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)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Celcuity Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male

Therapeutic area

Diseases [C] - Male Urogenital Diseases [C12]

Trial duration

28 Feb 2024 → ongoing

Decision date (initial)

2024-01-29

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Funding sources

Celcuity Inc.

External identifiers

EU CT number

2023-505898-32-00

ClinicalTrials.gov

NCT06190899

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Safety, Dose response, Therapy, Pharmacokinetic

Phase 1 Dose finding
• To assess the safety and tolerability of gedatolisib in combination with darolutamide in metastatic castration-resistant prostate cancer (mCRPC)
• To compare the Bayesian Optimal Interval (BOIN) utility score between the 2 arms
Phase 2 Dose Expansion
• To assess the antitumor activity of gedatolisib in combination with darolutamide as demonstrated by radiographic progression-free survival (rPFS)

Secondary objectives 5

1. Phase 1: To evaluate the pharmacokinetics (PK) of gedatolisib in combination with darolutamide
2. Phase 2: To assess the preliminary efficacy of gedatolisib in combination with darolutamide
3. Phase 2: To assess the safety and tolerability of gedatolisib in combination with darolutamide in mCPRC
4. Phase 2: To evaluate the PK of gedatolisib in combination with darolutamide
5. Phase 2: To assess preliminary efficacy of gedatolisib in combination with darolutamide in mCRPC

Conditions and MedDRA coding

Metastasic Castration-Resistant Prostate Cancer (mCRPC)

Study design 3 periods

Regulatory references

Scientific advice from competent authorities

European Medicines Agency, Food And Drug Administration

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 15

1. 1. Adult males ≥18 years of age
2. 2. Histologically or cytologically confirmed diagnosis of adenocarcinoma of the prostate without a small cell component and with <10% neuroendocrine type cells
3. 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. 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. 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: 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.
6. 6. Continued primary androgen deprivation with luteinizing hormone-releasing hormone (LHRH) analog (agonist or antagonist) if subject has not undergone bilateral orchiectomy
7. 7. Eastern Cooperative Oncology Group (ECOG) performance status score ≤1
8. 8. Life expectancy of at least 3 months
9. 9. 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)
10. 10. 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
11. 11. 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)
12. 12. Adequate bone marrow, hepatic, renal and coagulation function
13. 13. Must be willing and able to comply with protocol-specified schedules of assessments, treatment plans, laboratory tests, and other study procedures
14. 14. 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
15. 15. Ability to understand the investigational nature of the study and sign the informed consent form

Exclusion criteria 18

1. 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. 2. Adenocarcinoma of the prostate with a small cell component, or with ≥10% neuroendocrine type cells.
3. 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. 4. 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.
5. 5. Subjects with uncontrolled type 1 or type 2 diabetes.
6. 6. 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.
7. 7. 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).
8. 8. 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.
9. 9. 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.
10. 10. 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).
11. 11. Gastrointestinal tract disease resulting in an inability to absorb oral medication as well as history of inflammatory bowel disease.
12. 12. Unable to swallow oral medication tablets/capsules.
13. 13. On more than 10 mg of prednisolone/prednisone (or equivalent) per day.
14. 14. Known hypersensitivity to the study drugs or their components.
15. 15. History of drug-induced pneumonitis or interstitial lung disease.
16. 16. 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.
17. 17. 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.
18. 18. Subjects with rapidly progressive disease who are eligible for standard chemotherapy are excluded from enrollment.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 4

1. Phase 1: 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
2. Phase 1: BOIN utility score, which includes pre-defined toxicity criteria and 6-month radiographic progression-free survival (rPFS) binary outcomes
3. Phase 1: Incidence of dose-limiting toxicities (DLTs) and AEs graded according to NCI CTCAE v5.0
4. Phase 2: rPFS 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

Secondary endpoints 9

1. Phase 1: Gedatolisib maximum observed concentration (Cmax), area under the plasma concentration-time curve from time 0 to 24 hours (AUC0-24; Cycle 2 only), and area under the plasma concentration-time curve from 0 to last measurable concentration (AUC0-t)
2. Phase 2: rPFS rates at 9 and 12 months and overall rPFS
3. Phase 2: Overall response rate (ORR): percentage of subjects who achieved an objective response (OR) based on RECIST v1.1 with modifications as specified in PCWG3 criteria for all efficacy endpoints (complete response [CR] or partial response [PR])
4. Phase 2: Duration of response (DOR): time from the assessment of initial response (PR or better) to death or first documented disease progression, whichever occurs first
5. Phase 2: Clinical benefit rate (CBR): percentage of subjects with CR, PR, or stable disease (SD) ≥24 weeks
6. Phase 2: Disease control rate (DCR): percentage of subjects with CR, PR, or SD
7. Phase 2: Overall Survival (OS) rate at 18 and 24 months
8. Phase 2: Type, incidence, severity (as graded by NCI CTCAE v5.0), seriousness, and relationship to study medications of AEs and any laboratory abnormalities
9. Phase 2: PK parameters to be estimated by population PK analysis

Investigational products

Investigational medicinal products (IMPs), comparators, placebo, auxiliary

Test 2

Auxiliary 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Celcuity Inc.

Sponsor organisation

Celcuity Inc.

Address

2800 Campus Drive Suite 140

City

Minneapolis

Postcode

55441-2630

Country

United States

Scientific contact point

Organisation

Celcuity Inc.

Contact name

Celcuity Inc.

Public contact point

Organisation

Celcuity Inc.

Contact name

Celcuity Inc.

Third parties 8

Locations

2 EU/EEA countries · 9 investigational sites

By country

Investigational sites

Country notifications

Trial-start, recruitment-start, end and early-termination notifications submitted per Member State

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 16 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

7 submissions — initial application plus substantial / non-substantial modifications