A Study of LY2940680 in Small Cell Lung Cancer

Study Overview
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Brief Summary
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The purpose of this study is to find a recommended dose of LY2940680 that can be safely given in combination with etoposide and carboplatin followed by LY2940680 alone in participants with extensive-disease small cell lung cancer. The study will also compare progression-free survival in participants who are administered etoposide, carboplatin and LY2940680 followed by LY2940680 alone versus etoposide, carboplatin, and placebo followed by placebo alone.

Official Title
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A Phase 1b/2 Double-Blind Randomized Trial of the Hedgehog/SMO Antagonist LY2940680 in Combination With Carboplatin and Etoposide Followed by LY2940680 Versus Carboplatin and Etoposide Plus Placebo Followed by Placebo in Patients With Extensive-Stage Small Cell Lung Cancer

Conditions
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Small Cell Lung Carcinoma

Intervention / Treatment
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* Drug: LY2940680
* Drug: Carboplatin
* Drug: Etoposide
* Drug: Placebo


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histological or cytological diagnosis of Small Cell Lung Cancer (SCLC), including malignant pleural effusion that is extensive stage per the International Staging System Performance status of 0 to 1 on the Eastern Cooperative Oncology Group (ECOG) performance status schedule No prior systemic chemotherapy, immunotherapy, or biological therapy for SCLC Prior radiation therapy allowed to <25% of the bone marrow. Participants who have received prior radiation to the whole pelvis or chest for the treatment of SCLC are not eligible At least 1 unidimensionally measurable lesion meeting Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 Adequate organ function including the following: Adequate bone marrow reserve: absolute neutrophil count (ANC) ≥1.5 x 10^9/ liter (L), platelets ≥100 x 10^9/L, and hemoglobin ≥9 grams/deciliter (g/dL) Hepatic: bilirubin ≤1.5 times the upper limit of normal (ULN), alkaline phosphatase (AP), Serum alanine aminotransferase (ALT) and aspartate transaminase (AST) ≤3.0 x ULN (AP, AST, and ALT ≤5 x ULN is acceptable if liver has tumor involvement) Renal: calculated creatinine clearance (CrCl) ≥50 milliliters per minute (mL/min) based on the standard Cockcroft and Gault formula Estimated life expectancy of at least 12 weeks For women: Must be surgically sterile, post-menopausal, or compliant with a medically approved contraceptive regimen during and for 6 months after the treatment period; must have a negative serum pregnancy test within 7 days before study enrollment. For men: Must be surgically sterile or compliant with a contraceptive regimen during and for 6 months after the treatment period Availability of a tumor tissue sample Able to swallow capsules Exclusion Criteria: Currently enrolled in, or discontinued within the last 30 days from, a clinical trial involving an investigational product or non-approved use of a drug or device, or concurrently enrolled in any other type of medical research judged not to be scientifically or medically compatible with this study Have previously participated in a study involving LY2940680 Have previously received treatment with carboplatin or etoposide Have a mixed histological diagnosis of SCLC and Non-Small Cell Lung Cancer (NSCLC) Have a serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol Have an active infection [≥38.5 degrees Celsius and/or receiving Intravenous (IV) antibiotic therapy] Have a serious cardiac condition Have had a prior malignancy other than SCLC, carcinoma in situ of the cervix, or nonmelanoma skin cancer, unless that prior malignancy was diagnosed and definitively treated at least 5 years previously with no subsequent evidence of recurrence. Participants with a history of non-metastatic prostate cancer, including biochemical relapse only, will be eligible even if diagnosed less than 5 years previously Symptomatic central nervous system (CNS) metastases and asymptomatic CNS metastases requiring concurrent corticosteroid therapy. Treated stable CNS metastases are allowed; the participant must be stable after radiotherapy for ≥2 weeks and off of corticosteroids for ≥1 week Presence of clinically significant third-space fluid collections that cannot be controlled prior to study entry Significant weight loss (that is, ≥10%) over the 6-week period prior to study entry Concurrent administration of any other antitumor therapy. An exception will be made for non-metastatic prostate cancer participants continuing androgen blockade therapy only or breast cancer participants continuing adjuvant antiestrogen therapy only (for example, an aromatase inhibitor) Females who are breastfeeding Have corrected QT interval (QTc) of >470 millisecond (msec) on screening electrocardiogram (ECG) Have received medications that are strong inhibitors of Cytochrome P450 3A4 (CYP3A4) within 7 days prior to receiving study drug

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: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase 1b: LY2940680 + C + E<br>Phase 1b Dose Escalation: Cycles 1-6 (21 day cycles) LY2940680 administered orally, once daily at escalating doses (100 milligrams [mg] up to 400 mg) in combination with etoposide (E) 100 milligram per square meter (mg/m^2) administered by intravenous (IV) infusion on days 1, 2, 3 of each cycle and carboplatin (C) Area Under the Curve [AUC] 5 (mg•min/mL) administered by IV infusion on day 1 each cycle. Phase 1b Maintenance: Cycles 7+ (21 day cycles) LY2940680 administered orally, once daily at the same dose as induction. Participants receiving benefit may continue until disease progression, unacceptable toxicity, or discontinuation. | Drug: LY2940680<br>* Administered orally<br>Drug: Carboplatin<br>* Administered IV<br>Drug: Etoposide<br>* Administered IV<br>|
| Placebo Comparator: Phase 2: Placebo + C + E<br>Induction: Cycles 1-6 (21 day cycles) Placebo administered orally once daily in combination with etoposide 100 mg/m2 administered by IV infusion on days 1, 2, 3 of each cycle and carboplatin AUC 5 administered by IV infusion on day 1 each cycle. Maintenance: Cycles 7+ (21 day cycles) Placebo administered orally once daily. Participants receiving benefit may continue until disease progression, unacceptable toxicity, or discontinuation. | Drug: Carboplatin<br>* Administered IV<br>Drug: Etoposide<br>* Administered IV<br>Drug: Placebo<br>* Administered orally<br>|
| Experimental: Phase 2: LY2940680 + C+ E<br>Induction: Cycles 1-6 (21 day cycles) LY2940680 (dose to be determined in Phase 1b portion) administered orally once daily in combination with etoposide 100 mg/m^2 administered by IV infusion on days 1, 2, 3 of each cycle and carboplatin AUC 5 administered by IV infusion on day 1 each cycle. Maintenance: Cycles 7+ (21 day cycles). LY2940680 (dose to be determined in Phase 1 portion) administered orally once daily. | Drug: LY2940680<br>* Administered orally<br>Drug: Carboplatin<br>* Administered IV<br>Drug: Etoposide<br>* Administered IV<br>|

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 LY2940680: Maximum Tolerated Dose (MTD) | MTD was defined as the highest tested dose that has <33% probability of causing a dose-limiting toxicity(DLT). DLT was defined as an AE during Cycle 1 that is possibly related to the study drug and fulfills any one of the following criterion using the National Cancer Institute(NCI) Common Terminology Criteria for Adverse Events(CTCAE),version 4.0:Grade 3 non-hematological toxicity except nausea, vomiting, constipation, diarrhea, fatigue, or anorexia that is manageable with appropriate care,transient(i.e., ≤5 days) Grade 3 elevations of alanine aminotransferase(ALT) and/or aspartate aminotransferase(AST), without evidence of other hepatic injury, in the setting of preexisting hepatic metastasis, ≥Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia of any duration,CTCAE Grade 4 hematological toxicity of >5 days duration and any febrile neutropenia. any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose-limiting. | Baseline to Completion of the Phase 1b (Up To 12 Months) | 
| Phase 2: Progression-Free Survival |  | Randomization to Measured Progressive Disease or Death of Any Cause (Estimated as 18 Months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase 1b and 2: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY2940680, LSN3185556 at the Recommended Dose |  | Cycle (C)1 Day (D) 1:Predose,0.5 ,1, 2, 4, 6, 8h; C2 D1:Pr,0.5,1,2,4,6,8 hours | 
| Phase 1b and 2: Pharmacokinetics (PK): Maximum Concentration (Cmax) of Carboplatin and Etoposide at the Recommended Dose |  | Cycle (C)1 Day (D) 1:Predose,0.5 ,1, 2, 4, 6, 8h; C2 D1:Pr,0.5,1,2,4,6,8 hours | 
| Phase 1b and 2: Pharmacokinetics: Area Under the Curve ( AUC₀-₂₄) for LY2940680 and LSN3185556 at the Recommended Dose |  | Cycle (C)1 Day (D) 1:Predose,0.5 ,1, 2, 4, 6, 8h; C2 D1:Pr,0.5,1,2,4,6,8 hours | 
| Phase 1b and 2: Pharmacokinetics: Area Under the Curve ( AUC₀-₂₄) for Etoposide and as AUC₀-₆ for Carboplatin at the Recommended Dose |  | Cycle (C)1 Day (D) 1:Predose,0.5 ,1, 2, 4, 6, 8h; C2 D1:Pr,0.5,1,2,4,6,8 hours | 
| Phase 1b: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Overall Response Rate [ORR]) | ORR was defined as the percentage of all randomized participants with the best overall response of PR or CR using Response Evaluation Criteria in Solid Tumors (RECIST v1.1). CR is the disappearance of all target lesions. Any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 mm. Tumor marker results must have normalized. PR is at least a 30% decrease in the sum of diameter of target lesions, taking as reference the baseline sum diameters. | Baseline to Study Completion Up to 39 Months | 
| Phase 1b: Percentage Inhibition of Expression Levels of Gli1 in Skin Cells | The gene expression data (Gli1) was normalized and the level of percentage of Gli1 inhibition post treatment was calculated. | Baseline, Cycle 2 Day 1, Cycle 7 Day 1 | 
| Phase 2: Overall Survival |  | Randomization to Study Completion (Estimated as 38 Months) | 
| Phase 2: Percent Change in Tumor Size (CTS) |  | Randomization to End of Cycle 2 (Estimated as 24 Months) | 
| Phase 2: Number of Participants With a Complete or Partial Tumor Response (Overall Response Rate) |  | Randomization to Study Completion (Estimated as 38 Months) | 
| Phase 1b and 2: Pharmacokinetics: Time to Maximal Concentration (Tmax) of LY2940680 andLSN3185556 at the Recommended Dose |  | Cycle (C)1 Day (D) 1:Predose,0.5 ,1, 2, 4, 6, 8h; C2 D1:Pr,0.5,1,2,4,6,8 hours | 
| Phase 1b and 2: Pharmacokinetics: Time to Maximal Concentration (Tmax) of Carboplatin and Etoposide at the Recommended Dose |  | Cycle (C)1 Day (D) 1:Predose,0.5 ,1, 2, 4, 6, 8h; C2 D1:Pr,0.5,1,2,4,6,8 hours |