FDA Awards Orphan Drug Designation to PT217 for Neuroendocrine Carcinoma

US FDA

The FDA has granted orphan drug designation to PT217 for use as a potential therapeutic option in patients with neuroendocrine carcinoma, according to an announcement by drug developer, Phanes Therapeutics, Inc.¹

The safety, tolerability, and preliminary efficacy of the first-in-class, bispecific antibody designed to target DLL3 and CD47 is being examined in patients with DLL3-expressing neuroendocrine carcinomas as part of the ongoing phase 1/2 SKYBRIDGE study (NCT05652686).²

Previously, PT217 was granted fast track designation from the FDA for patients with extensive-stage small cell lung cancer (SCLC) with disease progression after platinum-based chemotherapy with or without a checkpoint inhibitor,³ and an orphan drug designation for those with SCLC.⁴ Moreover, it was announced earlier this year that the drug developer, Phanes Therapeutics, Inc., entered into a clinical supply agreement with Roche to examine the agent in combination with atezolizumab (Tecentriq).¹

The SKYBRIDGE study is comprised of 2 parts and is currently recruiting patients with histologically or cytologically confirmed unresectable advanced or metastatic SCLC, large cell neuroendocrine carcinoma of the lung, or extrapulmonary neuroendocrine carcinoma who previously received standard-of-care therapy and progressed after treatment or whom treatment was not available or not tolerated.² Notably, those with mixed histologies are able to participate only if the neuroendocrine carcinoma or small tumor cells component is predominant and accounts for at least half of the overall tumor tissue.

Patients need to be at least 18 years of age, have measurable disease by RECIST 1.1 criteria, have an ECOG performance status of 0 or 1, a life expectancy of more than 3 months, acceptable organ function, and be able to provide a formalin-fixed, paraffin-embedded tumor tissue sample to be evaluated for DLL3 expression and other key biomarkers. All acute adverse effects experienced from prior treatments must have resolved to grade 1 or less by National Cancer Institute Common Terminology Criteria for Adverse Events v5.0. If patients experienced alopecia or neuropathy, their effects must have resolved to baseline status.

Patients with autoimmune disease requiring systemic treatment within the past year, a condition calling for systemic treatment with steroids or other immunosuppressive drugs within 2 weeks before study treatment, or who experienced grade 3 or higher immune-related toxicities, will be excluded.

Other exclusion criteria include uncontrolled pleural effusion, pericardial effusion, or ascites in need of drainage procedures; untreated brain or central nervous system metastases; a known concurrent malignancy that is progressing or needed treatment for active disease within the past 2 years; exposure to an investigational drug within 4 weeks before start of study treatment; prior exposure to T-cell engagers, CAR T-cell therapy, natural killer (NK) cell–engagers, or therapies targeting DLL3 or CD47; impaired cardiac function or significant diseases; and uncontrolled hypertension; among others.

The study utilizes a standard 3+3 dose-escalation design. PT217 will be evaluated at a starting dose of 0.2 mg/kg given once weekly. The agent will also be evaluated at the following dose levels: 0.6 mg/kg once weekly, 2 mg/kg once weekly, 6 mg/kg once weekly, and 12 mg/kg once weekly.

The dose-expansion cohorts will include patients with SCLC, large cell neuroendocrine carcinoma of the lung, and extrapulmonary neuroendocrine carcinoma; 50% of patients will need to have SCLC and large cell neuroendocrine carcinoma. Safety and pharmacokinetic (PK) data from part A of the trial will be utilized to inform the dose level examined in cohort 1. A different dose level from cohort 1 will be examined in cohort 2; this dose can be higher or lower than what is under evaluation in cohort 1 but cannot exceed the maximum tolerated dose (MTD) of the agent.

The primary outcome measures of the research will be to determine the dose-limiting toxicities, the MTD, and the recommended phase 2 dose of PT217, as well as to examine the safety of the agent. Secondary outcome measures will include objective response rate, disease control rate, progression-free survival, overall survival at 6 months, and other PK measures. Investigators will also assess pharmacodynamic markers of the agent’s biological activity and pre-treatment DLL3 expression via immunohistochemistry as it correlates with primary end points.

References

1. Phanes Therapeutics’ PT217 receives orphan drug designation for neuroendocrine carcinoma from the FDA. News release. Phanes Therapeutics, Inc. August 16, 2024. Accessed August 19, 2024. https://www.phanesthera.com/news/phanes-therapeutics-pt217-receives-orphan-drug-designation-for-neuroendocrine-carcinoma-from-the-fda/
2. A study of PT217 in patients with neuroendocrine carcinomas expressing DLL3 (the SKYBRIDGE study). ClinicalTrials.gov. Updated June 7, 2024. Accessed August 19, 2024. https://clinicaltrials.gov/study/NCT05652686
3. Phanes Therapeutics’ PT217 granted fast track designation by the FDA. News release. Phanes Therapeutics. April 8, 2024. Accessed August 19, 2024. https://www.phanesthera.com/news/phanes-therapeutics-pt217-granted-fast-track-designation-by-the-fda/
4. Phanes Therapeutics' PT217 receives orphan drug designation for small cell lung cancer from the FDA. News release. Phanes Therapeutics. June 21, 2022. Accessed August 19, 2024. https://www.phanesthera.com/news/phanes-therapeutics-pt217-receives-orphan-drug-designation-for-small-cell-lung-cancer-from-the-fda/