Neo-Adjuvant Bladder Urothelial Carcinoma COmbination-immunotherapy

Urothelial Carcinoma Clinical Trial

— NABUCCO  

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03387761
• Other study ID #: N17NAB
• Secondary ID: CA209-9Y4
• Status: Completed
• Phase: Phase 1
• Start date: January 15, 2018
• Est. completion date: September 13, 2021

Study information

• Verified date: October 2023
• Source: The Netherlands Cancer Institute
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

Description:

This is an 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):

• 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) were 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 was safety. We determined the number of patients that had surgical resection <12 weeks from first infusion, as this is an endpoint that is clinically meaningful for this population. After surgery, patients attended 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 were followed according to standard clinical guidelines. Tumor biopsies/material preservation were required at baseline and during surgery.

In cohort 2, we randomized patients between 2 arms. Here, the main secondary outcomes were:

• 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 was defined as the 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).

Recruitment information / eligibility

• Status: Completed
• Enrollment: 54
• Est. completion date: September 13, 2021
• Est. primary completion date: July 19, 2021
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

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 (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

Related Conditions & MeSH terms

• Carcinoma
• Carcinoma, Transitional Cell
• Urothelial Carcinoma

Intervention

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
• 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

Locations

Country	Name	City	State
Netherlands	Antoni van Leeuwenhoek ziekenhuis	Amsterdam	NH
Netherlands	Radboud UMC	Nijmegen
Netherlands	UMC Utrecht	Utrecht

Sponsors (2)

Lead Sponsor	Collaborator
The Netherlands Cancer Institute	Bristol-Myers Squibb

Country where clinical trial is conducted

Netherlands, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Efficacy of immunotherapy, assessed by by the percentage of pathological complete response rate (pCR) after cystectomy (Cohort 1, followed by Cohort 2a versus 2b)	pCR rate after cystectomy according to pathological response criteria	At 12 weeks
Secondary	Differences in immune infiltrates in responders vs nonresponders	Resistance mechanisms are explored by comparing immune (cell) infiltrates in responders and nonresponders in pre- and post treatment tissue [Multiplex immunohistochemistry, RNA seq]	At 12 weeks
Secondary	T-cell (dys)functionality as measured by comparing the transcriptome of tumor-specific T cells in intra-patient pre- and post therapy tissue	This component is done in a minority of patients on T cell lysates if a re-TUR (transurethral resection) pre-treatment was done.	At 12 weeks
Secondary	Explore whether radiomics-based predictive models can be established for immunotherapy responders vs non-responders (Cohort 1)	CT and MRI images will be assessed in this manner to optimize recognition of an immunotherapy response.	At 12 weeks
Secondary	Provide an estimate of =grade 3 immune-related toxicity in cohorts 2a versus 2b	Immune-related toxicity were compared between cohhort 1 and cohort 2 and between cohorts 2a and 2b	At 12 weeks
Secondary	Monitor peri-surgical complications.	peri-operative complications and morbidity were graded according to the Clavien-Dindo classification.	Until 90 days after surgery.
Secondary	ctDNA in plasma during follow-up	Assessment of ctDNA in plasma during follow-up and at recurrence	During follow-up and with disease recurrence
Secondary	As part of regular follow-up after radical surgery, follow-up CT scans were made after 1 and 2 years.	As part of regular follow-up after radical surgery, follow-up CT scans were made after 1 and 2 years. Additional scans were performed according to local standards.	Until 2 years after surgery (not part of primary study assessment)