Gedatolisib in Combination With Darolutamide in Metastatic Castration-Resistant Prostate Cancer

A Phase 1/2, Open-Label, Randomized, Dose Finding and Dose Expansion Study of Gedatolisib in Combination With Darolutamide in Metastatic Castration-Resistant Prostate Cancer (mCRPC)

This is a Phase 1/2, open-label, randomized, dose finding and dose expansion study to evaluate the safety, preliminary efficacy, and PK of gedatolisib in combination with darolutamide in subjects with mCRPC.

Study Overview

• Status: Recruiting
• Conditions: Prostate Cancer; Prostatic Neoplasms, Castration-Resistant; Genital Diseases, Male; Prostatic Disease; mCRPC (Metastatic Castration-resistant Prostate Cancer); Urogenital Diseases, Male
• Intervention / Treatment: Drug: Gedatolisib; Drug: Darolutamide

Detailed Description

This is a Phase 1/2, open-label, randomized, dose finding and dose expansion study to evaluate the safety, preliminary efficacy, and pharmacokinetics of gedatolisib, a pan-PI3K/mTOR inhibitor, in combination with darolutamide, a next-generation androgen receptor inhibitor, in patients with metastatic castration-resistant prostate cancer following progression on a next-generation androgen receptor inhibitor. The aim of the Phase 1 portion of the study is to evaluate dose limiting toxicities and to determine the recommended Phase 2 dose. The aim of the Phase 2 portion of the study is to further assess the safety and preliminary efficacy of the drug combination.

• Study Type: Interventional
• Enrollment (Estimated): 54
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Genelle Brower, RN; Phone Number: 844-310-3900; Email: gbrower@celcuity.com

Study Locations

• France
  • Clermont-Ferrand, France, 63011
    • Not yet recruiting
    • Centre Jean Perrin
  • Marseille, France, 13009
    • Not yet recruiting
    • Institut Paoli-Calmettes
  • Nice, France, 06100
    • Not yet recruiting
    • Centre Antoine Lacassagne
  • Villejuif, France, 94805
    • Not yet recruiting
    • Institut Gustave Roussy
• Spain
  • Barcelona, Spain, 08036
    • Recruiting
    • Hospital Clinic Barcelona
  • Barcelona, Spain, 08908
    • Recruiting
    • Institut Catala d'Oncologia
  • Madrid, Spain, 28007
    • Not yet recruiting
    • Hospital General Universitario Gregorio Maranon
  • Madrid, Spain, 28045
    • Recruiting
    • Hospital 12 de Octubre
  • Valencia, Spain, 46009
    • Not yet recruiting
    • Instituto Valenciano de Oncologia
• United Kingdom
  • Cambridge, United Kingdom, CB20QQ
    • Not yet recruiting
    • Cambridge University Hospitals NHS Foundation Trust - Addenbrooke's Hospita
  • Southampton, United Kingdom, SO16 6YD
    • Not yet recruiting
    • University Hospital Southampton NHS Foundation Trust - Southampton General Hospital
  • Sutton, United Kingdom, SM25PT
    • Recruiting
    • Royal Marsden NHS Foundation Trust
• United States
  • Michigan
    • Detroit, Michigan, United States, 48201
      • Recruiting
      • Barbara Ann Karmanos Cancer Institute

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria

1. Adult males ≥18 years of age
2. Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate without a small cell component and with <10% neuroendocrine type cells
3. Subjects must have metastatic castration-resistant prostate cancer (mCRPC; i.e., developed progression of metastases following surgical castration or during medical androgen ablation therapy)
4. Metastatic disease identified by conventional imaging: computed tomography (CT), magnetic resonance imaging (MRI), or technetium 99m-methyl diphosphonate (99mTc-MDP) bone scintigraphy. Measurable and non-measurable disease are allowed, but metastases visible only on prostate-specific membrane antigen (PSMA) positron emission tomography (PET) will not be allowed for eligibility purposes.

5. Progressive mCRPC based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with modifications as specified in Prostate Cancer Working Group 3 (PCWG3) criteria as defined by at least one of the following criteria:

   5.1. Prostate-specific antigen (PSA) progression defined as a minimum of 2 rising PSA levels with a minimum of a 1-week interval between each determination. A minimum PSA of 1.0 ng/mL is required for study entry.

   5.2. Soft-tissue progression defined as an increase ≥20% in the sum of the longest diameter (LD) of all target lesions based on the smallest sum LD since treatment started or the appearance of one or more new lesions. 5.3. Progression of bone disease (measurable disease) or 2 or more new bone lesions by bone scan.

6. Continued primary androgen deprivation with luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist) if the subject has not undergone bilateral orchiectomy
7. Eastern Cooperative Oncology Group (ECOG) performance status score ≤1
8. Progression during treatment with one next-generation androgen receptor signaling inhibitor for metastatic disease (e.g., abiraterone, enzalutamide, apalutamide, darolutamide)
9. Completion of prior treatment with an androgen receptor inhibitor (ARi) ≥4 weeks before the first dose of the study drug
10. At least 2 weeks beyond treatment with a targeted therapy or major surgery and at least 3 weeks beyond any other systemic anticancer therapy and/or radiation therapy, and resolution of all toxicities related to prior therapies or surgical procedures to baseline (except alopecia, Grade 1 peripheral neuropathy)
11. Adequate bone marrow, hepatic, renal and coagulation function

Exclusion Criteria

1. History of malignancies other than adequately treated non-melanoma skin cancer or other solid tumors curatively treated with no evidence of disease for ≥3 years
2. Adenocarcinoma of the prostate with a small cell component, and with ≥10% neuroendocrine type cells
3. Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (AKT) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor
4. Prior treatment with chemotherapy or radiopharmaceutical therapy for mCRPC (except prior chemotherapy plus ADT for castration-sensitive disease, including docetaxel plus darolutamide).
5. Subjects with uncontrolled type 1 or type 2 diabetes

9. Known and untreated, or active, brain or leptomeningeal metastases. Subjects with previously treated central nervous system (CNS) metastases may be enrolled in the study if they meet the following criteria: do not require supportive therapy with steroids; do not have seizures and do not exhibit uncontrolled neurological symptoms; stable disease confirmed by radiographic assessment within at least 4 weeks prior to randomization 10. History of clinically significant cardiovascular abnormalities 11. Gastrointestinal tract disease resulting in an inability to absorb oral medication as well as history of inflammatory bowel disease 12. Unable to swallow oral medication tablets/capsules

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

3

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase 1 Arm 1; Arm 1 - 120 mg of gedatolisib (administered once weekly for 3 weeks on/1 week off) in combination with darolutamide 600 mg (two 300 mg tablets) orally administered twice daily (equivalent to a total daily dose of 1200 mg on Days 1-28 of each cycle)	Drug: Gedatolisib; Gedatolisib is a potent reversible inhibitor that selectively targets all Class I PI3K isoforms and mTOR.; Drug: Darolutamide; Darolutamide is a novel androgen receptor inhibitor that has been studied and received approval for treatment of patients with nonmetastatic CRPC and in metastatic hormone-sensitive prostate cancer.; Other Names: NUBEQA
Experimental: Phase 1 Arm 2; Arm 2 - 180 mg of gedatolisib (administered once weekly for 3 weeks on/1 week off) in combination with darolutamide 600 mg (two 300 mg tablets) orally administered twice daily (equivalent to a total daily dose of 1200 mg on Days 1-28 of each cycle)	Drug: Gedatolisib; Gedatolisib is a potent reversible inhibitor that selectively targets all Class I PI3K isoforms and mTOR.; Drug: Darolutamide; Darolutamide is a novel androgen receptor inhibitor that has been studied and received approval for treatment of patients with nonmetastatic CRPC and in metastatic hormone-sensitive prostate cancer.; Other Names: NUBEQA
Experimental: Phase 2; The recommended Phase 2 dose (RP2D) of gedatolisib (administered once weekly for 3 weeks on/1 week off) in combination with darolutamide 600 mg (two 300 mg tablets) orally administered twice daily (equivalent to a total daily dose of 1200 mg on Days 1-28 of each cycle)	Drug: Gedatolisib; Gedatolisib is a potent reversible inhibitor that selectively targets all Class I PI3K isoforms and mTOR.; Drug: Darolutamide; Darolutamide is a novel androgen receptor inhibitor that has been studied and received approval for treatment of patients with nonmetastatic CRPC and in metastatic hormone-sensitive prostate cancer.; Other Names: NUBEQA

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1: Assessment of the safety and tolerability of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC)	Type, incidence, severity (as graded by National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0), seriousness, and relationship to study medications of adverse events (AEs) and any laboratory abnormalities	Cycle 1, Day 1 to end of safety follow up (each cycle is 28 days and safety follow up will continue until 30 days after last dose of study medication)
Phase 1: Identification of the recommended Phase 2 dose (RP2D) of gedatolisib in combination with darolutamide in mCRPC	Incidence of dose-limiting toxicities (DLTs) and AEs graded according to NCI CTCAE v5.0	Through Phase I completion, an average of 1 year.
Phase 2: Assessment of the antitumor activity of gedatolisib in combination with darolutamide in each arm as demonstrated by radiographic progression-free survival (rPFS) by arm	Radiographic progression-free survival rate at 6 months as measured by the Kaplan-Meier (K-M) method and assessed based on Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 with modifications as specified in Prostate Cancer Working Group 3 (PCWG3) criteria	6 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the preliminary efficacy of gedatolisib in combination with darolutamide by arm	Radiographic progression-free survival rates at 9 and 12 months and overall rPFS Overall Survival (OS) rate at 18 and 24 months	9 and 12 months post Cycle 1 Day 1 (each cycle is 28 days); 18 and 24 months post Cycle 1 Day 1 (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: Celcuity Inc
• Investigators: Study Director: Nadene Zack, MS, Celcuity Inc

Study record dates

Study Major Dates

• Study Start (Actual): January 1, 2024
• Primary Completion (Estimated): November 1, 2025
• Study Completion (Estimated): November 1, 2027

Study Registration Dates

• First Submitted: December 13, 2023
• First Submitted That Met QC Criteria: January 2, 2024
• First Posted (Actual): January 5, 2024

Study Record Updates

• Last Update Posted (Actual): April 9, 2024
• Last Update Submitted That Met QC Criteria: April 5, 2024
• Last Verified: January 1, 2024

More Information

Terms related to this study

• Keywords: Prostate Cancer; PI3K; Protein Kinase Inhibitors; Prostatic Neoplasms, Castration-Resistant; Prostatic Disease; Genital Diseases, Male; Darolutamide; mCRPC (metastatic castration-resistant prostate cancer); Gedatolisib; Urogenital Diseases, Male
• Additional Relevant MeSH Terms: Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Genital Neoplasms, Male; Prostatic Neoplasms; Prostatic Neoplasms, Castration-Resistant; Prostatic Diseases; Urogenital Diseases; Male Urogenital Diseases; Genital Diseases; Genital Diseases, Male; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protein Kinase Inhibitors; Gedatolisib
• Other Study ID Numbers: CELC-G-201

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No