NCT07206563

Penfluridol for Relapsed/Refractory Small Cell Cancers

Penfluridol for Relapsed/Refractory Small Cell Lung Carcinoma and Small Cell Cervical Cancer: An Open-Label, Multicenter, Single-Arm Ib/II Trial

• Status: Not Yet Recruiting
• Phase: Phase 1 / Phase 2
• Study type: Interventional
• Enrollment: 33 (estimated)
• Sponsor: Union Hospital, Tongji Medical College, Huazhong University of Science and Technology · Academic / Other
• Sex: All
• Age: 18 Years – 75 Years
• Healthy volunteers: Not accepted

Summary

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.

Detailed description

Rationale and Preclinical Justification Small-cell carcinoma of the lung (SCLC) and cervix (SCCC) represent aggressive malignancies with a paucity of effective therapeutic options upon relapse, leading to dismal survival outcomes. To address this unmet need, a high-throughput drug screening was conducted utilizing patient-derived organoid (PDO) models of SCLC and SCCC. This screening identified penfluridol, a first-generation antipsychotic drug with a long-established human safety profile, as a potent inhibitor of small-cell carcinoma growth. Its anti-tumor efficacy is mechanistically attributed to dual pathways: 1) antagonism of dopamine receptor D2 (DRD2), a target implicated in cancer stem cell maintenance and proliferation, and 2) induction of metabolic stress via inhibition of glycolysis, leading to AMPK/FOXO3a-mediated apoptosis. Notably, penfluridol's inherent ability to penetrate the blood-brain-barrier positions it as a potential therapeutic candidate for addressing the common site of metastasis in SCLC. This study aims to clinically reposition penfluridol based on this compelling preclinical evidence. Study Design and Technical Considerations This is an open-label, multicenter, seamless Phase Ib/II trial. The design integrates a dose-finding phase followed by an efficacy expansion phase to efficiently evaluate both safety and preliminary activity. Phase Ib (Dose Escalation): Utilizes a standard 3+3 design to determine the Recommended Phase II Dose (RP2D). The starting dose is 20 mg orally once weekly, with planned escalation to 40 mg and 60 mg. The RP2D will be defined as the highest dose at which ≤1 of 6 patients experiences a dose-limiting toxicity (DLT) during the first 21-day cycle. Pharmacokinetic profiling will be performed to characterize exposure at each dose level. Phase II (Expansion Cohort): Aims to estimate the objective response rate (ORR) at the RP2D. The study employs a Simon's two-stage minimax design to test the null hypothesis that the true ORR is ≤10% against an alternative of ≥30%, with 90% power and a one-sided alpha of 0.05. This design allows for early termination for futility. Biomarker Strategy: The protocol incorporates a comprehensive exploratory biomarker plan. This includes correlative analyses of DRD2 expression in archival tumor tissue, serial monitoring of cell-free DNA (cfDNA) for dynamic changes in tumor burden, and assessment of metabolic response via FDG-PET imaging to elucidate potential biomarkers of response and resistance. Safety Monitoring Focus Given penfluridol's known safety profile from psychiatric use, the protocol institutes enhanced, protocol-specified monitoring for specific risks. This includes regular assessments for extrapyramidal symptoms (using the RSESE scale) and rigorous cardiac monitoring (serial ECGs for QTc interval assessment) beyond standard CTCAE reporting. An independent Data Monitoring Committee (IDMC) will review accumulating safety and efficacy data.

Conditions

• Small Cell Carcinoma
• Small Cell Carcinoma of Lung
• Small Cell Lung Cancer ( SCLC )
• Small Cell Cervical Carcinoma

Interventions

Type	Name	Description
DRUG	Penfluridol Monotherapy for Relapsed/Refractory Small-Cell Lung or Cervical Cancer	Intervention: 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.

Timeline

• Start date: 2025-10-01
• Primary completion: 2027-10-01
• Completion: 2028-10-01
• First posted: 2025-10-03
• Last updated: 2025-10-03

Locations

1 site across 1 country: China