A Phase 1b Trial in Patients With Renal Cell Cancer

Study Overview
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Brief Summary
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The purpose of this study is to determine a safe dose of LY573636-sodium to be given in combination with sunitinib to patients with metastatic Renal Cell Carcinoma (RCC) and to determine any side effects that may be associated with LY573636-sodium and sunitinib combination in this patient population. The tumor response rate will also be assessed.

Official Title
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A Phase 1b Study of LY573636-sodium in Combination With Sunitinib Malate in Patients With Metastatic Renal Cell Cancer

Conditions
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Metastatic Renal Cell Cancer

Intervention / Treatment
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* Drug: Drug: LY573636-sodium
* Drug: Sunitinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants must have a histologically confirmed diagnosis of metastatic Renal Cell Carcinoma (RCC) Participants must have received no prior treatment with a cytotoxic-based chemotherapy regimen Participants must have measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines Have adequate hematologic, hepatic and renal function Have a serum albumin level greater than equal to 3.0 grams/Liter (g/L) Participants with reproductive potential should use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drug Exhibit participant compliance and geographic proximity that allow for adequate follow-up Have given written informed consent approved by Lilly and the ethical review board (ERB)/institutional review board (IRB) governing the site Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, cancer-related hormonal therapy, or other investigational therapy, for at least 4 weeks (6 weeks for mitomycin-C or nitrosoureas) prior to study enrollment and recovered from the acute effects of therapy (except alopecia). Participants who have received whole-brain radiation must wait 90 days before starting study therapy Exclusion Criteria: Have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry Have received a prior cytotoxic chemotherapy-based systemic therapy for metastatic RCC Have had any of the following within 12 months prior to study drug administration: myocardial infarction, severe/unstable angina, coronary/peripheral artery bypass graft, congestive heart failure (CHF), cerebrovascular accident, transient ischemic attack, or pulmonary embolism Ongoing cardiac arrhythmias greater than New York Health Association Class II (Protocol Attachment JZAI.4), atrial fibrillation of any grade, or prolongation of the QTc interval to greater than 450 milliseconds (msec) for males or greater than 470 msec for females Have uncontrolled hypertension [greater than 150/100 millimeters of mercury (mm Hg) despite optimal medical therapy], or history of poor compliance with antihypertensive treatment Participants with documented central nervous system or leptomeningeal metastasis (brain metastasis) at the time of study entry. Participants with signs or symptoms of neurological compromise should have appropriate radiographic imaging performed before study entry Participants with serious concomitant OR pre-existing disorders, including active bacterial, fungal, or viral infection, incompatible with the study (at the discretion of the investigator) Participants receiving warfarin therapy for treatment of venous thrombosis or other prothrombotic conditions Participants with a second primary malignancy that could affect interpretation of the results. NOTE: Participants with adequately treated carcinoma of the skin (excluding melanoma) and participants with a prior history of malignancy who have been disease-free for greater than 2 years are eligible Participants who have previously completed or withdrawn from this study or any other study investigating LY573636 Participants who have previously received sunitinib Participants who are unable to swallow capsules Participants who require concomitant use of potent Cytochrome P450 3A4 (CYP3A4) inducers or inhibitors Women who are pregnant or lactating

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: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: LY573636 +sunitinib<br> | Drug: Drug: LY573636-sodium<br>* Participant specific dose based on height, weight and gender to target a specific exposure range, administered intravenously on Day 4 of a 42-day (6-week) cycle. Dose will be escalated to reach the maximum tolerated dose (MTD). A cohort of participants enrolled after MTD will receive albumin-tailored doses. Participants may continue on treatment until clinical or objective disease progression.<br>* Other names: Tasisulam;Drug: Sunitinib<br>* 37.5 or 50 milligrams (mg), administered orally, daily for a 42-day (6-week) cycle. Participants may continue on treatment until clinical or objective disease progression.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose for Phase 2 Studies of LY573636-Sodium Combined With Sunitinib in Participants With Metastatic Renal Cell Carcinoma | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD). MTD is the highest dose with <33% of participants having a dose-limiting toxicity (DLT) during the first 6-week cycle of treatment. DLT is an adverse event (AE) that is likely related to study drug or combination and fulfills any 1 of the following: Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 neutropenia lasting ≥5 days; Gr 4 neutropenia with fever; Gr 4 thrombocytopenia; Gr ≥3 thrombocytopenia with bleeding; Gr ≥3 nonhematologic toxicity (excluding controllable nausea/vomiting or diarrhea and alopecia); Gr 3 electrolyte toxicity that is not resolved with standard treatments; Gr ≥3 elevated hepatic enzyme abnormalities in the setting of preexisting hepatic metastasis may not be considered a DLT; a DLT can be declared if a participant experiences increasing toxicity during treatment. | Predose up to 42 days postdose in Cycle 1 (6 weeks per cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics: Maximum Concentration (Cmax) of LY573636 | Time frame: Cycle 1:day 4: pre-dose, start of infusion, end of infusion,30min,1h,2h,4h,6h,8h,10h,22h,46h,70h,166h,360h post infusion, day 25: predose, during infusion, end of infusion,30min,30min,1h,2h,4h,6h,8h,10h,22h,46h,70h,166h,360h post infusion. | Predose up to 2 hours postdose in Cycles 1 and 2 (6 weeks per cycle) | 
| Number of Participants With Tumor Responses | Tumor response was assessed by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. Number of participants with tumor responses = number of participants with complete response (CR) + number of participants with partial response (PR). CR is disappearance of all target and non-target lesions; PR is ≥30% decrease in sum of longest diameter of target lesions. | Baseline to end of treatment up to 66 weeks | 
| Sunitinib Pharmacokinetics in the Presence of LY573636: Area Under the Curve (AUC) | Time frame: Cycle 1 day 4: pre-dose, start of infusion, end of infusion,30min,1h,2h,4h,6h,8h,10h,22h,46h,70h,166h,360h post infusion, day 25: predose, during infusion, end of infusion,30min,30min,1h,2h,4h,6h,8h,10h,22h,46h,70h,166h,360h post infusion. | Days 1 to 42 in Cycle 1 (6 weeks per cycle) | 
| Pharmacokinetics: Area Under the Curve of LY573636 Above the Albumin Corrected Threshold (AUCalb) | LY573636 has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. Time frame: Cycle 1:day 4: pre-dose, start of infusion, end of infusion,30min,1h,2h,4h,6h,8h,10h,22h,46h,70h,166h,360h post infusion, day 25: predose, during infusion, end of infusion,30min,30min,1h,2h,4h,6h,8h,10h,22h,46h,70h,166h,360h post infusion. Cycle 2: predose and end of infusion. | Days 1 to 42 in Cycles 1 and Cycle 2 (6 weeks per cycle) | 
| The Number of Participants With Clinically Significant Effects | Clinically significant effects were defined as serious and other non-serious adverse events. A summary of serious and all other non-serious adverse events is located in the Reported Adverse Events module. | Baseline to study completion up to 70 weeks |