An open label, single-arm, phase 2 study of perioperative sacituzumab govitecan in combination with zimberelimab and domvanalimab for patients with muscle invasive bladder cancer ineligible for cisplatin-based chemotherapy. (PeRioperative Immunotherapy combined with Sacituzumab govitecan in Muscle invasive blAdder cancer)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fundacion Para El Progreso De La Oncologia En Cantabria

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04], Diseases [C] - Male Urogenital Diseases [C12], Diseases [C] - Female Urogenital Diseases and Pregnancy Complications [C13]

Trial duration

13 Jan 2025 → ongoing

Decision date (initial)

2024-02-21

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

No

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Efficacy

To evaluate the efficacy measured as pathologic complete response (pCR) rates of the combo Sacituzumab govitecan (SG) + Zimberelimab
(AB 122) (ZIM) + Domvanalimab (AB 154) (DOM) in the perioperative setting in patients with MIBC who are either unfit for platinum-based
chemotherapy or unwilling to receive that therapy.

Secondary objectives 6

1. to evaluate the downstaging rate induced by the combo
2. To measure overall survival (OS) and disease-free survival (DFS) in the study population
3. To evaluate the safety of the combo measured as: o the incidence, nature, and severity of adverse events (AEs) o the incidence of relevant delay to the definitive surgical approach
4. To identify predictive biomarkers associated with response to SG + ZIM + DOM.
5. To gain knowledge about the role of ctDNA in the perioperative setting
6. To explore the role of adjuvant ZIM+DOM in selected patients after definitive surgical treatment

Conditions and MedDRA coding

Bladder Cancer

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Willing and able to provide written informed consent.
2. Ability to comply with the study procedures and requirements and restrictions in this protocol
3. Age ≥ 18 years.
4. Muscle invasive urothelial carcinoma of the bladder stage cT2-T4cN0- 1cM0. Patients with other histological subtypes [i.e. squamous, adenocarcinoma, etc] can also be included
5. Fit and planned for cystectomy (according to local guidelines)
6. Refusal of neoadjuvant cisplatin-based chemotherapy or patients in whom neoadjuvant cisplatin-based therapy is not appropriate. (This will be determined by the investigator and not solely based in Galsky Criteria)
7. Representative formalin-fixed paraffin-embedded (FFPE) tumor specimens (blocks preferred) or at least 15 unstained slides, with an associated pathology report, for testing at the study sponsor site. Patients with fewer than 15 unstained slides available at baseline (but no fewer than 10) may be eligible following discussion with the PI of the study.
8. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2.
9. Adequate hematologic and end-organ function tests defined by the following: a. WBC ≥ 2.0x109 /L, b. Neutrophils ≥1.5x109 /L, c. Platelets ≥100 x109 /L, d. Hemoglobin ≥ 10 g/dL, e. Creatinine clearance ≥ 30 mL/min as assessed by the CockcroftGault (https://www.mdcalc.com/calc/43/creatinine-clearance-cockcroftgault-equation) f. AST ≤ 2.5 x ULN, g. ALT ≤2.5 x ULN, h. Bilirubin ≤1.5 X ULN.
10. Adequate coagulation (Prothrombin Time [PT]) or International Normalized Ratio [INR] and Activated Partial Thromboplastin Time [aPTT]) ≤ 1.5xULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants.
11. Negative pregnancy test within 3 days of Day 1 Cycle 1 for female patients of childbearing potential.
12. Male patients and female patients of childbearing potential who engage in heterosexual intercourse must agree to use protocol-specified method(s) of contraception as described in annex 5

Exclusion criteria 17

1. Concurrent enrollment in another interventional clinical trial, unless in a follow-up period or it is an observational study.
2. 2. Having received previous anticancer therapy
3. Underlying medical conditions that might make the administration of study drugs hazardous or that might obscure the interpretation of adverse events
4. Patient receiving treatment with inhibitors or inducers of UGT1A1 at the time of enrollment.
5. Patient receiving treatment with high dose systemic corticosteroids (>10 mg of prednisone or its equivalent) within 2 weeks of C1D1.
6. Patients who have received a vaccination within 30 days prior to inclusion (examples include, but are not limited to, intranasal influenza vaccines, typhoid [oral] vaccines, and Bacillus Calmette-Guerin [BCG]). Patients are allowed to receive the COVID-19 vaccine to reduce the risk and complications of COVID-19 infection. The study visits should continue as planned if vaccination occurs while the patient is on the study.
7. Malignancy, other than bladder cancer, in the previous 2 years. Patients with low-risk prostate cancer (defined as Stage T1/T2a, Gleason score ≤ 6, and PSA ≤ 10 ng/mL) appropriately treated or that are treatment-naive and undergoing active surveillance are eligible. Also, noninvasive malignancies such as cervical carcinoma in situ, nonmelanomatous carcinoma of the skin, or ductal carcinoma in situ of the breast, that have undergone potentially curative therapy are not excluded.
8. Major surgical procedure within 4 weeks prior to enrollment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis or treatment of its bladder cancer
9. Severe infection within 4 weeks prior to enrollment in the study including but not limited to hospitalization for complications of infection, bacteremia, or severe pneumonia.
10. Met any of the following criteria for cardiac disease: a. Myocardial infarction or unstable angina pectoris within 6 months of enrollment. b. History of serious ventricular arrhythmia (ie, ventricular tachycardia or ventricular fibrillation), high-grade atrioventricular block, or other cardiac arrhythmias requiring antiarrhythmic medications (except for atrial fibrillation that is well controlled with antiarrhythmic medication). c. History of QT interval prolongation.
11. Patient currently on dialysis.
12. Gastrointestinal perforation within 6 months of enrollment.
13. Patients who have organ allografts
14. Other concurrent medical or psychiatric conditions that, in the Investigator's opinion, may be likely to confound study interpretation or prevent completion of study procedures and follow-up examinations.
15. Known allergy or hypersensitivity to study drugs formulations.
16. Patients who have invasive catheters that under the investigator criteria might put the patient at risk of developing severe complications due to neutropenia [i.e. percutaneous nephrostomy
17. Females who are pregnant, lactating, or intend to become pregnant during their participation in the study.

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. Efficacy of the combination of sacituzumab govitecan, zimberelimab and domvanalimab measured as pathologic complete response (pCR) rates. pCR is defined as absence of residual viable tumor (ypT0) in the radical cystectomy specimen and in the resected lymph nodes (ypN0) (posttreatment).

Secondary endpoints 10

1. Efficacy of the combination of sacituzumab govitecan, zimberelimab and domvanalimab measured as the downstaging rates after neoadjuvant treatment. Downstaging is defined as any non-muscle invasive residual disease after treatment in the cystectomy specimen (i.e ypTis, ypTa, ypT1).
2. Efficacy of neoadjuvant sacituzumab govitecan, zimberelimab and domvanalimab with respect to anti-tumor effects based on investigator assessed disease free survival (DFS). DFS event is defined as any of the following: development of distant metastasis of bladder carcinoma or presence of pelvic recurrence of bladder carcinoma (including soft tissue and regional lymph nodes) or death from any cause
3. Efficacy of neoadjuvant sacituzumab govitecan, zimberelimab and domvanalimab with respect to anti-tumor effects based on overall survival (OS). OS is defined as the time from informed consent signature to death from any cause.
4. Safety and tolerability of the combination of sacituzumab govitecan, zimberelimab and domvanalimab measured as the incidence, nature and severity of adverse events (AEs).
5. Number of patients undergoing cystectomy later than 12 weeks after the last dose of sacituzumab govitecan, zimberelimab and domvanalimab treatment in the pre-operative setting.
6. Cancer associated fibroblast (CAFs) as predictors of response. The differences in CAFs clusters (i.e. subpopulations) will be measured by scRNA seq and signatures analysis in responders vs non-responders, and assessed in combination with other clinical and molecular characteristics.
7. Immune sub-populations as predictors of response
8. ctDNA as a predictor of benefit and marker of relapse.a. ct DNA levels will be measured at baseline, at the end of the neoadjuvant treatment before the cystectomy, after the cystectomy [at the beginning of the adjuvant phase], at the completion of the adjuvant treatment in the cohort assigned to this therapy, and thereafter every three months during follow-up visits for the first year (at weeks 16, 28, 40 and 52) in patients with pCR and negative ctDNA.
9. Efficacy of adjuvant zimberelimab and domvanalimab in a selected population [not pCR and/or +ctDNA] with respect to anti-tumor effects based on investigator assessed disease free survival (DFS). DFS event is defined as any of the following: development of distant metastasis of bladder carcinoma or presence of pelvic recurrence of urothelial carcinoma (including soft tissue and regional lymph nodes) or death from any cause.
10. Efficacy of adjuvant zimberelimab and domvanalimab in a selected population [not pCR and/or +ctDNA] with respect to anti-tumor effects based on overall survival (OS). OS is defined as the time from informed consent signature to death from any cause.

Investigational products

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

Test 3

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fundacion Para El Progreso De La Oncologia En Cantabria

Sponsor organisation

Fundacion Para El Progreso De La Oncologia En Cantabria

Address

Avenida Valdecilla S/n

City

Santander

Postcode

39008

Country

Spain

Scientific contact point

Organisation

Fundacion Para El Progreso De La Oncologia En Cantabria

Contact name

Project Management Unit

Public contact point

Organisation

Fundacion Para El Progreso De La Oncologia En Cantabria

Contact name

Project Management Unit

Third parties 2

Locations

1 EU/EEA country · 10 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 5 files

Public protocol annexes, IB summaries, regulatory submissions and post-authorisation documents registered in CTIS.

Application history

5 submissions — initial application plus substantial / non-substantial modifications