A Study of Sasanlimab in People With Non-muscle Invasive Bladder Cancer

Study Overview
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Brief Summary
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The purpose of this study is to learn about the safety and effects of the study medicine (sasanlimab) in people with non-muscle invasive bladder cancer. This study is seeking participants whose bladder cancer is still in early stages, has not spread outside of the bladder, has been removed with surgery, and is high risk (Part A) or was previously treated with BCG (Bacillus Calmette Guerin), a standard treatment for bladder cancer (Part B). In Part A (enrollment closed), each participant was assigned to one of three study treatment groups. One group is given sasanlimab and BCG at the study clinic. The second group is given sasanlimab and BCG at the study clinic. This group will receive BCG for the first six weeks only. The third group is given BCG only and will not receive sasanlimab. In Part B of the study, each new participant will be assigned to a study treatment group based on the type of their bladder tumor. - Both groups will be given sasanlimab at the study clinic. On August 31, 2022, the Sponsor announced the discontinuation of enrollment to Part B. The decision to discontinue enrollment to Part B was not made for safety reasons.

Detailed Description
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CREST: Combination of sasanlimab and alternative BCG Regimens to Evaluate outcomes with Subcutaneous anti-PD-1 Treatment Phase 3 Design with two Cohorts. Cohort A consists of 3 study Arms (A, B and C) of BCG naive participants. Arms A and B consist of two study drugs, PF-06801591 plus BCG. Arm C consists of one study drug, BCG. Cohort B consists of B1 and B2, which test PF-06801591 and include participants who have BCG unresponsive CIS (B1) or BCG unresponsive papillary only disease (B2). The study is designed to demonstrate that PF-06801591 plus Bacillus Calmette Guerin (BCG) (induction and maintenance periods) is superior to BCG alone (induction and maintenance periods) in prolonging event free survival (EFS) in participants with high-risk naïve non-muscle invasive bladder cancer (NMIBC) and to demonstrate that PF-06801591 plus BCG (induction period only) is superior to BCG alone (induction and maintenance periods) in prolonging EFS in participants with high-risk NMIBC. The study is also designed to estimate the CR rate of PF-06801591 alone in participants with BCG unresponsive CIS and to evaluate the EFS of PF-06801591 alone in participants with BCG unresponsive NMIBC. On August 31, 2022, the Sponsor announced the discontinuation of enrollment to Part B, which enrolled participants with BCG unresponsive NMIBC. The decision to discontinue enrollment to Part B was not made for safety reasons.

Official Title
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A Phase 3, Multinational, Randomized, Open-Label, Three Parallel-Arm Study of PF-06801591, an Anti-PD-1 Antibody, in Combination With Bacillus Calmette-Guerin (BCG Induction With or Without BCG Maintenance) Versus BCG (Induction and Maintenance) in Participants With High-Risk, BCG-Naïve Non-Muscle Invasive Bladder Cancer or PF-06801591 as a Single Agent in Participants With BCG-Unresponsive NMIBC

Conditions
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Non-muscle Invasive Bladder Cancer

Intervention / Treatment
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* Drug: PF-06801591
* Drug: Bacillus Calmette-Guerin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological confirmed diagnosis of high risk non-muscle invasive transitional cell carcinoma (TCC) of the urothelium of the urinary bladder (tumors of mixed transitional/non-transitional cell histology are allowed, but TCC must be the predominant histology) Complete resection of all Ta/T1 papillary disease (including participants with concurrent CIS), with most recent positive TURBT occurring within 12 weeks prior to randomization or study intervention. A second TURBT must have been performed if indicated according to the current locally applicable guidelines, ie, American Urological Association, European Association of Urology (Cohorts B1 and B2 only): Histological confirmed diagnosis of BCG-unresponsive high-risk, non-muscle invasive TCC of the urothelium within 12 months (CIS only) or 6 months (recurrent Ta/T1 disease) of completion of adequate BCG therapy. Have refused or are ineligible for radical cystectomy Exclusion Criteria: Evidence of muscle-invasive, locally advanced or metastatic urothelial cancer or concurrent extravesical, non-muscle invasive TCC of the urothelium (Cohort A only): Intravesical BCG therapy within 2 years prior to randomization. Prior intravesical chemotherapy for NMIBC is allowed. (Cohorts B1 and B2 only): Any systemic or intravesical chemotherapy or immunotherapy from the time of most recent positive TURBT to initiation of study intervention. Prior immunotherapy with anti PD-1, anti PD-L1, anti PD-L2, or anti cytotoxic T-lymphocyte-associated antigen-4 (CTLA-4) antibody Prior treatment with immunostimulatory agents including interleukin (IL)-2, IL-15, interferon (INF) Prior radiation therapy to the bladder (Cohorts B1 and B2 only): Prior participation in Cohort A of this study.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: PF-06801591 + BCG induction and maintenance<br>PF-06801591 in combination with Bacillus Calmette Guerin(induction+maintenance). | Drug: PF-06801591<br>* A monoclonal antibody (mAb) that blocks the interaction between PD-1 and PD-L1/PD-L2.<br>* Other names: Sasanlimab;Drug: Bacillus Calmette-Guerin<br>* Immunotherapy treatment approved by FDA for patients with high-risk non-muscle invasive bladder cancer<br>* Other names: BCG;|
| Experimental: PF-06801591 + BCG induction only<br>PF-06801591 in combination with Bacillus Calmette Guerin (induction only). | Drug: PF-06801591<br>* A monoclonal antibody (mAb) that blocks the interaction between PD-1 and PD-L1/PD-L2.<br>* Other names: Sasanlimab;Drug: Bacillus Calmette-Guerin<br>* Immunotherapy treatment approved by FDA for patients with high-risk non-muscle invasive bladder cancer<br>* Other names: BCG;|
| Active Comparator: BCG induction and maintenance<br>Bacillus Calmette Guerin (induction and maintenance). | Drug: Bacillus Calmette-Guerin<br>* Immunotherapy treatment approved by FDA for patients with high-risk non-muscle invasive bladder cancer<br>* Other names: BCG;|
| Experimental: BCG Unresponsive CIS<br>PF-06801591 | Drug: PF-06801591<br>* A monoclonal antibody (mAb) that blocks the interaction between PD-1 and PD-L1/PD-L2.<br>* Other names: Sasanlimab;|
| Experimental: BCG Unresponsive NMIBC<br>PF-06801591 | Drug: PF-06801591<br>* A monoclonal antibody (mAb) that blocks the interaction between PD-1 and PD-L1/PD-L2.<br>* Other names: Sasanlimab;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Event free survival (Cohort A: Arm A compared to Arm C) | Event free survival is defined as the time from randomization to date of EFS event. | 55 months after first participant randomized | 
| Event free survival (Cohort A: Arm B compared to Arm C) | Event free survival is defined as the time from randomization to date of EFS event. | 55 months after first participant randomized | 
| Complete response rate (Cohort B1) (Obsolete after stopping enrollment in Cohort B) | Complete response (CR) rate defined as the proportion of participants in the analysis population with CR. | Registration to 12 months after last participant initially assessed | 
| Event free survival (Cohort B2) (Obsolete after stopping enrollment in Cohort B) | Event free survival is defined as the time from first dose to date of EFS event. | Registration to 12 months after last participant initially assessed | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival (Cohort A: Arm A compared to Arm C) | Overall survival is defined as the time from the date of randomization to the date of death due to any cause. | Randomization up to 60 months from last participant randomized | 
| Overall Survival (Cohort A: Arm B compared to Arm C) | Overall survival is defined as the time from the date of randomization to the date of death due to any cause. | Randomization up to 60 months from last participant randomized | 
| Complete response rate in participants with CIS at randomization (Cohort A: Arm A, B, C) | Complete response (CR) rate defined as the proportion of participants in the analysis population with CR. | Randomization up to 60 months from last participant randomized | 
| Disease-specific survival (Cohort A: Arm A, B, C) | Disease specific survival (DSS) is defined as the time from randomization to death resulting from bladder cancer. | Randomization up to 60 months from last participant randomized | 
| Health-related quality of life as measured by EORTC QLQ-C30 (European Organization for Treatment of Cancer Quality of Life Questionnaire for cancer patients) (Obsolete for Cohort B after stopping enrollment) | EORTC QLQ-C30: included functional scales (physical, role, cognitive, emotional, and social), global health status, symptom scales (fatigue, pain, nausea/vomiting) and single items (dyspnoea, appetite loss, insomnia, constipation/diarrhea and financial difficulties). | Randomization up to 60 months from last participant randomized | 
| ctrough of PF-06801591 when in combination with BCG (induction and maintenance or induction). Cohort A: Arms A and B only. | Ctrough will be summarized in Cohort A Arms A and B only. | Randomization up to 24 months | 
| Incidence of ADA/Nab of PF-06801591 when in combination with BCG (induction and maintenance or induction). Cohort A: Arms A and B only. | Immunogenicity will be evaluated for Cohort A Arms A and B only. | Randomization up to 24 months | 
| Tumor sample biomarker status based on PD-L1 expression (high or low) (Obsolete for Cohort B after stopping enrollment) | Evaluate PD-L1 expression. | Baseline | 
| Duration of CR for participants with CIS at randomization (Obsolete for Cohort B after stopping enrollment) | Duration of CR is defined as time from first CR to first recurrence or death due to any cause, whichever occurs first. | Randomization/registration up to 60 months from last participant randomized | 
| Time to recurrence of low grade disease (Cohort A: Arm A, B, C) | Time to recurrence defined as time from randomization to the date of first documentation of recurrence of low grade disease or death due to any cause, whichever occurs first. | Randomization up to 60 months from last participant randomized | 
| Time to cystectomy (Obsolete for Cohort B after stopping enrollment) | Time to cystectomy is defined as time from randomization/registration to cystectomy in participants with NMIBC | Randomization/registration to date of cystectomy (up to 5 years after last participant is randomized) | 
| Health-related quality of life as measured by PTAB (Patient Treatment Administration Burden Questionnaire) (Obsolete for Cohort B after stopping enrollment) | PTAB is a 2-item PRO designed to assess, from the patient perspective, any pain associated with the treatment administration and the burden of the amount of time required to complete the treatment administration procedures (1 item each). | Randomization/registration up to 24 months | 
| Percentage of Participants With All Causality and Treatment-related Treatment-emergent Adverse Events (TEAEs), Serious Adverse Events (SAEs), and Withdrawals Due to TEAEs (Obsolete for Cohort B after stopping enrollment) | An adverse event (AE) is any untoward medical occurrence attributed to study drug in a participant who received study drug. AEs comprised both SAEs and non-SAEs. Causality assessment is made by the investigator. Grading is per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. | Baseline up to 60 months from the last participant randomized | 
| Percentage of Participants With Laboratory Abnormalities (Obsolete for Cohort B after stopping enrollment) | Percentage of participants with laboratory test abnormalities without regard to baseline abnormality. Grading is per the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Event (CTCAE) version 3.0. | Baseline up to 60 months from last participant randomized | 
| Health-related quality of life as measured by EORTC QLQ-NMIBC24 (European Organization for Treatment of Cancer in patients with non-muscle invasion bladder cancer) (Obsolete for Cohort B after stopping enrollment) | EORTC-QLQ-NMIBC24 has 24 items which can be grouped into 6 subscales: urinary symptoms (7 items), malaise (2 items), future worries (4 items), bloating/flatulence (2 items), sexual functioning (2 items), and male sexual issues (2 items). The NMIBC24 also assesses intravesical treatment, female sexual issues, sexual intimacy, risk of contaminating a partner, and sexual enjoyment (1 item each). | Randomization/registration up to 60 months from the last participant randomized | 
| Complete response rate at 12 months (Cohort B1) (Obsolete after stopping enrollment in Cohort B) | Complete response (CR) rate defined as the proportion of participants in the analysis population with CR at 12 months. | 12 months after last participant's initial assessment | 
| Event Free Survival (Cohort B1) (Obsolete after stopping enrollment in Cohort B) | Time from first dose to date of EFS event. | Registration to 5 years after last participant randomized. | 
| Overall Survival (Cohorts B1 and B2) (Obsolete after stopping enrollment in Cohort B) | Time from the date of first dose to the date of death due to any cause. | Registration to 5 years after last participant randomized. | 
| ctrough of PF-06801591 (Cohorts B1 and B2) (Obsolete after stopping enrollment in Cohort B) | Ctrough will be summarized | Registration up to 24 months | 
| Incidence of ADA/Nab of PF-06801591 (Cohorts B1 and B2) (Obsolete after stopping enrollment in Cohort B) | Immunogenicity will be evaluated for participants with BCG unresponsive NMIBC, including those with CIS. | Registration up to 24 months | 
| cmax of PF-06801591 (Cohort B2 only) (Obsolete after stopping enrollment in Cohort B) | Cmax will be summarized in Cohort B2 only. | Registration up to 24 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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CREST, Sasanlimab, PF-06801591, Bacillus Calmette Guerin, BCG, Bladder cancer