Bladder Preservation with Sacituzumab Govitecan + Zimberelimab for MuscleInvasive Bladder cancer in cisplatin-unfit and unwilling for cystectomy patients: phase II trial (preSAVE trial)

Overview

Sponsor-declared trial summary

Key facts

Sponsor

Fondazione IRCCS Istituto Nazionale Dei Tumori

Participant type

Patients

Age range

18-64 years, 65+ years

Gender

Male and Female

Therapeutic area

Diseases [C] - Neoplasms [C04]

Decision date (initial)

2025-10-15

Transition trial

No

Low-intervention

No

Rare-disease indication

No

Vulnerable population

Yes

Funding sources

Gilead Sciences, Inc., a Delaware corporation

External identifiers

EU CT number

2024-516943-14-01

ClinicalTrials.gov

NCT06528483

Trial design

CTIS Part I — objectives, methods, condition coding

Main objective

Scope: Others

To assess event-free survival (EFS) in patients treated with SG + ZIM

Secondary objectives 5

1. To assess clinical or pathological downstaging after SG + Zimberelimab treatment
2. To assess clinical or pathological upstaging after SG + Zimberelimab treatment
3. To assess efficacy and safety of SG + Zimberelimab in platinum-unfit and unwilling to cystectomy UC patients
4. To determine the predictive role of miRNA in patients who achieve clinical or pathological downstaging after SG + Zimberelimab treatment
5. To determine the predictive role of ctDNA in patients who achieve clinical or pathological downstaging after SG + Zimberelimab treatment

Conditions and MedDRA coding

Muscle-Invasive Bladder cancer

Study design 1 period

Regulatory references

Plan to share IPD

No

Eligibility criteria

Principal inclusion / exclusion criteria as submitted by sponsor

Inclusion criteria 12

1. Participant is at least 18 years old of age, at the time of providing informed consent
2. The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
3. Eastern Cooperative Oncology Group (ECOG) Performance Status 0-2. Evaluation of ECOG is to be performed within 7 days prior to the first dose of study intervention.
4. Patients deemed ineligible for Radical Cystectomy (RC) + Retroperitoneal lymphnode dissection (RPNLD) by a urologist and/or oncologist and/or anesthesiology.
5. Cisplatin unfit patients as per Galsky criteria (ECOG Performance Status of 2 and/or creatinine-clearance < 60 ml/min and/or CTCAE Gr ≥ 2 hearing loss and/or CTCAE Gr ≥ 2 neuropathy).
6. Cisplatin-fit patients are admitted if they are unwilling to undergo Radical Cystectomy (RC) and unwilling for cisplatin-based chemotherapy.
7. Patients deemed eligible for surgery will be included if they will be unwilling to undergo RC and will be ineligible and/or unwilling to cisplatin-based chemotherapy.
8. cT2-cT4 bladder cancer patients with predominant urothelial histology or Squamous cell histologic variant with histological confirmed diagnosis of muscle-invasive bladder cancer (MIBC) obtained via a diagnostic or maximal TURBT performed within 90 days before enrollment.
9. cN0-1 bladder cancer patients with predominant urothelial histology or Squamous cell histologic variant.
10. Have adequate organ function as defined as follow (Specimens must be collected within 10 days prior to the start of study intervention): a. Adequate hematologic counts without transfusional or growth factor support within 2 weeks of study treatment initiations (hemoglobin ≥ 9 g/dL, ANC ≥ 1500/mm3, and platelets ≥ 100,000/μL). b. Adequate hepatic function (bilirubin ≤ 1.5 × ULN, AST and ALT ≤ 2.5 × ULN or ≤ 5 × ULN if known liver metastases, and serum albumin > 3 g/dL). c. Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation. d. International normalized ratio (INR)/PT and PTT or aPTT ≤ 1.5 ULN unless patient is currently receiving therapeutic anticoagulant therapy.
11. Patients with HIV must be on antiretroviral therapy (ART) and have a well-controlled HIV infection/disease defined as: a. Patients on ART must have a CD4+ T-cell count ≥ 350 cells/mm3 at time of screening. b. Patients on ART must have achieved and maintained virologic suppression defined as confirmed HIV RNA level below 50 copies/mL or the lower limit of qualification (below the limit of detection) using the locally available assay at the time of screening and for at least 12 weeks prior to screening. c. Patients on ART must have been on a stable regimen, without changes in drugs or dose modification, for at least 4 weeks prior to study entry (Day 1). d. The combination ART regimen must not contain any medications that may interfere with SN-38 metabolism
12. Women of childbearing potential (WOCBP) and males with a WOCBP partner could be included if they accept to use highly effective contraception or be abstinent from heterosexual intercourse and refrain from donating sperm or eggs, as specified in Appendix 2.

Exclusion criteria 28

1. Patients with evidence of metastatic disease or N2-N3 disease according to AJCC/TNM staging VIII edition, defined by imaging
2. Positive serum pregnancy test (Appendix 2) or women who are breastfeeding.
3. Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
4. Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section 4.6.2.
5. Have had a prior anticancer biologic agent within 4 weeks prior to enrollment or have had prior chemotherapy or targeted small molecule therapy. Patients participating in observational studies are eligible.
6. Have previously received topoisomerase 1 inhibitors.
7. Have an active second malignancy. Note: patients with a history of malignancy that have been completely treated, with no evidence of active cancer for 3 years prior to enrollment, or patients with surgically cured tumors with low risk of recurrence (eg, nonmelanoma skin cancer, histologically confirmed complete excision of carcinoma in situ, or similar) are allowed to enroll. Other exception are localized prostate cancer with a Gleason score of 6 (treated within the last 24 months or untreated and under surveillance) and localized prostate cancer with a Gleason score of 3+4 that has been treated more than 6 months prior to full study screening and considered to have a very low risk of recurrence.
8. Patients with Non-Muscle Invasive bladder Cancer (NMIBC)
9. Patients with absolute contraindication to immunotherapy as active autoimmune disease that has required systemic treatment in past 2 years or hypersensitivity to Zimberelimab
10. Patients with absolute contraindication to Sacitizumab Govitecan (hypersensitivity to SG)
11. Urothelial Carcinomas of other sites (eg, upper tract [ureter, renal pelvis], urethra)
12. Additional non-urothelial malignancy that is progressing or has required active anticancer treatment < o equal to 3 years of study initiation. Participants with basal cell carcinoma of the skin, squamous cell carcinoma of the skin or carcinoma in situ (eg, breast carcinoma, cervical cancer) who have undergone potentially curative therapy are not excluded. Participants with curatively treated localized prostate cancer are not excluded
13. Has received any prior systemic treatment, chemoradiation and/or radiation therapy for MIBC or NMIBC. Prior treatment for NMIBC with intravesical instillation therapy such as Bacillus Calmette-Guérin or intravesical chemotherapy is permitted. Prior systemic (including but not limited to anti-PD-1/L1 treatment) received for NMIBC is not permitted
14. Any prior radiotherapy to the bladder
15. Prior partial cystectomy of the bladder to remove any NIMBC or MIBC
16. Patients with neuroendocrine histology will be excluded.
17. Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn’s disease) or GI perforation within 6 months of enrollment.
18. Have active serious infection requiring antibiotics.
19. Have known history of HIV-1 or 2 (or positive HIV-1/2 antibody, if done at screening) with detectable viral load OR taking medications that may interfere with SN-38 metabolism.
20. Have active hepatitis B virus (HBV) or hepatitis C virus (HCV). In patients with a history of HBV or HCV, patients with detectable viral loads will be excluded. a. Patients who test positive for hepatitis B surface antigen (HBsAg). Patients who test positive for hepatitis B core antibody (anti-HBc) will require HBV DNA by quantitative polymerase chain reaction (PCR) for confirmation of active disease. b. Patients who test positive for HCV antibody. Patients who test positive for HCV antibody will require HCV RNA by quantitative PCR for confirmation of active disease. Patients with a known history of HCV or a positive HCV antibody test will not require a HCV antibody at screening and will only require HCV RNA by quantitative PCR for confirmation of active disease.
21. Have 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.
22. Any medical condition that, in the investigator’s or sponsor’s opinion, poses an undue risk to the patient’s participation in the study.
23. Use of other investigational drugs (drugs not marketed for any indication) within 28 days or 5 half-lives (whichever is longer) of first dose of study drug.
24. Psychiatric or substance abuse disorder that would interfere with the participants’ ability to cooperate with the requirements of the study.
25. Have received a live virus vaccination within 30 days of planned treatment start. Seasonal flu and COVID-19 vaccines that do not contain live virus are permitted.
26. Have an active autoimmune disease that required systemic treatment in past 2 years (ie, with use of disease-modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (eg, thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency) is not considered a form of systemic treatment.
27. Are receiving chronic systemic steroids (> 10 mg/day prednisone equivalent). Use of topical, inhalational, intranasal, and intraocular steroids will be permitted.
28. Meet 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).

Endpoints

Primary and secondary outcome measures (English text)

Primary endpoints 1

1. To assess event-free survival (EFS). Event’s components: clinical evidence of new or progressing nodal or any distant metastatic disease, radical cystectomy, or death due to any cause from date of inclusion to the first documentation of a EFS event. Patients last known to be EFS event-free are censored at the date of last event-free cystoscopy and/or CT scan. Those patients without disease assessment who are still alive will be censored at date of inclusion in the trial

Secondary endpoints 3

1. To assess clinical or pathological downstaging after SG + Zimberelimab treatment
2. To assess efficacy and safety of SG + Zimberelimab in unfit and unwilling to cystectomy UC patients
3. To determine the predictive role of biomarkers in tissue and blood in patients who achieve clinical or pathological downstaging after SG + Zimberelimab treatment

Investigational products

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

Test 2

Sponsors and contacts

Sponsor organisations, regulatory contacts, third parties

Fondazione IRCCS Istituto Nazionale Dei Tumori

Sponsor organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Address

Via Giacomo Venezian 1

City

Milan

Postcode

20133

Country

Italy

Scientific contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Prof. Giuseppe Procopio

Public contact point

Organisation

Fondazione IRCCS Istituto Nazionale Dei Tumori

Contact name

Prof. Giuseppe Procopio

Locations

1 EU/EEA country · 7 investigational sites

By country

Investigational sites

Results and documents

Annex IV summary of results, Annex V layperson summary, and all documents registered in CTIS for this trial

Documents 9 files

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

Application history

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