A Study of LY3039478 in Participants With Advanced Cancer

NCT01695005 | Completed Phase 1 Results FDA Drug

• 2 other identifiers: 14547I6F-MC-JJCA
• Study Type: interventional
• Target: 247
• Locations: 6 countries
• Sites: 11

Brief Summary

The purpose of this study is to find a recommended dose level of LY3039478 that can safely be taken by participants with advanced cancer or cancer that has spread to other parts of the body, including but not limited to lymphoma. The study will also explore changes to various markers in blood cells and tissue. Finally, the study will help to document any tumor activity this drug may have.

Conditions

Neoplasm Metastasis; Lymphoma; Neoplasms

Outcome Measures

Primary Outcomes (5)

• Part A and F: Number of Participants With Dose Limiting Toxicities (DLTs)

  DLT was defined as an adverse event (AE) during Cycle 1 (Up to 28 Days) that was related to LY3039478 and fulfilled any 1 of the following criterion using the National Cancer Institute Common Terminology Criteria for Adverse Events, version 4.0 (NCI-CTCAE v 4.0): CTCAE Grade 3 non-hematological toxicity with a few exceptions, CTCAE Grade 4 hematological toxicity of greater than 5 days duration, any febrile neutropenia,Grade 3 thrombocytopenia with bleeding or Grade 4 thrombocytopenia, Any other significant toxicity deemed by the primary investigator and Lilly clinical research personnel to be dose limiting (for example, any toxicity that is possibly related to the study medication that requires the withdrawal of the participant from the study during Cycle 1).

  Baseline through the end of Cycle 1, Up to 28 Days

• Part A: Recommended Phase 2 Dose of LY3039478 : Maximum Tolerated Dose (MTD)

  MTD is defined as the highest tested dose that has less than 33% probability of causing a DLT during Cycle 1.

  Baseline though the end of cycle 1 (28 days cycle)

• Part B, C, D and E: Recommended Phase 2 Dose of LY3039478 : Maximum Tolerated Dose (MTD)

  MTD is defined as the highest tested dose that has less than 33% probability of causing a DLT during Cycle 1.

  Baseline through the end of cycle 1 (28 days Cycle)

• Part F1 and F2: Recommended Phase 2 Dose of LY3039478

  Parts F1 and F2 compared loading dose three time per week with prednisone versus two times per week with prednisone. Even though the trial may have found an MTD, it did not identify an Recommended Phase 2 dose (RP2D).

  Baseline Up to 2 Months

• Part B, C, D, E and F: Percentage of Participants With Complete Response (CR) or Partial Response (PR) (Objective Response Rate [ORR])

  Objective response is complete response (CR) + partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST 1.1 ) guidelines. CR is disappearance of all target and non-target lesions; PR is greater than or equal to (\>=) 30% decrease in sum of longest diameter of target lesions. Objective response rate is calculated as a total number of participants with CR or PR divided by the total number of participants treated multiplied by 100. Analysis Population Description: Part D: 50 mg LY3039478 (Cohort 5) was assessed using Cheson criteria. Zero participants were analyzed for Part D: 50 mg LY3039478 (Cohort 4) because data were not collected. Data was not reported because both enrolled participants discontinued treatment early-one on Day 1 due to investigator decision and the other on Day 26 due to myocardial infarction, with no efficacy assessments performed.

  Baseline to Disease Progression or Participant Discontinuation (Up To 20 Months)

Secondary Outcomes (12)

• Parts A, B, C, D and E: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3039478

  Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours; Day 22: Predose, 0.5,1,2,4,6-8,8-10,24-30 hours

• Part F1 Cohort1 and Part F2 Cohort 1: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3039478

  Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours; Day 22: Predose, 0.5,1,2,4,6-8,8-10,24-30 hours

• Parts A and B: PK: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC[0-∞]) of LY3039478

  Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours

• Part F1 Cohort1 and Part F2 Cohort 1: PK: Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC[0-∞]) of LY3039478

  Day 1: Predose,0.5,1,2,4,6-8,8-10,24-30 hours

• Parts A and B: PK: Area Under the Concentration-Time Curve From Time 0 to Tau (AUC[0-Tau]) of LY3039478

  Day 22: Predose,0.5,1,2,4,6-8,8-10,24-30 hours

Study Arms (4)

LY3039478 - Dose Escalation

EXPERIMENTAL

Part A: LY3039478 administered orally three times per week (TIW) at escalating doses (2.5 milligrams \[mg\], 5 mg, 10 mg, 20 mg, 30 mg, 45 mg, 60 mg, 75 mg and 100 mg) for two 28 day cycles. Participants receiving benefit may continue until disease progression

Drug: LY3039478

LY3039478 - Cohort Expansion

EXPERIMENTAL

Part B,C,D \& E:LY3039478 administered orally three times per week(TIW) at a fixed dose determined in Part A for two 28 day cycles.Participants receiving benefit may continue until disease progression.The doses administered were as follows:Part B:50 mg or 75 mg for participants(pts) who had tumors with molecular alterations related to the Notch pathway;Part C:50 mg or 75 mg for pts who had Leiomyosarcoma(LMS),50 mg or 75 mg for pts who had other Sarcoma, 50 mg for pts who had gastrointestinal stromal tumors(GIST);Part D: 75 mg for pts in the Triple Negative Breast Cancer cohort,75 mg for pts in Cholangiocarcinoma cohort,50 mg for pts in Triple Negative Breast Cancer cohort,50 mg for pts in the Hepatocellular Carcinoma cohort,50 mg for pts in the Cholangiocarcinoma cohort, 50 mg for pts in the Chronic lymphocytic leukemia(CLL) cohort, 50 mg for pts in the Mature T cell, B cell or Natural Killer(NK) cell neoplasms cohort; Part E: 50 mg for pts in the Triple Negative Breast Cancer cohort.

Drug: LY3039478

Dose 1 LY3039478 + Prednisone

EXPERIMENTAL

Part F1: Participants received a loading dose of 75 mg or 100 mg administered 3 times per week for 2 weeks during Cycle 1. 50 mg LY3039478 administered orally TIW (twice a week in cycle 1) for 28 day cycles. 20 mg Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only (28 day cycles). Participants receiving benefit may continue until disease progression.

Drug: LY3039478; Drug: Prednisone

Dose 2 LY3039478 + Prednisone

EXPERIMENTAL

Part F2: Participants received a loading dose of 75 mg, 100 mg or 125 mg 2 times per week for 2 weeks during Cycle 1. 50 mg LY3039478 administered orally TIW for 28 day cycles. 20 mg Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only (28 day cycles). Participants receiving benefit may continue until disease progression.

Drug: LY3039478; Drug: Prednisone

Interventions

LY3039478 DRUG

Administered orally

Dose 1 LY3039478 + Prednisone; Dose 2 LY3039478 + Prednisone; LY3039478 - Cohort Expansion; LY3039478 - Dose Escalation

Prednisone DRUG

Administered orally

Dose 1 LY3039478 + Prednisone; Dose 2 LY3039478 + Prednisone

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 (Part A): The participant must have histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced or metastatic.
• For Part B: All participants must have a histological evidence of their advanced or metastatic cancer and prescreened alterations in a defined pathway.
• For Part C: All participants must have histological evidence of advanced or metastatic specific subtypes of soft tissue sarcoma.
• For Part D: All participants must have histological evidence of advanced or metastatic cancer and prescreened alterations in a defined pathway.
• Cohort 1: Participants must have triple negative breast cancer.
• Cohort 2: Participants must have hepatocellular carcinoma (HCC). These participants should have Child-Pugh stage A.
• Cohort 3: Participants must have cholangiocarcinoma.
• Cohort 4: Participants must have chronic lymphocytic leukemia.
• Cohort 5: Participants must have a mature T cell, B cell, or natural killer (NK) cell neoplasm.
• For Part E: Participants must have adenoid cystic carcinoma (ACC).
• For Part F dose confirmation: Participants must have leiomyosarcoma and prescreened alterations in a defined pathway.
• As defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1), the Revised Response Criteria for Malignant Lymphoma or the Response Assessment in Neuro Oncology (RANO) criteria for glioblastoma:
• For Dose Escalation (Part A): Have measurable or nonmeasurable disease.
• For Parts B, C, D, E and F: Have measurable disease or reliable biomarker measure.

You may not qualify if:

• Have symptomatic or non stable central nervous system (CNS) malignancy.
• Females who are pregnant or lactating.
• Have active bacterial, fungal, and/or known viral infection.
• Have malabsorptive syndromes, enteropathies, gastroenteritis (acute or chronic), or diarrhea (acute or chronic).
• Participants with HCC that:
• Have known HCC with fibro-lamellar or mixed histology.
• Have presence of clinically relevant ascites.
• Have had a liver transplant.
• Have active or uncontrolled clinically serious hepatitis B virus or hepatitis C virus infection.

Sponsors & Collaborators

• Eli Lilly and Company: lead

Study Sites (11)

University of Miami School of Medicine

Miami, Florida, 33136, United States

Location

Harvard Medical School

Boston, Massachusetts, 02215, United States

Location

University of Michigan

Ann Arbor, Michigan, 48109, United States

Location

Columbia University Medical Center

New York, New York, 10032, United States

Location

Montefiore Medical Center

The Bronx, New York, 10461, United States

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Copenhagen, 2100, Denmark

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Paris, 75248, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Villejuif, 94805, France

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Tübingen, 72076, Germany

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

Barcelona, 08035, Spain

Location

For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.

London, SE1 9RT, United Kingdom

Location

Related Publications (4)

• Michot JM, Balogh Z, Brown JR, Ribrag V, Hollebecque A, Bahleda R, Quivoron C, Ammari S, Scoazec JY, Benhadji KA, Massard C. Notch pathway inhibition with crenigacestat (LY3039478) in a phase I first-in-human clinical trial for patients with relapsed or refractory non-Hodgkin lymphoma and B-cell chronic lymphocytic leukemia. Ther Adv Drug Saf. 2025 Jul 31;16:20420986241311461. doi: 10.1177/20420986241311461. eCollection 2025.

  PMID: 40756609 DERIVED

• Azaro A, Baldini C, Rodon J, Soria JC, Yuen E, Lithio A, Oakley G, Benhadji KA, Massard C. Phase 1 study of 2 high dose intensity schedules of the pan-Notch inhibitor crenigacestat (LY3039478) in combination with prednisone in patients with advanced or metastatic cancer. Invest New Drugs. 2021 Feb;39(1):193-201. doi: 10.1007/s10637-020-00944-z. Epub 2020 Sep 11.

  PMID: 32915419 DERIVED

• Mir O, Azaro A, Merchan J, Chugh R, Trent J, Rodon J, Ohnmacht U, Diener JT, Smith C, Yuen E, Oakley GJ 3rd, Le Cesne A, Soria JC, Benhadji KA, Massard C. Notch pathway inhibition with LY3039478 in soft tissue sarcoma and gastrointestinal stromal tumours. Eur J Cancer. 2018 Nov;103:88-97. doi: 10.1016/j.ejca.2018.08.012. Epub 2018 Sep 12.

  PMID: 30218977 DERIVED

• Massard C, Azaro A, Soria JC, Lassen U, Le Tourneau C, Sarker D, Smith C, Ohnmacht U, Oakley G, Patel BKR, Yuen ESM, Benhadji KA, Rodon J. First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer. Ann Oncol. 2018 Sep 1;29(9):1911-1917. doi: 10.1093/annonc/mdy244.

  PMID: 30060061 DERIVED

Related Links

• Click here for more information about this study: A Study of LY3039478 in Participants with Advanced Cancer

MeSH Terms

Conditions

Neoplasms; Neoplasm Metastasis; Lymphoma

Interventions

crenigacestat; Prednisone

Condition Hierarchy (Ancestors)

Neoplastic Processes; Pathologic Processes; Pathological Conditions, Signs and Symptoms; Neoplasms by Histologic Type; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Pregnadienediols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Polycyclic Compounds

Limitations and Caveats

1. There was no recommended phase II dose declared from Part F1 or F2. Expansion cohort was not triggered. 2. For outcome measure number 8 (Part A and B ((AUC \[0-∞\]) of LY3039478), AUC0-inf parameter cannot be calculated (per analysis plan) for Part B: 50 mg LY3039478 due to insufficient length of PK sampling to 8h for a drug half-life of around 5-6 hours.

Results Point of Contact

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

ClinicalTrials.gov@lilly.com

800-545-5979

Study Officials

• 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: GT60
• Restrictive Agreement: Yes

Study Design

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

Study Record Dates

• First Submitted: September 24, 2012
• First Posted: September 27, 2012
• Study Start: October 1, 2012
• Primary Completion: June 26, 2018
• Study Completion: June 26, 2018
• Last Updated: December 26, 2025
• Results First Posted: December 26, 2025

Record last verified: 2025-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (5); DK (1); FR (2); ES (1); GB (1); DE (1)