Penfluridol for Relapsed/Refractory Small-Cell Carcinoma of the Lung or Cervix: A Multicenter, Open-Label, Single-Arm Phase Ib/II Trial This study evaluates the safety and anti-tumor activity of oral penfluridol, a first-generation antipsychotic that pre-clinically inhibits small-cell carcinoma (SCC) growth via DRD2 blockade, metabolic reprogramming and apoptosis induction. After ≥2 prior systemic regimens, 33 adult patients (18-75 y) with measurable, metastatic or recurrent lung or cervical SCC will be enrolled across five Chinese centers. A 3+3 dose-escalation (Ib) will establish the recommended Phase II dose (RP2D); an expansion cohort (II) will examine objective response rate (ORR, RECIST 1.1). Secondary end-points include duration of response, progression-free survival, overall survival, safety and exploratory biomarkers. Key inclusion: ECOG 0-1, adequate organ function, no active brain metastases. Penfluridol is administered once weekly, dose-escalated from 20 mg to RP2D, continued until progression or intolerance. Patients receive free study drug, PET imaging and laboratory monitoring.
Patients aged 18 to 75 years, inclusive, regardless of gender.
Histologically or cytologically confirmed small-cell carcinoma of the lung or cervix that is not curable by surgery or radiochemotherapy.
Have received at least two prior systemic treatment regimens, including etoposide and platinum-based chemotherapy, and have experienced disease progression.
No receipt of investigational or approved cytotoxic chemotherapy within 28 days before enrollment; no receipt of alkylating agents within 42 days before enrollment; no receipt of investigational or approved targeted therapy within 28 days or 5 half-lives before enrollment (whichever is shorter, but not less than 14 days); no radiotherapy within 14 days before enrollment.
Histological diagnosis of squamous cell carcinoma, adenocarcinoma, or other non-small-cell types of lung or cervical cancer.
Concurrent enrollment in another clinical trial, unless it is an observational, non-interventional study or the follow-up period of an interventional study.
Known hypersensitivity to any component of penfluridol or similar compounds with comparable chemical or biological properties.
Prior exposure to penfluridol.
Single group
Penfluridol Monotherapy for Relapsed/Refractory Small-Cell Lung or Cervical Cancer
DrugIntervention: Penfluridol, an oral antipsychotic drug, is used as monotherapy. It targets DRD2, inhibits glycolysis, and induces apoptosis. Dosing Schedule: Phase Ib: 3+3 dose-escalation design. Initial dose 20 mg weekly, escalating to 40 mg, then 60 mg until recommended Phase II dose (RP2D) is determined based on 21-day DLT assessment. Phase II: Expansion cohort at RP2D to further evaluate safety and estimate ORR. Duration: Treatment continues until progression, unacceptable toxicity, withdrawal, or investigator decision. Monitoring: Regular AE/SAE monitoring using NCI-CTCAE v5.0. Assessments include weekly vital signs, biweekly blood tests, and ECGs every 2 weeks. Tumor response evaluated by RECIST 1.1 criteria with imaging every 2-3 cycles. Dose Modification: Adjustments made for EPS, QTc prolongation, and proteinuria. Rationale for Single-Arm Design: Chosen due to the ultra-rare patient population and lack of established comparators. Efficient for determining RP2D and ORR.
Recommended Phase II Dose (RP2D) of penfluridol [Phase Ib]
To determine the Recommended Phase II Dose (RP2D) of oral penfluridol for the treatment of relapsed/refractory small cell lung cancer and small cell cervical cancer.
Objective Response Rate (ORR) [Phase II]
To evaluate the antitumor activity of oral penfluridol at the RP2D as measured by the Objective Response Rate.
Incidence of Treatment-Emergent Adverse Events (TEAEs)
To evaluate the safety and tolerability profile of oral penfluridol.
Duration of Response (DOR)
To assess the durability of tumor responses.
Progression-Free Survival (PFS)
To assess disease control.
Overall Survival (OS)
To evaluate the overall survival benefit.
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