A Study LY2228820 for Recurrent Ovarian Cancer

Study Overview
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Brief Summary
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A study for women with ovarian cancer that has returned at least 6 months after platinum-based chemotherapy.

Detailed Description
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Phase 1b is unblinded and will have a small number of participants that will take LY2228820 plus gemcitabine and carboplatin to test the safety of the combination and determine a recommended dose for the Phase 2 portion. Phase 2 will be blinded and all study participants will receive carboplatin and gemcitabine. Participants of one group will receive LY2228820, and the other group will receive placebo. If the participant achieves at least stable disease, there is a maintenance phase following the first 6 cycles. The participant will take either LY2228820 or placebo. The participant will continue therapy until disease progression or other discontinuation criteria are fulfilled.

Official Title
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A Randomized, Double-Blind, Placebo-Controlled Phase 1b/2 Study of LY2228820, a p38 MAPK Inhibitor, Plus Gemcitabine and Carboplatin Versus Gemcitabine and Carboplatin for Women With Platinum-Sensitive Ovarian Cancer

Conditions
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Epithelial Ovarian Cancer, Fallopian Tube Cancer, Primary Peritoneal Cancer

Intervention / Treatment
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* Drug: LY2228820
* Drug: Carboplatin
* Drug: Placebo
* Drug: Gemcitabine


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Have been diagnosed with ovarian, fallopian tube, or primary peritoneal cancer Have been treated one time with a platinum-based chemotherapy and your disease has come back at least six months after you completed treatment Are able to swallow tablets Have given written informed consent prior to any study procedures Have adequate blood counts, hepatic and renal function Have performance status equal to or less than 2 on Eastern Cooperative Oncology Group (ECOG) scale Have negative pregnancy test, and if participant is of child bearing potential must use birth control while on study and for three months after stopping study drug Exclusion Criteria: Have been previously treated with Gemcitabine for ovarian, fallopian tube or primary peritoneal cancer Are currently enrolled or discontinued less than 14 days from another clinical trial Have a history of inflammatory bowel disease (Crohn's disease or ulcerative colitis) Have taken certain medications or had grapefruit juice within 7 days of initial dose of study drug, as levels of the study drug may be affected. Must not be pregnant or breastfeeding. Have malignancy or metastasis of the central nervous system Have borderline malignancy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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Female

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: Randomized
Intervention Model: Parallel Assignment
Masking: Triple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b (Cohort 1) LY2228820 200 milligrams (mg)<br>Cohort 1: Cycles 1-6 (21 day cycles)- LY2228820 200 mg administered orally every 12 hours on days 1-10. Gemcitabine 1000 milligrams per square meter (mg/m^2) administered intravenously (IV) over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3.. Cohort 1: Cycles 7+ (28 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-14. | Drug: LY2228820<br>* Administered Orally<br>Drug: Carboplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;|
| Experimental: Phase 1b (Cohort 2) LY2228820 300 mg<br>Cohort 2: Cycles 1-6 (21 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-10. Gemcitabine 1000 mg/m^2 administered IV over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3. Cohort 2: Cycles 7+ (28 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-14. | Drug: LY2228820<br>* Administered Orally<br>Drug: Carboplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;|
| Experimental: Phase 2 (Arm A) LY2228820 200 mg<br>Arm A: Cycles 1-6 (21 day cycles)- LY2228820 200 mg administered orally every 12 hours on days 1-10. Gemcitabine 1000 mg/m^2 administered IV over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3. Arm A: Cycles 7+ (28 day cycles)- LY2228820 300 mg administered orally every 12 hours on days 1-14. | Drug: LY2228820<br>* Administered Orally<br>Drug: Carboplatin<br>* Administered IV<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;|
| Placebo Comparator: Phase 2 (Arm B) Placebo<br>Arm B: Cycles 1-6 (21 day cycles)- Placebo administered orally every 12 hours on days 1-10. Gemcitabine 1000 mg/m^2 administered IV over 30 minutes on days 3 and 10. Carboplatin dose Area Under Curve (AUC) 4 (maximum dose 600 mg) administered IV over 30 minutes on day 3. Arm B: Cycle 7+ (28 day cycles)- Placebo administered orally on days 1-14 to maintain blind. | Drug: Carboplatin<br>* Administered IV<br>Drug: Placebo<br>* Administered Orally<br>Drug: Gemcitabine<br>* Administered IV<br>* Other names: LY188011;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b: Recommended Phase 2 Dose of LY2228820 in Combination With Gemcitabine and Carboplatin (Maximum Tolerated Dose [MTD]) | Recommended Phase 2 dose of LY2228820 that could be safely administered in combination with gemcitabine and carboplatin based on defined dose limiting toxicities (DLT) assessment and MTD definition. The MTD is defined as the highest dose level at which no more than 33% of patients experience a DLT during Cycle 1 that does not exceed the single-agent MTD for LY2228820 (300 mg Q12H). | Cycle 1 (21 Days) | 
| Phase 2: Progression-free Survival (PFS) in Participants Treated With LY2228820 Plus Gemcitabine and Carboplatin Versus Placebo Plus Gemcitabine and Carboplatin | PFS was defined as time from date of randomization to the date of investigator-determined objective progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 or death due to any cause, whichever occurred first. Progressive disease (PD) is defined as at least a 20% increase in the sum of the largest diameter (LD) of target lesions, taking as reference the smallest sum LD recorded since the treatment started or the appearance of one or more new lesions. | Randomization to Date of Disease Progression or Death from any cause (up to 3 years) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 2: Percentage of Participants Who Achieve Complete Response or Partial Response (Overall Response Rate) | Overall Response Rate was estimated as the percentage of participants with best response of Complete Response (CR) or Partial Response (PR), based on RECIST version 1.1 divided by the total number of randomized participants. CR is defined as disappearance of all target lesions. PR is defined as at least 30% disease in the sum of the largest diameter (LD) of target lesions, taking as reference the baseline sum LD. | Baseline to Disease Progression (up to 3 years) | 
| Phase 2: Overall Survival | Data presented are the median overall survival in months for participants in the Phase 2 treatment arms. | Baseline to Date of Death from any cause (up to 5 years) | 
| Phase 1b and 2: Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 8 Hours (AUC 0-8) of LY2228820 | PK parameters after administration of LY2228820 for both Phase 1b and Phase 2. | Phase1b:Cycle(C)1 Day(D)1:Predose(PRD),0.5,1,2,4,6,8 hours(hr)postdose(PD); C1D10:PRD,0.5,1,2,8hrPD; C2D10:PRD,0.5,1,2,4,6,8,12hrPD; C7D3:PRD,0.5,1,2,4,6hrPD; Phase 2: C1D3:PRD,0.5,1,2,4,6,8hrPD; C1D10:PRD,0.5,1,2,4,6,8hrPD; C7D3:PRD,0.5,1,2,4,6,8hrPD | 
| Phase 2: Change From Baseline in Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) Total Score | The Functional Assessment of Cancer Therapy-Ovarian Cancer (FACT-O) instrument measures health related quality of life (HRQoL) in participants with ovarian cancer. The instrument is organized into sections of physical, social/family, emotional, functional well-being and ovarian subscales with a 5-point rating scale in which 0 = not at all and 4 = very much. Data presented here are change from baseline at follow-up in the FACT-O Total Score. The total score is the sum of Physical Well Being (PWB) + Social Well-being (SWB) + Emotional Well Being (EWB) + Family Well-being (FWB) + Ovarian Cancer Subscale (OCS). The FACT-O Total score range 0 - 152 with higher scores indicating better quality of life. | Baseline, Study Completion (up to 3 years) |