Dose-Escalation Study of LY573636-sodium and Liposomal Doxorubicin in Patients With Advanced Solid Tumors

Study Overview
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Brief Summary
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The goal of this study is to determine the dose of LY573636-sodium (hereafter referred to as LY573636) that can be administered safely in combination with liposomal doxorubicin in patients with advanced cancer who have failed a prior treatment. The study consists of a dose escalation phase to the maximum tolerated dose (MTD) and a dose confirmation phase in patients with platinum resistant epithelial ovarian, fallopian tube or primary peritoneal cancer who have never been treated with doxorubicin.

Official Title
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A Phase 1b, Multicenter, Dose-Escalation Study of LY573636-sodium in Combination With Liposomal Doxorubicin in Patients With Advanced Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: LY573636-sodium
* Drug: Liposomal Doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: You must have a histologically confirmed solid malignancy that is unresectable and/or metastatic which has progressed after receiving standard approved chemotherapy You must have a solid malignancy for which an anthracycline-based regimen is felt to be a reasonable treatment option You must have measurable disease or non-measurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST) You must have a serum albumin level greater than or equal to 3.0 grams/deciliter (g/dL) (30 g/L) You must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale You must have tumor progression after receiving standard/approved chemotherapy You must be reliable and willing to make yourself available for the duration of the study and are willing to follow study procedures Women must be sterile, post-menopausal or on a contraception and men must be sterile or on contraception Your test results assessing the function of your blood, kidneys, liver, and heart are satisfactory Ovarian patients in the confirmation phase must have failed to achieve at least a partial response to a first-line platinum-based therapy (platinum-refractory) or have progression in less than 6 months after a response to a first-line platinum-based therapy (platinum-resistant) Ovarian patients in the confirmation phase must have measurable disease by RECIST Ovarian patients in the confirmation phase must be liposomal doxorubicin or doxorubicin naive and not amendable to curative therapy Exclusion Criteria: You cannot have received other investigational drugs within the last 28 days You cannot have other on-going serious illnesses including active bacterial, fugal, or viral infections You cannot have current hematologic malignancies, acute or chronic leukemia, or brain metastasis You cannot currently be receiving warfarin (Coumadin®) therapy You cannot have known positive test results in human immunodeficiency, hepatitis B surface antigen or hepatitis C antibodies You cannot have a history of cardiac disease or clinical evidence of congestive heart failure Ovarian patients in the confirmation phase who have received 2 or more cytotoxic regimens for platinum-resistant disease You cannot currently be receiving amiodarone, quinidine, propofol, and clozapine If you are taking esomeprazole or pantoprazole you must be able to stop taking this medication within 72 hours before and after LY573636 administration

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 + Liposomal Doxorubicin<br> | Drug: LY573636-sodium<br>* Individualized dose is dependent on participant's height, weight, gender and is adjusted to target a specific exposure range corrected for a participant's laboratory parameters. Intravenous dosing is done on Day 1 of a 28-day cycle. Participants may continue on study drug until disease progression, unacceptable toxicity, cumulative dose of 550 milligrams per square meter (mg/m²) of liposomal doxorubicin or doxorubicin is reached, or other withdrawal criterion is met.<br>* Other names: Tasisulam-sodium;Drug: Liposomal Doxorubicin<br>* 40 mg/m² on Day 1, given intravenously of each 28-day cycle Participants may continue on study drug until disease progression, unacceptable toxicity, cumulative dose of 550 mg/m² of liposomal doxorubicin or doxorubicin is reached, or other withdrawal criterion are met.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose | Recommended Phase 2 dose was determined by maximum tolerated dose (MTD), which is corrected for the participant's predose albumin to identify the albumin-corrected exposure range of LY 573636 when combined with liposomal doxorubicin. MTD is the highest dose with <33% of participants having a dose-limiting toxicity (DLT) in the first 28-day cycle of treatment. DLT is an adverse event (AE) that is likely related to the study drug or combination and fulfills any 1 of the following: Common Terminology Criteria for AE (CTCAE, Version 3.0) Grade (Gr) 4 hematologic toxicity; Gr 3 nonhematologic toxicity (excluding controllable nausea/vomiting or diarrhea and alopecia); Gr 3 electrolyte toxicity that is not resolved with standard treatments. Those who enter the study with Gr 2 hepatic enzyme abnormalities, DLT for an isolated Gr 3 hepatic enzyme abnormality is determined by investigators; a DLT can be declared if a participant experiences increasing toxicity during treatment. | Predose up to 28 days postdose in Cycle 1 | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Events | Clinically significant events are defined as serious adverse events (SAEs), regardless of causality, during the study including the 30-day follow-up period. A summary of SAEs and other nonserious adverse events is located in the Reported Adverse Event section. Death due to progressive disease was not considered as an SAE. | Baseline to study completion up to 18.49 months | 
| Pharmacokinetics: Maximum Concentration (Cmax) of LY573636 |  | Predose, 30 minutes (min), 2 hours (h), 4 h, 166 h, 360 h and 698 h postdose in Cycle 1; Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 2; Predose, 166h, 360h and 698 h postdose in Cycle 3 | 
| Number of Participants With Tumor Response | Number of participants with tumor response = number of participants with complete response (CR) + number of participants with partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) guidelines. CR is the disappearance of all target and non-target lesions; PR is a ≥30% decrease in the sum of longest diameter of target lesions. | Baseline to measured progressive disease up to 4.7 months | 
| 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. | Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 1; Predose, 30 min, 2 h, 4 h, 166 h, 360 h and 698 h postdose in Cycle 2; Predose, 166h, 360h and 698 h postdose in Cycle 3 |