SKYBRIDGE study: An open-label, multicenter, dose escalation and dose expansion phase I/II study of PT217 as a monotherapy and in combination with an atezolizumab, in patients with SCLC, LCNEC and EP-NEC known to express DLL3

BackgroundNeuroendocrine carcinomas (NECs) are poorly differentiated cancers with a high proliferation rate and median survival of 7.7 months. They can be divided into two groups: (i) lung, comprising ∼90% of cases, including small cell lung cancer (SCLC) and large cell neuroendocrine carcinoma of the lung (LCNEC), and (ii) extra-pulmonary NECs (EP-NEC), comprising ∼10% of all NECs. Immune checkpoint inhibitors have been introduced to platinum-based frontline treatment for SCLC. Despite the initial impressive responses in frontline treatment, patients develop resistance to treatment and deteriorate rapidly. High mortality rates and a lack of response durability or alternative treatment options highlight a significant unmet medical need. One unifying feature of all NECs is the consistent expression of delta-like protein 3 (DLL3) selectively on cancer cells. High DLL3 expression has been reported to negatively correlate with survival in NEC and may be a prognostic biomarker in advanced NEC patients. Targeting the highly expressed DLL3 with an immune-oncology mechanism is an attractive approach.Trial designPT217 is an IgG1 based anti-DLL3/anti-CD47 bispecific antibody that can target tumor cells expressing DLL3 and/or overexpressing CD47, subsequently leading to immune cell-mediated cancer cell death. The SKYBRIDGE study is a Dose Escalation and a multi cohort study for monotherapy Expansion and Immunotherapy combination to generate a safety and efficacy signal for further drug development. Cohorts include PT217 monotherapy and combinations with Atezolizumab in frontline and relapsed SCLC, LCNEC and EP-NEC. Two frontline cohorts, one in SCLC and one in LCNEC and EP-NEC, will add PT217 as a maintenance therapy following chemotherapy induction, with the goal of extending progression free survival. In addition, a cohort in frontline SCLC will combine PT217 with Atezolizumab as a maintenance therapy after completion of platinum-based chemotherapy and Atezolizumab induction. The study is adaptive and based upon emerging data an increase in sample size and additional cohorts may be added.Clinical trial identificationNCT05652686.Legal entity responsible for the studyPhanes Therapeutics, Inc.FundingPhanes Therapeutics, Inc.DisclosureA.I. Spira: Financial Interests, Personal, Other, Consulting or Advisory Role: Incyte, Mirati Therapeutics, Gritstone Oncology, Jazz Pharmaceuticals, Janssen Research & Development, Mersana, Gritstone Bio, Daiichi Sankyo/AstraZeneca, Array Biopharma, Blueprint Medicines; Financial Interests, Personal, Other, Consulting or Advisory Role / Honoraria: Amgen, Novartis, Takeda, AstraZeneca/MedImmune, Merck, Bristol Myers Squibb; Financial Interests, Personal, Other, Honoraria: CytomX Therapeutics, Janssen Oncology, Bayer; Financial Interests, Institutional, Officer, CEO: NEXT Oncology Virginia; Financial Interests, Personal, Stocks/Shares: Eli Lilly; Financial Interests, Institutional, Local PI: LAM Therapeutics, Roche, AstraZeneca, Boehringer Ingelheim, Astellas Pharma, MedImmune, Novartis, Newlink Genetics, Incyte, AbbVie, Ignyta, Trovagene, Takeda, Macrogenics, CytomX Therapeutics, Astex Pharmaceuticals, Bristol Myers Squibb, Loxo, Arch Therapeutics, Gritstone, Plexxikon, Amgen, Daiichi Sankyo, ADCT, Janssen Oncology, Mirati Therapeutics, Rubius, Synthekine, Mersana, Blueprint Medicines, Kezar, Revolution Med. All other authors have declared no conflicts of interest.