Dose-Finding, Safety and Efficacy Study of RX-0201 Plus Everolimus in Metastatic Renal Cell Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose of RX-0201, up to a target dose of 250 mg/m^2/day, when given in combination with everolimus (Stage 1), and to assess the safety and efficacy of RX-0201 plus everolimus, in subjects with metastatic renal cell cancer (Stage 2).

Detailed Description
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This multi-center, open-label, randomized, parallel group study of RX-0201 in combination with everolimus, versus everolimus alone to treat subjects with advanced renal cell carcinoma will be conducted in 2 stages. Stage 1 will be an open-label, dose-escalation study of RX-0201 to identify a safe and tolerable dose of RX-0201 up to a target dose of 250 mg/m^2/day when given in combination with everolimus. Stage 2 will be a randomized, open-label, 2-arm study of RX-0201 in combination with everolimus versus everolimus alone. Subjects will receive RX-0201, at the dose identified in Stage 1, in combination with everolimus or everolimus alone, for up to 8 cycles to determine safety and efficacy of the combination.

Official Title
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A Multicenter, Open-label, Phase 1b/2 Study to Evaluate the Safety and Efficacy of RX-0201 in Combination With Everolimus to Treat Subjects With Advanced Renal Cell Carcinoma

Conditions
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Metastatic Renal Cell Cancer

Intervention / Treatment
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* Drug: RX-0201


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Males and females ≥ 18 years of age at screening Histological or cytological diagnosis of renal cell cancer with a clear-cell component Measurable or evaluable disease defined by Response Evaluation Criteria for Solid Tumors (RECIST) ver. 1.1 Must have received at least one course of therapy with a VEGFR-targeting tyrosine kinase inhibitor (eg, sorafenib, sunitinib, axitinib, pazopanib or tivozanib) and progressed within 6 months of planned first dose of study treatment ECOG performance status of 0,1 or 2 Life expectancy > 3 months Provide written informed consent Exclusion Criteria: Brain metastases or cranial epidural disease unless adequately treated with radiotherapy and/or surgery and stable for at least 3 months before planned first dose of study drug Radiation therapy for bone metastasis within 2 weeks, any other external radiation therapy within 4 weeks before planned first dose of study drug. Systemic treatment with radionuclides within 6 weeks before planned first dose of study drug. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible Prior treatment with everolimus, or any other specific or selective TORC1/PI3K/AKT inhibitor (eg, temsirolimus) Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before planned first dose of study drug Receipt of any type of anticancer antibody (including investigational antibody) within 4 weeks before planned first dose of study drug Taking strong inducers or inhibitors of CYP450s for subjects receiving everolimus Chronic treatment with corticosteroids or other immunosuppressive agents Concomitant anticoagulation at therapeutic doses with oral anticoagulants or platelet inhibitors Subjects with a known hypersensitivity to everolimus or other rapamycins (sirolimus, temsirolimus) or to its excipients Major surgery within 2 months before planned first dose of study drug Myocardial infarction within the previous 6 months before planned first dose of study drug Active infection requiring parenteral antibiotics within 2 weeks before planned first dose of study drug Diagnosis of another malignancy within 2 years before planned first dose of study drug, except for superficial skin cancers, or localized, low grade tumors Prior or current history of hepatitis B, hepatitis C or human immunodeficiency virus Sexually active fertile subjects (male and female) must agree to use medically accepted methods of contraception during the course of the study and for 30 days after the last dose of study treatment

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
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: RX-0201 plus everolimus (Stage 1 & 2)<br>RX-0201 and everolimus will be taken together as described in the Interventions description. | Drug: RX-0201<br>* RX-0201 will be administered in a dose up to 250mg/m^2/day as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles in Stage 1. In Stage 2, RX-0201 will be administered the dose determined in Stage 1 as a continuous infusion for a cycle of 21 days (14 days infused followed by 7 days off) for up to 8 cycles.<br>* Other names: Archexin;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Incidence of Dose-limiting Toxicities (DLTs) (Stage 1) | Incidence of adverse events and clinical laboratory abnormalities defined as dose-limiting toxicities | after 1 cycle (3 weeks) of treatment with RX-0201 and everolimus | 
| Progression Free Survival (Stage 2) | Median PFS. Progression determined by RECIST v1.1 | 4 months of treatment with RX-0201 and everolimus | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Steady State Concentration (Css) of RX-0201 (Stage 1) | Css of RX-0201 at the beginning and end of the 14 day continuous infusion | predose, 1, 2, 3, 4, 6, and 24 hours after start of Cycle 1 RX-0201 infusion, and then immediately prior to the end of Cycle 1 infusion (Day 15), 1, 2, 3, 4, 6, and 24 hours after infusion is stopped | 
| Incidence of Adverse Events, Changes in Clinical Laboratory Tests and Vital Signs Over Time (Stage 1 and Stage 2) | safety of RX-0201 was evaluated through reporting using the grading system in the CTCAE version 4.03 for adverse events and laboratory abnormalities. All statistical methods for safety were descriptive in nature. | up to 24 weeks of treatment with RX-0201 plus everolimus and at least 30 days of safety follow up | 
| Best Overall Response as Determined by RECIST v1.1. | Best overall response as determined by RECIST v1.1. Not Evaluable included the subjects who had completed at least one treatment cycle but no overall response evaluation. Not Done included the subjects who dropped out from the study without completing any treatment cycle and overall response evaluation. The best overall response for each subject from all post-baseline time point overall responses was used. The best overall response was the best response recorded from the start of the treatment until disease progression/recurrence, or occurrence of intolerable toxicity, whatever came first. | Baseline and at weeks 6, 12, 18, and 24 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal cell carcinoma, clear cell, renal cancer, metastatic renal cancer, Carcinoma, Renal Cell*/therapy, Humans, Kidney Neoplasms*/therapy