A Study of LY2940680 in Small Cell Lung Cancer

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

Status

Terminated

Phases

Phase 1Phase 2

Study type

Interventional

Source

ClinicalTrials.gov

Registry ID

NCT01722292

Enrollment

Registered

2012-11-06

Start date

2013-01-31

Completion date

2015-02-28

Last updated

2018-12-28

For informational purposes only — not medical advice. Sourced from public registries and may not reflect the latest updates. Terms

Conditions

Small Cell Lung Carcinoma

Brief summary

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.

Interventions

DRUGLY2940680

Administered orally

DRUGCarboplatin

Administered IV

DRUGEtoposide

Administered IV

DRUGPlacebo

Administered orally

Study design

Allocation

RANDOMIZED

Intervention model

PARALLEL

Primary purpose

TREATMENT

Masking

QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)

Eligibility

Sex/Gender

ALL

Age

18 Years to No maximum

Healthy volunteers

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

Design outcomes

Primary

Measure	Time frame	Description
Phase 1b: Recommended Phase 2 Dose of LY2940680: Maximum Tolerated Dose (MTD)	Baseline to Completion of the Phase 1b (Up To 12 Months)	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.
Phase 2: Progression-Free Survival	Randomization to Measured Progressive Disease or Death of Any Cause (Estimated as 18 Months)	—

Secondary

Measure	Time frame	Description
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])	Baseline to Study Completion Up to 39 Months	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.
Phase 1b: Percentage Inhibition of Expression Levels of Gli1 in Skin Cells	Baseline, Cycle 2 Day 1, Cycle 7 Day 1	The gene expression data (Gli1) was normalized and the level of percentage of Gli1 inhibition post treatment was calculated.
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 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	—
Phase 2: Overall Survival	Randomization to Study Completion (Estimated as 38 Months)	—
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	—

Countries

United Kingdom, United States

Participant flow

Pre-assignment details

Due to strategic reasons, the Phase 2 portion was not initiated, and further clinical development was stopped. Phase 1b study completer was defined as completion of the dose-limiting toxicity (DLT) period (1 cycle- 21 days cycle for LY2940680 in combination with carboplatin and etoposide.

Participants by arm

Arm	Count
Phase 1b: 100 mg LY2940680 + C +E 100 mg LY2940680 administered orally once daily (QD) for 6 cycles. 100 mg per square meter (mg/m\^2) etoposide (E) administered by intravenous (IV) infusion on days 1, 2, 3 of each cycle. Area under the Curve \[AUC\] 5 milligrams\minute\milliliters (mg•min/mL) carboplatin (C) administered by IV infusion on day 1 each cycle. Maintenance: Single-agent LY2940680 administered orally QD at the same dose as induction at Cycles 7+ (21 day cycles). Participants receiving benefit may continue until disease progression, unacceptable toxicity, or discontinuation.	6
Phase 1b: 200 mg LY2940680 + C + E 200 mg LY2940680 administered orally once daily (QD) for 6 cycles. 100 mg per square meter (mg/m\^2) etoposide (E) administered by intravenous (IV) infusion on days 1, 2, 3 of each cycle. Area under the Curve \[AUC\] 5 milligrams\minute\milliliters (mg•min/mL) carboplatin (C) administered by IV infusion on day 1 each cycle. Maintenance: Single-agent LY2940680 administered orally QD at the same dose as induction at Cycles 7+ (21 day cycles). Participants receiving benefit may continue until disease progression, unacceptable toxicity, or discontinuation.	6
Phase 1b: 400 mg LY2940680 + C + E 400 mg LY2940680 administered orally once daily (QD) for 6 cycles. 100 mg per square meter (mg/m\^2) etoposide (E) administered by intravenous (IV) infusion on days 1, 2, 3 of each cycle. Area under the Curve \[AUC\] 5 milligrams\minute\milliliters (mg•min/mL) carboplatin (C) administered by IV infusion on day 1 each cycle. Maintenance: Single-agent LY2940680 administered orally QD at the same dose as induction at Cycles 7+ (21 day cycles). Participants receiving benefit may continue until disease progression, unacceptable toxicity, or discontinuation.	14
Total	26

Baseline characteristics

Characteristic	Phase 1b: 100 mg LY2940680 + C +E	Total	Phase 1b: 400 mg LY2940680 + C + E	Phase 1b: 200 mg LY2940680 + C + E
Age, Continuous	64.3 years STANDARD_DEVIATION 9.35	62.2 years STANDARD_DEVIATION 11.33	60.2 years STANDARD_DEVIATION 12.19	64.8 years STANDARD_DEVIATION 11.96
Ethnicity (NIH/OMB) Hispanic or Latino	0 Participants	1 Participants	0 Participants	1 Participants
Ethnicity (NIH/OMB) Not Hispanic or Latino	6 Participants	25 Participants	14 Participants	5 Participants
Ethnicity (NIH/OMB) Unknown or Not Reported	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) American Indian or Alaska Native	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Asian	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Black or African American	0 Participants	3 Participants	1 Participants	2 Participants
Race (NIH/OMB) More than one race	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Native Hawaiian or Other Pacific Islander	0 Participants	0 Participants	0 Participants	0 Participants
Race (NIH/OMB) Unknown or Not Reported	0 Participants	1 Participants	0 Participants	1 Participants
Race (NIH/OMB) White	6 Participants	22 Participants	13 Participants	3 Participants
Region of Enrollment United Kingdom	1 participants	6 participants	4 participants	1 participants
Region of Enrollment United States	5 participants	20 participants	10 participants	5 participants
Sex: Female, Male Female	3 Participants	13 Participants	7 Participants	3 Participants
Sex: Female, Male Male	3 Participants	13 Participants	7 Participants	3 Participants

Adverse events

Event type	EG000 affected / at risk	EG001 affected / at risk	EG002 affected / at risk
deaths Total, all-cause mortality	— / —	— / —	— / —
other Total, other adverse events	6 / 6	6 / 6	14 / 14
serious Total, serious adverse events	3 / 6	6 / 6	8 / 14

Outcome results

Primary

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.

Time frame: Baseline to Completion of the Phase 1b (Up To 12 Months)

Population: All participants who received at least one dose of study drug and were enrolled in Phase1b of the study.

Arm	Measure	Value (NUMBER)
Phase 1b	Phase 1b: Recommended Phase 2 Dose of LY2940680: Maximum Tolerated Dose (MTD)	400 milligrams (mg)

Primary

Phase 2: Progression-Free Survival

Time frame: Randomization to Measured Progressive Disease or Death of Any Cause (Estimated as 18 Months)

Population: Zero participants analyzed. Due to strategic reasons, the Phase 2 portion was not initiated, and further clinical development was stopped.

Secondary