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Trial record 1 of 1 for:    NCT03387761
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Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)

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ClinicalTrials.gov Identifier: NCT03387761
Recruitment Status : Completed
First Posted : January 2, 2018
Last Update Posted : April 28, 2022
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Study Description
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Brief Summary:
In cohort 1 of this study, we used an attenuated schedule of neoadjuvant ipilimumab and nivolumab. This cohort has now fully enrolled, and all eligible patients had resection of the bladder <12 weeks from 1st cycle (23/24, 96%). In the current multicenter extension (cohort 2), n=30 patients will be randomized between two neoadjuvant treatment schemes, both based upon an attenuated schedule of neoadjuvant ipilimumab and nivolumab.

Condition or disease Intervention/treatment Phase
Urothelial Carcinoma Drug: Ipilimumab Drug: Nivolumab Phase 1

Detailed Description:

This is a open-label phase Ib trial to evaluate three different schedules of preoperative ipilimumab and nivolumab. Urothelial cancer patients will be included that are diagnosed with either:

  • cT3-4aN0M0 OR
  • T1-4aN1-3M0

Cohort 1 (n=24) (Completed):

  • Day 1: Ipilimumab 3 mg/kg
  • Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
  • Day 43: Nivolumab 3 mg/kg
  • Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection

Patients in cohort 2 (n=30) will be randomized between cohort 2a and 2b

Cohort 2a (n=15):

  • Day 1: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
  • Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg
  • Day 43: Nivolumab 3 mg/kg
  • Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection

Cohort 2b (n=15):

  • Day 1: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg
  • Days 22: Ipilimumab 1 mg/kg + Nivolumab 3 mg/kg
  • Day 43: Nivolumab 3 mg/kg
  • Day 56-84: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection

The primary endpoint for cohort 1 in this trial is safety. We will determine the number of patients that have surgical resection <12 weeks from first infusion, as this is an endpoint that is clinically meaningful for this population. After surgery, patients attend study visits at day 8 and day 29 . Their final study visit for physical examination and laboratory testing is at day 57 (+/- 7 days), which is scheduled to anticipate late-onset adverse events (particularly endocrine). After this final visit, patients will be followed according to standard clinical guidelines. Tumor biopsies/material preservation is required at baseline and during surgery.

In cohort 2, we will randomize patients between 2 arms. Here, the main secondary outcomes are:

  • To compare the efficacy of pre-operative ipilimumab + nivolumab in cohort 1 (sequenced ipilimumab/nivolumab), versus cohort 2a (ipi 3 mg/kg and nivo 1 mg/kg) and cohort 2b (ipi 1 mg/kg and nivo 3 mg/kg). Efficacy is defined as pCR rate at resection.
  • Provide an estimate of ≥grade 3 immune-related toxicity in the ipi3/nivo1 and ipi1/nivo3 cohorts as opposed to the initial cohort (Cohort 1)

An important additional secondary endpoint is translational. The main testable hypothesis is that a significant percentage of nonresponse can be explained by immune-inhibitory processes. Absence of immune infiltrates, presence of significant numbers of regulatory T-cells and presence of significant numbers of myeloid-derived suppressor cells will be compared between responders and nonresponders. The efficacy will be defined as the percentage of pathological complete response (pCR) at cystectomy (secondary endpoint).

Study Design
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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 54 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description: Multicenter, open-label phase 1b clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Phase 1B Study to Assess Safety and Efficacy of Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)
Actual Study Start Date : January 15, 2018
Actual Primary Completion Date : July 19, 2021
Actual Study Completion Date : September 13, 2021

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Cohort 1: Ipi + Nivo
  • 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

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
Other Names:
  • BMS-734016
  • Yervoy

Drug: Nivolumab

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

Other Names:
  • BMS-936558
  • Opdivo
Experimental: Cohort 2a: high-Ipi + low-Nivo
  • 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

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
Other Names:
  • BMS-734016
  • Yervoy

Drug: Nivolumab

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

Other Names:
  • BMS-936558
  • Opdivo
Experimental: Cohort 2b: low-Ipi + high-Nivo
  • 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

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
Other Names:
  • BMS-734016
  • Yervoy

Drug: Nivolumab

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

Other Names:
  • BMS-936558
  • Opdivo


Outcome Measures
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Primary Outcome Measures :
  1. Number of patients that have surgical resection <12 weeks after study start (Cohort 1) [ Time Frame: At 12 weeks ]
    Percentage of patients that underwent surgery within 12 weeks after study start will be assessed


Secondary Outcome Measures :
  1. Efficacy of immunotherapy, assessed by by the percentage of pathological complete response rate (pCR) after cystectomy (Cohort 1, followed by Cohort 2a versus 2b) [ Time Frame: At 12 weeks ]
    pCR rate after cystectomy according to pathological response criteria

  2. Differences in immune infiltrates in responders vs nonresponders [ Time Frame: At 12 weeks ]
    Resistance mechanisms are explored by comparing immune (cell) infiltrates in responders and nonresponders in pre- and post treatment tissue [Multiplex immunohistochemistry, RNA seq]

  3. T-cell (dys)functionality as measured by comparing the transcriptome of tumor-specific T cells in intra-patient pre- and post therapy tissue [ Time Frame: At 12 weeks ]
    This component is done in a minority of patients on T cell lysates if a re-TUR (transurethral resection) pre-treatment was done.

  4. Explore whether radiomics-based predictive models can be established for immunotherapy responders vs non-responders (Cohort 1) [ Time Frame: At 12 weeks ]
    CT and MRI images will be assessed in this manner to optimize recognition of an immunotherapy response.

  5. Provide an estimate of ≥grade 3 immune-related toxicity in cohorts 2a versus 2b [ Time Frame: At 12 weeks ]
    Immune-related toxicity will be compared versus cohort 1 and between cohorts 2a and 2b

  6. Monitor peri-surgical complications. [ Time Frame: Until 90 days after surgery. ]
    peri-operative complications and morbidity will be graded according to the Clavien-Dindo classification.

  7. ctDNA in plasma during follow-up [ Time Frame: During follow-up and with disease recurrence ]
    Assessment of ctDNA in plasma during follow-up and at recurrence

  8. As part of regular follow-up after radical surgery, follow-up CT scans will we be made after 1 and 2 years. [ Time Frame: Until 2 years after surgery (not part of primary study assessment) ]
    As part of regular follow-up after radical surgery, follow-up CT scans will we be made after 1 and 2 years. Additional scans should be performed according to local standards.


Eligibility Criteria
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Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Willing and able to provide informed consent
  2. Age ≥ 18 years
  3. 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.

5. 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.

10. 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.

Exclusion Criteria:

  1. 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.
  2. Documented history of severe autoimmune disease (e.g. inflammatory bowel disease, myasthenia gravis).
  3. Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy.
  4. Known history of Human Immunodeficiency Virus, positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA), active tuberculosis, or other active infection requiring therapy at the time of inclusion.
  5. Underlying medical conditions that, in the investigator's opinion, will make the administration of study drug hazardous or obscure the interpretation of adverse events
  6. 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.
  7. Use of other investigational drugs before study drug administration

  8. 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.

  9. Pregnant and lactating female patients.
  10. 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.
  11. 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.
  12. 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.
  13. Previous intravenous chemotherapy for bladder cancer. Prior chemoradiation is allowed.
  14. Patients in whom use of a colon segment for urinary diversion is planned
Contacts and Locations
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Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03387761


Locations
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Netherlands
Antoni van Leeuwenhoek ziekenhuis
Amsterdam, NH, Netherlands, 1066CX
Radboud UMC
Nijmegen, Netherlands
UMC Utrecht
Utrecht, Netherlands
Sponsors and Collaborators
The Netherlands Cancer Institute
Bristol-Myers Squibb
Investigators
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Principal Investigator: Michiel MS van der Heijden, Dr. NKI-AvL
More Information
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Publications automatically indexed to this study by ClinicalTrials.gov Identifier (NCT Number):

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Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT03387761    
Other Study ID Numbers: N17NAB
CA209-9Y4 ( Other Identifier: Bristol-Myers Squibb )
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: April 28, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes
Keywords provided by The Netherlands Cancer Institute:
Urothelial cancer
Bladder cancer
Cancer
Resectable
Operable
 immunotherapy
Ipilimumab
Nivolumab
Neo-Adjuvant
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Nivolumab
 Ipilimumab
Antineoplastic Agents, Immunological
Antineoplastic Agents
Immune Checkpoint Inhibitors
Molecular Mechanisms of Pharmacological Action