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Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)

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ClinicalTrials.gov Identifier: NCT03387761
Recruitment Status : Recruiting
First Posted : January 2, 2018
Last Update Posted : September 14, 2020
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Tracking Information
First Submitted Date  ICMJE November 24, 2017
First Posted Date  ICMJE January 2, 2018
Last Update Posted Date September 14, 2020
Actual Study Start Date  ICMJE January 15, 2018
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: October 8, 2019)
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
Original Primary Outcome Measures  ICMJE
 (submitted: December 22, 2017)
Safety as measured by the number of patients that have surgical resection <12 weeks after study start [ Time Frame: At 12 weeks ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 10, 2020)
  • 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
  • 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]
  • 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.
  • 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.
  • 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
  • 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.
  • 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. ]
    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.
Original Secondary Outcome Measures  ICMJE
 (submitted: December 22, 2017)
  • Efficacy of immunotherapy, assessed by by the percentage of pathological complete response rate (pCR) at cystectomy [ Time Frame: At 12 weeks ]
  • Resistance mechanisms are explored by comparing immune (cell) infiltrates in responders and nonresponders [Multiplex immunohistochemistry, RNA seq] [ Time Frame: At 12 weeks ]
  • T-cell (dys)functionality is measured by comparing the transcriptome of tumor-specific T cells in intra-patient pre- and post therapy comparisons. [ Time Frame: re-TUR for T cell lysate transcriptome analysis (screening) and T cell lysate transcriptome analysis on cystectomy tissue (week 9-11) ]
    This component is done in a minority of patients on T cell lysates if a re-TUR pre-treatment was done.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy
Official Title  ICMJE Phase 1B Study to Assess Safety and Efficacy of Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)
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.
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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Intervention Model Description:
Multicenter, open-label phase 1b clinical trial
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Urothelial Carcinoma
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • 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.
    Interventions:
    • Drug: Ipilimumab
    • Drug: Nivolumab
  • 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
    Interventions:
    • Drug: Ipilimumab
    • Drug: Nivolumab
  • 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
    Interventions:
    • Drug: Ipilimumab
    • Drug: Nivolumab
Publications * 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 Oct 12. doi: 10.1038/s41591-020-1085-z. [Epub ahead of print]

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: October 8, 2019)
54
Original Estimated Enrollment  ICMJE
 (submitted: December 22, 2017)
24
Estimated Study Completion Date  ICMJE June 1, 2021
Estimated Primary Completion Date January 1, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
  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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Michiel MS van der Heijden, Dr. +3120 512 9111 ms.vd.heijden@nki.nl
Contact: Nick N van Dijk, M.D. +3120 512 9111 n.v.dijk@nki.nl
Listed Location Countries  ICMJE Netherlands
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03387761
Other Study ID Numbers  ICMJE N17NAB
CA209-9Y4 ( Other Identifier: Bristol-Myers Squibb )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
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
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party The Netherlands Cancer Institute
Study Sponsor  ICMJE The Netherlands Cancer Institute
Collaborators  ICMJE Bristol-Myers Squibb
Investigators  ICMJE
Principal Investigator: Michiel MS van der Heijden, Dr. NKI-AvL
PRS Account The Netherlands Cancer Institute
Verification Date September 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP