Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy

NCT03387761 | Completed Phase 1 DMC

• 2 other identifiers: N17NABCA209-9Y4
• Study Type: interventional
• Target: 54
• Locations: 1 country
• Sites: 3

Brief Summary

In cohort 1 of this study, we used an attenuated schedule of neoadjuvant ipilimumab and nivolumab. In the multicenter extension (cohort 2), 30 patients were randomized between two neoadjuvant treatment schemes, both based upon an attenuated schedule of neoadjuvant ipilimumab and nivolumab.Both cohorts are completed.

Conditions

Urothelial Carcinoma

Keywords

Urothelial cancer; Bladder cancer; Cancer; Resectable; Operable; immunotherapy; Ipilimumab; Nivolumab; Neo-Adjuvant

Outcome Measures

Primary Outcomes (1)

• Number of patients that had surgical resection <12 weeks after study start (Cohort 1)

  Percentage of patients that underwent surgery within 12 weeks after study start were assessed

  At 12 weeks

Secondary Outcomes (8)

• Efficacy of immunotherapy, assessed by by the percentage of pathological complete response rate (pCR) after cystectomy (Cohort 1, followed by Cohort 2a versus 2b)

  At 12 weeks

• Differences in immune infiltrates in responders vs nonresponders

  At 12 weeks

• T-cell (dys)functionality as measured by comparing the transcriptome of tumor-specific T cells in intra-patient pre- and post therapy tissue

  At 12 weeks

• Explore whether radiomics-based predictive models can be established for immunotherapy responders vs non-responders (Cohort 1)

  At 12 weeks

• Provide an estimate of ≥grade 3 immune-related toxicity in cohorts 2a versus 2b

  At 12 weeks

Study Arms (3)

Cohort 1: Ipi + Nivo

EXPERIMENTAL

* Day 1: Ipilimumab 3 mg/kg i.v. * Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v.

Drug: Ipilimumab; Drug: Nivolumab

Cohort 2a: high-Ipi + low-Nivo

EXPERIMENTAL

* Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. * Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84

Drug: Ipilimumab; Drug: Nivolumab

Cohort 2b: low-Ipi + high-Nivo

EXPERIMENTAL

* Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v. * Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg i.v. * Day 43: Nivolumab 3 mg/kg i.v. * Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection, day 56-84

Drug: Ipilimumab; Drug: Nivolumab

Interventions

Ipilimumab DRUG

For Cohort 1: * Day 1: Ipilimumab 3 mg/kg * Days 22: Ipilimumab 3 mg/kg For Cohort 2a: * Day 1: Ipilimumab 3 mg/kg * Days 22: Ipilimumab 3 mg/kg For Cohort 2b: * Day 1: Ipilimumab 1 mg/kg * Days 22: Ipilimumab 1 mg/kg

Also known as: BMS-734016, Yervoy

Cohort 1: Ipi + Nivo; Cohort 2a: high-Ipi + low-Nivo; Cohort 2b: low-Ipi + high-Nivo

Nivolumab DRUG

For Cohort 1: * Day 22: Nivolumab 1 mg/kg * Day 43: Nivolumab 3 mg/kg For Cohort 2a: * Days 1 and 22: Nivolumab 1 mg/kg * Day 43: Nivolumab 3 mg/kg For Cohort 2b: \- Days 1, 22 and 43: Nivolumab 3 mg/kg

Also known as: BMS-936558, Opdivo

Cohort 1: Ipi + Nivo; Cohort 2a: high-Ipi + low-Nivo; Cohort 2b: low-Ipi + high-Nivo

Eligibility Criteria

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

You may qualify if:

• Willing and able to provide informed consent
• Age ≥ 18 years
• High-risk resectable urothelial cancer (upper urinary tract allowed) defined as stage III UC:
• cT3-4aN0M0 OR cT1-4aN1-3M0 4. Refusal of neoadjuvant/induction cisplatin-based chemotherapy or patients in whom neoadjuvant cisplatin based therapy is not appropriate.
• \. World Health Organization (WHO) performance Status 0 or 1. 6. Urothelial cancer is the dominant histology (\>70%). 7. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from diagnostic TUR available (or any other FFPE tumor specimens for upper tract tumors).8. Screening laboratory values must meet the following criteria: WBC ≥ 2.0x109/L, Neutrophils ≥1.0x109/L, Platelets ≥100 x109/L, Hemoglobin ≥5.5 mmol/L, GFR\>30 ml/min, AST ≤ 2.5 x ULN, ALT ≤2.5 x ULN, Bilirubin ≤1.5 X ULN 9. Negative pregnancy test within 2 weeks of Day 1 Cycle 1 for female patients of childbearing potential.
• \. For female patients of childbearing potential to use a highly effecting form(s) of contraception (i.e. one that results in a low failure rate \[\<1% per year\] when used consistently and correctly) and to continue its use for 180 days after the last dose of immunotherapy Adequate contraceptive methods are: condom, sterilization, other barrier contraceptive measures preferably in combination with condoms, oral contraceptives, intra-uterine device.

You may not qualify if:

• Subjects with active autoimmune disease in the past 2 years. Patients with diabetes mellitus, properly controlled hypothyroidism or hyperthyroidism, vitiligo, psoriasis or other mild skin disease can still be included.
• Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
• Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy.
• Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events
• Medical condition requiring the use of immunosuppressive medications, with the exceptions of intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses, which are not to exceed 10 mg/day of prednisone, or an equivalent corticosteroid. Steroids as premedication for hypersensitivity reactions (eg, CT scan premedication) will be allowed.
• Use of other investigational drugs before study drug administration
• Malignancy, other than urothelial cancer, in the previous 2 years, with a high chance of recurrence (estimated \>10%). Patients with low risk prostate cancer (defined as Stage T1/T2a, Gleason score
• ≤ 6, and PSA ≤ 10 ng/mL) who are treatment-naive and undergoing active surveillance are eligible.
• Pregnant and lactating female patients.
• Major surgical procedure within 4 weeks prior to enrolment or anticipation of need for a major surgical procedure during the course of the study other than for diagnosis.
• Severe infections within 4 weeks prior to enrolment in the study including but not limited to hospitalization for complications of infection, bacteraemia, or severe pneumonia.
• Significant cardiovascular disease, such as New York Heart Association cardiac disease (Class II or greater), myocardial infarction within 3 months prior to enrolment, unstable arrhythmias, or unstable angina.
• Previous intravenous chemotherapy for bladder cancer. Prior chemoradiation is allowed.
• Patients in whom use of a colon segment for urinary diversion is planned

Sponsors & Collaborators

• The Netherlands Cancer Institute: lead
• Bristol-Myers Squibb: collaborator

Study Sites (3)

Antoni van Leeuwenhoek ziekenhuis

Amsterdam, North Holland, 1066CX, Netherlands

Location

Radboud UMC

Nijmegen, Netherlands

Location

UMC Utrecht

Utrecht, Netherlands

Location

Related Publications (3)

• Stockem CF, van Dorp J, van Dijk N, Vis DJ, Harkes R, van den Broek B, Alkemade M, Broeks A, Hendricksen K, Boellaard TN, de Feijter JM, van Montfoort ML, Daletzakis A, van der Heijden AG, Meijer RP, Mehra N, Wessels LFA, van Rhijn BWG, Suelmann BBM, van der Heijden MS. Final clinical analysis of pre-operative ipilimumab and nivolumab in locally advanced urothelial cancer and exploration of tumor-draining lymph node composition: The NABUCCO trial. Eur J Cancer. 2025 Oct 16;229:115731. doi: 10.1016/j.ejca.2025.115731. Epub 2025 Aug 21.

  PMID: 40934711 DERIVED

• van Dorp J, Pipinikas C, Suelmann BBM, Mehra N, van Dijk N, Marsico G, van Montfoort ML, Hackinger S, Braaf LM, Amarante T, van Steenis C, McLay K, Daletzakis A, van den Broek D, van de Kamp MW, Hendricksen K, de Feijter JM, Boellaard TN, Meijer RP, van der Heijden AG, Rosenfeld N, van Rhijn BWG, Jones G, van der Heijden MS. High- or low-dose preoperative ipilimumab plus nivolumab in stage III urothelial cancer: the phase 1B NABUCCO trial. Nat Med. 2023 Mar;29(3):588-592. doi: 10.1038/s41591-022-02199-y. Epub 2023 Feb 2.

  PMID: 36732628 DERIVED

• van Dijk N, Gil-Jimenez A, Silina K, Hendricksen K, Smit LA, de Feijter JM, van Montfoort ML, van Rooijen C, Peters D, Broeks A, van der Poel HG, Bruining A, Lubeck Y, Sikorska K, Boellaard TN, Kvistborg P, Vis DJ, Hooijberg E, Schumacher TN, van den Broek M, Wessels LFA, Blank CU, van Rhijn BW, van der Heijden MS. Preoperative ipilimumab plus nivolumab in locoregionally advanced urothelial cancer: the NABUCCO trial. Nat Med. 2020 Dec;26(12):1839-1844. doi: 10.1038/s41591-020-1085-z. Epub 2020 Oct 12.

  PMID: 33046870 DERIVED

MeSH Terms

Conditions

Carcinoma, Transitional Cell; Urinary Bladder Neoplasms; Neoplasms

Interventions

Ipilimumab; Nivolumab

Condition Hierarchy (Ancestors)

Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Urologic Neoplasms; Urogenital Neoplasms; Neoplasms by Site; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Urinary Bladder Diseases; Urologic Diseases; Male Urogenital Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins

Study Officials

• Michiel MS van der Heijden, Dr.

  NKI-AvL

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Model Details: Multicenter, open-label phase 1b clinical trial

Study Record Dates

• First Submitted: November 24, 2017
• First Posted: January 2, 2018
• Study Start: January 15, 2018
• Primary Completion: July 19, 2021
• Study Completion: January 7, 2025
• Last Updated: March 5, 2025

Record last verified: 2025-03

Data Sharing

• IPD Sharing: Will not share

Locations

NL (3)