Trial of an Alternative Cabozantinib Dosing Schedule in Metastatic Renal Cell Carcinoma

Study Overview
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Brief Summary
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This is a multi-site, single arm phase II trial of cabozantinib for IMDC all-risk frontline metastatic renal cell carcinoma (mRCC) patients OR any line mRCC patients who have not previously been treated with cabozantinib.

Detailed Description
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This is a multi-site, single arm phase II trial of cabozantinib for IMDC all-risk frontline metastatic renal cell carcinoma (mRCC) patients OR any line mRCC patients who have not previously been treated with cabozantinib. Study will accrue a total of 49 patients who would start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments. The de-escalation would be fine-tuned and adjustments would be made in 10 mg average daily dosing increments by utilizing alternate day dosing schedules (e.g 60 mg/40 mg every other day) rather than decreasing by 20 mg (table 1). The maximum dose of cabozantinib is 60 mg daily. Cycles would be 28 days, with weekly follow-up for cycle 1 and bi-weekly follow-up for cycle 2 to allow for prompt dose adjustments, and then monthly. At each check-in, patients that have met the established protocol criteria (outlined in Section 6.3) and were not yet at the maximum dose of 60 mg daily would be eligible for dose-escalation. Patients would also be dose de-escalated as determined by the investigator. Patients who de-escalate may be allowed to re-escalate in the future.

Official Title
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GU-187: Phase II Trial of an Alternative Cabozantinib Dosing Schedule in Metastatic Renal Cell Carcinoma

Conditions
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Metastatic Renal Cell Carcinoma, Clear-cell Metastatic Renal Cell Carcinoma

Intervention / Treatment
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* Drug: Cabozantinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: - Histologically or cytologically confirmed advanced RCC with any clear cell or non-clear cell component. 100% sarcomatoid is permissible. At least one measurable lesion as defined by RECIST version 1.1 Patient may have had any number of prior therapies a. At least 10 pts will be included that have not been treated with a prior VEGF TKI. These patients could be first line, or could have had prior single agent or combination immunotherapy b. Patients being treated in the first line setting must either be IMDC favorable risk or ineligible to receive an immune checkpoint inhibitor No evidence of pre-existing uncontrolled hypertension as assessed by investigator. Patients may undergo adjustments or additions to their antihypertensive regimen before or during screening to achieve optimal BP control. Age > 18 years. ECOG performance status 0 - 2 Patients must have normal organ and marrow function as defined below • Leukocytes > 2,000/mcL • Absolute neutrophil count > 1,500/mcL • Platelets > 100,000/mcL • Hgb > 9 g/dL (>90 g/L • Total bilirubin ≤ 1.5 x ULN (with the exception of of individuals with Gilberts syndrome who may have a bilirubin <3.0 mg/dL) • AST/ALT (SGOT/SGPT)/ALP < 3 x ULN ALP ≤ 5x ULN with documented bone metastases. Albumin > 2.8 g/dL • Creatinine clearance > 30 Ml/min/1.73 m2 for patients with creatinine levels above institutional normal Total bilirubin ≤ 1.5 x ULN (for subjects with Gilbert's disease ≤ 3X ULN) PT/INR or PTT > 1.3 x the laboratory ULN Ability to understand and willingness to sign a written informed consent and HIPAA 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 Exclusion Criteria: Patients who have had systemic anti-cancer therapy or radiotherapy within 14 days prior to entering the study. a. Radiation therapy for bone metastases within 2 weeks, any other radiation therapy within 4 weeks, or systemic treatment with radionuclides within 6 weeks before first dose of study treatment. Ongoing clinically relevant complications from prior radiation therapy would preclude eligibility. Patients with prior therapy with cabozantinib. Patients may not be receiving any other investigational agents History of allergic reactions or hypersensitivity attributed to compound of similar chemical or biologic composition to the agent(s) used in this study Current use or anticipated need for treatment with drugs or foods that are known strong CYP3A4 inhibitors and inducers. Refer to Section 5.3.2 for detailed information. The topical use of these medications (if applicable), such as 2% ketoconazole cream, is allowed. 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: a. Prophylactic use of low-dose aspirin for cardio-protection (per local applicable guidelines) and low-dose low molecular weight heparins (LMWH). b. 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. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements. a. Cardiovascular disorders: i. Congestive heart failure New York Heart Association Class 3 or 4, unstable angina pectoris, serious cardiac arrhythmias. ii. QTcF > 500 msec within 14 days before first dose of study treatment. iii. Uncontrolled hypertension defined as sustained blood pressure (BP) > 140 mm Hg systolic or > 90 mm Hg diastolic despite optimal antihypertensive treatment. iv. 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, sub-segmental PE or DVT within 6 months are allowed if stable, asymptomatic, and treated with a stable dose of permitted anticoagulation (see exclusion criterion #6) for at least 1 week before first dose of study treatment. b. Gastrointestinal (GI) disorders including those associated with a high risk of perforation or fistula formation: i. 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. ii. 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. Cavitating pulmonary lesion(s) or known endotracheal or endobronchial disease manifestation. Lesions invading or encasing any major blood vessels. Subjects with lesions invading the intrahepatic vasculature, including portal vein, hepatic vein, and hepatic artery, are eligible. 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. Patients are excluded if they have active, symptomatic brain metastases or leptomeningeal metastases. Subjects with known brain metastases are eligible if metastases have been treated and there is no magnetic resonance imaging (MRI) evidence of progression for four weeks (after treatment is complete and within 28 days prior to study drug administration). Second malignancy requiring active systemic treatment. Exceptions include non-melanoma skin cancers, localized breast or prostate cancer on adjuvant hormonal therapy. Gastrointestinal abnormalities including: Inability to swallow tablets; Requirement for intravenous alimentation; Prior surgical procedures affecting absorption including total gastric resection; Active gastrointestinal bleeding as evidenced by hematemesis, hematochezia or melena in the past 3 months without evidence of resolution documented by endoscopy or colonoscopy; Malabsorption syndromes Significant baseline hepatic impairment, as cabozantinib is typically dose-adjusted with hepatic dysfunction. Known HIV-positive patients on combination antiretroviral therapy are ineligible because of the potential for pharmacokinetic interactions with cabozantinib. Pregnant or breast feeding. Refer to section 4.4 for further detail. Clinically significant hematuria, hematemesis, or hemoptysis of > 0.5 tsp (2.5ml) of red blood, or other history of significant bleeding within 12 weeks before the first dose of study treatment Other clinically significant disorders: serious non-healing wound/ulcer/bone fracture; uncompensated/symptomatic hypothyroidism; moderate to severe hepatic impairment (Child-Pugh B or C)

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Interventional Model Description: 49 patients will start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cabozantinib<br>Cabozantinib treatment will start at 40 mg of cabozantinib daily and dose escalate or de-escalate based on pre-specified criteria and at set dosing schedules to allow for smaller median dose changes between adjustments. The de-escalation would be fine-tuned and adjustments would be made in 10 mg average daily dosing increments by utilizing alternate day dosing schedules (e.g 60 mg/40 mg every other day) rather than decreasing by 20 mg (table 1). The maximum dose of cabozantinib is 60 mg daily. Cycles would be 28 days, with weekly follow-up for cycle 1 and bi-weekly follow-up for cycle 2 to allow for prompt dose adjustments, and then monthly. At each check-in, patients that have met the established protocol criteria (outlined in Section 6.3) and were not yet at the maximum dose of 60 mg daily would be eligible for dose-escalation. Patients would also be dose de-escalated as determined by the investigator. Patients who de-escalate may be allowed to re-escalate in the future. | Drug: Cabozantinib<br>* Cabozantinib initiated at 40 mg daily. Dose-escalate or de-escalate based on pre-specified criteria and at set dosing schedules<br>* Other names: XL184;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| To show that alternative cabozantinib dosing can improve average daily dose compared to historical controls | Determine average daily dose of cabozantinib by considering the proportion of patients with average daily dose greater than the median reported in METEOR (42.8 mg), and; 2) by comparing the median average daily dose in this study population to the trial results | 2 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Decreased overall toxicity compared to historical controls | Demonstrate that alternative dosing can change overall toxicity compared to historical controls by monitoring grade ≥ 3 adverse events compared to historical controls | 2 years | 
| Improved median duration of time on drug compared to historical controls | Show that alternative scheduling can change median duration of time on drug compared to historical controls | 2 years |