Camidanlumab tesirine in patients with relapsed or refractory lymphoma: a phase 1, open-label, multicentre, dose-escalation, dose-expansion study

Abstract

Background: Novel approaches are required to improve outcomes in relapsed or refractory classical Hodgkin lymphoma and non-Hodgkin lymphoma. We aimed to evaluate camidanlumab tesirine, an anti-CD25 antibody-drug conjugate, in this patient population.

Methods: This was a phase 1, dose-escalation (part 1), dose-expansion (part 2), multicentre trial done in 12 hospital sites (seven in the USA and five in the UK). Adults (≥18 years old) with pathologically confirmed relapsed or refractory classical Hodgkin lymphoma or non-Hodgkin lymphoma, an Eastern Cooperative Oncology Group performance status 0-2, who had no therapies available to them with established clinical benefit for their disease stage were enrolled. Camidanlumab tesirine was administered intravenously (3-150 μg/kg) once every 3 weeks. Primary objectives were to assess dose-limiting toxicity, determine maximum tolerated dose and recommended expansion dose(s), and assess safety of camidanlumab tesirine. Safety was assessed in all treated patients; antitumour activity was assessed in patients with one or more valid baseline and post-baseline disease assessment and in those who had disease progression or died after first study-drug dose. This trial was registered with ClinicalTrials.gov, NCT02432235.

Findings: Between Oct 5, 2015, and Jun 30, 2019, 133 patients were enrolled (77 [58%] had classical Hodgkin lymphoma and 56 (42%) had non-Hodgkin lymphoma). Median follow-up was 9·2 months (IQR 4·2-14·3). Eight dose-limiting toxicities were reported in five (6%) of 86 patients who were evaluable; the maximum tolerated dose was not reached. The recommended doses for expansion were 30 μg/kg and 45 μg/kg for patients with classical Hodgkin lymphoma and 80 μg/kg for patients with T-cell non-Hodgkin lymphomas. No recommended doses for expansion were defined for B-cell non-Hodgkin lymphomas. Grade 3 or worse treatment-emergent adverse events (reported by ≥10% of the 133 patients) included increased γ-glutamyltransferase (20 [15%] patients), maculopapular rash (16 [12%]), and anaemia (15 [11%]); 74 (56%) patients had serious treatment-emergent adverse events, most commonly pyrexia (16 [12%]). One (1%) fatal treatment-emergent adverse event and two (2%) deaths outside the reporting period were considered at least possibly study-drug related. Antitumoural activity was seen in classical Hodgkin and non-Hodgkin lymphomas; notably in all patients with classical Hodgkin lymphoma, the overall response was 71% (95% CI 60-81).

Interpretation: These results warrant evaluation of camidanlumab tesirine as a potential treatment option for relapsed or refractory lymphoma, particularly in patients with classical Hodgkin lymphoma.

Funding: ADC Therapeutics.

Conflict of interest statement

Declaration of interests MH reports grants from Takeda, Spectrum Pharmaceuticals, Astellas Pharma; and personal fees from Janssen, Incyte Corporation, ADC Therapeutics, Celgene Corporation, Pharmacyclics, Omeros, AbGenomics, Verastem, TeneoBio, Sanofi Genzyme, BeiGene, and AstraZeneca, outside the submitted work. GPC reports personal fees from ADC Therapeutics, during the study; personal fees from Roche, Takeda, Bristol-Myers Squibb, Merck Sharp & Dohme, Celleron, BeiGene, Gilead, Novartis, Celgene, and Amgen, outside the submitted work. PFC reports grants from ADC Therapeutics, during the the study; grants from Genentech, outside the submitted work; and personal fees from ADC Therapeutics, Kite Therapeutics, Amgen, Bayer, Verastem, Seattle Genetics, TG Therapeutics, and Celgene, outside the submitted work. FS reports personal fees from Imbrium Therapeutics, outside the submitted work. AS reports personal fees from ADC Therapeutics, during the study. AD reports grants from ADC Therapeutics; grants, personal fees and non-financial support from Roche/Genentech, Celgene; grants and personal fees from Gilead/Kite, Accerta Pharma/AstraZeneca, Karyopharma; and personal fees from Janssen, MorphoSys, and Takeda, during the conduct of the study. JR reports personal fees from Takeda, ADC Therapeutics, Bristol-Myers Squibb, Novartis, Kite Pharma, Seattle Genetics; and reports his spouse holds stocks in AstraZeneca, GlaxoSmithKline, and ADC Therapeutics, outside of the submitted work. TM reports personal fees and non-financial support from Amgen; non-financial support from Jazz, Pfizer, Bayer, Kyowa Kirin, and Celgene; personal fees and non-financial support from Gilead/Kite; and personal fees from Novartis, Daiichi Sankyo, Atara, Takeda, Janssen, Roche, and AstraZeneca, outside the submitted work. JMZ reports personal fees from Seattle Genetics, Kyowa Kirin, and Verastem, outside the submitted work. PF reports personal fees from ADC Therapeutics, Takeda, Roche, and Merck, outside the submitted work. KH reports personal fees from ADC Therapeutics, during the study. HGC reports personal fees from, employment with, and stocks in ADC Therapeutics, during the study. ShH reports personal fees from ADC Therapeutics, during the study. JB reports personal fees from, employment with, and stocks in ADC Therapeutics, during the study. JF reports personal fees from ADC Therapeutics, during the study. JW reports personal fees from, employment with, and stocks in ADC Therapeutics, during the study. StH reports grants and personal fees from ADC Therapeutics, Celgene, Kyowa Hakko Kirin, Seattle Genetics, Millennium/Takeda, Verastem and Secura Bio, Aileron, Forty Seven, Trillium Therapeutics, and Affimed; personal fees from C4 Therapeutics, Janssen, Kura Oncology, Myeloid Therapeutics, Vividion Therapeutics, Portola Pharmaceuticals, Acrotech, Astex, BeiGene, Miragen, Merck, Innate Pharma, Bristol-Myers Squibb, Mundipharma, and ONO Pharma; and grants from Daiichi Sankyo, outside the submitted work. AK declares no competing interests.

Copyright © 2021 Elsevier Ltd. All rights reserved.

Figures

Figure 1.. Trial profile

*One patient received an unplanned overdose of 300 μg/kg for the first dose but continued in the study with subsequent dosing, as planned, at 30 μg/kg. †Other reasons for treatment discontinuation in the cHL cohort included transition to transplant (n=7), decision by patient (n=2), per protocol temporary halt on the study (screening and dosing) (n=2), and treatment discontinuation due to GBS risk (n=1). ‡Other reasons for treatment discontinuation in the NHL cohort included decision by patient (n=2), lack of response (n=1), and partial clinical hold by the US FDA (n=1). §Other reasons for study discontinuation in the cHL cohort included study terminated by the Sponsor (n=8), toxicity (n=1), and transition to palliative care (n=1). ║Other reasons for study discontinuation in the NHL cohort included decision by Sponsor (n=3), toxicity (n=1), transition to palliative care (n=1), and partial clinical hold by the US FDA (n=1). #Progressive disease or death was not reported for these three patients. cHL, classical Hodgkin lymphoma; DLT, dose-limiting toxicity; FDA, Food and Drug Administration; GBS, Guillain–Barré syndrome; IHC, immunohistochemistry; NHL, non-Hodgkin lymphoma.

Figure 2.. Swimmer plot showing treatment responses for patients with (A) cHL and (B) NHL (efficacy analysis set)

Each bar represents one patient. *Only for censored patients who discontinued trial due to reasons other than progression or who go on to a different anticancer treatment. cHL, classical Hodgkin lymphoma; NHL, non-Hodgkin lymphoma

Figure 3.. Kaplan–Meier curves showing: A) median DoR and B) median PFS for all doses and for the 45 μg/kg dose cohort; and C) median OS for all doses in patients with cHL

Number of patients at risk includes patients who remained for observation at a specific time point, while censored numbers include patients censored cumulatively prior to that time point. cHL, classical Hodgkin lymphoma; DoR, duration of response; OS, overall survival; PFS, progression-free survival.