A phase I, open-label, dose-escalation study to evaluate the safety, tolerability, pharmacokinetics, and antitumor activity of ADCT-601 in patients with advanced solid tumours

Abstract

Background: AXL, a member of the TAM family of receptor tyrosine kinases, is overexpressed in various cancers and overexpression is linked to metastasis, poor survival, and drug resistance. ADCT-601, an AXL-targeted antibody-drug conjugate, has shown potent and durable antitumor activity in preclinical human cancer models via AXL-mediated delivery of a pyrrolobenzodiazepine dimer warhead. Here we report interim data from a phase 1 clinical trial of ADCT-601 (NCT03700294; ADC Therapeutics) in patients (pt) with selected advanced solid tumors. Methods: This phase 1 dose-escalation and dose-expansion study is currently enrolling pts aged ≥18 years with relapsed or refractory tumors. The primary objective is to characterize the safety and tolerability of ADCT-601 and to identify the recommended dose for future studies. Pts receive intravenous infusions of ADCT-601 once every 3 weeks starting at 50 µg/kg, with subsequent cohorts enrolled at escalating doses according to a standard 3 + 3 design. Results: As of data cutoff (April 12, 2019), 8 pts were treated at doses of 50–100 µg/kg. The median (range) age was 70 (46–77) years. Pathological subtypes enrolled are colorectal cancer (4 pts) and chondrosarcoma, head and neck carcinoma, ovarian carcinoma, and esophageal carcinoma (1 pt each). Six pts had received ≥4 previous lines of therapy. One pt treated at 100 µg/kg had a dose-limiting toxicity of grade 3 hematuria, which resulted in hospitalization and was possibly related to ADCT-601. The most common treatment-emergent adverse events, regardless of relationship to ADCT-601, were abdominal pain, erythema, fatigue, peripheral edema, and maculopapular rash (each occurring in 2 pts). The following 4 pts had undergone disease assessment at data cutoff: 1 pt (chondrosarcoma) had a partial response, 1 pt (head and neck carcinoma) had stable disease, and 2 pts (ovarian carcinoma and esophageal carcinoma) had progressive disease. Conclusions: This study is continuing to enroll pts and will identify the recommended dose of ADCT-601. Updated results, including pharmacokinetic data, will be presented at the meeting. Clinical trial identification: NIH (https://clinicaltrials.gov/ct2/show/NCT03700294) October 9, 2018. Editorial acknowledgement: Editorial support was provided by Sindhu Doppalapudi and Becky Salisbury at Fishawack Communications Ltd, funded by ADC Therapeutics Ltd. Legal entity responsible for the study: ADC Therapeutics. Funding: ADC Therapeutics. Disclosure: A.W. Tolcher: Advisory / Consultancy, Research grant / Funding (institution): AbbVie; Advisory / Consultancy, Research grant / Funding (institution): ADC Therapeutics; Advisory / Consultancy, Research grant / Funding (institution): Adagene; Advisory / Consultancy: Agenus; Advisory / Consultancy: AroBioTX; Advisory / Consultancy, Research grant / Funding (institution): Ascentage; Advisory / Consultancy: Aximmune; Advisory / Consultancy: Bayer; Advisory / Consultancy: BioInvent; Advisory / Consultancy, Research grant / Funding (institution): Birdie; Advisory / Consultancy: Boston Bio; Advisory / Consultancy: EMD Serono; Advisory / Consultancy: Forbius; Advisory / Consultancy: HBM Partners; Advisory / Consultancy: Ignyta; Advisory / Consultancy: Immunome; Advisory / Consultancy: Immunomet; Advisory / Consultancy: Jazz; Advisory / Consultancy: Mekanistic; Advisory / Consultancy: Nanobiotix; Advisory / Consultancy: NBE Therapeutics; Advisory / Consultancy: Nuvalent; Advisory / Consultancy: Pelican; Advisory / Consultancy, Research grant / Funding (institution): Pfizer; Advisory / Consultancy: Pierre Fabre; Advisory / Consultancy: Ridgeway; Advisory / Consultancy: Scitemex; Advisory / Consultancy: Sesen; Advisory / Consultancy: Seattle Genetics; Advisory / Consultancy: Sunshine Guojian; Advisory / Consultancy, Research grant / Funding (institution): Symphogen; Advisory / Consultancy: Syneos; Research grant / Funding (institution): Aminex; Research grant / Funding (institution): Asana; Research grant / Funding (institution): Arrys; Research grant / Funding (institution): CStone; Research grant / Funding (institution): Deciphera; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Inhibrx; Research grant / Funding (institution): Innate; Research grant / Funding (institution): Kiromie; Research grant / Funding (institution): Mersana; Research grant / Funding (institution): NatureWise; Research grant / Funding (institution): NextCure; Research grant / Funding (institution): NittoBiopharma; Research grant / Funding (institution): Pieris; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Tizone; Research grant / Funding (institution): Zymeworks. G. Falchook: Licensing / Royalties: Wolters Kluwer; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: Fujifilm; Advisory / Consultancy, Research grant / Funding (institution), Travel / Accommodation / Expenses: EMD Serono; Travel / Accommodation / Expenses: Bristol-Myers Squibb; Research grant / Funding (institution), Travel / Accommodation / Expenses: Millennium; Speaker Bureau / Expert testimony: Total Health Conferencing; Research grant / Funding (institution): 3-V Biosciences; Research grant / Funding (institution): Abbvie; Research grant / Funding (institution): ADC Therapeutics; Research grant / Funding (institution): Aileron; Research grant / Funding (institution): American Society of Clinical Oncology; Research grant / Funding (institution): Amgen; Research grant / Funding (institution): ARMO; Research grant / Funding (institution): AstraZeneca; Research grant / Funding (institution): BeiGene; Research grant / Funding (institution): Bioatla; Research grant / Funding (institution): Biothera; Research grant / Funding (institution): Celldex; Research grant / Funding (institution): Celgene; Research grant / Funding (institution): Ciclomed; Research grant / Funding (institution): Curegenix; Research grant / Funding (institution): Curis; Research grant / Funding (institution): DelMar; Research grant / Funding (institution): eFFECTOR; Research grant / Funding (institution): Eli Lilly; Research grant / Funding (institution): Exelixis; Research grant / Funding (institution): Genmab; Research grant / Funding (institution): GlaxoSmithKline; Research grant / Funding (institution): Hutchinson MediPharma; Research grant / Funding (institution): Ignyta; Research grant / Funding (institution): Incyte; Research grant / Funding (institution): Jacobio; Research grant / Funding (institution): Jounce; Research grant / Funding (institution): Kolltan; Research grant / Funding (institution): Loxo; Research grant / Funding (institution): MedImmune; Research grant / Funding (institution): Merck; Research grant / Funding (institution): miRNA Therapeutics; Research grant / Funding (institution): National Institutes of Health; Research grant / Funding (institution): Novartis; Research grant / Funding (institution): OncoMed; Research grant / Funding (institution): Oncothyreon; Research grant / Funding (institution): Precision Oncology; Research grant / Funding (institution): Regeneron; Research grant / Funding (institution): Rgenix; Research grant / Funding (institution): Strategia; Research grant / Funding (institution): Syndax; Research grant / Funding (institution): Taiho; Research grant / Funding (institution): Takeda; Research grant / Funding (institution): Tarveda; Research grant / Funding (institution): Tesaro; Research grant / Funding (institution): Tocagen; Research grant / Funding (institution): U.T. MD Anderson Cancer Center; Research grant / Funding (institution): Vegenics. J.C. 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