Brief Title
Pre-operative Immunotherapy in Stage II-III Urothelial Cancer
Official Title
A Phase 1b Trial in Stage II-III Urothelial Cancer to Explore Pre-operative Immunotherapy
Brief Summary
This is a phase 1b feasibility study of pre-operative immunotherapy in PD-L1 positive
resectable stage II-III urothelial cancer patients. This study can be adapted or expanded
based on the results obtained.
Detailed Description
This is a phase 1b feasibility study of pre-operative immunotherapy in PD-L1 positive
resectable stage II-III urothelial cancer patients.
Urothelial cancer patients will be included that are diagnosed with either:
- cT2-4aN0M0 OR
- cT1-4aN1-3M0
PD-L1 status will be determined. When PD-L1 CPS is ≥10%, patients will be treated with three
cycles nivolumab 240 mg, q3wk, on day 1, 22, 43.
The primary endpoint is feasibility of pre-operative nivolumab in PD-L1 positive resectable
stage II-III urothelial cancer patients.
After surgery, patients attend study visits at day 8 and at 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. 90 days postoperative, surgical complications
according to the Clavien-dindo classification will be evaluated. Thereafter, patients will be
followed according to standard clinical guidelines. Tumor biopsies/material preservation is
required at baseline and during surgery.
Main secondary endpoints are:
- To identify pathological complete response rates of nivolumab in PD-L1 positive
resectable stage II-III urothelial cancer patients
- To describe immune-related grade 3/4 and all grade toxicities
- To describe RFS and OS
- Translational: Effects of immunotherapy on the tumor microenvironment based on RNA
signatures and changes in immune infiltrates between baseline and resection.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Feasibility of pre-operative nivolumab in PD-L1 positive resectable stage II-III urothelial cancer patients
Secondary Outcome
Pathological complete response rates of nivolumab in PD-L1 positive resectable stage II-III urothelial cancer patients
Condition
Urothelial Carcinoma
Intervention
Nivolumab
Study Arms / Comparison Groups
Nivolumab monotherapy
Description: Day 1: nivolumab 240 mg Day 22: nivolumab 240 mg Day 43: nivolumab 240 mg
Publications
* Includes publications given by the data provider as well as publications identified by National Clinical Trials Identifier (NCT ID) in Medline.
Recruitment Information
Recruitment Status
Drug
Estimated Enrollment
15
Start Date
August 23, 2021
Completion Date
April 30, 2023
Primary Completion Date
April 30, 2023
Eligibility Criteria
Inclusion criteria:
1. Willing and able to provide informed consent
2. Age ≥ 18 years
3. Resectable muscle-invasive UC (upper urinary tract allowed), defined as:
- cT2-4aN0M0 OR
- cT1-4aN1-3M0
4. World Health Organization (WHO) performance Status 0 or 1.
5. Urothelial cancer is the dominant histology (>70%).
6. Formalin-fixed paraffin-embedded (FFPE) tumor specimens in paraffin blocks from
diagnostic TUR available (or equivalent FFPE tumor specimens for upper tract tumors;
at least two biopsy cores available).
7. PD-L1 status must be determined using the 22C3 pharmDx test. Combined positivity score
(CPS) must be >10..
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
as per Cockcroft-Gault formula, AST ≤ 1.5 x ULN, ALT ≤1.5 x ULN, Bilirubin ≤1.5 X ULN
9. Negative pregnancy test (βHCG in blood or urine) for female patients of childbearing
potential within 2 weeks prior to Day 1 Cycle 1.
10. Highly effective contraception for both male and female subjects if the risk of
conception exists. Female patients of childbearing potential must comply with
contraception methods as requested by the study protocol.
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 infection or tuberculosis, or other
active infection requiring therapy at the time of inclusion.
5. Positive tests for Hepatitis B surface antigen or Hepatitis C ribonucleic acid (RNA),
6. Underlying medical conditions that, in the investigator's opinion, will make the
administration of study drug hazardous or obscure the interpretation of adverse events
7. 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 (e.g., CT
scan premedication) will be allowed.
8. Use of other investigational drugs before study drug administration
9. 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.
10. Pregnant and lactating female patients.
11. 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.
12. Severe infections within 2 weeks prior to enrolment in the study including but not
limited to hospitalization for complications of infection, bacteremia, or severe
pneumonia.
13. 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 and unstable angina.
14. Previous intravenous chemotherapy for bladder cancer. Prior low-dose sensitizing
chemotherapy used for combined modality treatment, or radiation alone, is allowed if
patients have recurred after an initial response. Patients with residual disease after
(chemo)radiation for bladder cancer are not eligible.
15. Patients in whom use of a colon segment for urinary diversion is planned.
Gender
All
Ages
18 Years - N/A
Accepts Healthy Volunteers
No
Contacts
, 020-512 9111, [email protected]
Location Countries
Netherlands
Location Countries
Netherlands
Administrative Informations
NCT ID
NCT04871594
Organization ID
M21TUR
Responsible Party
Sponsor
Study Sponsor
The Netherlands Cancer Institute
Collaborators
4SC AG
Study Sponsor
, ,
Verification Date
July 2022