Clinical Trials /

Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma



This is an open label, non-randomized phase 2 study of the combination of pembrolizumab and cabozantinib to assess overall response rate (ORR), progression free survival at 6 months (PFS6), and overall survival (OS) in patients with metastatic urothelial carcinoma (UC) ineligible for cisplatin.

Related Conditions:
  • Transitional Cell Carcinoma
Recruiting Status:



Phase 2

Trial Eligibility



  • Brief Title: Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma
  • Official Title: Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma (PemCab)

Clinical Trial IDs

  • ORG STUDY ID: HCI104688
  • NCT ID: NCT03534804


  • Metastatic Urothelial Carcinoma
  • Bladder Cancer


CabozantinibXL184Cabozantinib and Pembrolizumab, all patients
PembrolizumabCabozantinib and Pembrolizumab, all patients


This is an open label, non-randomized phase 2 study of the combination of pembrolizumab and cabozantinib to assess overall response rate (ORR), progression free survival at 6 months (PFS6), and overall survival (OS) in patients with metastatic urothelial carcinoma (UC) ineligible for cisplatin.

Trial Arms

Cabozantinib and Pembrolizumab, all patientsExperimental
  • Cabozantinib
  • Pembrolizumab

Eligibility Criteria

        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.

          -  The following qualifications for patients with locally advanced or metastatic
             urothelial carcinoma:

               -  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;

               -  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

               -  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

          -  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

          -  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

               -  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

          -  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

        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

          -  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.
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Overall Response Rate (ORR)
Time Frame:12 months
Safety Issue:
Description:To evaluate measurable disease overall response rate (ORR). Subjects will be evaluated by CT scans at regular intervals for disease assessment by RECISTv1.1 criteria for the duration of treatment

Secondary Outcome Measures

Measure:Progression-free survival (PFS) at 6 months (PFS6)
Time Frame:6 months
Safety Issue:
Description:To evaluate progression-free survival (PFS) at 6 months (PFS6). Subjects will be evaluated by CT scans at regular intervals for disease assessment by RECISTv1.1 criteria for the duration of treatment.
Measure:Overall Survival (OS)
Time Frame:Patients are expected to stay on treatment for approximately 12 months; 18 months
Safety Issue:
Description:To evaluate Overall Survival (OS). Subjects will be evaluated using Kaplan-Meier estimation for survival for up to 6 months after discontinuation of study treatment; patients surviving longer than 6 months will be censored.
Measure:Occurrence of Adverse Events and Serious Adverse Events
Time Frame:12 months
Safety Issue:
Description:To evaluate toxicities associate with the combination treatment. Adverse events will be collected beginning with study treatment and tabulated according to drug attribution.


Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of Utah

Last Updated

August 6, 2021