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Brief Title: Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy

Phase 1B Study to Assess Safety and Efficacy of Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy (NABUCCO)

INTRODUCTION

  • Org Study ID: N17NAB
  • Secondary ID: CA209-9Y4
  • NTC ID: NCT03387761
  • Sponsor: The Netherlands Cancer Institute

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).


  • Overall Status
    Recruiting
  • Start Date
    January 15, 2018
  • Phase
    Phase 1
  • Study Type
    Interventional

PRIMARY OUTCOMES

Primary Outcome 1 - Measure: Number of patients that have surgical resection <12 weeks after study start (Cohort 1)

Primary Outcome 1 - Timeframe: At 12 weeks

CONDITION

  • Urothelial Carcinoma

ELIGIBILITY


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

Gender: All

Minimum Age: N/A

Maximum Age: 18 Years

Healthy Volunteers: No

OFFICIAL INFORMATION

Name: Michiel MS van der Heijden, Dr.

Role: Principal Investigator

Affiliation: NKI-AvL

Overall Contact

Name: Michiel MS van der Heijden, Dr.

Phone: +3120 512 9111

Email: ms.vd.heijden@nki.nl

LOCATION

Facility Status Contact
Facility: Antoni van Leeuwenhoek ziekenhuis
Amsterdam, NH 1066CX
Netherlands 		Status: Recruiting Contact:
Nick van Dijk, MD
+31205121664
n.v.dijk@nki.nl

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