A Study of LY2603618 in Combination With Gemcitabine in Participants With Solid Tumors

Study Overview
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Brief Summary
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The primary objective of this study is to evaluate the safety and tolerability of LY2603618 in combination with the standard dose of gemcitabine up to the global recommended dose of LY2603618 in Japanese participants with solid advanced or metastatic tumors.

Official Title
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A Phase 1 Dose-Escalation Study of LY2603618 in Combination With Gemcitabine in Japanese Patients With Solid Tumors

Conditions
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Solid Tumors

Intervention / Treatment
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* Drug: LY2603618
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have histological or cytological or imaging evidence of a diagnosis of cancer that is advanced and/or metastatic disease Participant who is planned to have gemcitabine therapy at the proposed doses because he/she was not able to benefit from standard therapy and/or therapies known to provide clinical benefit or there is no standard therapy for the advanced and/or metastatic disease globally Have given written informed consent prior to any study-specific procedures Have adequate hematologic, hepatic and renal function Have a performance status of 0-2 on the Eastern Cooperative Oncology Group (ECOG) scale Have discontinued all previous therapies for cancer, including chemotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 30 days (42 days for mitomycin C or nitrosoureas) prior to study enrollment and recovered from the acute effects of therapy Prior radiation therapy for treatment of cancer is allowed to less than 25% of the bone marrow, and participants must have recovered from the acute toxic effects of their treatment prior to study enrollment. Prior radiation to the whole pelvis is not allowed. Prior radiotherapy must be completed at least 30 days prior to study enrollment Males and females with reproductive potential must agree to use medically approved contraceptive precautions during the study and for 3 months after the last infusion of study drug Females with child bearing potential (not surgically sterilized and between menarche and 1 year post menopause) must have had a negative urine pregnancy test less than 7 days prior to the enrollment Are reliable and willing to make themselves available for the duration of the study and are willing to follow study procedures Have an estimated life expectancy of at least 12 weeks Exclusion Criteria: Are currently enrolled in, or discontinued within the last 30 days from, a clinical study involving an off-label use of an investigational drug or device (other than the study drug used in this study), or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have serious preexisting medical conditions or serious concomitant systemic disorders that would compromise the safety of the participant or his/her ability to complete the study Have interstitial pneumonitis or pulmonary fibrosis, or previous history of them Have symptomatic central nervous system malignancy or metastasis Have current active infection Females who are pregnant or lactating Have known positive test results in human immunodeficiency virus (HIV), hepatitis B surface antigen (HBSAg), or hepatitis C antibodies (HCAb) Participants with acute or chronic leukemia or with any other disease likely to have a significant bone marrow infiltration Have previously completed or withdrawn from this study or any other study investigating LY2603618 or any other checkpoint kinase (Chk1) inhibitor Have known allergy to gemcitabine or LY2603618 or any ingredient of gemcitabine or LY2603618 (like Captisol®) Have an abnormal electrocardiogram (ECG) result that would put the participant at unnecessary risk in the opinion of the investigator

Ages Eligible for Study
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Minimum Age: 20 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: LY2603618 + Gemcitabine<br>Gemcitabine 1000 milligrams per meter squared (mg/m^2) administered intravenously on days 1, 8 and 15 of at least one 28-day cycle. 170 or 230 mg LY2603618 administered intravenously on days 2, 9 and 16 of at least one 28-day cycle. Participants experiencing benefit may continue on the combination therapy until discontinuation criteria are met. | Drug: LY2603618<br>* Administered intravenously<br>Drug: Gemcitabine<br>* Administered intravenously<br>* Other names: LY188011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Participants With Dose Limiting Toxicity (DLT) | DLT is defined as adverse event (AE) during Cycle 1 (Days 1 through 28) that was possibly related to the study drug and toxicities considered by the investigator as dose limiting. A summary of other nonserious AEs, and all serious adverse events (SAE's), regardless of causality, is located in the Reported Adverse Events section. | Cycle 1 (28 Days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacokinetics (PK): Maximum Plasma Concentration (Cmax) of LY2603618 |  | Cycle 1 (days 2 and 16) & 2 (day 2): Predose, End of Infusion, 1 hour (h), 3h, 6h, 24h (days 3 and 17), 48h (days 4 and 18 cycle 1 only), 72h (days 5 and 19) | 
| Number of Participants With Best Overall Response of Complete Response (CR), Partial Response (PR), or Stable Disease (SD) (Best Overall Response) | Participants achieved disease control if they had a best overall response of PR, CR or SD according to RECIST v1.1 (SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD); PR at least 30% decrease and PD at least 20% increase in the sum of diameter of target lesions; CR: disappearance of all target lesions). Two determinations of PR or better before progression, but not qualifying for a CR, are required for a best response of PR. Best response of SD is defined as disease that does not meet the criteria for CR, PR or PD and has been evaluated at least 6 weeks after the first gemcitabine administration. | Baseline to Measured Progressive Disease (Up to 52 Months) | 
| PK: Area Under the Plasma Concentration vs. Time Curve From Time Zero to Infinity [AUC(0-∞)] of LY2603618 |  | Cycle 1 (days 2 and 16) & 2 (day 2): Predose, End of Infusion, 1 hour (h), 3h, 6h, 24h (days 3 and 17), 48h (days 4 and 18 cycle 1 only), 72h (days 5 and 19) | 
| PK: Cmax of Gemcitabine |  | Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m | 
| PK: Cmax of Gemcitabine Metabolite Deoxydifluorouridine (dFdU) |  | Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m | 
| PK: AUC(0-∞) of Gemcitabine |  | Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m | 
| PK: AUC(0-∞) of Gemcitabine Metabolite dFdU |  | Cycle 1 (days 1 and 15) & 2 (day 1): Predose, End of Infusion, 10 minutes (m), 30m, 60m, 120m |