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

NCT02784795 | Terminated Phase 1 Results

• 3 other identifiers: 16209I6F-MC-JJCD2015-004421-14
• Study Type: interventional
• Target: 94
• Locations: 4 countries
• Sites: 11

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.

Conditions

Solid Tumor; Breast Cancer; Colon Cancer; Cholangiocarcinoma; Soft Tissue Sarcoma

Keywords

Notch Inhibitor

Outcome Measures

Primary Outcomes (1)

• Number of Participants With LY3039478 Dose-Limiting Toxicities (DLT) in Part A, B, C, D and 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.

  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])

Secondary Outcomes (8)

• 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

• 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

• 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

• 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

• 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

Study Arms (12)

Part A: 25 milligram (mg) LY3039478 + 200 mg Taladegib (Cohort 1)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Taladegib

Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 1 - Dose Escalation)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: LY3023414

Part B: 50 mg LY3039478 + 150 mg LY3023414 (Cohort 2)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: LY3023414

Part B: 25 mg LY3039478 + 200 mg LY3023414 (Cohort 3)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: LY3023414

Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 4 - Dose Confirmation)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: LY3023414

Part C: 25 mg LY3039478 + 100 mg Abemaciclib (Cohort 1)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Abemaciclib

Part C: 50 mg LY3039478 + 100 mg Abemaciclib (Cohort 2)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Abemaciclib

Part C: 25 mg LY3039478 + 150 mg Abemaciclib (Cohort 3)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Abemaciclib

Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Cisplatin; Drug: Gemcitabine

Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Cisplatin; Drug: Gemcitabine

Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Gemcitabine; Drug: Carboplatin

Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)

EXPERIMENTAL

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.

Drug: LY3039478; Drug: Gemcitabine; Drug: Carboplatin

Interventions

LY3039478 DRUG

Administered orally

Part A: 25 milligram (mg) LY3039478 + 200 mg Taladegib (Cohort 1); Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 1 - Dose Escalation); Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 4 - Dose Confirmation); Part B: 25 mg LY3039478 + 200 mg LY3023414 (Cohort 3); Part B: 50 mg LY3039478 + 150 mg LY3023414 (Cohort 2); Part C: 25 mg LY3039478 + 100 mg Abemaciclib (Cohort 1); Part C: 25 mg LY3039478 + 150 mg Abemaciclib (Cohort 3); Part C: 50 mg LY3039478 + 100 mg Abemaciclib (Cohort 2); Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2); Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1); Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1); Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)

Taladegib DRUG

Administered orally

Also known as: LY2940680

Part A: 25 milligram (mg) LY3039478 + 200 mg Taladegib (Cohort 1)

Abemaciclib DRUG

Administered orally

Also known as: LY2835219

Part C: 25 mg LY3039478 + 100 mg Abemaciclib (Cohort 1); Part C: 25 mg LY3039478 + 150 mg Abemaciclib (Cohort 3); Part C: 50 mg LY3039478 + 100 mg Abemaciclib (Cohort 2)

Cisplatin DRUG

Administered IV

Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2); Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1)

Gemcitabine DRUG

Administered IV

Part D: 50 mg LY3039478 + 25 mg/m2 Cisplatin + 1000 mg/m2 Gemcitabine (Cohort 2); Part D:25 mg LY3039478+25 Milligram/Square Meter (mg/m2) Cisplatin+1000 mg/m2 Gemcitabine (Cohort 1); Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1); Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)

Carboplatin DRUG

Administered IV

Part E: 25 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 1); Part E: 50 mg LY3039478 + 1000 mg/m2 Gemcitabine + Carboplatin (Cohort 2)

LY3023414 DRUG

Administered orally

Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 1 - Dose Escalation); Part B: 25 mg LY3039478 + 150 mg LY3023414 (Cohort 4 - Dose Confirmation); Part B: 25 mg LY3039478 + 200 mg LY3023414 (Cohort 3); Part B: 50 mg LY3039478 + 150 mg LY3023414 (Cohort 2)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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.

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (11)

Sylvester Comprehensive Cancer Center

Miami, Florida, 33136, United States

Location

Karmanos Cancer Institute

Detroit, Michigan, 48201, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

University of Texas MD Anderson Cancer Center

Houston, Texas, 77030, United States

Location

Rigshospitalet

Copenhagen, København Ø, 2100, Denmark

Location

Institut Bergonie

Bordeaux, 33076, France

Location

Centre Leon Berard

Lyon, 69373, France

Location

Gustave Roussy

Villejuif, 94805, France

Location

Hospital Universitari Vall d'Hebron

Barcelona, 08035, Spain

Location

Fundacion Jimenez Diaz

Madrid, 28040, Spain

Location

Hospital Madrid Norte Sanchinarro

Madrid, 28050, Spain

Location

Related Publications (2)

• Massard C, Cassier PA, Azaro A, Anderson B, Yuen E, Yu D, Oakley G 3rd, Benhadji KA, Pant S. A phase 1b study of crenigacestat (LY3039478) in combination with gemcitabine and cisplatin or gemcitabine and carboplatin in patients with advanced or metastatic solid tumors. Cancer Chemother Pharmacol. 2022 Oct;90(4):335-344. doi: 10.1007/s00280-022-04461-z. Epub 2022 Aug 28.

  PMID: 36030462 DERIVED

• Azaro A, Massard C, Tap WD, Cassier PA, Merchan J, Italiano A, Anderson B, Yuen E, Yu D, Oakley G 3rd, Benhadji KA, Pant S. A phase 1b study of the Notch inhibitor crenigacestat (LY3039478) in combination with other anticancer target agents (taladegib, LY3023414, or abemaciclib) in patients with advanced or metastatic solid tumors. Invest New Drugs. 2021 Aug;39(4):1089-1098. doi: 10.1007/s10637-021-01094-6. Epub 2021 Mar 8.

  PMID: 33686452 DERIVED

Related Links

• Click here for more information about this study:A Study of LY3039478 in Participants With Advanced or Metastatic Solid Tumors

MeSH Terms

Conditions

Breast Neoplasms; Colonic Neoplasms; Cholangiocarcinoma; Sarcoma

Interventions

crenigacestat; LY2940680; abemaciclib; Cisplatin; Gemcitabine; Carboplatin; LY3023414

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Colorectal Neoplasms; Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Adenocarcinoma; Carcinoma; Neoplasms, Glandular and Epithelial; Neoplasms by Histologic Type; Neoplasms, Connective and Soft Tissue

Intervention Hierarchy (Ancestors)

Chlorine Compounds; Inorganic Chemicals; Nitrogen Compounds; Platinum Compounds; Heterocyclic Compounds; Deoxycytidine; Cytidine; Pyrimidine Nucleosides; Pyrimidines; Heterocyclic Compounds, 1-Ring; Coordination Complexes; Organic Chemicals

Limitations and Caveats

This study was terminated without triggering the dose expansion cohorts for Parts D and E due to business considerations.

Results Point of Contact

• Title: Chief Medical Officer
• Organization: Eli Lilly and Company

ClinicalTrials.gov@lilly.com

800-545-5979

Study Officials

• Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

  Eli Lilly and Company

  STUDY DIRECTOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: As per the study protocol design description, the study was conducted as multicenter, nonrandomized, open-label, Phase 1b study consisting of 5 separate, parallel dose escalations in patients with advanced/metastatic cancer from a variety of solid tumors followed by a dose-confirmation phase in specified tumor types.

Study Record Dates

• First Submitted: May 25, 2016
• First Posted: May 27, 2016
• Study Start: November 4, 2016
• Primary Completion: August 9, 2018
• Study Completion: February 13, 2020
• Last Updated: August 21, 2025
• Results First Posted: August 21, 2025

Record last verified: 2025-08

Locations

FR (3); DK (1); US (4); ES (3)