FL118 for Treating Patients With Advanced Pancreatic Ductal Adenocarcinoma

First-in-Human Phase I Trial of FL118 in Patients With Advanced Pancreatic Ductal Adenocarcinoma

This phase I trial tests the safety, side effects, and best dose of FL118 in treating patients with pancreatic ductal adenocarcinoma that may have spread from where it first started to nearby tissue, lymph nodes, or distant parts of the body (advanced). FL118 is a small anti-tumor molecule that inhibits the expression of multiple cancer-associated anti-apoptotic proteins. An anti-apoptotic protein is a protein that interferes with or inhibits cell death. In adults, apoptosis is used to rid the body of cells that have been damaged beyond repair. Apoptosis also plays a role in preventing cancer. If apoptosis is for some reason prevented, it can lead to uncontrolled cell production that can subsequently develop into a tumor. FL118 has been shown to inhibit or block the proteins that prevent damaged/mutated (genetically changed) cells from dying, and, by doing so, prevent the growth of cancerous cells and tumor development.

Study Overview

• Status: Withdrawn
• Conditions: Stage II Pancreatic Cancer AJCC v8; Stage III Pancreatic Cancer AJCC v8; Stage IV Pancreatic Cancer AJCC v8; Metastatic Pancreatic Ductal Adenocarcinoma; Locally Advanced Pancreatic Ductal Adenocarcinoma; Advanced Pancreatic Ductal Adenocarcinoma; Unresectable Pancreatic Ductal Adenocarcinoma; Refractory Pancreatic Ductal Adenocarcinoma
• Intervention / Treatment: Procedure: Biospecimen Collection; Procedure: Magnetic Resonance Imaging; Procedure: Computed Tomography; Procedure: Biopsy; Drug: DDX5 Degrader FL118

Detailed Description

PRIMARY OBJECTIVES:

I. To establish the safety, schedule, and dosing of DDX5 degrader FL118 (FL118) in patients with advanced pancreatic ductal adenocarcinoma (PDAC).

II. To determine the pharmacokinetics (PK) of FL118 in patients with advanced PDAC.

SECONDARY OBJECTIVES:

I. To determine the pharmacodynamics (PD) of FL118 in patients with advanced PDAC.

II. To determine the preliminary antineoplastic efficacy of FL118 in patients with advanced PDAC.

EXPLORATORY OBJECTIVES:

I. To evaluate biomarkers predictive of response or resistance. II. Evaluate changes in the tumor microenvironment. III. To determine the significance of somatic and germline DNA damage repair mutations as predictive biomarkers of antineoplastic activity.

OUTLINE: This is a dose-escalation study of FL118 followed by a dose-expansion study.

Patients receive FL118 orally (PO) on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples and computed tomography (CT) or magnetic resonance imaging (MRI) throughout the trial. Patients may optionally undergo biopsy at screening and on study.

After completion of study treatment, patients are followed up at 30 days and then every 3 months for up to 12 months.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Age ≥ 18 years old
• Have a histologically or cytologically confirmed advanced PDAC (locally advanced/unresectable or metastatic for part A (dose escalation) and metastatic for part B (dose expansion)
• Progression on or intolerance to 1st line therapy for advanced disease. Note that completion of adjuvant or neoadjuvant chemotherapy within 6 months from relapsed disease is considered one line of therapy for locally advanced/unresectable or metastatic disease
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Have a life expectancy of greater than 3 months
• Have measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria present
• Patient willing to undergo tumor biopsy at baseline and on treatment if there is a lesion that can safely be biopsied based on investigator assessment. If this is not feasible, adequate archival tumor tissue must be available
• Absolute neutrophil count (ANC): ≥ 1,500/mL
• Platelets: ≥ 100,000/mL
• Hemoglobin: ≥ 9 g/dL
• Creatinine clearance ≥ 60 mL/min (per Cockroft-Gault equation)
• Total bilirubin: ≤ 1.5 X upper limit of normal (ULN) or, direct bilirubin ≤ ULN for subjects with total bilirubin levels > 1.5 ULN
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]): ≤ 2.5 X ULN or, ≤ 5 X ULN for subjects with liver metastases
• Albumin: ≥ 3 gm/dL
• For females of reproductive potential (those who have not been surgically sterilized or have not been free from menses for > 1 year): use of highly effective contraception for at least 1 month prior to screening and agree to use such a method during study participation and, for an additional 6 months after the end of FL118 oral administration
• For males of reproductive potential: use of condoms or other methods to ensure effective contraception with partner during the study participation and for an additional 3 months after the end of FL118 oral administration
• Be willing and able to comply with all study procedures and, availability for the duration of the study
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• Has a major surgical procedure within 4 weeks prior to the planned first day of study drug dosing
• Received a prior treatment intended for antitumor effect (medication, surgery, radiotherapy, etc.) within 2 weeks prior to the planned first day of study drug dosing (or patient who received mitomycin C or nitrosourea within 6 weeks prior to the planned first day of study drug dosing)
• Has an active infection requiring systemic therapy
• Has a history of organ transplantation
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the screening visit through the trial period after the last dose of trial treatment
• Has congestive heart failure (class III or IV New York Heart Association), acute coronary syndrome, acute cerebrovascular episode, acute peripheral vascular disease, or clinically significant cardiac arrhythmia within 6 months prior to the planned first day of study drug dosing
• Has clinically significant venous thromboembolic event (VTE), defined as lower extremity deep venous thrombosis or pulmonary embolism, within the past 3 months. Patients who are on a stable anticoagulant dose for VTE prophylaxis or treatment for at least 14 days are allowed to participate
• Bowel obstruction or perforation within the past 3 months
• Refractory malignant ascites or pleural effusions (requiring weekly para- or thoracentesis or indwelling catheter for palliation). Patients with less frequent/as needed para- or thoracentesis are allowed to participate
• Has difficulty taking oral medications, a digestive malabsorptive condition other than pancreatic exocrine insufficiency controlled with pancreatic enzyme replacement, or concurrent disease that significantly affects gastrointestinal function
• Any condition which in the investigator's opinion deems the participant an unsuitable candidate to receive study drug

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (FL118); Patients receive FL118 PO on days 1, 8, and 15 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo collection of blood samples and CT or MRI throughout the trial. Patients may optionally undergo biopsy at screening and on study.

Procedure: Biospecimen Collection; Undergo collection of blood samples; Other Names: Biological Sample Collection; Biospecimen Collected; Specimen Collection; Procedure: Magnetic Resonance Imaging; Undergo MRI; Other Names: MRI; Magnetic Resonance; Magnetic Resonance Imaging Scan; Medical Imaging, Magnetic Resonance / Nuclear Magnetic Resonance; MR; MR Imaging; MRI Scan; NMR Imaging; NMRI; Nuclear Magnetic Resonance Imaging; sMRI; Magnetic resonance imaging (procedure); MRIs; Structural MRI; Procedure: Computed Tomography; Undergo CT; Other Names: CT; CAT; CAT Scan; Computed Axial Tomography; Computerized Axial Tomography; Computerized Tomography; CT Scan; tomography; Computerized axial tomography (procedure); Procedure: Biopsy; Undergo biopsy; Other Names: Bx; BIOPSY_TYPE; Drug: DDX5 Degrader FL118; Given PO; Other Names: FL 118; FL-118; FL118

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events	Toxicity and adverse events will be assessed using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0.	Up to 30 days
Maximum tolerated dose (MTD)	The MTD will be determined from the observed dose limiting toxicities per cohort using an accelerated dose-escalation design.	4 weeks from administation
Recommended phase 2 dose	The recommended phase 2 dose will be determined based on the MTD (or highest dose administered if the MTD is not reached), the pharmacokinetic/pharmacodynamic modeling, and overall clinical safety and efficacy data.	4 weeks from administration
Half life	PK parameters of half-life area	On days 1, 2, 15, and 16 of cycle 1 in dose-escalation phase
Maximum plasma concentration	PK parameters of maximum plasma concentration	On days 1, 2, 15, and 16 of cycle 1 in dose-escalation phase
Area under the curve	PK parameter area under the curve	On days 1, 2, 15, and 16 of cycle 1 in dose-escalation phase
CL/F	apparent clearance of the analyte in the plasma	On days 1, 2, 15, and 16 of cycle 1 in dose-escalation phase

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Pharmacodynamics parameters	Will be collected at baseline and day 23	At baseline and cycle 2 day 23
Overall response rate	Will be assessed use a two-stage, single-arm Simon minimax design.	Up to 12 months
Disease control rate	The disease control (complete response + partial response + stable disease) will be summarized using frequencies and relative frequencies. The disease control rate will be estimated with a 95% credible region obtained by Jeffrey's prior method.	Up to 12 months
Progression-free survival	Will be summarized using standard Kaplan-Meier methods, where estimates of median survival will be obtained with 95% confidence intervals.	From treatment until disease progression, death from disease, or last follow up, assessed up to 12 months
Overall survival	Will be summarized using standard Kaplan-Meier methods, where estimates of median survival will be obtained with 95% confidence intervals.	From treatment until death due to any cause or last follow up, assessed up to 12 months

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Investigators: Principal Investigator: Christos Fountzilas, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Estimated): October 1, 2025
• Primary Completion (Estimated): October 1, 2027
• Study Completion (Estimated): October 1, 2027

Study Registration Dates

• First Submitted: December 6, 2023
• First Submitted That Met QC Criteria: January 4, 2024
• First Posted (Actual): January 16, 2024

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: January 15, 2025
• Last Verified: January 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Endocrine System Diseases; Neoplasms by Site; Neoplasms; Neoplasms by Histologic Type; Digestive System Neoplasms; Digestive System Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Neoplasms, Glandular and Epithelial; Carcinoma; Pancreatic Neoplasms; Adenocarcinoma
• Other Study ID Numbers: I 3555023 (Other Identifier: Roswell Park Cancer Institute); NCI-2023-08681 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes