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)
- Trial ID
- 2023-505898-32-00
- Protocol
- CELC-G-201
- Sponsor
- Celcuity Inc.
Trial statistics
Diseases & Conditions
Objectives
This Phase 1/2 study evaluates gedatolisib in combination with darolutamide in patients with metastatic castration-resistant prostate cancer (mCRPC). The primary objectives are divided by study phase. In Phase 1, the primary objectives are to assess the safety and tolerability of gedatolisib in combination with darolutamide in mCRPC and to compare the Bayesian Optimal Interval (BOIN) utility score between the two treatment arms. In Phase 2, the primary objective is to assess the antitumor activity of gedatolisib in combination with darolutamide as demonstrated by radiographic progression-free survival (rPFS). These objectives are clinically relevant for establishing the optimal dosing regimen and evaluating the therapeutic potential of this combination therapy in a patient population with limited treatment options.
The secondary objectives include:
• Phase 1: To evaluate the pharmacokinetics (PK) of gedatolisib in combination with darolutamide
• Phase 2: To assess the preliminary efficacy of gedatolisib in combination with darolutamide in mCRPC
• Phase 2: To assess the safety and tolerability of gedatolisib in combination with darolutamide in mCRPC
• Phase 2: To evaluate the pharmacokinetics of gedatolisib in combination with darolutamide
Participants
The clinical trial enrolled a total of **14 participants**, all of whom were **adult males** aged **18 years and older**. The study population consisted of patients with **metastatic castration-resistant prostate cancer (mCRPC)** who had histologically or cytologically confirmed **adenocarcinoma of the prostate** without a small cell component and with less than 10% neuroendocrine type cells. Participants were required to have developed progression of metastases following surgical castration or during medical **androgen ablation therapy**, with metastatic disease identified by conventional imaging such as **computed tomography (CT)**, **magnetic resonance imaging (MRI)**, or bone scintigraphy. All subjects demonstrated progressive mCRPC based on **Response Evaluation Criteria in Solid Tumors (RECIST) v1.1** with modifications specified in **Prostate Cancer Working Group 3 (PCWG3)** criteria, including prostate-specific antigen progression, soft-tissue progression, or progression of bone disease. Eligible participants had an **Eastern Cooperative Oncology Group (ECOG) performance status** score of 1 or less and a life expectancy of at least 3 months. Key selection criteria required that subjects had experienced progression on or after treatment with one **next generation androgen receptor signaling inhibitor** for metastatic disease and had completed prior treatment with an androgen receptor inhibitor at least 4 weeks before the first dose of study drug. Participants were required to have adequate bone marrow, hepatic, renal, and coagulation function, and to be at least 2 weeks beyond treatment with targeted therapy or major surgery.
Plans and Procedures
This is a **Phase 1/2**, **open-label**, **randomized**, dose finding and dose expansion study evaluating **gedatolisib** in combination with **darolutamide** in patients with **metastatic castration-resistant prostate cancer**. The trial is designed to assess the safety, tolerability, and antitumor activity of this combination therapy. The study consists of two distinct phases: Phase 1 focuses on dose finding to determine the optimal dose of gedatolisib when combined with darolutamide by assessing safety and tolerability and comparing the **Bayesian Optimal Interval** utility score between treatment arms, while Phase 2 aims to evaluate the antitumor activity of the selected dose combination as measured by **radiographic progression-free survival**. The trial involves the administration of gedatolisib as a **powder for infusion** via **infusion**, darolutamide as a **film-coated tablet** via **oral use**, and **dexamethasone** as **soluble tablets** or **oral solution** via **oral use** serving as an auxiliary medicinal product.
The primary endpoints for Phase 1 include the type, incidence, severity, seriousness, and relationship to study medications of **adverse events** and laboratory abnormalities graded according to **National Cancer Institute Common Terminology Criteria for Adverse Events** version 5.0, the BOIN utility score incorporating pre-defined toxicity criteria and 6-month radiographic progression-free survival binary outcomes, and the incidence of **dose-limiting toxicities**. For Phase 2, the primary endpoint is the radiographic progression-free survival rate at 6 months as measured by the **Kaplan-Meier** method and assessed based on **Response Evaluation Criteria in Solid Tumors** version 1.1 with modifications as specified in **Prostate Cancer Working Group 3** criteria. Secondary endpoints for Phase 1 include **pharmacokinetic** parameters such as **maximum observed concentration**, **area under the plasma concentration-time curve** from time 0 to 24 hours, and area under the plasma concentration-time curve from 0 to last measurable concentration. Phase 2 secondary endpoints encompass radiographic progression-free survival rates at 9 and 12 months and overall radiographic progression-free survival, **overall response rate**, **duration of response**, **clinical benefit rate**, **disease control rate**, **overall survival** rate at 18 and 24 months, adverse events assessment, and pharmacokinetic parameters estimated by population pharmacokinetic analysis.
Eligible participants include adult males aged 18 years or older with histologically or cytologically confirmed diagnosis of **adenocarcinoma** of the prostate without a small cell component and with less than 10% neuroendocrine type cells. Subjects must have metastatic castration-resistant prostate cancer with metastatic disease identified by conventional imaging such as **computed tomography**, **magnetic resonance imaging**, or **technetium 99m methyl diphosphonate bone scintigraphy**. Progressive metastatic castration-resistant prostate cancer must be demonstrated based on Response Evaluation Criteria in Solid Tumors version 1.1 with modifications as specified in Prostate Cancer Working Group 3 criteria, defined by **prostate-specific antigen** progression, soft-tissue progression, or progression of bone disease. Participants must have experienced progression on or after treatment with one next generation **androgen receptor signaling inhibitor** for metastatic disease and must have completed prior treatment with an androgen receptor inhibitor at least 4 weeks before the first dose of study drug or at least 2 weeks if the terminal androgen receptor inhibitor half-life is less than 24 hours. Subjects with known **BRCA mutation** positive status should have received **PARP inhibitor** therapy before trial entry unless contraindicated or unavailable. Additional inclusion criteria require continued primary androgen deprivation with **luteinizing hormone-releasing hormone** analog if bilateral **orchiectomy** has not been performed, **Eastern Cooperative Oncology Group** performance status score of 1 or less, life expectancy of at least 3 months, adequate bone marrow, hepatic, renal and coagulation function, and willingness to comply with protocol-specified schedules and contraception requirements for the duration of the active treatment period and for at least 12 weeks after the last dose of study treatment.
The estimated recruitment start date for the trial is February 1, 2024, with an estimated end date of February 26, 2029, indicating an overall trial duration of approximately 5 years. The length of participant involvement will depend on individual response to treatment and disease progression, with subjects remaining in the study until disease progression, unacceptable toxicity, withdrawal of consent, or other protocol-specified discontinuation criteria are met. Conditions that may lead to early termination from the study include the occurrence of dose-limiting toxicities, unacceptable adverse events, disease progression as defined by protocol criteria, participant withdrawal of consent, investigator decision based on safety concerns, or non-compliance with study procedures. Throughout the study, participants will undergo scheduled visits for safety assessments, efficacy evaluations, and pharmacokinetic sampling as specified in the protocol to monitor treatment response and tolerability.
Treatment
The experimental treatment **Gedatolisib** (sponsor product code PF-05212384) is supplied as a **powder for infusion** and administered via **intravenous infusion**. This investigational agent contains gedatolisib as the active substance of chemical origin. The product is manufactured by Celcuity Inc. and represents one of the test medicinal products in this Phase 1/2 dose finding and dose expansion study in **metastatic castration-resistant prostate cancer**.
The experimental treatment **Darolutamide** (BAY 1841788, also known as ODM-201) is supplied as a **film-coated tablet** containing 300 mg of darolutamide as the active substance of chemical origin. The product is administered via **oral use** and is manufactured by Bayer AG. This investigational agent serves as a test medicinal product in combination with gedatolisib.
**Dexamethasone** is utilized as an auxiliary medicinal product in this clinical trial and is available in multiple pharmaceutical formulations. Dexamethasone 2 mg **soluble tablets** manufactured by Glenmark Pharmaceuticals Europe Limited (marketing authorization number PL 25258/0161) are administered via **oral use**. Additionally, dexamethasone is available as an **oral solution** for oral administration. The active substance dexamethasone is of chemical origin and is classified under ATC code H02AB02.
The Phase 1 dose finding component of the study aims to assess the safety and tolerability of gedatolisib in combination with darolutamide and to compare the Bayesian Optimal Interval utility score between treatment arms. The Phase 2 dose expansion component evaluates the antitumor activity of the combination as demonstrated by **radiographic progression-free survival**.
Efficacy
Efficacy will be assessed through distinct parameters for Phase 1 and Phase 2 of the trial. In Phase 1, the Bayesian Optimal Interval (BOIN) utility score will be evaluated, which incorporates pre-defined toxicity criteria and 6-month radiographic progression-free survival (rPFS) binary outcomes. The primary efficacy endpoint for Phase 2 is the rPFS rate at 6 months, measured by the Kaplan-Meier method and assessed based on Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 with modifications as specified in Prostate Cancer Working Group 3 (PCWG3) criteria.
Secondary efficacy assessments in Phase 2 include rPFS rates at 9 and 12 months and overall rPFS. Overall response rate (ORR) will be determined as the percentage of subjects achieving an objective response, defined as complete response (CR) or partial response (PR), based on RECIST version 1.1 with PCWG3 modifications. Duration of response (DOR) will be measured as the time from initial response assessment to death or first documented disease progression. Additional efficacy parameters include clinical benefit rate (CBR), defined as the percentage of subjects with CR, PR, or stable disease (SD) lasting 24 weeks or longer, and disease control rate (DCR), defined as the percentage of subjects with CR, PR, or SD. Overall survival (OS) rates will be evaluated at 18 and 24 months.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Adult males ≥18 years of age
- Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate without a small cell component and with <10% neuroendocrine type cells
- Subjects must have metastatic castration-resistant prostate cancer (mCRPC; i.e., developed progression of metastases following surgical castration or during medical androgen ablation therapy)
- 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.
- 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: a. 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. b. 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. c. Progression of bone disease (measurable disease) or 2 or more new bone lesions by bone scan.
- Continued primary androgen deprivation with luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist) if subject has not undergone bilateral orchiectomy
- Eastern Cooperative Oncology Group (ECOG) performance status score ≤1
- Life expectancy of at least 3 months
- Subjects must meet the following prior therapy criteria: a. Progression on or after treatment with one next generation androgen receptor signaling inhibitor for metastatic disease (e.g., abiraterone, enzalutamide, apalutamide, darolutamide) b. Subjects with known BRCA mutation positive status should have recevied PARP inhibitor therapy before trial entry (unless contraindicated or unavailable)
- Completion of prior treatment with an androgen receptor inhibitor (ARi) ≥4 weeks before first dose of study drug or ≥2 weeks if the therminal ARi half-life is <24 hours
- 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)
- Adequate bone marrow, hepatic, renal and coagulation function
- Must be willing and able to comply with protocol-specified schedules of assessments, treatment plans, laboratory tests, and other study procedures
- Must agree to follow the contraception requirements for the duration of the active treatment period and for at least 12 weeks after the last dose of study treatment
- Ability to understand the investigational nature of the study and sign the informed consent form
Exclusion Criteria
- 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
- Adenocarcinoma of the prostate with a small cell component, or with ≥10% neuroendocrine type cells.
- Prior treatment with a phosphoinositide 3-kinase (PI3K) inhibitor, a protein kinase B (AKT) inhibitor, or a mechanistic target of rapamycin (mTOR) inhibitor.
- Prior treatment with chemotherapy or radiopharmaceutical therapy for mCRPC. a. Prior docetaxel in combination with ADT and ARi (darolutamide or abiraterone) for castration sensitive prostate cancer (CSPC) is allowed.
- Subjects with uncontrolled type 1 or type 2 diabetes.
- Known active human immunodeficiency virus (HIV) infection. a. Subjects with well-controlled HIV infection may be allowed if CD4+ T-cell (CD4+) counts >350 cells/μL. b. Subjects without a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infections may be eligible for enrollment.
- Known history/positive serology for acute or chronic hepatitis B virus (HBV) infection (unless immune due to vaccination or resolved natural infection): a. Positive test for antibodies to hepatitis B core antigens (anti-HBc), and negative test for antibodies to hepatitis B surface antigens (anti-HBs). b. Positive for hepatitis B surface antigen (HBsAg).
- Known seropositive for, or active infection with, hepatitis C virus (HCV). a. Subjects with positive hepatitis C virus antibodies are eligible with negative polymerase chain reaction (PCR) test for HCV.
- Known and untreated, or active, brain or leptomeningeal metastases. a. 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.
- History of clinically significant cardiovascular abnormalities such as: a. Congestive heart failure (New York Heart Association [NYHA] classification ≥II (NYHA 1994) within 6 months of study entry. b. Myocardial infarction within 12 months of study entry. c. History of any uncontrolled (or untreated) clinically significant cardiac arrhythmias, (e.g., ventricular tachycardia), complete left bundle branch block, high grade atrioventricular (AV) block (e.g., bifascicular block, Mobitz type II and third-degree AV block), supraventricular, nodal arrhythmias, or conduction abnormality in the previous 12 months. d. Uncontrolled hypertension defined by systolic blood pressure (SBP) ≥160 mmHg and/or diastolic blood pressure (DBP) ≥100 mmHg, with or without antihypertensive medication (initiation or adjustment of antihypertensive medication[s] is allowed prior to screening). e. Long QT syndrome, family history of idiopathic sudden death or congenital long QT syndrome, or any of the following: i. Risk factors for Torsades de Pointes (TdP) including uncorrected hypokalemia or hypomagnesemia or history of clinically significant/symptomatic bradycardia. ii. On screening, inability to determine the corrected QT interval using Fridericia’s formula (QTcF) on the electrocardiogram (ECG; i.e., unreadable or not interpretable) or QTcF >470 msec (determined by mean of triplicate ECGs at screening).
- Gastrointestinal tract disease resulting in an inability to absorb oral medication as well as history of inflammatory bowel disease.
- Unable to swallow oral medication tablets/capsules.
- On more than 10 mg of prednisolone/prednisone (or equivalent) per day.
- Known hypersensitivity to the study drugs or their components.
- History of drug-induced pneumonitis or interstitial lung disease.
- Current uncontrolled medical conditions that, in the opinion of the Investigator, could limit a subject’s ability to undertake study therapy or comply with study requirements.
- Current participation in another interventional clinical trial. a. Subjects must agree not to participate in another clinical trial (other than observational trials) at any time during participation in CELC-G-201.
- Subjects with rapidly progressive disease who are eligible for standard chemotherapy are excluded from enrollment.
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 France | Recruiting | 01 Feb 2024 | 15 |
 Spain | Recruiting | 01 Feb 2024 | 25 |
Sites & Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
DEXAMETHASONE | Other | — | ORAL USE | — | — | SUB07017MIG |
Dexamethasone 2 mg soluble tablets | Other | SOLUBLE TABLETS | ORAL USE | — | — | PRD3258606 |
BAY 1841788 | Test | FILM-COATED TABLET | ORAL USE | — | — | PRD1849573 |
Gedatolisib | Test | POWDER FOR INFUSION | INFUSION | — | — | PRD9979206 |