Sacituzumab Govitecan in Patients With Metastatic Castration-Resistant Prostate Cancer Progressing on Second Generation AR-Directed Therapy

Study Overview
=================
Brief Summary
-----------------
This study will investigate the safety and efficacy of Sacituzumab Govitecan in patients with metastatic castration-resistant prostate cancer progressing on second generation AR-directed therapy (e.g., enzalutamide, darolutamide, apalutamide and/or abiraterone).

Detailed Description
-----------------
This study will investigate the safety and efficacy of Sacituzumab Govitecan in patients with metastatic castration-resistant prostate cancer progressing on second generation AR-directed therapy. Patients who have progressed while on therapy with combination enzalutamide/abiraterone or ARN-509/abiraterone as part of ongoing clinical trials are allowed and may be enrolled in the study. To better understand the heterogeneity of response and in particular to identify patients likely to benefit, an extensive correlative biomarker program will be included to collect and analyze tumor tissue biopsies, circulating tumor cells (CTCs), and circulating tumor DNA (ctDNA). A validated predictive biomarker would benefit the individual patient by enabling him to be treated with a safe effective oral drug and avoid one from which he is unlikely to benefit. It is also essential for prostate cancer drug development because the increasing availability of more life-prolonging therapies is making it more difficult to prove a survival benefit for the next promising agent.

Official Title
-----------------
A Multi-arm, Phase 2 Study to Evaluate the Safety and Efficacy of Sacituzumab Govitecan in Patients With Metastatic Castration-Resistant Prostate Cancer Who Have Progressed on Second Generation AR-Directed Therapy

Conditions
-----------------
Prostate Cancer

Intervention / Treatment
-----------------
* Drug: Sacituzumab Govitecan


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion Criteria: Documented histological or cytological evidence of adenocarcinoma of the prostate Documented metastatic disease on bone scan and/or CT scans Currently receiving enzalutamide, darolutamide, apalutamide and/or abiraterone. Subjects who have received combination enzalutamide/abiraterone or combination apalutamide/abiraterone as part of clinical trials are allowed but will need to be receiving only a single agent ARSI at the time of study enrollment. Subjects who have received any other therapeutic investigational product directed towards the AR or androgen biosynthesis are allowed. Prior treatment with first-generation AR antagonists (i.e., bicalutamide, nilutamide, flutamide) before second generation AR-directed therapy is allowed. Demonstrated disease progression while on enzalutamide, darolutamide, apalutamide, and/or abiraterone. Progressive disease is defined by one or more of the following: A rise in PSA on two successive determinations at least one week apart and PSA level ≥2 ng/mL Soft-tissue progression defined by RECIST 1.1 Bone disease progression defined by PCWG2 with ≥2 new lesions on bone scan A minimum serum PSA level of ≥2 ng/mL that is rising based on the PCWG2 criteria ≥18 y ears of age Castrate levels of testosterone (<50 ng/dL [1.74 nmol/L]) Undergone orchiectomy, or have been on LHRH agonists or antagonists, for at least 3 months prior to study treatment start. Subjects on LHRH agonists/antagonists must remain on these agents for the duration of the study ECOG Performance Status of 0-1 Normal organ function with acceptable initial laboratory values within 30 days of study treatment start: WBC ≥3000/μl ANC ≥1000/μl Platelet count ≥100,000/μl HGB ≥9 g/dL Adequate hepatic function as evidenced by AST/ALT levels <3X the ULN and bilirubin levels of <2.0 mg/dl. Adequate renal function as evidenced by serum creatinine of <2.0 mg/dL Able to provide written informed consent, or have a legal representative provide written informed consent Subjects must have a previously-acquired biopsy from a metastatic site available Subjects must be willing and able (in the opinion of the treating physician) to undergo one research biopsy for the investigational component of this study Subjects who have partners of child-bearing potential must be willing to use at least two forms of effective birth control (one form must be a barrier method) during the treatment period and for 90 days after last dose of IMMU-132. Subjects must also agree to not donate sperm through 90 days following the last dose of IMMU-132. Exclusion Criteria: Received prior cytotoxic chemotherapy such as docetaxel, cabazitaxel or platinum chemotherapy for metastatic prostate cancer, castration sensitive or castration resistant, within two years prior to study entry. Neoadjuvant chemotherapy is allowed. Completed sipuleucel-T (Provenge ®) treatment within 30 days of study treatment start. Received any therapeutic investigational agent within 2 weeks of study treatment start. Received palliative radiotherapy within 4 weeks of study treatment start. Received herbal products or alternative therapies that may decrease PSA levels or that may have hormonal anti-prostate cancer activity (e.g., saw palmetto, PC-SPES, PC-HOPE, St. John's wort, selenium supplements, grape seed extract, etc.) within 4 weeks of study treatment start or plans to initiate treatment with these products/alternative therapies during the entire duration of the study. Active CNS metastases from prostate cancer. Subjects with treated epidural disease are eligible to enroll. Subjects with treated brain metastases can be included as long as >4 weeks have elapsed since last treatment (radiotherapy or surgery) for brain metastases, the subject is neurologically and radiographically stable, and is not receiving corticosteroids for brain metastases. Subjects with untreated brain metastases are excluded. Brain imaging (CT or MRI) is not required at baseline if brain metastases are not clinically suspected. A history within the last 3 years of another invasive malignancy (excluding non-melanoma skin cancer). A QTcF interval of >470 msec on the initial Screening ECG; if the Screening ECG QTcF interval is >470 msec, then it may be repeated two more times, and if the mean QTcF of the 3 ECGs is ≤470 msec, the subject may be enrolled. A history of clinically significant cardiac arrhythmias including ventricular tachycardia, ventricular fibrillation, torsades de pointes and second degree or third degree atrioventricular heart block without a permanent pacemaker in place. Subjects with resolved or rate-controlled atrial fibrillation/atrial flutter are allowed. NYHA Class III or IV congestive heart failure, unstable angina, myocardial infarction/acute coronary syndrome within the preceding 6 months. Diabetes mellitus with more than 2 episodes of diabetic ketoacidosis in the 12 months preceding study treatment start. Inadequately controlled hypertension (defined as blood pressure >150mmHg systolic and/or >100 mmHg diastolic despite antihypertensive medication) or any history of hypertensive crisis or hypertensive encephalopathy. History of loss of consciousness or transient ischemic attack within 12 months before study treatment start. Known active HIV, Hepatitis B, or Hepatitis C infections. Any other medical, psychiatric, or social condition, including substance abuse, which in the opinion of the Investigator would preclude safe participation in the study.

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
Male

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Sacituzumab Govitecan Treatment<br>Subjects enrolled in this study will receive Sacituzumab Govitecan in addition to their single agent ARSI as treatment for Castrate-Resistant Prostate Cancer. Dose will be calculated per protocol in milligrams based on the subject's body weight at the beginning of each cycle or more frequently if weight changes >10%. Subjects will be treated on days 1 and 8 in a 21-day cycle, minimum 3 cycles. | Drug: Sacituzumab Govitecan<br>* Sacituzumab Govitecan is a novel Antibody Drug Conjugate (ADC) based on a humanized anti-Trop-2 antibody (hRS7) conjugated to SN-38 payload.<br>* Other names: IMMU-132;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| PSA response rate | Subjects who achieve ≥50% PSA decline at or before 9 weeks of therapy with Sacituzumab Govitecan (IMMU-132) are considered to have responded. PSA responses will be analyzed by descriptive statistics and summarized in tabular format (frequency tables). The overall PSA response rate will be reported along with the corresponding 95% confidence interval which will be constructed using the Wilson score method. | up to 9 weeks | 
| 6-Month Median Progression Free Survival | Proportion of participants remaining alive and progression free (using PCWG2 criteria) 6 months from time of starting treatment as estimated by the Kaplan-Meier method. | 6 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression Free Survival Rate | The probability distribution of Progression Free Survival (PFS) will be estimated using the Kaplan-Meier method. The median will be estimated from this distribution. Subjects who have not died or progressed (using PCWG2 criteria) will be censored at the date of last assessment. | Up to 2 years from start of treatment | 
| Radiologic Response Rate | The number of participants with progressive disease, stable disease, partial response and complete response will be summarized in tabular format. The overall response rate will be reported along with the corresponding 95% confidence interval which will be constructed using the Wilson score method. | up to 2 years from start of treatment | 
| Median Overall Survival | Overall Survival (OS) is the duration from start of treatment until death from any cause. The probability distribution of OS will be estimated using the Kaplan-Meier method. The median will be estimated from this distribution. Subjects who have not died will be censored at the date of last contact. | Up to 2 years from start of treatment | 
| Toxicity rates (Grade 2, Grade 3, Grade 4, Grade ≥ 2, Grade ≥ 3, etc.) | Toxicities will be summarized by type and severity in tabular format. Toxicity rates (Grade 2, Grade 3, Grade 4, Grade ≥ 2, Grade ≥ 3, etc.) will be calculated and reported along the corresponding 95% confidence intervals. The 95% confidence intervals will be constructed using the Wilson score method. | Up to 9 weeks from start of treatment | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
Prostate