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About
TITAN-TCC (0416-ASG) is a Phase 2, open-label study of nivolumab (BMS-936558) monotherapy with additional nivolumab/ipilimumab "boost" cycles in previously untreated* and platinum-based pretreated, 2nd and 3rd line, advanced or metastatic transitional cell carcinoma subjects. Nivolumab is a fully human PD-1 antibody which blocks the respective immune checkpoint in a ligand (PD-L1/PD-L2) independent manner.
[*Update from Jan-2020: First-line cohort was stopped and the inclusion of these patients was terminated]
Full description
This is a Phase 2, single arm study of a tailored immunotherapy approach with nivolumab in adult (≥ 18 years) subjects with previously untreated (1st line)* or pretreated (2nd and 3rd line), surgically unresectable or metastatic TCC (further designated "advanced TCC"). The study targets to recruit 130 untreated (1st line) and 120 pretreated (2nd / 3rd line) patients, respectively. Tumor tissue obtained at least 2 years prior to screening must be available for a central pathology assessment. Subjects must have advanced (not amenable to curative surgery or radiation) or metastatic TCC, and must not have received more than two prior platinum-based chemotherapies for the treatment of advanced TCC.
[*Update from Jan-2020: First-line cohort was stopped and the inclusion of these patients was terminated. According protocol v.5.0 80 2nd/3rd-line patients need to be included]
Enrollment
Sex
Ages
Volunteers
Inclusion criteria
Signed Written Informed Consent
Target Population
Histological evidence of metastatic or surgically unresectable transitional cell carcinoma of the bladder, urethra, ureter, or renal pelvis. Minor histologic variants of transitional cell carcinoma (e.g. squamous cell, comprising <50 % of the tumor overall) are acceptable.
Subjects must have advanced or surgically unresectable TCC (cT4b, any N or any T, N2-N3 or any M1) or having progressed during or after platinum-based first line therapy and up to 1 further treatment line (2nd and 3rd line cohort). Subjects, who have received neoadjuvant or adjuvant cisplatin based chemotherapy are eligible and considered first line provided that progression has occurred >12 months from last therapy [for chemoradiation and adjuvant treatment] or >12 months from last surgery [for neoadjuvant treatment]; in all other patients who received cisplatin based neoadjuvant and/or adjuvant chemotherapy and progression within 12 months this will be considered one line of therapy. [*Update January 2020:First-line cohort has been stopped since 31-Jan-2019 and wont be restarted]
KPS of at least 70% (See Appendix 1)
Measurable disease as per RECIST v1.1 (See Appendix 2)
Formalin-fixed paraffin embedded tumor tissue obtained within 2 years prior to screening must be available and received by the central pathology (tumor block is preferred, alternatively 15 unstained slides). Note that:
Age and Reproductive Status
Males and Females, ≥ 18 years of age
Women of childbearing potential (WOCBP) must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of HCG) within 24 hours prior to the start of study drug.
Women must not be breastfeeding
Women of childbearing potential (WOCBP) must agree to follow instructions for method(s) of contraception for a period of 30 days (duration of ovulatory cycle) plus the time required for the investigational drug to undergo five half lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. WOCBP should use an adequate method to avoid pregnancy for 23 weeks (30 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
Males who are sexually active with WOCBP must agree to follow instructions for method(s) of contraception for a period of 90 days (duration of sperm turnover) plus the time required for the investigational drug to undergo five half lives. The terminal half lives of nivolumab and ipilimumab are up to 25 days and 18 days, respectively. Males who receive nivolumab combined with ipilimumab who are sexually active with WOCBP must continue contraception for 31 weeks (90 days plus the time required for nivolumab to undergo five half-lives) after the last dose of investigational drug.
Investigators shall counsel WOCBP and male subjects who are sexually active with WOCBP on the importance of pregnancy prevention and the implications of an unexpected pregnancy Investigators shall advise WOCBP and male subjects who are sexually active with WOCBP on the use of highly effective methods of contraception. Highly effective methods of contraception have a failure rate of < 1% when used consistently and correctly.
At a minimum, subjects must agree to the use of two methods of contraception, with one method being highly effective and the other method being either highly effective or less effective as listed below:
HIGHLY EFFECTIVE METHODS OF CONTRACEPTION
Male condoms with spermicide
Hormonal methods of contraception including combined oral contraceptive pills, vaginal ring, injectables, implants and intrauterine devices (IUDs) such as Mirena® by WOCBP subject or male subject's WOCBP partner. Female partners of male subjects participating in the study may use hormone based contraceptives as one of the acceptable methods of contraception since they will not be receiving study drug
Nonhormonal IUDs, such as ParaGard®
Tubal ligation
Vasectomy
Complete Abstinence*
LESS EFFECTIVE METHODS OF CONTRACEPTION
Diaphragm with spermicide
Cervical cap with spermicide
Vaginal sponge
Male Condom without spermicide
Progestin only pills by WOCBP subject or male subject's WOCBP partner
Female Condom*.
Exclusion criteria
Target Disease Exceptions
Medical History and Concurrent Diseases
Prior systemic treatment with more than two different chemotherapy regimen (Sequential chemotherapy as a planned sequence to optimize response will count as 1 regimen)
Prior treatment with an anti-PD-1, anti-PD-L1, anti-PD-L2, anti-CD137, or anti CTLA 4 antibody, or any other antibody or drug specifically targeting T-cell co-stimulation or checkpoint pathways.
Any active or recent history of a known or suspected autoimmune disease or recent history of a syndrome that required systemic corticosteroids (> 10 mg daily prednisone equivalent) or immunosuppressive medications except for syndromes which would not be expected to recur in the absence of an external trigger. Subjects with vitiligo or type I diabetes mellitus or residual hypothyroidism due to autoimmune thyroiditis only requiring hormone replacement are permitted to enroll.
Any condition requiring systemic treatment with corticosteroids (> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days prior to first dose of study drug. Inhaled steroids and adrenal replacement steroid doses > 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
Prior malignancy active within the previous 3 years except for
Human immunodeficiency virus (HIV) infection or known acquired immunodeficiency syndrome (AIDS).
Any positive test for hepatitis B or hepatitis C virus indicating acute or chronic infection.
Known medical condition (eg, a condition associated with diarrhea or acute diverticulitis) that, in the investigator's opinion, would increase the risk associated with study participation or study drug administration or interfere with the interpretation of safety results.
Major surgery (eg, nephrectomy) less than 28 days prior to the first dose of study drug.
Anti-cancer therapy less than 28 days prior to the first dose of study drug or palliative, focal radiation therapy less than 14 days prior to the first dose of study drug.
Presence of any toxicities attributed to prior anti-cancer therapy other than neuropathy, alopecia and fatigue, that have not resolved to Grade 1 (NCI CTCAE v4) or baseline before administration of study drug.
Physical and Laboratory Test Findings
Any of the following laboratory test findings:
WBC < 2,000/mm^3
Neutrophils < 1,500/mm^3
Platelets < 100,000/mm^3
AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can have total bilirubin < 3.0 mg/dL)
Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance < 40 mL/min (measured or calculated by Cockroft-Gault formula):
Allergies and Adverse Drug Reaction
Other Exclusion Criteria
Eligibility criteria for this study have been carefully considered to ensure the safety of the study subjects and that the results of the study can be used. It is imperative that subjects fully meet all eligibility criteria.
Subject Re-enrollment: This study permits the re-enrollment of a subject that has discontinued the study as a pre-treatment failure (ie, subject has not been registered / has not been treated). If re-enrolled, the subject must be re-consented.
Primary purpose
Allocation
Interventional model
Masking
169 participants in 1 patient group
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Data sourced from clinicaltrials.gov
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