Phase 3 Multinational Randomized Study of Sasanlimab with Bacillus Calmette-Guerin in High-Risk Non-Muscle Invasive Bladder Cancer

Trial ID: 2023-509089-39-00
Protocol: B8011006
Sponsor: Pfizer Inc.

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Diseases & Conditions

Bladder cancer

Objectives

The primary objective of this study is to evaluate the efficacy of **sasanlimab** (PF-06801591), an anti-PD-1 antibody, in combination with Bacillus Calmette-Guerin (BCG) compared to BCG alone in participants with high-risk, BCG-naïve **Non-Muscle Invasive Bladder Cancer** (NMIBC). Specifically, the study aims to demonstrate that the combination of PF-06801591 and BCG, both induction and maintenance, is superior in prolonging event-free survival (EFS) compared to BCG alone in this patient population. This is clinically relevant as it may offer a more effective treatment option for patients with high-risk NMIBC, potentially reducing the risk of disease progression and improving patient outcomes.

Secondary objectives include:

For Cohort A, to demonstrate that PF-06801591 combined with BCG (induction and maintenance) is superior to BCG alone in prolonging overall survival (OS) in participants with high-risk NMIBC.
For Cohorts B1 and B2, to evaluate the duration of complete response (CR) and estimate the CR rate at 12 months for PF-06801591 in participants with BCG-unresponsive carcinoma in situ (CIS) in Cohort B1. Additionally, to evaluate the EFS, time to cystectomy, and OS in participants with BCG-unresponsive NMIBC treated with PF-06801591 in both Cohorts B1 and B2.

These secondary objectives aim to further assess the potential benefits of PF-06801591 in different subgroups of NMIBC, providing insights into its efficacy and impact on survival and disease management.

Participants

The clinical trial involves a total of **757 participants** diagnosed with **Non-Muscle Invasive Bladder Cancer** (NMIBC). The study population includes both male and female subjects, aged 18 years and older, with a confirmed histological diagnosis of high-risk, non-muscle invasive transitional cell carcinoma of the urothelium of the urinary bladder. Participants were selected based on their ability to provide informed consent and their willingness to comply with the study's requirements. The trial includes individuals who have adequate bone marrow, renal, and liver function, as well as an ECOG Performance Status of 2 or less. The study population is characterized by a diverse age range and includes both genders, with lifestyle factors such as diet and physical activity not specified. Participants are required to have undergone complete resection of all Ta/T1 papillary disease and have available tumor tissue for PD-L1 expression assessment. The trial also includes a vulnerable population, as indicated by the selection criteria. The sponsor has not provided specific information regarding lifestyle considerations or additional demographic details beyond the inclusion criteria.

Plans and Procedures

The clinical trial is a **Phase 3**, multinational, randomized, open-label study designed to evaluate the efficacy of **sasanlimab**, an anti-PD-1 antibody, in combination with Bacillus Calmette-Guerin (BCG) or as a single agent in participants with high-risk, non-muscle invasive bladder cancer (NMIBC). The trial consists of three parallel arms, with participants either receiving sasanlimab in combination with BCG induction and maintenance, sasanlimab with BCG induction only, or BCG induction and maintenance alone. The primary objective is to assess the event-free survival (EFS) in BCG-naïve participants and the complete response (CR) rate in BCG-unresponsive participants.

The trial is expected to last approximately seven years, with an estimated recruitment start date of December 30, 2019, and an estimated end date of November 2, 2026. Participants will be involved in the study for a maximum treatment period of 104 weeks. The study includes several key visits: an initial screening visit to confirm eligibility, regular follow-up visits to monitor treatment response and safety, and an end-of-study visit to assess final outcomes. Participants will be required to comply with scheduled visits, treatment plans, laboratory tests, and other procedures throughout the study duration.

Inclusion criteria require participants to be at least 18 years of age, with a histologically confirmed diagnosis of high-risk NMIBC. Participants must have completed a resection of all Ta/T1 papillary disease and have adequate bone marrow, renal, and liver function. Exclusion criteria are not specified in the provided data. Conditions that may lead to early termination from the study include non-compliance with study procedures or the occurrence of adverse events that compromise participant safety. The study is not classified as low intervention and does not involve a pediatric formulation.

Treatment

The clinical trial involves the administration of **sasanlimab**, a recombinant humanized monoclonal antibody of biological/biotechnological origin. Sasanlimab is provided in the form of a **solution for injection** and is administered via the **subcutaneous route**. The maximum daily dose of sasanlimab is 600 mg, with a total maximum dose of 10,200 mg over the course of the treatment period, which spans up to 104 weeks. The pharmaceutical formulation is not specifically designed for pediatric use. The active substance, sasanlimab, is a protein of other origin, and it is also known by its synonyms, including ANTI-PDCD1 IGG4 HUMANISED MONOCLONAL ANTIBODY, PF-06801591, and RN-888.

In this study, sasanlimab is evaluated in combination with Bacillus Calmette-Guerin (BCG) therapy or as a single agent. BCG therapy, a standard-of-care treatment for non-muscle invasive bladder cancer (NMIBC), is used as a comparator treatment. BCG is administered as an induction therapy with or without maintenance, depending on the cohort. The trial aims to assess the efficacy of sasanlimab in prolonging event-free survival (EFS) in participants with high-risk, BCG-naïve NMIBC and to evaluate the complete response (CR) rate and EFS in participants with BCG-unresponsive NMIBC.

Efficacy

Efficacy in this clinical trial will be assessed using specific endpoints tailored to the different cohorts involved. For Cohort A, the primary efficacy endpoint is **event-free survival (EFS)** as assessed by the investigator. In Cohorts B1 and B2, the primary endpoints include the **complete response (CR)** rate as assessed by the Blinded Independent Central Review (BICR) and EFS as determined by the investigator. These endpoints are designed to evaluate the effectiveness of PF-06801591, an anti-PD-1 antibody, in combination with Bacillus Calmette-Guerin (BCG) or as a single agent in participants with high-risk, non-muscle invasive bladder cancer (NMIBC).

Inclusion and Exclusion Criteria

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Inclusion Criteria

Participant must be ≥18 years of age, at the time of signing the informed consent (except in Japan, where participants must be ≥20 years).
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) defined as any of the following per World Health Organization grading system. a. T1 tumor b. High-grade Ta tumor c. Carcinoma in situ (CIS)
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 for participants in Cohort A, or within 12 weeks prior to initiation of study intervention for participants in Cohorts B1 and B2. A second TURBT must have been performed if indicated according to the current locally applicable guidelines, ie, American Urological Association, European Association of Urology.
Availability of the tumor tissue from the most recent TURBT for the assessment of the PD-L1 expression. If a second TURBT was performed, as indicated according to the current locally applicable guidelines, the tumor tissue from the TURBT procedure that supports the primary diagnosis for study eligibility should be the tumor tissue used for the PDL1 expression testing.
ECOG Performance Status (PS) ≤ 2.
Adequate Bone Marrow Function (without hematopoietic growth factor or transfusion support within 14 days prior to study randomization for participants in Cohort A, or within 14 days prior to initiation of study intervention for participants in Cohorts B1 and B2 ), including: a. Absolute neutrophil count (ANC) ≥1,500/mm3 or ≥1.5 x 109/L; b. Platelets ≥100,000/mm3 or 100 x 109/L; c. Hemoglobin ≥9 g/dL (≥5.6 mmol/L).
Adequate renal function defined by an estimated creatinine clearance ≥30 mL/min according to the Cockcroft Gault formula or by 24-hour urine collection for creatinine clearance, or according to local institutional standard method.
Adequate liver function, including: a. Total serum bilirubin ≤1.5 × the upper limit of normal range (ULN). Participants with Gilbert syndrome who should have total serum bilirubin <3 x ULN; b. Aspartate and alanine aminotransferase (AST and ALT) ≤ 2.5 × ULN.
Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
Male or Female Contraceptive use by men or women should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies
Capable of giving signed informed consent as described in Section 10.1.3 which includes compliance with the requirements and restrictions listed in the informed consent document (ICD) and in this protocol
Cohorts B1 and B2 only 12. Histological confirmed diagnosis of BCG-unresponsive high-risk, nonmuscle invasive TCC of the urothelium of the urinary bladder defined as any of the following: a) Cohort B1: persistent or recurrent CIS alone or with concomitant recurrent Ta/T1 disease within 12 months of completion of adequate BCG therapy. Stage and grade must be confirmed by the BICR prior to registration; b) Cohort B2: recurrent high-grade Ta/T1 disease within 6 months of completion of adequate BCG therapy; c) Cohort B2: T1 high-grade disease at the first evaluation following an adequate (at least 5 of 6 doses) induction BCG course. It is not required that the participant receive BCG maintenance or a second induction course of BCG per inclusion criterion 13.
Cohorts B1 and B2 only 13. Have received adequate BCG therapy defined as at least one of thefollowing: a) At least 5 of 6 doses of an initial induction course plus at least 2 of 3 doses of maintenance therapy; b) At least 5 of 6 doses of an initial induction course plus at least 2 of 6 doses of a second induction course. Note: The 2 courses described in "a" and "b" should have been administered within a 12 months period (ie the second course started within 12 months from the start of the first course). Note: Additional doses or courses of BCG above the minimum 5 + 2 described in "a" and "b" are allowed, and these do not have to be within the 12 month period. Note: The BCG dose administered in maintenance courses may be 1/2 or 1/3 dose in the event of a BCG shortage, according to NCCN and AUA treatment guidelines. Note: Prior BCG courses must have been comprised ONLY of one or more of the following strains: TICE, RIVM, TOKYO172, IMURON-VAC or Verity BCG (BCG-1), D2PB302, Danish (SSI).
Cohorts B1 and B2 only 14. Have refused or are ineligible for radical cystectomy.

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Exclusion Criteria

1.Evidence of muscle-invasive, locally advanced or metastatic urothelial cancer or concurrent extravesical, non-muscle invasive TCC of the urothelium. For Cohort B1, absence of muscle-invasive and extravesical disease must be confirmed by the BICR prior to registration.
2.Active or prior autoimmune disease that might deteriorate when receiving an immunostimulatory agent. Participants with diabetes type I, vitiligo, psoriasis, or hypo or hyperthyroid disease not requiring immunosuppressive treatment are eligible.
3.Severe active infections including pulmonary tuberculosis requiring systemic therapeutic oral or IV antibiotics within 2 weeks prior to randomization for participants in Cohort A, or within 2 weeks prior to initiation of study intervention for participants in Cohorts B1 and B2. Patients receiving prophylactic antibiotics (e.g., for prevention of a urinary tract infection) are eligible.
4.Other malignancy within 5 years prior to randomization for participants in Cohort A, or within 5 years prior to initiation of study intervention for participants in Cohorts B1 and B2, except for adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the breast or of the cervix, or low-grade (Gleason 6 or below) prostate cancer on surveillance without any plans for treatment intervention (eg, surgery, radiation, or castration) or other concurrent malignancy the investigator feels has a very low likelihood to become metastatic after discussion with the sponsor.
5.Clinically significant multiple or severe drug allergies, intolerance to topical corticosteroids, or severe post-treatment hypersensitivity reactions (including, but not limited to, erythema multiforme major, linear immunoglobulin A [IgA] dermatosis, toxic epidermal necrolysis, and exfoliative dermatitis
6.Current unstable liver or biliary disease per investigator assessment defined by the presence of ascites, encephalopathy, coagulopathy, hypoalbuminaemia, oesophageal or gastric varices, persistent jaundice, or cirrhosis. NOTE: Stable chronic liver disease (including Gilbert's syndrome, asymptomatic gallstones, and chronic stable hepatitis B or C - eg, presence of hepatitis B surface antigen [HBsAg] or positive hepatitis C antibody test result at screening or within 3 months prior to randomization for participants in Cohort A, or within 3 months prior to initiation of study intervention for participants in Cohorts B1 and B2) is acceptable if the participant otherwise meets entry criteria.
7.Cohort A: Intravesical BCG therapy within 2 years prior to randomization. Cohorts B1 and B2: Any systemic or intravesical chemotherapy or immunotherapy from the time of most recent positive TURBT to initiation of study intervention (single-dose intravesical chemotherapy as part of the most recent positive TURBT according to the current locally applicable guidelines is allowed). Prior intravesical chemotherapy for NMIBC is allowed in all Cohorts.
8.Prior immunotherapy with anti PD-1, anti PD-L1, anti PD-L2, or anti cytotoxic Tlymphocyteassociated antigen-4 (CTLA-4) antibody.
9.Prior treatment with immunostimulatory agents including interleukin (IL)-2, IL-15, interferon (INF)-gamma.
10.Prior radiation therapy to the bladder.
11.Treatment with systemic anti-cancer therapy including investigational agents within 4 weeks prior to randomization for participants in Cohort A, or within 4 weeks prior to initiation of study intervention for participants in Cohorts B1 and B2
12.Vaccination with live attenuated vaccines within 4 weeks prior to randomization for participants in Cohort A, or within 4 weeks prior to initiation of study intervention for participants in Cohorts B1 and B2 is prohibited; however, inactivated vaccines are permitted
13.Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids, and adrenal replacement doses >10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Prior/Concurrent Clinical Study Experience Participation in other studies involving investigational drug(s) within 4 weeks prior to randomization; for participants in Cohort A, or within 4 weeks prior to initiation of study intervention for participants in Cohorts B1 and B2.
15.Cohort A: Known or documented absolute and/or relative contraindication of adjuvant intravesical BCG treatment: a. Prior BCG sepsis or systemic infection (including current urinary tract infection) b. Total bladder incontinence defined as use more than 6 pads in 24 hours c. Adverse experience to previous BCG instillation that resulted in treatment discontinuation or precludes re-treatment.

Trial Status by Country

Country	Status	Start of Recruitment	Planned Patients
Belgium	Not Recruiting	30 Dec 2019	4
France	Not Recruiting	30 Dec 2019	57
Germany	Not Recruiting	30 Dec 2019	22
Italy	Not Recruiting	30 Dec 2019	46
Poland	Not Recruiting	30 Dec 2019	79
Spain	Not Recruiting	30 Dec 2019	105