapeutics: Research Funding; Kite Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees. Menne:ADC Therapeutics: Research Funding; Amgen: Consultancy, Speakers Bureau; Takeda: Consultancy, Speakers Bureau; Gilead: Consultancy, Speakers Bureau. Boni:ADC Therapeutics: Employment, Equity Ownership. Cruz:ADC Therapeutics: Employment, Equity Ownership. Feingold:ADC Therapeutics: Employment, Equity Ownership. He:ADC Therapeutics: Employment, Equity Ownership. Wuerthner:ADC Therapeutics: Employment, Equity Ownership. Horwitz:Portola: Consultancy; Corvus: Consultancy; Mundipharma: Consultancy; Millennium/Takeda: Consultancy, Research Funding; Trillium: Consultancy; Aileron Therapeutics: Consultancy, Research Funding; Spectrum: Research Funding; Kyowa-Hakka-Kirin: Consultancy, Research Funding; ADC Therapeutics: Consultancy, Research Funding; Innate Pharma: Consultancy; Seattle Genetics: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Forty Seven: Consultancy, Research Funding; Infinity/Verastem: Consultancy, Research Funding.