Brief Title
Checkpoint Inhibition With or Without Domatinostat in Urothelial Cancer
Official Title
DOmaTinostat, Nivolumab and Ipilimumab A Phase 1b Study in Stage II-III URothelial cANcer to Explore Pre-operative - TURANDOT
Brief Summary
This is a feasibility study of the addition of domatinostat to pre-operative immune
checkpoint inhibitors in patients with muscle invasive urothelial cancer. This study can be
adapted or expanded to a phase 2 study based on results obtained.
Detailed Description
This is a phase 1b safety, feasibility and proof-of-principle study of the addition of
domatinostat to pre-operative immune checkpoint inhibition (CPI) with nivolumab and
ipilimumab.
Urothelial cancer patients will be included that are diagnosed with either:
- cT2-4aN0M0 OR
- cT1-4aN1-3M0
PD-L1 status will determine the treatment cohort. Within each cohort, patients will be
randomized to receive CPI + domatinostat or CPI alone
Cohort A (PD-L1 CPS≥10% pts):
- Arm A1: Domatinostat 200mg BID d1-56 + nivolumab 240 mg, q3wk, day 1, 22, 43
- Arm A2: 3x nivolumab 240 mg, q3wk, day 1, 22, 43
Cohort B (PD-L1 CPS<10% pts):
- Arm B1: Domatinostat 200mg QD d1-56 + ipilimumab 240 mg day 1, ipilimumab 240 mg +
nivolumab 80 mg day 22, nivolumab 240 mg, day 43
- Arm B2: ipilimumab 240 mg day 1, ipilimumab 240 mg + nivolumab 80 mg day 22, nivolumab
240 mg, day 43
The primary endpoint is feasibility of neo-adjuvant domatinostat + nivolumab +/- ipilimumab
defined by percentage of patients who are able to have surgical resection within 12 weeks
from start of treatment as this is an endpoint that is clinically meaningful for this
population.
After surgery, patients attend study visits at day 8, 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. After this final visit, patients will be followed
according to standard clinical guidelines. Tumor biopsies/material preservation is required
at baseline and during surgery.
Main secondary endpoints are:
- Efficacy, defined as pathological complete response (pCR) (pT0N0 or pTisN0)
- Provide an estimate of all grade toxicities
- Relapse free survival (RFS) and overall survival (OS) An important additional secondary
endpoint is translational. RNA signatures associated with pathological response and RFS
will be determined, as well as characterization of changes in immune infiltrates between
baseline and resection.
Study Phase
Phase 1
Study Type
Interventional
Primary Outcome
Feasibility to complete pre-operative treatment and surgical resection within 12 weeks
Secondary Outcome
Efficacy of domatinostat and immunotherapy
Condition
Urothelial Carcinoma
Intervention
Domatinostat
Study Arms / Comparison Groups
Cohort A1: domatinostat + nivolumab
Description: Day 1-56: domatinostat 200 mg BID 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
40
Start Date
September 15, 2021
Completion Date
April 30, 2023
Primary Completion Date
April 30, 2023
Eligibility Criteria
Inclusion Criteria:
- Resectable muscle-invasive UC (upper urinary tract allowed), defined as: cT2-4aN0M0 OR
cT1-4aN1-3M0
- World Health Organization (WHO) performance Status 0 or 1.
- Urothelial cancer is the dominant histology (>70%).
- 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).
- PD-L1 status must be determined
- 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 ≤ 1.5 x ULN, ALT ≤1.5 x ULN, Bilirubin ≤1.5 X ULN
- Negative pregnancy test (βHCG in urine) within 2 weeks of Day 1 Cycle 1 for female
patients of childbearing potential.
- Highly effective contraception for both male and female subjects if the risk of
conception exists. Female patients of childbearing potential must have a negative
urine or serum pregnancy test before receiving the first dose of study medication and
must comply with contraception methods as requested by the study protocol
Exclusion Criteria:
- 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.
- Documented history of severe autoimmune disease (e.g. inflammatory bowel disease,
myasthenia gravis).
- Prior CTLA-4 or PD-1/PD-L1-targeting immunotherapy.
- Known history of Human Immunodeficiency Virus infection, or tuberculosis, or other
active infection requiring therapy at the time of inclusion.
- 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.
- Underlying medical conditions that, in the investigator's opinion, will make the
administration of study drug hazardous or obscure the interpretation of adverse events
- 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.
- Use of other investigational drugs four weeks before study drug administration
- 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.
- Pregnant and lactating female patients.
- 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.
- 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.
- 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.
- Conditions requiring systemic anti-arrhythmic therapy known to prolong QT/QTc
interval.
- Patients with QTcF interval >480 msec on at least two separate and consecutive ECGs at
screening or a medical history of long-QT-Syndrome.
- Previous intravenous chemotherapy for bladder cancer. Prior low-dose sensitizing
chemotherapy used for combined modality treatment, or radiation alone, is allowed.
- 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
April 2021