1204TiP - Iadademstat in combination with paclitaxel in relapsed/refractory small cell lung carcinoma (SCLC) and extrapulmonary high grade neuroendocrine carcinoma (NEC)

Background

Patients (pts) with extensive-stage (ES) SCLC or extra-pulmonary grade 3 (G3) NEC rapidly develop progressive disease after 1^st -line cytotoxic chemotherapy, and efficacious 2^nd -line treatment options are needed. Lysine Specific Demethylase 1 (LSD1, aka KDM1A) is involved in repressing transcription by removing methyl groups from mono- and di-methylated lysine 4 of histone 3, epigenetic hallmarks commonly associated with actively transcribed genes. LSD1 over-expression is associated with tumor progression and worse prognosis, and its inhibition reduces cancer cell growth, migration, and invasion. The epigenetic drug iadademstat (aka ORY-1001 or iada) is a highly potent and selective LSD1 inhibitor (LSD1i) in phase 2 clinical development for malignant indications. Iada and other LSD1is are effective in in vitro and in vivo models of SCLC by preventing INSM1 recruitment of LSD1 which results in NOTCH signaling activation, reduced NE differentiation and tumor growth inhibition. Additionally, LSD1is have been implicated in reversing chemoresistance, synergizing with paclitaxel, and enhancing immunostimulatory responses by increasing MHC-Class I expression, IFN-Type I responses and T-cell infiltration and activity.

Trial design

NCT05420636 is a multi-center, non-randomized phase II study to treat up to 42 pts with iada (150 mg oral, 5d on-2d off every week) and paclitaxel (80 mg/m2 IV weekly) in 21 day cycles. Eligibility includes adult pts with metastatic/unresectable SCLC (cohort 1) or extra pulmonary G3 NEC or metastatic/unresectable prostate or bladder cancer with G3 NE or small cell component (cohort 2), who have received 1 to 3 prior lines of therapy and progressed on or after platinum-based chemotherapy. Pts must have measurable disease, normal organ, and marrow function, stable brain mets, ECOG status ≤1 and not have received prior taxanes for metastatic disease. The primary endpoint is ORR per RECIST 1.1; secondary endpoints include rate of ≥ grade 3 toxicities, PFS, OS and DoR. Exploratory endpoints include host inflammatory cytokine and immune profile, and epigenomic and genomic analysis of tumor and peripheral blood samples.

Clinical trial identification

NCT05420636.

Editorial acknowledgement

Legal entity responsible for the study

Fox Chase Cancer Center.

Funding

Oryzon.

Disclosure

N. Vijayvergia: Non-Financial Interests, Institutional, Local PI: BMS, ITM; Financial Interests, Personal, Advisory Board: Taiho, ITM; Non-Financial Interests, Institutional, Principal Investigator: Oryzon, Puma; Non-Financial Interests, Personal, Advisory Role: Rayze Bio. P. Ghatalia: Non-Financial Interests, Institutional, Research Funding: BMS, Oryzon, Merck. D. Faller: Financial Interests, Personal, Full or part-time Employment: Oryzon. A. Limon: Financial Interests, Personal, Full or part-time Employment: Oryzon. H.P. Soares: Financial Interests, Personal, Advisory Board: Tersera, Ipsen, AstraZeneca, Novartis, ITM. J. whetstine: Financial Interests, Institutional, Research Funding: Oryzon, Salarius Pharma; Financial Interests, Personal, Advisory Board: QSonica, Vyne Therapeutics, Daiichi Sankyo, Lily Asia Ventures. H. Borghaei: Financial Interests, Personal, Advisory Board: BMS, Genentech, Eli-Lilly, Merck, EMD-serono, AstraZeneca, Novartis, Genmab, Regeneron, Amgen, Takeda, PharmaMar, Jazz Pharma, Mirati, Daiichi, Guardant, Natera, Oncocyte, BeiGene, iTeo, Boehringer Ingelheim, Puma, BerGenbio, Janssen; Financial Interests, Personal, Other, Training discussion: Pfizer; Financial Interests, Personal, Other, DSMB: Novartis; Financial Interests, Institutional, Other, Clinical trial support: BMS, Amgen; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory role: Sonnetbio; Financial Interests, Personal, Stocks/Shares, Options for scientific advisory board: Nucleai, Inspira (Rgenix); Financial Interests, Institutional, Trial Chair, Investigator initiated trial support: BMS; Financial Interests, Institutional, Coordinating PI, Investigator initiated trial support: Amgen, Lilly; Financial Interests, Personal and Institutional, Trial Chair, Chair steering committee: Miratti; Financial Interests, Personal and Institutional, Steering Committee Member: Amgen, AstraZeneca; Financial Interests, Personal, Steering Committee Member, Also trial support: BMS; Other, Other, DSMB: Novartis, Takeda, Incyte, Springworks. All other authors have declared no conflicts of interest.