A Study of LY3039478 in Participants With Advanced Cancer

A Phase 1 Study of LY3039478 in Patients With Advanced or Metastatic Cancer

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.

Study Overview

• Status: Completed
• Conditions: Neoplasms; Lymphoma; Neoplasm Metastasis
• Intervention / Treatment: Drug: LY3039478; Drug: Prednisone

Detailed Description

In Part A of this study, participants with advanced/metastatic cancer (including lymphoma) will receive increasing doses of LY3039478 to define the dose level for Part B, C, D and E. In Part B, C, D and E LY3039478 will be explored at a predefined fixed dose level. Participants in Part B and D must have a defined alteration in a certain molecular pathway. Enrollment of participants in Part B, C, D and E will start once Part A is completed. In Part F participants will receive increasing doses of LY3039478 in combination with prednisone to define the maximum tolerated dose level.

• Study Type: Interventional
• Enrollment (Actual): 247
• Phase: Phase 1

Contacts and Locations

Study Locations

• Denmark
  • Copenhagen, Denmark, 2100
    • 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.
• France
  • Paris, France, 75248
    • 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, France, 94805
    • 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.
• Germany
  • Tübingen, Germany, 72076
    • 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.
• Spain
  • Barcelona, Spain, 08035
    • 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.
• United Kingdom
  • London, United Kingdom, SE1 9RT
    • 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.
• United States
  • Florida
    • Miami, Florida, United States, 33136
      • University of Miami School of Medicine
  • Massachusetts
    • Boston, Massachusetts, United States, 02215
      • Harvard Medical School
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan
  • New York
    • New York, New York, United States, 10032
      • Columbia University Medical Center
    • The Bronx, New York, United States, 10461
      • Montefiore Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

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 (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.
• For Parts B, C, D, E and F: Have available tumor tissue.
• Have adequate organ function.
• Have a performance status of less than or equal to 1 on the Eastern Cooperative Oncology Group (ECOG) scale and life expectancy of more than 12 weeks.

Exclusion Criteria:

• 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.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: LY3039478 - Dose Escalation; 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; Administered orally
Experimental: LY3039478 - Cohort Expansion; 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; Administered orally
Experimental: Dose 1 LY3039478 + Prednisone; 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; Administered orally; Drug: Prednisone; Administered orally
Experimental: Dose 2 LY3039478 + Prednisone; 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; Administered orally; Drug: Prednisone; Administered orally

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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 Outcome Measures

Outcome Measure	Measure Description	Time Frame
Parts A, B, C, D and E: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3039478	Parts A and B: Pharmacokinetics (PK): Maximum Concentration (Cmax) of LY3039478 Analysis Population Description: Per Protocol, only sparse samples were analyzed for this outcome measure. There were no Sparse Day 22 samples for Part B: 50 mg & 75 mg LY3039478, Part C: 50 mg &75 LY3039478, Part D: 50 mg & 75 LY3039478 and Part E: 50 mg 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	Part F1 Cohort 1 and Part F2 and 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	PK: Area Under the Concentration-Time Curve From time 0 to Infinity (AUC[0-∞]) of LY3039478 Analysis Population Description: One participant assigned to the Part A: 45 mg group LY3039478 arm received 75 mg in error on Day 1 and had evaluable PK data. Therefore, this participant is included in the Part A: 75 mg LY3039478 arm PK analysis population (N=6), though only N=5 is shown in the Participant Flow module.	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	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	PK: Area Under the Concentration-Time Curve From Time 0 to Tau (AUC[0-Tau]) of LY3039478 Analysis Population Description: Per protocol, AUC0-tau was not analyzed for participants undergoing sparse PK sampling. Part B 50mg participants only underwent sparse PK sampling.	Day 22: 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 Tau (AUC[0-Tau]) of LY3039478	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
Parts A, B, C, D and E: PK: Time to Maximum Concentration (Tmax) of LY3039478	Pharmacokinetics: Time to Maximum Concentration (Tmax) of LY3039478 Analysis Population Description: Per Protocol, only sparse samples were analyzed for this outcome measure. There were no Sparse Day 22 samples for Part B: 50 mg & 75 mg LY3039478, Part C: 50 mg &75 LY3039478, Part D: 50 mg & 75 LY3039478 and Part E: 50 mg 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: PK: Time to Maximum Concentration (Tmax) of LY3039478	Part F1 Cohort1 and Part F2 Cohort 1: PK: Time to Maximum Concentration (Tmax) 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 A: 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 ≥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.	Baseline to Disease Progression or Participant Discontinuation (Up To 17 Months)
Part B, C, D, E and F: Duration of Response (DoR)	The time from the date of first evidence of a confirmed complete to the date of objective progression or the date of death from any cause (whichever is earlier) as classified by RECIST 1.1 guidelines. For each participant who is not known to have died or to have had a progression of disease as of the data-inclusion cut-off date, duration of response will be censored at the date of last objective response assessment prior to the date of any subsequent systemic anticancer therapy. Progressive Disease (PD) is an increase of at least 20% in the sum of the diameters of target lesions, taking as reference the smallest sum on study (included baseline sum if that was the smallest on study). In addition, the sum must have demonstrated an absolute increase of at least 5 mm (the appearance of 1 or more new lesions was considered progression).	Date of Complete Response or Partial Response to Date of Objective Disease Progression or Death Due to Any Cause (Up To 20 Months)
Part B, C, D, E and F: Progression Free Survival (PFS)	Progression-free survival(PFS) time is defined as the time from the date of study enrollment to the first date of PD(symptomatic or objective) or death due to any cause,whichever occurs first.For participants who are not known to have died or progressed as of the data-inclusion cut-off date,PFS time will be censored at the date of the last objective progression-free disease assessment prior to the date of any subsequent systemic anticancer therapy. Progressive Disease(PD) is an increase of at least 20% in the sum of the diameters of target lesions,taking as reference the smallest sum on study(included baseline sum if that was the smallest on study).In addition, the sum must have demonstrated an absolute increase of at least 5 mm(the appearance of 1 or more new lesions was considered progression). Analysis Population Description Continued:Part D:50 mg LY3039478(Cohort 4) and Part D:50 mg LY3039478(Cohort 5) were not assessed according to RECIST criteria due to their type of disease.	Baseline to Objective Progression or Death from Any Cause (Up To 17 Months)
Part B, C, D, E and F: Overall Survival (OS)	Overall Survival (OS) was defined as the time from the date of study enrollment to the date of death from any cause. For participants not known to have died as of the data cut-off date, OS time was censored at the last contact date the participants was known to be alive prior to the cut-off date.	Baseline to Date of Death from Any Cause (Up To 49 Months)

Collaborators and Investigators

• Sponsor: Eli Lilly and Company
• Investigators: Study Director: 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST), Eli Lilly and Company

Publications and helpful links

General Publications

• 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.
• 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.
• 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.
• 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.

Helpful Links

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

Study record dates

Study Major Dates

• Study Start: October 1, 2012
• Primary Completion (Actual): June 26, 2018
• Study Completion (Actual): June 26, 2018

Study Registration Dates

• First Submitted: September 24, 2012
• First Submitted That Met QC Criteria: September 24, 2012
• First Posted (Estimated): September 27, 2012

Study Record Updates

• Last Update Posted (Actual): December 26, 2025
• Last Update Submitted That Met QC Criteria: December 5, 2025
• Last Verified: December 1, 2025

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplastic Processes; Lymphatic Diseases; Lymphoproliferative Disorders; Immunoproliferative Disorders; Pathological Conditions, Signs and Symptoms; Hemic and Lymphatic Diseases; Neoplasms; Lymphoma; Neoplasm Metastasis; Polycyclic Compounds; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds; Pregnadienediols; Prednisone; crenigacestat
• Other Study ID Numbers: 14547; I6F-MC-JJCA (Other Identifier: Eli Lilly and Company)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No