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A Study of LY3039478 in Participants With Advanced Cancer

Primary Purpose

Neoplasms, Neoplasm Metastasis, Lymphoma

Status

Completed

Phase

Phase 1

Locations

International

Study Type

Interventional

Intervention

LY3039478

Prednisone

About this trial

This is an interventional treatment trial for Neoplasms

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

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.

Sites / Locations

University of Miami School of Medicine
Harvard Medical School
University of Michigan
Montefiore Medical Center
Columbia University Medical Center
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.
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.
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.
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.
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.
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.

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm Type

Experimental

Arm Label

LY3039478 - Dose Escalation

LY3039478 - Cohort Expansion

Dose 1 LY3039478 + Prednisone

Dose 2 LY3039478 + Prednisone

Arm Description

Part A: LY3039478 administered orally three times per week (TIW) at escalating doses (2.5 milligrams [mg] to 100 mg) for two 28 day cycles. Participants receiving benefit may continue until disease progression

Part B, C, D and 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.

Part F1: LY3039478 administered orally TIW for 28 day cycles. 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.

Part F2: LY3039478 administered orally TIW (twice a week in cycle 1) for 28 day cycles. Prednisone will be co-administered with LY3039478 for the first 2 weeks in cycle 1 only. Participants receiving benefit may continue until disease progression.

Outcomes

Primary Outcome Measures

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

Part B, C, D, E and F: Number of Participants with Tumor Response

Secondary Outcome Measures

Pharmacokinetics: Maximum Concentration (Cmax) of LY3039478

Pharmacokinetics: Time to Maximum Concentration (Tmax) of LY3039478

Part A: Number of Participants with Tumor Response

Part B, C, D, E and F: Duration of Response (DoR)

Part B, C, D, E and F: Progression Free Survival (PFS)

Part B, C, D, E and F: Overall Survival (OS)

Full Information

NCT ID

NCT01695005

First Posted

September 24, 2012

Last Updated

August 6, 2018

Sponsor

Eli Lilly and Company

1. Study Identification

Unique Protocol Identification Number

NCT01695005

Brief Title

A Study of LY3039478 in Participants With Advanced Cancer

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

August 2018

Overall Recruitment Status

Completed

Study Start Date

October 2012 (undefined)

Primary Completion Date

June 26, 2018 (Actual)

Study Completion Date

June 26, 2018 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Eli Lilly and Company

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Yes

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

5. Study Description

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Neoplasms, Neoplasm Metastasis, Lymphoma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

237 (Actual)

8. Arms, Groups, and Interventions

Arm Title

LY3039478 - Dose Escalation

Arm Type

Experimental

Arm Description

Arm Title

LY3039478 - Cohort Expansion

Arm Type

Experimental

Arm Description

Arm Title

Dose 1 LY3039478 + Prednisone

Arm Type

Experimental

Arm Description

Arm Title

Dose 2 LY3039478 + Prednisone

Arm Type

Experimental

Arm Description

Intervention Type

Drug

Intervention Name(s)

LY3039478

Intervention Description

Administered orally

Intervention Type

Drug

Intervention Name(s)

Prednisone

Intervention Description

Administered orally

Primary Outcome Measure Information:

Title

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

Time Frame

Baseline to disease progression or participant discontinuation (estimated 8 -12 weeks)

Title

Part B, C, D, E and F: Number of Participants with Tumor Response

Time Frame

Baseline to disease progression or participant discontinuation (estimated 8 -12 weeks)

Secondary Outcome Measure Information:

Title

Pharmacokinetics: Maximum Concentration (Cmax) of LY3039478

Time Frame

Predose up to 30 hours post dose

Title

Pharmacokinetics: Time to Maximum Concentration (Tmax) of LY3039478

Time Frame

Predose up to 30 hours post dose

Title

Part A: Number of Participants with Tumor Response

Time Frame

Baseline to disease progression or participant discontinuation (estimated 8 -12 weeks)

Title

Part B, C, D, E and F: Duration of Response (DoR)

Time Frame

Date of Complete Response or Partial Response to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 6 Months)

Title

Part B, C, D, E and F: Progression Free Survival (PFS)

Time Frame

Baseline to Objective Progression or Death from Any Cause (Estimated up to 6 Months)

Title

Part B, C, D, E and F: Overall Survival (OS)

Time Frame

Baseline to Date of Death from Any Cause (Estimated up to 14 Months)

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)

Organizational Affiliation

Eli Lilly and Company

Official's Role

Study Director

Facility Information:

Facility Name

University of Miami School of Medicine

City

Miami

State/Province

Florida

ZIP/Postal Code

33136

Country

United States

Facility Name

Harvard Medical School

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

University of Michigan

City

Ann Arbor

State/Province

Michigan

ZIP/Postal Code

48109

Country

United States

Facility Name

Montefiore Medical Center

City

Bronx

State/Province

New York

ZIP/Postal Code

10461

Country

United States

Facility Name

Columbia University Medical Center

City

New York

State/Province

New York

ZIP/Postal Code

10032

Country

United States

Facility Name

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.

City

Kobenhavn

ZIP/Postal Code

2100

Country

Denmark

Facility Name

City

Paris

ZIP/Postal Code

75248

Country

France

Facility Name

City

Villejuif

ZIP/Postal Code

94805

Country

France

Facility Name

City

Tübingen

ZIP/Postal Code

72076

Country

Germany

Facility Name

City

Barcelona

ZIP/Postal Code

08035

Country

Spain

Facility Name

City

London

ZIP/Postal Code

SE1 9RT

Country

United Kingdom

12. IPD Sharing Statement

Citations:

PubMed Identifier

32915419

Citation

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.

Results Reference

derived

PubMed Identifier

30218977

Citation

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.

Results Reference

derived

PubMed Identifier

30060061

Citation

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.

Results Reference

derived

Links:

URL

https://www.lillytrialguide.com/en-US/studies/solid-tumor/JJCA#?postal=

Description

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