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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 : March 12, 2018
Sponsor:
Collaborator:
Bristol-Myers Squibb
Information provided by (Responsible Party):
The Netherlands Cancer Institute

Brief Summary:
In this single-arm trial we will investigate the safety of short-term preoperative therapy with ipilimumab and nivolumab in patients with high-risk resectable urothelial cancer. We will determine the number of patients that have surgical resection at <12 weeks, as this is an endpoint that is clinically meaningful for this population. 24 patients will be included. All patients will be receiving a sequenced scheme of Nivolumab and Ipilimumab.

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

Detailed Description:

This is a Phase Ib single-arm trial to evaluate the safety of short-term preoperative therapy with ipilimumab and nivolumab in patients with high-risk resectable urothelial cancer (upper urinary tract allowed), defined as:

  • T3-4aN0 OR
  • T1, cN+ OR
  • T1, any N, resectable retroperitoneal lymph node metastasis

The primary endpoint of this trial is safety. We will determine the number of patients that have surgical resection at < 12 weeks, as this is an endpoint that is clinically meaningful for this population. patients. Patients will be receiving:

  • Day 1: Ipilimumab 3 mg/kg (wk1)
  • Days 22: Ipilimumab 3 mg/kg + Nivolumab 1 mg/kg (wk4)
  • Day 43: Nivolumab 3 mg/kg (wk 7)
  • Day 57-71: Radical cystectomy or nefro/ureterectomy with appropriate lymph node dissection (wk9-11) In the initial phase, 12 patients will be enrolled and followed until resection. If toxicity is manageable, enrolment will continue to a total of 24. CT scans will be required at baseline and week 7 to evaluate response to immunotherapy.

Post-cystectomy, a post-cystectomy study visit including laboratory tests will be performed on day 7 to evaluate toxicity. Patients attend their final study visit for physical examination and laboratory testing 28 days post-surgery. After this final visit, patients will be followed according to standard clinical guidelines. Tumor biopsies/material preservation is required at baseline and during surgery.

An important 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 : Interventional  (Clinical Trial)
Estimated Enrollment : 24 participants
Intervention Model: Single Group Assignment
Intervention Model Description: Single-arm open 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
Estimated Primary Completion Date : June 1, 2020
Estimated Study Completion Date : December 1, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Ipilimumab + Nivolumab
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
Day 1: Ipilimumab 3 mg/kg Days 22: Ipilimumab 3 mg/kg
Other Names:
  • BMS-734016
  • Yervoy

Drug: Nivolumab
Days 22: Nivolumab 1 mg/kg Day 43: Nivolumab 3 mg/kg
Other Names:
  • BMS-936558
  • Opdivo




Primary Outcome Measures :
  1. Number of patients that have surgical resection <12 weeks after study start [ 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) at cystectomy [ 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.



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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:

    cT3-4aN0 OR T1, cN+ OR T1, any N, resectable retroperitoneal lymph node metastasis

  4. Stage III (cT3-4aN0) patients who refuse neoadjuvant cisplatin based chemotherapy or in whom neoadjuvant cisplatin based therapy is not appropriate. Stage IV (lymph node metastases) cisplatin-eligible patients will be consulted on cisplatin-based chemotherapy as well.
  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.

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


Contacts
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

Locations
Netherlands
Antoni van Leeuwenhoek ziekenhuis Recruiting
Amsterdam, NH, Netherlands, 1066CX
Contact: Nick van Dijk, MD    +31205121664    n.v.dijk@nki.nl   
Contact: Michiel van der Heijden, MD, PhD    +31205128243    ms.vd.heijden@nki.nl   
Sponsors and Collaborators
The Netherlands Cancer Institute
Bristol-Myers Squibb
Investigators
Principal Investigator: Michiel MS van der Heijden, Dr. NKI-AvL

Responsible Party: The Netherlands Cancer Institute
ClinicalTrials.gov Identifier: NCT03387761     History of Changes
Other Study ID Numbers: N17NAB
First Posted: January 2, 2018    Key Record Dates
Last Update Posted: March 12, 2018
Last Verified: March 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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:
Carcinoma
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Nivolumab
Antibodies, Monoclonal
Antineoplastic Agents
Immunologic Factors
Physiological Effects of Drugs