| Eligibility |
Pre-Screening Eligibility
- Male or female subject aged = 18 years.
- Clinically, subject is a candidate for urothelial diagnostic procedure (fresh
soft-tissue biopsy or TURBT).
- Subject meets general medical criteria for consideration of treatment with
immunotherapy using a checkpoint inhibitor.
Treatment Inclusion Criteria:
- Histologically proven transitional cell or urothelial carcinoma.
- Patients with locally advanced or metastatic urothelial carcinoma must meet one of the
following:
- Patients who are not eligible for cisplatin-containing chemotherapy AND whose
tumors express PD-L1 (Combined Positive Score (CPS) = 10 as determined by an
FDA-approved test; OR
- Patients who are not eligible for any platinum-containing chemotherapy regardless
of PD-L1 status.
- Metastatic (any N+ or M1) or locally advanced, unresectable (T4bN0) disease.
- Measurable disease is required as determined by RECIST v1.1.
- Performance Status ECOG 0-2
- Cisplatin-ineligibility based on =1 of the following:
- Estimated creatinine clearance between =30 and <60 ml/min (Cockcroft-Gault
formula)
- ECOG PS>1
- Hearing loss
- Baseline neuropathy > grade 1.
- Patient refusal
- Be greater to or equal to 18 years of age on day of signing informed consent.
- Serum albumin = 2.8 g/dl
- Alkaline phosphatase (ALP) = 3 × upper limit of normal (ULN). ALP = 5 × ULN with
documented bone metastases.
- Negative serum or urine pregnancy test at screening for women of childbearing
potential.
- Highly effective contraception for both male and female subjects throughout the study
and for at least 120 days after last pembrolizumab treatment administration if the
risk of conception exists.
- Must have recovered from adverse effects of any prior surgery, radiotherapy or other
antineoplastic therapy to grade = 2. If notrecovered to grade = 2, these must be
deemed to be irreversible adverse events related to prior surgery and/or radiation
therapy (such as incontinence or sexual dysfunction) per investigator clinical
judgment.
- Recovery to baseline or = Grade 2 CTCAE v5 from toxicities related to any prior
treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive
therapy. Alopecia, sensory neuropathy Grade = 2, or other Grade = 2 not constituting a
safety risk based on investigator's judgment are acceptable.
- Last dose of any radiation therapy > 2 weeks before first dose of study treatment.
- Able to provide informed consent and willing to sign an approved consent form that
conforms to federal and institutional guidelines.
- Adequate organ function as defined in the protocol
Exclusion Criteria:
- Prior chemotherapy for metastatic urothelial carcinoma.
- Prior chemotherapy for localized urothelial carcinoma that has been completed less
than 6 months before registration.
- Variant histologies other than urothelial carcinoma will not be allowed. Patients with
a component of variant histologies will be allowed to enroll, if urothelial carcinoma
is the predominant histology per investigator judgement. Patients with any component
of small cell will be excluded.
- Has received prior treatment with cabozantinib.
- Receipt of any type of small molecule kinase inhibitor (including investigational
kinase inhibitor) within 2 weeks before first dose of study treatment.
- Receipt of any type of cytotoxic, biologic, or other systemic anticancer therapy
(including investigational) within 4 weeks before first dose of study treatment.
- Has received prior therapy with an anti-PD-1, anti-PD-L1, or anti-PD-L2 agent or other
checkpoint inhibitors previously.
- Radiation therapy for bone metastasis = 2 weeks, any other radiation therapy within 4
weeks before first dose of study treatment. Systemic treatment with radionuclides
within 6 weeks before the first dose of study treatment. Subjects with clinically
relevant ongoing complications from prior radiation therapy are not eligible.
- Has known active central nervous system (CNS) metastases and/or carcinomatous
meningitis. Subjects with previously treated brain metastases may participate provided
they are stable (without evidence of progression by imaging for at least 4 weeks prior
to the first dose of trial treatment and any neurologic symptoms have returned to
baseline), have no evidence of new or enlarging brain metastases, and are not using
steroids for at least 7 days prior to trial treatment. This exception does not include
carcinomatous meningitis which is excluded regardless of clinical stability.
- Concomitant anticoagulation with oral anticoagulants except for those specified below.
Allowed anticoagulants are the following:
- Prophylactic use of low-dose aspirin for cardioprotection (per local applicable
guidelines) is permitted.
- Low-dose low molecular weight heparins (LMWH) are permitted.
- Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
rivaroxaban, edoxaban, or apixaban is allowed in subjects without known brain
metastases who are on a stable dose of the anticoagulant for at least 1 week before
the first dose of study treatment without, clinically significant hemorrhagic
complications from the anticoagulation regimen or the tumor.
- The subject has prothrombin time (PT)/INR or partial thromboplastin time (PTT)
test = 1.3 × ULN within 14 days before the first dose of study treatment.
- The subject has uncontrolled, significant intercurrent or recent illness
including, but not limited to, the following conditions:
- Cardiovascular disorders:
- Ongoing congestive heart failure exacerbation or New York Heart Association Class
4, unstable angina pectoris, serious cardiac arrhythmias.
- Uncontrolled hypertension defined as sustained blood pressure (BP) > 150 mm Hg
systolic or > 100 mm Hg diastolic despite optimal antihypertensive treatment.
Uncontrolled hypertension needs to be determined based on persistently high blood
pressure readings over more than 24 hours and should NOT be based on the blood
pressure readings from one clinic visit. Blood pressure readings done at home or
by primary care providers are acceptable. If a blood pressure reading on the day
of screening is high, but there are documented acceptable ( =150 mm Hg systolic
and =100 mm Hg diastolic) blood pressure readings prior to or after the screening
visit (with or without the use of anti-hypertensive medications), patient will
not be considered to have uncontrolled hypertension.
- Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI),
or other ischemic event, or symptomatic thromboembolic event (eg, deep venous
thrombosis, pulmonary embolism) occurring less than or equal to 6 months before
first dose of cabozantinib. [Note: Subjects with a diagnosis of deep vein
thrombosis (DVT) or incidentally detected asympotmatic and sub-segmental
pulmonary embolism (PE) on routine scans are allowed if on a stable dose of
anti-coagulation for at least 1 week before first dose of study treatment].
- Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5
teaspoon (2.5 ml) of red blood, or other history of significant bleeding
(eg, pulmonary hemorrhage) within 12 weeks before first dose.
- Gastrointestinal (GI) disorders including those associated with a high risk of
perforation or fistula formation:
- The subject has evidence of tumor invading the GI tract, active peptic ulcer
disease, inflammatory bowel disease (eg, Crohn's disease), diverticulitis,
cholecystitis, symptomatic cholangitis or appendicitis, acute pancreatitis, acute
obstruction of the pancreatic duct or common bile duct, or gastric outlet
obstruction.
- Abdominal fistula, GI perforation, bowel obstruction, or intra-abdominal abscess
within 6 months before first dose.
Note: Complete healing of an intra-abdominal abscess must be confirmed before first dose.
- Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
manifestation.
- Lesions invading or encasing any major blood vessels.
- Other clinically significant disorders that would preclude safe study participation
per investigator clinical judgement.
- Serious non-healing wound/ulcer/bone fracture.
- Uncompensated/symptomatic hypothyroidism.
- Moderate to severe hepatic impairment (Child-Pugh B or C).
- Other severe acute or chronic medical conditions including immune colitis,
inflammatory bowel disease, immune pneumonitis, pulmonary fibrosis or
psychiatric conditions including recent (within the past year) or active
suicidal ideation or behavior; or laboratory abnormalities that may increase
the risk associated with study participation or study treatment
administration or may interfere with the interpretation of study results
and, in the judgment of the investigator, would make the patient
inappropriate for entry into this study.
- Major surgery (eg, GI surgery, removal or biopsy of brain metastasis) within
8 weeks before first dose of study treatment. Complete wound healing from
major surgery must have occurred 1 month before first dose and from minor
surgery (eg, simple excision, tooth extraction) at least 10 days before
first dose. Subjects with clinically relevant ongoing complications per
investigator clinical judgement from prior surgery are not eligible.
- Corrected QT interval calculated by the Fridericia formula (QTcF) > 500 ms
per electrocardiogram (ECG) within 28 days before first dose of study
treatment.
Note: If a single ECG shows a QTcF with an absolute value > 500 ms, two additional ECGs at
intervals of approximately 3 min must be performed after the initial ECG, and the average
of these three consecutive results for QTcF will be used to determine eligibility.
- Diagnosis of another malignancy within 2 years before first dose of study treatment,
with the exception of those determined by the treating investigator to have a
negligible risk of metastasis or death (such as adequately treated carcinoma in situ
of the cervix, basal or squamous cell skin cancer, ductal carcinoma in situ treated
surgically with curative intent, localized prostate cancer treated with curative
intent and/or no intent for further treatment, or incidental prostate cancer)
- Current use of immunosuppressive medication, EXCEPT for the following: a. intranasal,
inhaled, topical steroids, or local steroid injection (e.g., intra-articular
injection); b. Systemic corticosteroids at physiologic doses = 10 mg/day of prednisone
or equivalent; c. Steroids as premedication for hypersensitivity reactions (e.g., CT
scan premedication).
- Has active autoimmune disease currently requiring systemic treatment with high dose
corticosteroids (dose more than physiologic replacement doses equivalent to prednisone
10 mg daily) or (disease modifying immunosuppressive agents). Replacement therapy
(e.g. thyroxine, insulin, or physiologic corticosteroid replacement therapy for
adrenal or pituitary insufficiency, intranasal, inhaled, topical steroids, or local
steroid injection) is not considered an exclusion.
- Active autoimmune disease that might deteriorate significantly when receiving an
immuno-stimulatory agent per treating physician's clinical judgment. Subjects with
diabetes type I, vitiligo, psoriasis, or hypo- or hyperthyroid diseases not requiring
immunosuppressive treatment are eligible.
- Prior organ transplantation including allogenic stem-cell transplantation.
- Has known history of (non-infectious) pneumonitis that required steroids or has
current pneumonitis.
- Has an active infection currently requiring systemic (intravenous) antibiotic therapy.
- Has a known history of active TB (Bacillus Tuberculosis).
- Has known active Hepatitis B (e.g., HBsAg reactive) or Hepatitis C (e.g., HCV RNA
[qualitative] is detected).
- Has a known history of Human Immunodeficiency Virus (HIV) (HIV 1/2 antibodies).
- Active and inactive vaccinations within 4 weeks of the first dose of pembrolizumab is
prohibited.
- Known prior severe hypersensitivity to investigational products or any component in
its formulations, including known severe hypersensitivity reactions to monoclonal
antibodies (NCI CTCAE v4.03 Grade = 3).
- Is pregnant or breastfeeding, or expecting to conceive or father children within the
projected duration of the trial, starting with the pre-screening or screening visit
through 120 days after the last dose of trial treatment.
- Subjects taking prohibited medications as described in Section 6.8. A washout period
of prohibited medications for a period of at least two weeks or as clinically
indicated should occur prior to the start of treatment.
- Inability to swallow tablets or evidence of impaired intestinal absorption Previous
systemic chemotherapy treatment for urothelial carcinoma, with the exception of
perioperative chemotherapy treatment alone or with concurrent radiation within 6
months prior to treatment.
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