Clinical trial NCT01695005: 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
Overall status: COMPLETED
Phase: PHASE1
Conditions: Neoplasms
Neoplasm Metastasis
Lymphoma
Lead sponsor: Eli Lilly and Company
Sponsor class: INDUSTRY
First posted: 2012-09-27
Enrollment: 237
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

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.

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.

Primary outcomes:
measure: Part A and F: Number of Participants with Dose Limiting Toxicities (DLTs)
timeFrame: Baseline to disease progression or participant discontinuation (estimated 8 -12 weeks)
measure: Part B, C, D, E and F: Number of Participants with Tumor Response
timeFrame: Baseline to disease progression or participant discontinuation (estimated 8 -12 weeks)
Secondary outcomes:
measure: Pharmacokinetics: Maximum Concentration (Cmax) of LY3039478
timeFrame: Predose up to 30 hours post dose
measure: Pharmacokinetics: Time to Maximum Concentration (Tmax) of LY3039478
timeFrame: Predose up to 30 hours post dose
measure: Part A: Number of Participants with Tumor Response
timeFrame: Baseline to disease progression or participant discontinuation (estimated 8 -12 weeks)
measure: Part B, C, D, E and F: Duration of Response (DoR)
timeFrame: Date of Complete Response or Partial Response to Date of Objective Disease Progression or Death Due to Any Cause (Estimated up to 6 Months)
measure: Part B, C, D, E and F: Progression Free Survival (PFS)
timeFrame: Baseline to Objective Progression or Death from Any Cause (Estimated up to 6 Months)
measure: Part B, C, D, E and F: Overall Survival (OS)
timeFrame: Baseline to Date of Death from Any Cause (Estimated up to 14 Months)
Other outcomes:
Locations:
city: Miami
country: United States
facility: University of Miami School of Medicine
state: Florida
city: Boston
country: United States
facility: Harvard Medical School
state: Massachusetts
city: Ann Arbor
country: United States
facility: University of Michigan
state: Michigan
city: Bronx
country: United States
facility: Montefiore Medical Center
state: New York
city: New York
country: United States
facility: Columbia University Medical Center
state: New York
city: Kobenhavn
country: Denmark
facility: 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: Paris
country: France
facility: 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: Villejuif
country: France
facility: 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: Tübingen
country: Germany
facility: 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: Barcelona
country: Spain
facility: 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: London
country: United Kingdom
facility: 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.
Study officials:
affiliation: Eli Lilly and Company
name: 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST)
role: STUDY_DIRECTOR
References:
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.
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.
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.