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]
Inclusion Criteria:
- Signed Written Informed Consent
- Subjects or legally acceptable representatives must have signed and dated an
IRB/IEC approved written informed consent form in accordance with regulatory and
institutional guidelines. This must be obtained before the performance of any
protocol related procedures that are not part of normal subject care.
- Subjects or legally acceptable representatives must be willing and able to comply
with scheduled visits, treatment schedule, laboratory testing, and other
requirements of the study.
- 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:
1. Fine Needle Aspiration [FNA] and bone metastases samples (without soft
tissue component) are not acceptable for submission).
2. Tumor lesions used for newly acquired biopsies should not be target lesions,
unless there are no other lesions.
- 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.
- Comment: Azoospermic males and WOCBP who are continuously not heterosexually
active are exempt from contraceptive requirements. However, WOCBP must still
undergo pregnancy testing as described in this section.
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*
- *Complete abstinence is defined as complete avoidance of heterosexual intercourse
and is an acceptable form of contraception for all study drugs. Subjects who
choose complete abstinence are not required to use a second method of
contraception, but female subjects must continue to have pregnancy tests.
Acceptable alternate methods of highly effective contraception must be discussed
in the event that the subject chooses to forego 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*.
- * A male and female condom must not be used together
Exclusion Criteria:
- Target Disease Exceptions
- Any history of or current CNS metastases. Baseline imaging of the brain by MRI
(preferred) or CT scan is required within 28 days prior to registration in
2nd/3rd line patients only.
- 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
1. locally curable cancers that have been apparently cured, such as basal or
squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ
of the prostate, cervix, or breast.
2. Patients in active surveillance for prostate cancer
- 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:
1. WBC < 2,000/mm^3
2. Neutrophils < 1,500/mm^3
3. Platelets < 100,000/mm^3
4. AST or ALT > 3 x ULN (> 5 x ULN if liver metastases are present)
5. Total Bilirubin > 1.5 x ULN (except subjects with Gilbert Syndrome, who can
have total bilirubin < 3.0 mg/dL)
6. Serum creatinine > 1.5 x upper limit of normal (ULN) or creatinine clearance
< 40 mL/min (measured or calculated by Cockroft-Gault formula):
- Female CrCl = [(140 - age in years) x weight in kg x 0.85] / [72 x
serum creatinine in mg/dL]
- Male CrCl = [(140 - age in years) x weight in kg x 1.00] / [72 x serum
creatinine in mg/dL]
- Allergies and Adverse Drug Reaction
- History of severe hypersensitivity reaction to any monoclonal antibody or any
constituent of the products.
- Other Exclusion Criteria
- Prisoners or subjects who are involuntarily incarcerated
- Subjects who are compulsorily detained for treatment of either a psychiatric or
physical (eg, infectious disease) illness
- Participation in another clinical intervention trial 30 days prior to
registration
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.
