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.
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.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
NONE
Enrollment
1,068
A monoclonal antibody (mAb) that blocks the interaction between PD-1 and PD-L1/PD-L2.
Immunotherapy treatment approved by FDA for patients with high-risk non-muscle invasive bladder cancer
Arizona Urology Specialists
Tucson, Arizona, United States
Arkansas Urology
Little Rock, Arkansas, United States
Koman Family Outpatient Pavilion
La Jolla, California, United States
Sulpizio Cardiovascular Center at UC San Diego Health
La Jolla, California, United States
UC San Diego Medical Center - La Jolla (Jacobs Medical Center / Thornton Pavilion)
La Jolla, California, United States
Cohort A: Event Free Survival (EFS) as Assessed by the Investigator: Arm A Versus Arm C
EFS: time from randomization till recurrence of high-grade disease, progression of disease, persistence of carcinoma in situ (CIS), death due to any cause, whichever occurred first. Recurrence of high-grade disease: re-appearance of high-grade disease after randomization/study intervention initiation, re-appearance of high-grade disease after complete response (CR) for CIS participants or re-appearance of high-grade disease before CR for CIS participants and concurrent papillary disease at baseline. Progression of disease defined as any of following: Lamina propria invasion, muscle invasive disease, lymph node positive disease, metastatic disease, high-grade stage of bladder cancer (non-invasive papillary carcinoma \[Ta\] or invasion into the lamina propria without invasion into the muscularis propria \[T1\]) in participants with CIS only at baseline before achieving CR. Persistence of CIS: persistent CIS after induction, re-induction. EFS estimated using Kaplan-Meier analysis.
Time frame: From randomization (Day 1) to first documentation of high-grade disease, progression of disease, persistence of CIS or death due to any cause, whichever occurred first (maximum follow up duration was up to 257.1 weeks)
Cohort A: EFS as Assessed by the Investigator: Arm B Versus Arm C
EFS: time from randomization till recurrence of high-grade disease, progression of disease, CIS, death due to any cause, whichever occurred first. Recurrence of high-grade disease: re-appearance of high-grade disease after randomization/study intervention initiation, re-appearance of high-grade disease after CR for CIS participants or re-appearance of high-grade disease before CR for CIS participants and concurrent papillary disease at baseline. Progression of disease defined as any of following: Lamina propria invasion, muscle invasive disease, lymph node positive disease, metastatic disease, high-grade stage of bladder cancer (non-invasive papillary carcinoma \[Ta\] or invasion into the lamina propria without invasion into the muscularis propria \[T1\]) in participants with CIS only at baseline before achieving CR. Persistence of CIS: persistent CIS after induction, re-induction. EFS estimated using Kaplan-Meier analysis.
Time frame: From randomization (Day 1) to the first documentation of high-grade disease, progression of disease, persistence of CIS or death due to any cause, whichever occurred first (maximum follow up duration was up to 257.1 weeks)
Cohort A: Overall Survival (OS) for Participants: Arm A Versus Arm C
Overall survival was defined as the time in months from the date of randomization to the date of death due to any cause. Participants last known to be alive will be censored at the date of last contact
Time frame: From randomization (Day 1) until date of death due to any cause or censoring date
Cohort A: OS of Participants: Arm B Versus Arm C
Overall survival was defined as the time in months from the date of randomization to the date of death due to any cause. Participants last known to be alive will be censored at the date of last contact.
Time frame: From randomization (Day 1) until date of death due to any cause or censoring date
Cohort A: Percentage of Participants With Complete Response (CR)as Assessed by Investigator: Participants With CIS at Baseline in Full Analysis Set
CR was defined as histologic disappearance of malignancy on bladder biopsy with negative cytology and cystoscopy or negative cytology and positive cystoscopy with biopsy-proven low-grade stage of bladder cancer defined as a non-invasive papillary carcinoma (Ta) lesion or non-malignant tissue for participants with CIS at randomization. 95% CI was based on Clopper-Pearson method.
Time frame: From randomization (Day 1) to the first documented CR (maximum follow up duration was up to 257.1 weeks)
Cohort A: Duration of CR as Assessed by the Investigator: Participants With CIS at Baseline in Full Analysis Set
Duration of CR was defined as the time from the first documentation of CR to the date of an EFS event for participants with CR. EFS was defined as the time in months from randomization until recurrence of high-grade disease, progression of disease, persistence of CIS or death due to any cause, whichever occurred first. CR was defined as histologic disappearance of malignancy on bladder biopsy with negative cytology and cystoscopy or negative cytology and positive cystoscopy with biopsy-proven low-grade stage of bladder cancer defined as a non-invasive papillary carcinoma (Ta) lesion or non-malignant tissue for participants with CIS at randomization. Kaplan-Meier method was used. 95% CI was estimated based on Brookmeyer and Crowley method.
Time frame: From date of first documentation of CR to date of an EFS event (maximum follow up duration was up to 257.1 weeks)
Cohort A: Time to Recurrence of Low-Grade Disease Assessed by the Investigator
Time to recurrence of low-grade disease was defined as the time from randomization to the date of first documentation of recurrence of low-grade disease. Recurrence of low-grade disease was defined as re-appearance of low-grade disease (low-grade Ta) after randomization based on positive biopsy, cystoscopy or cytology result. Kaplan-Meier method was used. 95% CI was estimated based on Brookmeyer and Crowley method.
Time frame: From randomization (Day 1) to the date of positive biopsy, cystoscopy or cytology results (maximum follow up duration was up to 257.1 weeks)
Cohort A: Time to Cystectomy
Time to cystectomy was defined as time from randomization to cystectomy. Participants without a cystectomy will be censored at death date or last date known to be alive.
Time frame: From randomization (Day 1) to date of cystectomy or censoring date
Cohort A: Disease Specific Survival (DSS) as Assessed by the Investigator
DSS was defined as the time from randomization to death resulting from bladder cancer, as assessed by the investigator. Participants last known to be alive will be censored at the date of last contact.
Time frame: From randomization (Day 1) to the first documentation of death from bladder cancer
Cohort A: Number of Participants With Treatment Emergent Adverse Events (TEAEs)
An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment up to 30 days after last dose of study treatment or 1 day before start day of new anti-cancer therapy.
Time frame: From first dose of study treatment (Day 1) up to 30 days after last dose of study treatment or 1 day before anti-cancer therapy
Cohort A: Number of Participants With Serious TEAEs
An adverse event (AE) was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment up to 30 days after last dose of study treatment or 1 day before start day of new anti-cancer therapy. A serious adverse event (SAE) was any untoward medical occurrence at any dose that: resulted in death or was life threatening or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant disability/incapacity, resulted in congenital anomaly/birth defect or other events.
Time frame: From first dose of study treatment (Day 1) up to 30 days after last dose of study treatment or 1 day before anti-cancer therapy
Cohort A: Number of Participants With Treatment Related TEAEs and Treatment Related SAEs
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment up to 30 days after last dose of study treatment or 1 day before start day of new anti-cancer therapy. A SAE was any untoward medical occurrence at any dose that: resulted in death or was life threatening or required inpatient hospitalization or prolongation of existing hospitalization or resulted in persistent or significant disability/incapacity resulted in congenital anomaly/birth defect or other events. Relatedness was based on the investigator's judgement.
Time frame: From first dose of study treatment (Day 1) up to 30 days after last dose of study treatment or 1 day before anti-cancer therapy
Cohort A: Number of Participant With Grade 3 or 4 and Grade 5 TEAEs Based on National Cancer Institute Common Terminology Criteria for Adverse Events (NCI CTCAE) Version 5.0
An AE was any untoward medical occurrence in a participant or clinical study participant, temporally associated with the use of study treatment, whether or not considered related to the study treatment. TEAEs were those events with onset dates occurring during the on-treatment period. On-treatment period was defined as the time from the first dose of study treatment up to 30 days after last dose of study treatment or 1 day before start day of new anti-cancer therapy. NCI-CTCAE version 5.0, severity was graded as Grade 1: Mild, Grade 2: Moderate, Grade 3: Severe and Grade 4 Life threatening and Grade 5: Death.
Time frame: From first dose of study treatment (Day 1) up to 30 days after last dose of study treatment or 1 day before anti-cancer therapy
Cohort A: Number of Participant With Laboratory Abnormalities as Based on Severity (as Graded by NCI CTCAE v5.0)
Laboratory parameters: hematocrit, hemoglobin, platelets, white blood cells, absolute neutrophil count, lymphocytes, monocytes, eosinophils, basophils, alanine aminotransferase, aspartate aminotransferase, lactate dehydrogenase, alkaline phosphatase, sodium, potassium, magnesium, chloride, total calcium and bilirubin, blood urea nitrogen, urea, creatinine, uric acid, glucose (non-fasted), albumin, phosphorus/phosphate, lipase, amylase, thyroid function test + reflex free thyroxine, free triiodothyronine, adrenocorticotropic hormone, international normalized ratio, partial thromboplastin time (PTT)/activated PTT, hepatitis B surface antigen, hepatitis C virus antibody. Severity grades per NCI-CTCAE v5.0: 1: Mild, 2: Moderate, 3: Severe, 4: Life threatening,5: Death.
Time frame: From first dose of study treatment (Day 1) up to 30 days after last dose of study treatment or 1 day before anti-cancer therapy
Cohort A: Change From Baseline in European Organization for Research and Treatment of Cancer (EORTC) Quality of Life Questionnaire Non-Muscle Invasive Bladder Cancer (QLQ-C) 30 Total Score
The EORTC QLQ-C30 was a 30 self-administered questionnaire, which comprised of 5 functional domain subscales (physical functioning subscale, a role functioning subscale, an emotional functioning subscale, a cognitive functioning subscale and a social functioning subscale), 3 symptom scale (fatigue, pain, nausea and vomiting), 6 single items (dyspnea, insomnia, appetite loss, constipation, diarrhea and financial impact) and a global health status/QoL scale. All the scales and single-item measures range in score from 0 (poor functioning/no symptoms) to 100 (excellent functioning/greater degree of symptoms). Higher scores on functional domains indicated higher levels of functioning and higher scores on symptom scale/single items indicated greater presence of symptoms.
Time frame: Baseline up to recurrence of high-grade disease or disease progression, consent withdrawal, lost to follow-up, or death
Cohort A: Change From Baseline in EORTC QLQ- Non-Muscle Invasive Bladder Cancer (NMIBC24) Total Score
The EORTC QLQ NMIBC24 is a PRO developed and tested by the EORTC group specifically for participants with non-muscle invasive bladder cancer. The 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). All of the subscales and single-item measures range in score from 0 (poor functioning/no symptoms) to 100 (excellent functioning/greater degree of symptoms). Higher scores indicate greater impairment, except for sexual function and sexual enjoyment items, where higher scores indicate better function.
Time frame: Baseline up to recurrence of high-grade disease or disease progression, consent withdrawal, lost to follow-up, or death
Cohort A: Change From Baseline in Patient Treatment Administration Burden (PTAB) Questionnaire Total Score
The PTAB questionnaire was a 2-item PRO designed to assess, from the participant 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). The items were scored on a range of 0 to 4, where 0=no pain/ not at all burdensome and 4= extremely severe pain/ extremely burdensome.
Time frame: Baseline up to 7 days after last dose of study treatment
Cohort A: Concentration at Trough (Ctrough) of PF-06801591 for Arms A and B Only
Concentration at Trough is defined as Predose/trough concentration Observed directly from data.
Time frame: Pre-dose on Day 1 of Cycles 1, 2, 4, 6, 8, 10 and 13 (1 cycle=4 weeks)
Cohort A: Number of Participants With Positive (Anti-Drug Antibody) ADA or (Neutralizing Antibody) NAb: Arms A and B Only
A participant was considered ADA (or NAb) positive if (1) baseline titer was missing or negative and participant had \>= 1 post-treatment positive titer (treatment-induced), or (2) positive titer at baseline and had a \>= 4-fold dilution increase in titer from baseline in \>= 1 post-treatment sample (treatment-boosted).
Time frame: From start of study treatment (Day 1) until 7 days after last dose of study treatment (maximum up to 125.1 weeks and 104.4 weeks of treatment exposure for Arm A and Arm B, respectively)
Cohort A: Number of Participants According to Tumor Sample Biomarker Status Based on Baseline Programmed Cell Death Ligand 1 (PD-L1) Expression
PD-L1 expression was defined as the number of PD-L1 positive cells and/or qualitative assessment of PD-L1 staining on tumor and immune cells in regions of interest that were defined by tumor cell morphology. PDL-1 status was high if \>=25% tumor cell or (immune cells present in the tumor area \> 1% and PD-L1 positive immune cells+ \>=25%) or (immune cells present in the tumor area = 1% and PD-L1 positive immune cells = 100%), and low if \< 25% tumor cell and \[(immune cells present in the tumor area \> 1% and immune cells \<25%) or (immune cells present in the tumor area = 1% and PD-L1 positive immune cells\< 100%) or immune cells present = 0\].
Time frame: From start of study treatment (Day 1) until 7 days after last dose of study treatment (maximum up to 125.1 weeks, 104.4 weeks and 110 weeks of treatment exposure for Arm A, Arm B and Arm C, respectively)
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