CREST - Phase 3 Study of Sasanlimab (PF-06801591) in Combination With Bacillus Calmette-Guerin (BCG) or as a Single Agent in Participants With High-Risk Non-Muscle Invasive Bladder Cancer who do not respond to BCG

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Pfizer Inc.

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Trial duration

1 Jul 2020 → ongoing

Decision date (initial)

2024-06-12

Transition trial

Yes

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Pfizer, Inc.

External identifiers

EU CT number

2023-509089-39-00

EudraCT number

2019-003375-19

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy, Pharmacokinetic, Pharmacoeconomic, Others, Pharmacodynamic, Safety

BCG-Naïve Cohort (Cohort A)
- To demonstrate that PF-06801591 + BCG (induction and maintenance) is superior to BCG (induction and maintenance) in prolonging event-free survival (EFS) in participants with high-risk NMIBC.
- To demonstrate that PF-06801591 + BCG (induction) is superior to BCG (induction and maintenance) in prolonging EFS in participants with highrisk NMIBC.

BCG-Unresponsive Cohorts (Cohorts B1 and B2)
-To estimate the CR rate of PF-06801591 in participants with BCGunresponsive CIS (Cohort B1 only)
- To evaluate the EFS of PF-06801591 in participants with BCGunresponsive NMIBC (Cohort B2 only)

Secondary objectives 2

1. Cohort A -To demonstrate that PF-06801591 + BCG (induction and maintenance) is superior to BCG (induction and maintenance) in prolonging overall survival (OS) in participants with high-risk NMIBC. -To demonstrate that PF-06801591 + BCG (induction) is superior to BCG (induction and maintenance) in prolonging OS in participants with highrisk NMIBC.
2. Cohorts B1 and B2 -To evaluate the duration of CR of PF- 06801591 in participants with BCG-unresponsive CIS (Cohort B1 only). -To estimate the CR rate of PF-06801591 at 12 months in participants with BCG-unresponsive CIS (Cohort B1 only) -To evaluate the EFS of PF-06801591 in participants with BCG unresponsive CIS (Cohort B1 only) -To evaluate the time to cystectomy of PF-06801591 in participants with BCG-unresponsive NMIBC .(Cohorts B1 and B2). -To evaluate OS of PF-06801591 in participants with BCG-unresponsive NMIBC treated with PF-06801591 (Cohorts B1 and B2).

Conditions and MedDRA coding

Non-Muscle Invasive Bladder Cancer

Regulatory references

Scientific advice from competent authorities

European Medicines Agency

Plan to share IPD

Yes

IPD plan description

Pfizer will provide access to individual de-identified participant data and related study documents (e.g. protocol, Statistical Analysis Plan (SAP), Clinical Study Report (CSR)) upon request from qualified researchers, and subject to certain criteria, conditions, and exceptions. Further details on Pfizer's data sharing criteria and process for requesting access can be found at: https://www.pfizer.com/science/clinical_trials/trial_data_and_results/data_requests

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 14

1. 1. Participant must be ≥18 years of age, at the time of signing the informed consent (except in Japan, where participants must be ≥20 years).
2. 2. 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)
3. 3. 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.
4. 4. 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.
5. 5. ECOG Performance Status (PS) ≤ 2.
6. 6. 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).
7. 7. 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.
8. 8. 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.
9. 9. Willing and able to comply with scheduled visits, treatment plan, laboratory tests, and other procedures.
10. 10. 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
11. 11. 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
12. 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.
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).
14. Cohorts B1 and B2 only 14. Have refused or are ineligible for radical cystectomy.

Exclusion criteria 15

1. 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. 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. 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. 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. 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. 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. 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. 8.Prior immunotherapy with anti PD-1, anti PD-L1, anti PD-L2, or anti cytotoxic Tlymphocyteassociated antigen-4 (CTLA-4) antibody.
9. 9.Prior treatment with immunostimulatory agents including interleukin (IL)-2, IL-15, interferon (INF)-gamma.
10. 10.Prior radiation therapy to the bladder.
11. 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. 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. 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.
14. 14. 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. 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.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 2

1. Cohort A: EFS as assessed by the investigator.
2. Cohorts B1 and B2: CR as assessed by the BICR. EFS as determined by the investigator

Secondary endpoints 1

1. OS

Investigational products

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

Test 1

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Pfizer Inc.

Sponsor organisation

Pfizer Inc.

Address

66 Hudson Boulevard East

City

New York

Postcode

10001-2189

Country

United States

Scientific contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Public contact point

Organisation

Pfizer Inc.

Contact name

Clinical Medical Lead

Locations

6 EU/EEA countries · 48 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 38 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