A Safety Study in Participants With Advanced Solid Tumors

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 (tasisulam) when used in 5 separate combinations with an approved cancer medication for treating participants with advanced cancer. Data from this study will be reviewed for any side effects or anti-tumor activity that may be associated with the LY573636 combination treatments.

Official Title
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A Phase 1 Multicenter, Dose-escalation Study of LY573636-sodium in Combination With 1) Gemcitabine HCl or 2) Docetaxel or 3) Temozolomide or 4) Cisplatin, or 5) Erlotinib in Patients With Advanced Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: Gemcitabine
* Drug: Docetaxel
* Drug: Temozolomide
* Drug: Cisplatin
* Drug: Erlotinib
* Drug: LY573636


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Participants who have histologically confirmed solid malignancy or lymphoma that is unresectable and/or metastatic for which monotherapy with gemcitabine HCl, docetaxel, temozolomide, cisplatin, or erlotinib would otherwise be appropriate Must have tumor progression after receiving standard/approved chemotherapy or limited treatment options Must have measurable or nonmeasurable disease Have given written informed consent prior to any study-specific procedures Must have adequate hepatic, hematologic and renal function Must 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. Endocrine therapies for the treatment of prostate cancer may be continued, at the discretion of the investigator. Whole brain radiation must have been completed 90 days before starting study therapy. Participants without evidence of brain metastases who have received prophylactic whole brain irradiation as part of standard of care for small cell lung cancer may be included in the study with a shorter washout period pending approval by the Lilly physician. Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drug. Females with child-bearing potential must have had a negative serum pregnancy test within 7 days prior to the first dose of study drug. Must have a serum albumin level greater than or equal to 3.0 g/dL (30 g/L). Must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale Exclusion Criteria: Have received treatment within 30 days of the initial dose of study drug with a drug that has not received regulatory approval for any indication Have serious preexisting medical conditions that in the opinion of the investigator would preclude participation in the study Participants with active central nervous system or 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 to rule out brain metastasis. Participants with stable CNS metastasis not requiring steroids may be eligible. Have a current hematologic malignancy (other than lymphoma) Participants with serious concomitant disorders, including active bacterial, fungal, or viral infection, incompatible with the study) Participants actively receiving warfarin (Coumadin®) therapy Participants who have previously completed or withdrawn from any study investigating LY573636 Participants with a known hypersensitivity to one of the combination drugs cannot be enrolled to the treatment arm which includes that chemotherapeutic combination Females who are pregnant or breast feeding Have known positive test results of HIV, hepatitis B, or hepatitis C Participants receiving amiodarone, quinidine, propofol, or clozapine. Participants receiving treatment with strong or moderate inhibitors of CYP2C19, including proton-pump inhibitors (PPIs). Esomeprazole or pantoprazole are allowed if not administered 72 hours before or 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
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Gemcitabine plus LY573636<br> | Drug: Gemcitabine<br>* 1000 mg/m2 administered intravenously on Days 1 and 15 of a 28 day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.<br>* Other names: LY18011;Drug: LY573636<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, or other withdrawal criteria are met.<br>* Other names: LY573636-sodium;|
| Experimental: Docetaxel plus LY573636<br> | Drug: Docetaxel<br>* 60 mg/m2 administered intravenously over 60 minutes on Day 1 of the 28-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.<br>Drug: LY573636<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, or other withdrawal criteria are met.<br>* Other names: LY573636-sodium;|
| Experimental: Temozolomide plus LY573636<br> | Drug: Temozolomide<br>* 200 mg/m2 administered orally on days 1-5 of a 28 day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.<br>Drug: LY573636<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, or other withdrawal criteria are met.<br>* Other names: LY573636-sodium;|
| Experimental: Cisplatin plus LY573636<br> | Drug: Cisplatin<br>* 75 mg/m2 administered intravenously on Day 1 of the 28-day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.<br>Drug: LY573636<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, or other withdrawal criteria are met.<br>* Other names: LY573636-sodium;|
| Experimental: Erlotinib plus LY573636<br> | Drug: Erlotinib<br>* 150 mg administered orally days 1-28 of a 28 day cycle until disease progression, unacceptable toxicity or other discontinuation criteria are met.<br>Drug: LY573636<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, or other withdrawal criteria are met.<br>* Other names: LY573636-sodium;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose-Limiting Toxicities Cycle 1 | A Dose-Limiting Toxicity (DLT) is defined as an Adverse Event (AE) that is likely related to the study medication or combination, and fulfills any one of the following criteria: Common Terminology Criteria for Adverse Events (CTCAE, Version 3.0) Grade 4 neutropenia lasting more than 5 days. Grade 4 neutropenia with fever or Grade 4 thrombocytopenia, regardless of duration; Grade ≥3 thrombocytopenia with bleeding, regardless of duration; Grade ≥3 nonhematologic toxicity (excluding nausea/vomiting or diarrhea that can be controlled with medication, and alopecia). Grade 3 electrolyte toxicity (for example, hypokalemia, hypophosphatemia) will not be considered a DLT unless it is considered related to the study drug or combination and does not resolve with standard replacement treatments within 42 days after Cycle 1 Day 1. A summary of other nonserious AEs and all Serious Adverse Events (SAE), regardless of causality is located in the Reported Adverse Event section. | Baseline to Cycle 1 (Up to Day 28) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetic (PK): Concentration Maximum (Cmax) | Cycle 2: predose,1h start of infusion, end of infusion, 30min,2h,4h,6h,22h,166h,334h,698h end of infusion. | Cycle 1: predose,0,30min,1h start of infusion, end of infusion, 30min,2h,4h,6h,22h,166h,334h,698h end of infusion. | 
| Percentage of Participants With a Complete (CR) or Partial Response (PR) (Best Overall Tumor Response) | Best overall tumor response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST, version 1.0) criteria. Complete Response (CR) was defined as the disappearance of all target lesions; Partial Response (PR) was defined as at least a 30% decrease in sum of longest diameter of target lesions. | Baseline to Study Completion (Up to 2 years) | 
| Number of Participants With a Clinically Significant Effects | Clinically significant effects are reported if a Grade 3 or higher treatment emergent adverse event (TEAE) and observed in ≥10% of participants or a toxicity possibly related to study drug based on Common Terminology Criteria for Adverse Events (CTCAE). A summary of other nonserious AEs and all SAEs, regardless of causality is located in the Reported Adverse Event section. | Baseline to Study Completion (Up to 2 years) | 
| PK: Area Under the Curve Albumin (AUCalb) | Cycle 2: predose,1h start of infusion, end of infusion, 30min,2h,4h,6h,22h,166h,334h,698h end of infusion. | Cycle 1: predose,0,30min,1h start of infusion, end of infusion, 30min,2h,4h,6h,22h,166h,334h,698h end of infusion. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced solid tumors, Unresectable, Metastatic, Limited treatment options, Measurable or nonmeasurable disease