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

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ClinicalTrials.gov Identifier: NCT03534804
Recruitment Status : Recruiting
First Posted : May 23, 2018
Last Update Posted : December 7, 2018
Sponsor:
Collaborator:
Exelixis
Information provided by (Responsible Party):
University of Utah

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Metastatic Urothelial Carcinoma Bladder Cancer Drug: Cabozantinib Drug: Pembrolizumab Phase 2

Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 39 participants
Intervention Model: Single Group Assignment
Intervention Model Description: This is an open label, non-randomized phase 2 study
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: Cabozantinib Plus Pembrolizumab as First-Line Therapy for Cisplatin-Ineligible Advanced Urothelial Carcinoma (PemCab)
Actual Study Start Date : September 18, 2018
Estimated Primary Completion Date : September 2023
Estimated Study Completion Date : September 2023


Arm Intervention/treatment
Experimental: Cabozantinib and Pembrolizumab, all patients Drug: Cabozantinib
Cabozantinib is administered at 40 mg oral daily
Other Name: XL184

Drug: Pembrolizumab
Pembrolizumab will be administered at a fixed dose of 200mg intravenously every 3 weeks.




Primary Outcome Measures :
  1. Overall Response Rate (ORR) [ Time Frame: 12 months ]
    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 :
  1. Progression-free survival (PFS) at 6 months (PFS6) [ Time Frame: 6 months ]
    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.

  2. Overall Survival (OS) [ Time Frame: Patients are expected to stay on treatment for approximately 12 months; 18 months ]
    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.

  3. Occurrence of Adverse Events and Serious Adverse Events [ Time Frame: 12 months ]
    To evaluate toxicities associate with the combination treatment. Adverse events will be collected beginning with study treatment and tabulated according to drug attribution.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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 standard of care eligibility criteria for consideration of treatment with immunotherapy using a checkpoint inhibitor following surgical resection.

Treatment Inclusion Criteria:

  • Histologically proven muscle-invasive transitional cell or urothelial carcinoma.
  • 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.
  • Adequate organ function as defined in the protocol
  • 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.
  • Recovery to baseline or ≤ Grade 1 CTCAE v4 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.

Exclusion Criteria:

  • 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.
  • Small-cell or sarcomatoid component in histology
  • 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 in the adjuvant setting.
  • 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 (eg, warfarin, direct thrombin and Factor Xa inhibitors) or platelet inhibitors (eg, clopidogrel).

Allowed anticoagulants are the following:

  • Low-dose aspirin for cardioprotection (per local applicable guidelines) is permitted.
  • Low-dose low molecular weight heparins (LMWH) are permitted.
  • Anticoagulation with therapeutic doses of LMWH is allowed in subjects without known brain metastases who are on a stable dose of LMWH for at least 6 weeks before first dose of study treatment, and who have had no 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 7 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.
    • Stroke (including transient ischemic attack [TIA]), myocardial infarction (MI), or other ischemic event, or thromboembolic event (eg, deep venous thrombosis, pulmonary embolism) within 6 months before first dose.
    • Class 3 congestive heart failure
  • 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.

  • 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.
  • 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.

    • 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 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 within 30 min 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 that has required systemic treatment in the past 2 years (i.e. with use of disease modifying 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 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 requiring systemic 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 and while on trial 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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03534804


Contacts
Contact: Jill Broghammer 801-213-6232 jill.broghammer@hci.utah.edu

Locations
United States, Utah
Huntsman Cancer Institute Recruiting
Salt Lake City, Utah, United States, 84112
Contact: Jill Broghammer    801-213-6232    jill.broghammer@hci.utah.edu   
Principal Investigator: Neeraj Agarwal, MD         
Sponsors and Collaborators
University of Utah
Exelixis

Responsible Party: University of Utah
ClinicalTrials.gov Identifier: NCT03534804     History of Changes
Other Study ID Numbers: HCI104688
First Posted: May 23, 2018    Key Record Dates
Last Update Posted: December 7, 2018
Last Verified: December 2018

Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:
Carcinoma
Urinary Bladder Neoplasms
Carcinoma, Transitional Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Neoplasms by Site
Urinary Bladder Diseases
Urologic Diseases
Pembrolizumab
Cisplatin
Antineoplastic Agents