Clinical Trials /

Cabozantinib in Combination With Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer

NCT04878029

Description:

This phase I/Ib trial seeks to find out the best dose, possible benefits and/or side effects of cabozantinib in combination with enfortumab vedotin in treating urothelial cancer that has spread to nearby tissues and lymph nodes (locally advanced) or other parts of the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to a toxic agent called vedotin. Enfortumab attaches to nectin-4 tumor cells in a targeted way and delivers vedotin to kill them. Cabozantinib in combination with enfortumab vedotin may be safe and effective in treating locally advanced or metastatic urothelial cancer.

Related Conditions:
  • Urothelial Carcinoma
Recruiting Status:

Not yet recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: Cabozantinib in Combination With Enfortumab Vedotin for Locally Advanced or Metastatic Urothelial Cancer
  • Official Title: A Phase I/Ib Open Label, Single-Arm Study of Cabozantinib in Combination With Enfortumab Vedotin (EV) in the Treatment of Locally Advanced or Metastatic Urothelial Cancer

Clinical Trial IDs

  • ORG STUDY ID: STUDY00002329
  • SECONDARY ID: NCI-2021-01365
  • SECONDARY ID: STUDY00002329
  • SECONDARY ID: WINSHIP5259-21
  • SECONDARY ID: P30CA138292
  • NCT ID: NCT04878029

Conditions

  • Infiltrating Bladder Urothelial Carcinoma With Squamous Differentiation
  • Locally Advanced Urothelial Carcinoma
  • Metastatic Urothelial Carcinoma
  • Unresectable Urothelial Carcinoma

Interventions

DrugSynonymsArms
Cabozantinib S-malateBMS-907351, Cabometyx, Cometriq, XL-184, XL184Treatment (cabozantinib, enfortumab vedotin)
Enfortumab VedotinAGS 22ME, AGS-22M6E, Anti-Nectin 4 ADC ASG-22CE, Anti-nectin-4 Monoclonal Antibody-Drug Conjugate AGS-22M6E, ASG-22CE, Enfortumab Vedotin-ejfv, PadcevTreatment (cabozantinib, enfortumab vedotin)

Purpose

This phase I/Ib trial seeks to find out the best dose, possible benefits and/or side effects of cabozantinib in combination with enfortumab vedotin in treating urothelial cancer that has spread to nearby tissues and lymph nodes (locally advanced) or other parts of the body (metastatic). Cabozantinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Enfortumab vedotin is a monoclonal antibody, enfortumab, linked to a toxic agent called vedotin. Enfortumab attaches to nectin-4 tumor cells in a targeted way and delivers vedotin to kill them. Cabozantinib in combination with enfortumab vedotin may be safe and effective in treating locally advanced or metastatic urothelial cancer.

Detailed Description

      PRIMARY OBJECTIVES:

      I. To determine the recommended phase II dose (RP2D) of cabozantinib s-malate (cabozantinib)
      and enfortumab vedotin 1.25 mg/kg on days 1, 8 and 15 of a 28-day cycle based on safety and
      tolerability. (Phase I dose escalation) II. To evaluate the ongoing safety and tolerability
      of cabozantinib and enfortumab vedotin in a dose expansion cohort. (Phase Ib dose expansion)

      SECONDARY OBJECTIVES:

      I. Obtain preliminary evidence of anti-tumor activity of the combination of cabozantinib and
      enfortumab vedotin by assessing the objective response rate (ORR) using Response Evaluation
      Criteria in Solid Tumors (RECIST) version (v)1.1.

      II. Progression-free survival (PFS). III. Overall survival (OS). IV. Disease control rate by
      RECIST v1.1.

      EXPLORATORY OBJECTIVES:

      I. To assess the pharmacokinetic (PK) profile of cabozantinib during treatment with
      enfortumab vedotin.

      II. To evaluate the effect of the combination on selected biomarkers in the tumor
      microenvironment, systemic circulation and gut microbiome and their relationship with
      efficacy of the combination.

      III. To evaluate quality of life, frailty and sarcopenia before, during and at the time of
      treatment completion.

      OUTLINE: This is dose-escalation study of cabozantinib.

      Patients receive cabozantinib orally (PO) once daily (QD) on days 1-28 and enfortumab vedotin
      intravenously (IV) on days 1, 8, and 15. Cycles repeat every 28 days in the absence of
      disease progression or unacceptable toxicity.

      After completion of study treatment, patients are followed up at 30 days and then every 12
      weeks.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (cabozantinib, enfortumab vedotin)ExperimentalPatients receive cabozantinib PO QD on days 1-28 and enfortumab vedotin IV on days 1, 8, and 15. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity.
  • Cabozantinib S-malate
  • Enfortumab Vedotin

Eligibility Criteria

        Inclusion Criteria:

          -  Histologically-documented urothelial carcinoma (squamous differentiation or mixed cell
             types allowed if urothelial carcinoma is present)

          -  Metastatic disease or unresectable locally-advanced disease

          -  Must have received prior treatment with a checkpoint inhibitor (CPI). A CPI is defined
             as a programmed cell death protein 1 (PD-1) or programmed death-ligand 1 (PD-L1)
             inhibitor alone or with any other combination

          -  Must either have prior treatment with platinum-containing chemotherapy or be
             ineligible at time of enrollment

          -  Recovery to baseline or =< grade 1 Common Terminology Criteria for Adverse Events
             (CTCAE) v5.0 from toxicities related to any prior treatments, unless AE(s) are
             clinically nonsignificant and/or stable on supportive therapy

          -  Tumor tissue samples must be available for submission prior to initiation of study
             treatment or patient must be willing to undergo repeat tumor biopsy

          -  Must have measurable disease according to Response Evaluation Criteria in Solid Tumors
             (RECIST) (Version 1.1)

          -  An Eastern Cooperative Oncology Group (ECOG) performance status score of =< 2

          -  Must be >= 18 years of age

          -  Absolute neutrophil count (ANC) >= 1500/uL without granulocyte colony-stimulating
             factor support (within 28 days before first dose of study treatment)

          -  White blood cell count >= 2500/uL (within 28 days before first dose of study
             treatment)

          -  Platelets >= 100,000/uL without transfusion (within 28 days before first dose of study
             treatment)

          -  Hemoglobin >= 9 g/dL (within 28 days before first dose of study treatment)

          -  Alanine aminotransferase (ALT), aspartate aminotransferase (AST), and alkaline
             phosphatase (ALP) =< 3 x upper limit of normal (ULN). ALP =< 5 x ULN with documented
             bone metastases (within 28 days before first dose of study treatment)

          -  Total bilirubin =< 1.5 x ULN (for subjects with Gilbert's disease =< 3 x ULN) (within
             28 days before first dose of study treatment)

          -  Prothrombin (PT)/international normalized ratio (INR) or partial thromboplastin time
             (PTT) test < 1.3 x the laboratory ULN unless participant is receiving anticoagulant
             therapy as long as PT or activated partial thromboplastin time (aPTT) is within
             therapeutic range of intended use of anticoagulants (within 28 days before first dose
             of study treatment)

          -  Calculated creatinine clearance >= 30 mL/min (>= 0.5 mL/sec) using the Cockcroft-Gault
             equation (within 28 days before first dose of study treatment)

          -  Urine protein/creatinine ratio (UPCR) =< 1 mg/mg (=< 113.2 mg/mmol), or 24-hour (h)
             urine protein =< 1 g (within 28 days before first dose of study treatment)

          -  Capable of understanding and complying with the protocol requirements and must have
             signed the informed consent document

          -  Sexually active fertile subjects and their partners must agree to use medically
             accepted methods of contraception (e.g., barrier methods, including male condom,
             female condom, or diaphragm with spermicidal gel) during the course of the study and
             for 4 months after the last dose of study treatment

          -  Female subjects of childbearing potential must not be pregnant at screening. Female
             subjects are considered to be of childbearing potential unless one of the following
             criteria are met: documented permanent sterilization (hysterectomy, bilateral
             salpingectomy, or bilateral oophorectomy) or documented postmenopausal status (defined
             as 12 months of amenorrhea in a woman > 45 years-of-age in the absence of other
             biological or physiological causes. In addition, females < 55 years-of-age must have a
             serum follicle stimulating (FSH) level > 40 mIU/mL to confirm menopause). Note:
             Documentation may include review of medical records, medical examinations, or medical
             history interview by study site

        Exclusion Criteria:

          -  Prior treatment with cabozantinib

          -  Prior enrollment in an enfortumab vedotin study or prior treatment with other
             monomethyl auristatin E (MMAE)-based antibody-drug conjugates (ADCs)

          -  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 2 weeks before first dose of study treatment

          -  Radiation therapy within 2 weeks before first dose of study treatment. Systemic
             treatment with radionuclides within 6 weeks before first dose of study treatment

          -  Known brain metastases or cranial epidural disease unless adequately treated with
             radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks
             prior to first dose of study treatment after radiotherapy or at least 4 weeks prior to
             first dose of study treatment after major surgery (e.g., removal or biopsy of brain
             metastasis). Subjects must have complete wound healing from major surgery or minor
             surgery before first dose of study treatment. Eligible subjects must be neurologically
             asymptomatic and without corticosteroid treatment at the time of first dose of study
             treatment

          -  Concomitant anticoagulation with coumarin agents (e.g., warfarin), direct thrombin
             inhibitors (e.g., dabigatran), direct factor Xa inhibitor betrixaban, or platelet
             inhibitors (e.g., clopidogrel). Allowed anticoagulants are the following:

               -  Prophylactic use of low-dose aspirin for cardio-protection (per local applicable
                  guidelines) and low-dose low molecular weight heparins (LMWH).

               -  Therapeutic doses of LMWH or anticoagulation with direct factor Xa inhibitors
                  rivaroxaban, edoxaban, or apixaban in subjects without known brain metastases who
                  are on a stable dose of the anticoagulant for at least 1 week before first dose
                  of study treatment without clinically significant hemorrhagic complications from
                  the anticoagulation regimen or the tumor

          -  The subject has uncontrolled, significant intercurrent or recent illness including,
             but not limited to, the following conditions:

               -  Cardiovascular disorders:

                    -  Congestive heart failure New York Heart Association Class 3 or 4, unstable
                       angina pectoris, serious cardiac arrhythmias.

                    -  Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm
                       Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive
                       treatment.

                    -  Stroke (including transient ischemic attack [TIA]), myocardial infarction
                       (MI), or other ischemic event, or thromboembolic event (e.g., deep venous
                       thrombosis, pulmonary embolism) within 6 months before first dose of study
                       treatment

                         -  Subjects with a diagnosis of incidental, subsegmental pulmonary
                            embolism (PE) or deep venous thrombosis (DVT) within 6 months are
                            allowed if stable, asymptomatic, and treated with a stable dose of
                            permitted anticoagulation for at least 1 week before first dose of
                            study treatment

               -  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 (e.g., 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 of study treatment.

                    -  Note: Complete healing of an intra-abdominal abscess must be confirmed
                       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 (e.g., pulmonary
             hemorrhage) within 12 weeks before first dose of study treatment

          -  Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease
             manifestation

          -  Lesions invading or encasing any major blood vessels

          -  Ongoing sensory or motor neuropathy grade >= 2

          -  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).

               -  Uncontrolled diabetes mellitus defined as a hemoglobin A1C >= 8%

          -  Major surgery (e.g., laparoscopic nephrectomy, GI surgery, removal or biopsy of brain
             metastasis) within 2 weeks before first dose of study treatment. Minor surgeries
             within 10 days before first dose of study treatment. Subjects must have complete wound
             healing from major surgery or minor surgery before first dose of study treatment.
             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 14 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

          -  Pregnant or lactating females

          -  Inability to swallow tablets

          -  Previously identified allergy or hypersensitivity to components of the study treatment
             formulations

          -  Any other active malignancy at time of first dose of study treatment or diagnosis of
             another malignancy within 3 years prior to first dose of study treatment that requires
             active treatment, except for locally curable cancers that have been apparently cured,
             such as basal or squamous cell skin cancer, superficial bladder cancer, or prostate,
             cervix, or breast
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of adverse events
Time Frame:Up to study completion (estimated 5 years)
Safety Issue:
Description:Will be assessed by the Common Terminology Criteria for Adverse Events version 5.0.

Secondary Outcome Measures

Measure:Objective response rate
Time Frame:Through study completion, an average of 1 year
Safety Issue:
Description:Based on cross-sectional imaging. Categorized according to Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria. ORR will be summarized with the 2-sided 95% confidence interval (CI) using the Clopper-Pearson method in the full analysis set (FAS).
Measure:Progression-free survival
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months.
Safety Issue:
Description:Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval.
Measure:Overall survival
Time Frame:From date of randomization until the date of first documented progression or date of death from any cause, whichever came first, assessed up to 100 months.
Safety Issue:
Description:Kaplan-Meier methods will be used to estimate median survival time or time-specific survival rate with 95% confidence interval.
Measure:Disease control rate (DCR)
Time Frame:Up to study completion (estimated 5 years)
Safety Issue:
Description:Defined as the percentage of patients who achieve complete response, partial response and stable disease as per RECIST v1.1. DCR will be summarized with the 2-sided 95% CI using the Clopper-Pearson method in the FAS.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:Emory University

Last Updated

May 7, 2021