A Phase 1 Study in Patients With Solid Tumors

Study Overview
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Brief Summary
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The primary objective of this study is to determine the maximum tolerated dose (MTD) regimen for the combination therapy of LY573636 and pemetrexed that may be safely administered to patients with a solid tumor that is not amenable to curative therapy.

Official Title
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A Phase 1b Study of LY573636-sodium in Combination With Alimta (Pemetrexed) in Patients With Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: LY573636
* Drug: Pemetrexed


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: You must have a diagnosis of a solid tumor malignancy that is not amenable to curative therapy You must have a serum albumin level greater than or equal to 3.0 grams per deciliter (g/dL) [30 grams per liter (g/L)] You must have a performance status of 0 or 1 on the Eastern Cooperative Oncology Group (ECOG) scale You must be reliable and willing to make yourself available for the duration of the study and are willing to follow study procedures Patients with reproductive potential should use medically approved contraceptive precautions during the trial and for 6 months following the last dose of study drugs Your test results assessing the function of your blood, kidneys, liver, and heart are satisfactory You must be willing to take folic acid, Vitamin B12, or prophylactic steroids You must able to interrupt the use of aspirin (other than an aspirin dose less than or equal to 1.3 grams per day) and/or other nonsteroidal anti-inflammatory agents for 2 days before, the day of, and 2 days after the dose of pemetrexed (5 days prior for long-acting agents, such as piroxicam) You must have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, immunotherapy, hormone therapy, or other investigational therapy for at least 4 weeks (6 weeks for mitomycin-C or nitrosoureas) before study enrollment and recovered from the acute effects of therapy (except alopecia). Patients who have received whole-brain radiation must wait 90 days before starting study therapy. You must sign an informed consent Exclusion Criteria: You cannot have received other investigational drugs within the last 30 days You cannot have other on-going serious illnesses including active bacterial, fugal, or viral infections You cannot require regular, periodic paracentesis or thoracentesis You cannot have active brain metastasis You cannot currently be receiving warfarin (Coumadin®) therapy You cannot be pregnant or lactating You cannot have received prior pemetrexed or LY573636 You cannot have a second primary malignancy that could affect interpretation of the study results

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: Experimental: Pemetrexed followed by LY573636<br>Pemetrexed on Day 1 followed by LY573636 on Day 4 | Drug: LY573636<br>* Individualized dose is dependent on a patient's height, weight, and gender and is adjusted to target a specific exposure range corrected for a patient's laboratory parameters. Intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent].<br>* Other names: Tasisulam;Drug: Pemetrexed<br>* 375 to 500 milligrams per square meter (mg/m^2), intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).<br>* Other names: Alimta;|
| Experimental: Experimental: LY573636 followed by Pemetrexed<br>LY573636 on Day 1, pemetrexed on Day 4 | Drug: LY573636<br>* Individualized dose is dependent on a patient's height, weight, and gender and is adjusted to target a specific exposure range corrected for a patient's laboratory parameters. Intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent].<br>* Other names: Tasisulam;Drug: Pemetrexed<br>* 375 to 500 milligrams per square meter (mg/m^2), intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).<br>* Other names: Alimta;|
| Experimental: Experimental: LY573636 and Pemetrexed on Day 1<br>LY573636 and Pemetrexed on Day 1 | Drug: LY573636<br>* Individualized dose is dependent on a patient's height, weight, and gender and is adjusted to target a specific exposure range corrected for a patient's laboratory parameters. Intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid [350 micrograms (µg) to 1000 µg orally, daily], Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone [4 milligrams (mg) orally, twice daily or equivalent].<br>* Other names: Tasisulam;Drug: Pemetrexed<br>* 375 to 500 milligrams per square meter (mg/m^2), intravenous dosing is completed once per cycle (cycle equals either 21 or 28 days). Patients may continue on study drug until disease progression, unacceptable toxicity, or other withdrawal criteria are met. Patients are pretreated with folic acid (350 µg to 1000 µg orally, daily), Vitamin B12 (1000 µg intramuscular injection every 9 weeks), and dexamethasone (4 mg orally, twice daily or equivalent).<br>* Other names: Alimta;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose | Based on maximum tolerated dose (MTD) in Cycle 1: highest dose where <33% participants (pts) had dose-limiting toxicity (DLT). DLTs were adverse events (AE) possibly related to study drug or AEs that met any of National Cancer Institute's (NCI) Common Terminology Criteria for AEs (CTAE): Grade (G) 4 neutropenia lasting ≥5 days; G4 neutropenia with fever, G4 thrombocytopenia, G3 thrombocytopenia with bleeding, ≥G3 non-hematologic toxicity (except nausea/vomiting and diarrhea controlled by medication; electrolyte toxicity resolved with standard replacement treatment; alopecia; and elevated alanine aminotransferase or aspartate aminotransferase with preexisting hepatic metastasis, if agreed by investigator). Investigators, with sponsor, could declare a DLT if pt experienced increasing toxicity during treatment and it was clear that further treatment would expose pt to excessive risk. Enrollment was stopped during the dose-escalation phase, thus further dose-escalation was not explored. | Baseline to toxicity [up to end of Cycle 1 (cycle = 21 or 28 days)] | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Clinically Significant Effects | Clinically significant effects were defined as serious and other non-serious adverse events (AEs) regardless of causality. A summary of serious and all other non-serious AEs is located in the Reported Adverse Events module. | Baseline to end of study (up to 1 year of treatment plus 30-day follow-up) | 
| Percentage of Participants With a Tumor Response | Tumor response was evaluated using Response Evaluation Criteria In Solid Tumors (RECIST) criteria and confirmed by repeat assessment. Complete Response (CR) was defined as the disappearance of all target lesions and the normalization of tumor marker levels for non-target lesions; Partial Response (PR) was defined as at least a 30% decrease in the sum of the longest diameter of target lesions. Percentage of participants with a tumor response = (number of participants with CR or PR/number of enrolled participants)*100. | Baseline to progressive disease (up to 1 year of treatment plus 30-day follow-up) | 
| Pharmacokinetics, Concentration Maximum (Cmax) of LY573636 |  | Cycles 1 and 2 on Day 4 (prior to and at the end of LY573636 infusion, 2 and 4 hours post LY573636 infusion), Day 8 (anytime), Day 15 (anytime) | 
| Pharmacokinetics, Area Under the Curve (AUC) of LY573636 | Area under the concentration-time curve above the albumin corrected threshold (AUCalb) is provided for LY573636, which has been found to be highly bound to albumin. AUCalb is a surrogate measure of exposure to unbound (free) LY573636. | Cycles 1 and 2 on Day 4 (prior to and at the end of LY573636 infusion, 2 and 4 hours post LY573636 infusion), Day 8 (anytime), Day 15 (anytime) | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Solid tumors