Bladder Preservation With Sacituzumab Govitecan + Zimberelimab for Muscle-Invasive Bladder Cancer

NCT06528483 | Not Yet Recruiting Phase 2

• 1 other identifier: PreSAVE INT 2024
• Study Type: interventional
• Target: 63
• Locations: 1 country
• Sites: 1

Brief Summary

Patients with MIBC N0/N1 unwilling or unfit for cystectomy will receive SG + Zimberelimab for 3 cycles of treatment prior of first radiological and TURB re-evaluation. Patients with stable disease or downstaging will continue Zimberelimab up to 1 year. The goal of this trial is to demonstate that Sacituzumab Govitecan + Zimberelimab can avoid cistectomy and can prolong or avoid recurrence to metastatic disease in selected patients with muscle-invasive bladder cancer. The primary endpoint of this trial is Event Free Survival that is defined as 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.

Conditions

Bladder Cancer; Bladder Urothelial Carcinoma; Bladder Neoplasm; Muscle-Invasive Bladder Carcinoma

Keywords

bladder cancer; muscle-invasive bladder cancer; bladder sparing

Outcome Measures

Primary Outcomes (1)

• Event-Free Survival (EFS)

  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

  24 months

Secondary Outcomes (6)

• clinical or pathological downstaging

  24 months

• Number of Participants treated with Pembrolizumab + Enfortumab Vedotin who experience AEs/SAEs

  24 months

• predictive role of miRNA in patients who achieve clinical or pathological downstaging after SG + Zimberelimab treatment

  24 months

• predictive role of ctDNA in patients who achieve clinical or pathological downstaging after SG + Zimberelimab treatment

  24 months

• role of 18FDG-PET in the prediction of response or relapse for N positive patients

  24 months

Study Arms (1)

Sacituzumab Govitecan + Zimberelimab

EXPERIMENTAL

patients will be treated with Sacituzumab Govitecan 1,8q21 plus + Zimberelimab q21 for 3 cycles then radiological imaging and TURB will be repeated and patients with Stability of disease or down staging will continue Zimberelimab until disease progression, or unacceptable toxicities or completion of treatment (16 cycles). Patients with progressive disease after 3 cycles of study intervention will be treated as per clinical practice.

Drug: Sacituzumab Govitecan + Zimberelimab

Interventions

Sacituzumab Govitecan + Zimberelimab DRUG

Sacituzumab Govitecan 7.5 mg/kg IV for 3 cycles Zimberelimab 360 mg IV for 16 cycles Patients will be treated with Sacituzumab Govitecan 1,8q21 plus + Zimberelimab q21 for 3 cycles then radiological imaging and TURB will be repeated and patients with Stability of disease or down staging will continue Zimberelimab until disease progression, or unacceptable toxicities or completion of treatment (16 cycles). Patients with progressive disease after 3 cycles of study intervention will be treated as per clinical practice.

Also known as: TRODELVY, AB122

Sacituzumab Govitecan + Zimberelimab

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Participant is at least 18 years old of age, at the time of providing informed consent.
• The participant (or legally acceptable representative if applicable) provides written informed consent for the trial.
• 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.
• Patients deemed ineligible for Radical Cystectomy (RC) + Retroperitoneal lymphnode dissection (RPNLD) by a urologist and/or oncologist and/or anesthesiology.
• 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).
• Cisplatin-fit patients are admitted if they are unwilling to undergo Radical Cystectomy (RC) and unwilling for cisplatin-based chemotherapy.
• 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.
• 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.
• cN0-1 bladder cancer patients with predominant urothelial histology or Squamous cell histologic variant
• Have adequate organ function as defined as follow (Specimens must be collected within 10 days prior to the start of study intervention):
• 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).
• 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).
• Creatinine clearance ≥ 30 mL/min as assessed by the Cockcroft-Gault equation.
• International normalized ratio (INR)/PT and PTT or aPTT ≤ 1.5 ULN unless patient is currently receiving therapeutic anticoagulant therapy.
• Patients with HIV must be on antiretroviral therapy (ART) and have a well-controlled

You may not qualify if:

• Positive serum pregnancy test (Appendices 9.4) or women who are breastfeeding.
• Known hypersensitivity to the study drug, its metabolites, or formulation excipient.
• Requirement for ongoing therapy with or prior use of any prohibited medications listed in Section.
• 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.
• Have previously received topoisomerase 1 inhibitors.
• 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.
• Patients with neuroendocrine histology will be excluded.
• Have active chronic inflammatory bowel disease (ulcerative colitis, Crohn's disease) or GI perforation within 6 months of enrollment.
• Have active serious infection requiring antibiotics.
• 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.
• 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.
• 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.
• 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.
• 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.
• Any medical condition that, in the investigator's or sponsor's opinion, poses an undue risk to the patient's participation in the study.

Sponsors & Collaborators

• Fondazione IRCCS Istituto Nazionale dei Tumori, Milano: lead
• Gilead Sciences: collaborator

Study Sites (1)

Fondazione Irccs Istituto Nazionale Dei Tumori Di Milano

Milan, 20133, Italy

Location

Related Publications (11)

• Bokarica P, Hrkac A, Gilja I. Re: J. Alfred Witjes, Thierry Lebret, Eva M. Comperat, et al. Updated 2016 EAU Guidelines on Muscle-invasive and Metastatic Bladder Cancer. Eur Urol 2017;71:462-75. Eur Urol. 2017 Aug;72(2):e45. doi: 10.1016/j.eururo.2017.02.031. Epub 2017 Mar 6. No abstract available.

  PMID: 28279514 BACKGROUND

• Softness K, Kaul S, Fleishman A, Efstathiou J, Bellmunt J, Kim SP, Korets R, Chang P, Wagner A, Olumi AF, Gershman B. Radical cystectomy versus trimodality therapy for muscle-invasive urothelial carcinoma of the bladder. Urol Oncol. 2022 Jun;40(6):272.e1-272.e9. doi: 10.1016/j.urolonc.2021.12.015. Epub 2022 Jan 17.

  PMID: 35058142 BACKGROUND

• Royce TJ, Feldman AS, Mossanen M, Yang JC, Shipley WU, Pandharipande PV, Efstathiou JA. Comparative Effectiveness of Bladder-preserving Tri-modality Therapy Versus Radical Cystectomy for Muscle-invasive Bladder Cancer. Clin Genitourin Cancer. 2019 Feb;17(1):23-31.e3. doi: 10.1016/j.clgc.2018.09.023. Epub 2018 Oct 4.

  PMID: 30482661 BACKGROUND

• Mitin T, Hunt D, Shipley WU, Kaufman DS, Uzzo R, Wu CL, Buyyounouski MK, Sandler H, Zietman AL. Transurethral surgery and twice-daily radiation plus paclitaxel-cisplatin or fluorouracil-cisplatin with selective bladder preservation and adjuvant chemotherapy for patients with muscle invasive bladder cancer (RTOG 0233): a randomised multicentre phase 2 trial. Lancet Oncol. 2013 Aug;14(9):863-72. doi: 10.1016/S1470-2045(13)70255-9. Epub 2013 Jul 1.

  PMID: 23823157 BACKGROUND

• James ND, Hussain SA, Hall E, Jenkins P, Tremlett J, Rawlings C, Crundwell M, Sizer B, Sreenivasan T, Hendron C, Lewis R, Waters R, Huddart RA; BC2001 Investigators. Radiotherapy with or without chemotherapy in muscle-invasive bladder cancer. N Engl J Med. 2012 Apr 19;366(16):1477-88. doi: 10.1056/NEJMoa1106106.

  PMID: 22512481 BACKGROUND

• Powles T, Park SH, Voog E, Caserta C, Valderrama BP, Gurney H, Kalofonos H, Radulovic S, Demey W, Ullen A, Loriot Y, Sridhar SS, Tsuchiya N, Kopyltsov E, Sternberg CN, Bellmunt J, Aragon-Ching JB, Petrylak DP, Laliberte R, Wang J, Huang B, Davis C, Fowst C, Costa N, Blake-Haskins JA, di Pietro A, Grivas P. Avelumab Maintenance Therapy for Advanced or Metastatic Urothelial Carcinoma. N Engl J Med. 2020 Sep 24;383(13):1218-1230. doi: 10.1056/NEJMoa2002788. Epub 2020 Sep 18.

  PMID: 32945632 BACKGROUND

• Powles T, Bellmunt J, Comperat E, De Santis M, Huddart R, Loriot Y, Necchi A, Valderrama BP, Ravaud A, Shariat SF, Szabados B, van der Heijden MS, Gillessen S; ESMO Guidelines Committee. Electronic address: clinicalguidelines@esmo.org. Bladder cancer: ESMO Clinical Practice Guideline for diagnosis, treatment and follow-up. Ann Oncol. 2022 Mar;33(3):244-258. doi: 10.1016/j.annonc.2021.11.012. Epub 2021 Nov 30. No abstract available.

  PMID: 34861372 BACKGROUND

• Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2017. CA Cancer J Clin. 2017 Jan;67(1):7-30. doi: 10.3322/caac.21387. Epub 2017 Jan 5.

  PMID: 28055103 BACKGROUND

• Lin N, Zhang M, Bai H, Liu H, Cui J, Ke X, Zhang H, Liu L, Yan D, Jiang Y, Zang A, Qi J, Wang L, Liu Z, Xu B, Zhang Y, Zhang Z, Zhao X, Hu C, Yang S, Zhou H, Shi J, Shao Z, Xiang Y, Zhu J, Song Y, Zhu J. Efficacy and safety of GLS-010 (zimberelimab) in patients with relapsed or refractory classical Hodgkin lymphoma: A multicenter, single-arm, phase II study. Eur J Cancer. 2022 Mar;164:117-126. doi: 10.1016/j.ejca.2021.07.021. Epub 2021 Aug 27.

  PMID: 34462189 BACKGROUND

• Loriot Y, Petrylak DP, Rezazadeh Kalebasty A, Flechon A, Jain RK, Gupta S, Bupathi M, Beuzeboc P, Palmbos P, Balar AV, Kyriakopoulos CE, Pouessel D, Sternberg CN, Tonelli J, Sierecki M, Zhou H, Grivas P, Barthelemy P, Tagawa ST. TROPHY-U-01, a phase II open-label study of sacituzumab govitecan in patients with metastatic urothelial carcinoma progressing after platinum-based chemotherapy and checkpoint inhibitors: updated safety and efficacy outcomes. Ann Oncol. 2024 Apr;35(4):392-401. doi: 10.1016/j.annonc.2024.01.002. Epub 2024 Jan 18.

  PMID: 38244927 BACKGROUND

• Grivas P, Pouessel D, Park CH, Barthelemy P, Bupathi M, Petrylak DP, Agarwal N, Gupta S, Flechon A, Ramamurthy C, Davis NB, Recio-Boiles A, Sternberg CN, Bhatia A, Pichardo C, Sierecki M, Tonelli J, Zhou H, Tagawa ST, Loriot Y. Sacituzumab Govitecan in Combination With Pembrolizumab for Patients With Metastatic Urothelial Cancer That Progressed After Platinum-Based Chemotherapy: TROPHY-U-01 Cohort 3. J Clin Oncol. 2024 Apr 20;42(12):1415-1425. doi: 10.1200/JCO.22.02835. Epub 2024 Jan 23.

  PMID: 38261969 BACKGROUND

MeSH Terms

Conditions

Urinary Bladder Neoplasms

Interventions

sacituzumab govitecan; zimberelimab

Condition Hierarchy (Ancestors)

Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Study Officials

• Giuseppe Procopio, MD

  Fondazione IRCCS Istituto Nazionale dei Tumori di Milano

  PRINCIPAL INVESTIGATOR

Central Study Contacts

Giuseppe Procopio, MD

CONTACT

+ 39 022390 1; giuseppe.procopio@istitutotumori.mi.it

Marco Stellato, MD

CONTACT

+39 022390 3813; marco.stellato@istititutotumori.mi.it

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 19, 2024
• First Posted: July 30, 2024
• Study Start: December 2, 2024
• Primary Completion (Estimated): December 31, 2026
• Study Completion (Estimated): December 31, 2029
• Last Updated: July 30, 2024

Record last verified: 2024-07

Data Sharing

• IPD Sharing: Will not share

Locations

IT (1)