A Study of LY3039478 in Participants With Advanced or Metastatic Solid Tumors

Phase 1

Terminated

Conditions: Soft Tissue Sarcoma
Colon Cancer
Solid Tumor
Breast Cancer
Cholangiocarcinoma

Interventions: Drug: LY3039478
Drug: Taladegib
Drug: LY3023414
Drug: Abemaciclib
Drug: Cisplatin
Drug: Gemcitabine
Drug: Carboplatin

Registration Number: NCT02784795

Lead Sponsor: Eli Lilly and Company

Brief Summary: The main purpose of this study is to evaluate the safety of the study drug known as LY3039478 in combination with other anticancer agents in participants with advanced or metastatic solid tumors.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 94

Inclusion Criteria

For all parts: The participant must be, in the judgment of the investigator, an appropriate candidate for experimental therapy after available standard therapies have failed to provide clinical benefit for their advanced or metastatic cancer.
- For dose escalation for all combinations: The participant must have histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced or metastatic.
- For Part A dose confirmation: All participants must have histological evidence of advanced or metastatic soft tissue sarcoma or breast cancer. Breast cancer participants must have prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway.
- For Part B dose confirmation: All participants must have histological evidence of advanced or metastatic colon cancer or soft tissue sarcoma. Colon cancer participants must have prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway.
- For Part C dose confirmation: All participants must have histological evidence of advanced or metastatic breast cancer and prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway.
- For Part D dose confirmation: All participants must have histological evidence of cholangiocarcinoma and prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. Participants must not have received >1 line of prior systemic therapy for metastatic or resectable disease (that is, participants may have received adjuvant gemcitabine and then later gemcitabine/cisplatin for recurrent metastatic disease).
- For Part E dose confirmation: All participants must have histological evidence of locally advanced or metastatic triple negative breast cancer (TNBC) and prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. Participants must not have received >2 lines of systemic treatment for advanced or metastatic TNBC.
Have adequate organ function.
Have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale.
Have discontinued all previous therapies for cancer.

Exclusion Criteria

Have current acute leukemia.
Have current or recent (within 3 months of study drug administration) gastrointestinal disease with chronic or intermittent diarrhea, or disorders that increase the risk of diarrhea, such as inflammatory bowel disease.

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Part A: 25 milligram (mg) LY3039478 + 200 mg Taladegib (Cohort 1)	LY3039478	25 mg LY3039478 given orally 3 times per week (TIW) in combination with 200 mg taladegib given orally once daily (QD) on a 28 day cycle. A single dose of 200 mg taladegib was also be given on day 1 during a 3-day lead-in period for pharmacokinetic (PK) evaluation. Participants receiving benefit may continue until disease progression.
Part B: 50 mg LY3039478 + 150 mg LY3023414 (Cohort 2)	LY3039478	50 mg LY3039478 given orally TIW in combination with 150 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 150 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 4 - Dose Confirmation)	LY3039478	25 mg LY3039478 given orally TIW in combination with 150 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 150 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part A: 25 milligram (mg) LY3039478 + 200 mg Taladegib (Cohort 1)	Taladegib	25 mg LY3039478 given orally 3 times per week (TIW) in combination with 200 mg taladegib given orally once daily (QD) on a 28 day cycle. A single dose of 200 mg taladegib was also be given on day 1 during a 3-day lead-in period for pharmacokinetic (PK) evaluation. Participants receiving benefit may continue until disease progression.
Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 1 - Dose Escalation)	LY3039478	25 mg LY3039478 given orally TIW in combination with 150 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 150 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 1 - Dose Escalation)	LY3023414	25 mg LY3039478 given orally TIW in combination with 150 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 150 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part B: 50 mg LY3039478 + 150 mg LY3023414 (Cohort 2)	LY3023414	50 mg LY3039478 given orally TIW in combination with 150 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 150 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part B: 25 mg LY3039478 + 200 mg LY3023414 (Cohort 3)	LY3039478	25 mg LY3039478 given orally TIW in combination with 200 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 200 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part B: 25 mg LY3039478 + 200 mg LY3023414 (Cohort 3)	LY3023414	25 mg LY3039478 given orally TIW in combination with 200 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 200 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 4 - Dose Confirmation)	LY3023414	25 mg LY3039478 given orally TIW in combination with 150 mg LY3023414 given orally twice daily (BID) on a 28 day cycle. A single dose of 150 mg LY3023414 was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part C: 25 mg LY3039478 + 100 mg Abemaciclib (Cohort 1)	Abemaciclib	25 mg LY3039478 given orally TIW in combination with 100 mg abemaciclib given orally BID on a 28-day cycle. A single dose of 100 mg abemaciclib was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part C: 25 mg LY3039478 + 150 mg Abemaciclib (Cohort 3)	LY3039478	25 mg LY3039478 given orally TIW in combination with 150 mg abemaciclib given orally BID on a 28-day cycle. A single dose of 150 mg abemaciclib was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1)	Cisplatin	25 mg LY3039478 given orally TIW in combination with 25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine given as intravenous (IV) infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2)	Cisplatin	50 mg LY3039478 given orally TIW in combination with 25 mg/m2 cisplatin and1000 mg/m2 gemcitabine given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part C: 25 mg LY3039478 + 100 mg Abemaciclib (Cohort 1)	LY3039478	25 mg LY3039478 given orally TIW in combination with 100 mg abemaciclib given orally BID on a 28-day cycle. A single dose of 100 mg abemaciclib was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part C: 50 mg LY3039478 + 100 mg Abemaciclib (Cohort 2)	LY3039478	50 mg LY3039478 given orally TIW in combination with 100 mg abemaciclib given orally BID on a 28-day cycle. A single dose of 100 mg abemaciclib was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part C: 50 mg LY3039478 + 100 mg Abemaciclib (Cohort 2)	Abemaciclib	50 mg LY3039478 given orally TIW in combination with 100 mg abemaciclib given orally BID on a 28-day cycle. A single dose of 100 mg abemaciclib was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part C: 25 mg LY3039478 + 150 mg Abemaciclib (Cohort 3)	Abemaciclib	25 mg LY3039478 given orally TIW in combination with 150 mg abemaciclib given orally BID on a 28-day cycle. A single dose of 150 mg abemaciclib was also be given on day 1 during a 3-day lead-in period for PK evaluation. Participants receiving benefit may continue until disease progression.
Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1)	LY3039478	25 mg LY3039478 given orally TIW in combination with 25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine given as intravenous (IV) infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1)	Gemcitabine	25 mg LY3039478 given orally TIW in combination with 25 mg/m2 cisplatin and 1000 mg/m2 gemcitabine given as intravenous (IV) infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2)	LY3039478	50 mg LY3039478 given orally TIW in combination with 25 mg/m2 cisplatin and1000 mg/m2 gemcitabine given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2)	Gemcitabine	50 mg LY3039478 given orally TIW in combination with 25 mg/m2 cisplatin and1000 mg/m2 gemcitabine given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)	Gemcitabine	50 mg LY3039478 given orally TIW in combination with 1000 mg/m2 gemcitabine and AUC dose of carboplatin given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1)	LY3039478	25 mg LY3039478 given orally TIW in combination with 1000 mg/m2 gemcitabine and area under the plasma concentration-time curve dose of (AUC) carboplatin given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1)	Gemcitabine	25 mg LY3039478 given orally TIW in combination with 1000 mg/m2 gemcitabine and area under the plasma concentration-time curve dose of (AUC) carboplatin given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1)	Carboplatin	25 mg LY3039478 given orally TIW in combination with 1000 mg/m2 gemcitabine and area under the plasma concentration-time curve dose of (AUC) carboplatin given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)	LY3039478	50 mg LY3039478 given orally TIW in combination with 1000 mg/m2 gemcitabine and AUC dose of carboplatin given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.
Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)	Carboplatin	50 mg LY3039478 given orally TIW in combination with 1000 mg/m2 gemcitabine and AUC dose of carboplatin given as IV infusions on days 1 and 8 of a 21 day cycle. Participants receiving benefit may continue until disease progression.

Primary Outcome Measures

Name	Time	Method
Number of Participants With LY3039478 Dose-Limiting Toxicities (DLT) in Part A, B, C, D and E	Baseline to toxicity (up to end of Cycle 1 [1Cycle = 28 days for Part A, B and C and 21 days for Part D, E])	DLT is defined as an adverse event (AE) during Cycle 1 (28 days for Part A, B and C and 21 days for Part D, E) that was possibly related to the study drug and met 1 of the following criteria: According to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0: ≥Grade 3 non-hematological toxicity except nausea/vomiting, diarrhea, or constipation that can be controlled with appropriate care; Grade 3 elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) lasting fewer than 8 days (without evidence of other hepatic injury); Grade 3 rash that resolves or improves to a Grade 2 or less within 7 days; CTCAE Grade 4 hematological toxicity of \>5 days duration; Grade 4 thrombocytopenia of any duration; Grade 3 thrombocytopenia with bleeding; Grade 3 febrile neutropenia.

Secondary Outcome Measures

Name	Time	Method
Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC[0-∞]) of LY3039478 in Combination With Taladegib, LY3023414, Abemaciclib, Cisplatin/Gemcitabine, and Gemcitabine/Carboplatin in Part A, B, C, D and E	Parts A/B/C Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30 hours post-dose; Parts D/E Day 1 (Cycle 1) and 15 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6-8, 24-30 hours post-dose	AUC\[0-∞\] of LY3039478 in combination with taladegib, LY3023414, abemaciclib, cisplatin/gemcitabine, and gemcitabine/carboplatin in dose escalation parts of Part A, B, C, D and E was evaluated.
PK: AUC[0-∞] of Taladegib and Its Active Metabolite LSN3185556, in Combination With LY3039478 (Part A)	Day -3 (Lead in) : pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30, 72 hours post-dose and Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose	AUC\[0-∞\] of taladegib and its active metabolite LSN3185556, in combination with LY3039478 (Part A) was evaluated.
PK: AUC[0-∞] of LY3023414 in Combination With LY3039478 on Day -3 (Part B)	Day -3 (Lead in): pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30, 72 hours post-dose	AUC\[0-∞\] of LY3023414 in combination with LY3039478 (Part B) on day -3 was evaluated.
PK: AUC[0-∞] of LY3023414 in Combination With LY3039478 on Day 22 (Part B)	Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose	AUC\[0-∞\] of LY3023414 in combination with LY3039478 (Part B) on day 22 was evaluated. LY3023414 PK data is summarized only for dose escalation patients in Part B with intensive PK sampling.
PK: AUC[0-∞] of Abemaciclib and AUC From Time Zero to the Last Measured Concentration Value (AUC[0-tlast]) of Its Major Active Metabolites LSN2839567 and LSN3106726, in Combination With LY3039478 on Day -3 (Part C)	Day -3 (Lead in): pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30, 72 hours post-dose	AUC\[0-∞\] of abemaciclib and AUC\[0-tlast\] of its major active metabolites LSN2839567 and LSN3106726, in combination with LY3039478 on Day 3 (Part C) was evaluated.
PK: AUC[0-∞] of Abemaciclib and AUC From Time Zero to the Last Measured Concentration Value (AUC[0-tlast]) of Its Major Active Metabolites LSN2839567 and LSN3106726, in Combination With LY3039478 on Day 22 (Part C)	Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose	AUC\[0-∞\] of abemaciclib and AUC\[0-tlast\] of its major active metabolites LSN2839567 and LSN3106726, in combination with LY3039478 on Day 22 (Part C) was evaluated.
Duration of Response (DoR)	Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression (Up To 12 Months)	DoR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date.
Progression Free Survival (PFS) Time in Part A, B, C, D and E	Baseline to Objective Disease Progression or Death (Up To 1.91 Months for Part A, 7.69 Months for Part B, 11.53 Months for Part C, 19.52 Months for Part D, 7.03 Months for Part E)	PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. PFS time was summarized using Kaplan-Meier estimates.

Trial Locations

Locations (11): Sylvester Comprehensive Cancer Center
🇺🇸
Miami, Florida, United States
Karmanos Cancer Institute
🇺🇸
Detroit, Michigan, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Rigshospitalet
🇩🇰
Copenhagen, København Ø, Denmark
Institut Bergonie
🇫🇷
Bordeaux, France
Centre Leon Berard
🇫🇷
Lyon Cedex 08, France
Gustave Roussy
🇫🇷
Villejuif Cedex, France
Hospital Universitari Vall d'Hebron
🇪🇸
Barcelona, Spain
Fundacion Jimenez Diaz
🇪🇸
Madrid, Spain
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Sylvester Comprehensive Cancer Center
🇺🇸Miami, Florida, United States