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A Study of LY3023414 in Participants With Advanced Cancer

Primary Purpose

Advanced Cancer, Metastatic Cancer, Non-Hodgkin's Lymphoma

Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
LY3023414
Midazolam
Fulvestrant
Pemetrexed
Cisplatin
Abemaciclib
Letrozole
Sponsored by
Eli Lilly and Company
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Advanced Cancer focused on measuring Advanced Breast Cancer, Advanced Lung Cancer, Mesothelioma, Lymphoma

Eligibility Criteria

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

Inclusion Criteria:

  • Parts A, A2 & B1: Participants must have pathological evidence of a diagnosis of advanced and/or metastatic cancer and must be, in the judgment of the investigator, an appropriate candidate for experimental therapy
  • Part B2: Participants must have advanced, recurrent, or metastatic breast cancer that is refractory to aromatase inhibitors (AI) with either disease recurrence or disease progression; must be hormone receptor positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative; must be of postmenopausal status or beginning ovarian suppression with a luteinizing hormone-releasing hormone (LHRH) agonist
  • Part B3 only: Participants must have malignant pleural or peritoneal mesothelioma
  • Part B4 only: Participants must have malignant pleural or peritoneal mesothelioma and appropriate candidate for treatment with cisplatin/pemetrexed; no prior systemic chemotherapy
  • Part B5 only: Participants must have histologically confirmed diagnosis of B-cell iNHL, with histological subtype; prior treatment with ≥2 prior chemotherapy- or immunotherapy-based regimens for iNHL
  • Part B6 only: Participants must have squamous NSCLC; documented evidence of an activating molecular aberration of the PI3K/mTOR pathway
  • Parts B2, B3 & B6 only: Must have adequate tumor tissue sample from archival biopsy available, or willingness to undergo a fresh tumor biopsy
  • Parts B3, B4, B5 & B6: No previous treatment with any PI3K and/or mTOR inhibitor
  • Part B7: Must have a diagnosis of HR+ and HER2- breast cancer; have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease; no previous treatment or currently receiving 1 of the following treatments for locoregionally recurrent or metastatic breast cancer (chemotherapy, endocrine therapy, CDK4/6 inhibitor, and PI3K and/or mTOR inhibitor)
  • Measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1), modified RECIST or Revised Response Criteria for Malignant Lymphoma
  • Have adequate organ function, including: Absolute neutrophil count (ANC) at least 1.5 x 109/Liter (L), platelets at least 100 x 109/L, and hemoglobin at least 8 grams/deciliter (g/dL); bilirubin no more than 1.5 times upper limits of normal; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.0 times upper limits of normal; Serum creatinine no more than 1.5 times upper limits of normal or calculated creatinine clearance >45 milliliters/minute (mL/min)
  • Have a performance status of at least 1 on the Eastern Cooperative Oncology Group (ECOG) scale and life expectancy >6 months
  • Have discontinued all previous cancer therapies (except nonsteroidal aromatase inhibitors for participants in Part B2), and any agents that have not received regulatory approval for any indication, for at least 21 days or 5 half lives prior to study enrollment, whichever is shorter, and recovered from the acute effects of therapy. Participants must have discontinued mitomycin-C or nitrosourea therapy for at least 42 days
  • Are able to swallow capsules

Exclusion Criteria:

  • Have serious preexisting medical conditions
  • Have symptomatic central nervous system (CNS) malignancy (with the exception of medulloblastoma) or metastasis (screening not required).
  • Have known acute or chronic leukemia or current hematologic malignancies (except iNHL for patients in Part B5) that, in the judgment of the investigator and sponsor, may affect the interpretation of results
  • Have an active fungal, bacterial, and/or known viral infection
  • Have a second primary malignancy that in the judgment of the investigator and sponsor may affect the interpretation of results (Part B only)
  • Part B1 only: No concomitant medications that are strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or midazolam
  • Intolerance to any previous treatment with any phosphatidylinositol-3-kinase (PI3K) and/or mammalian target of rapamycin (mTOR) inhibitor.
  • Participants with active alcohol abuse, as determined by the investigator
  • Have a history of New York Heart Association (NYHA) Class ≥3, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug administration
  • Have QT corrected interval of >450 milliseconds (msec) on screening electrocardiogram (ECG)
  • Have insulin-dependent diabetes mellitus or a history of gestational diabetes mellitus.
  • Part B only: Hypersensitivity to study drugs given in combination with LY3023414

Sites / Locations

  • UCLA Medical Center
  • Memorial Sloan Kettering Cancer Center
  • Peggy and Charles Stephenson Oklahoma Cancer Center
  • Penn Presbyterian Medical Center
  • Sarah Cannon Cancer Center
  • Tennessee Oncology PLLC
  • Azienda Ospedaliero - Universitaria S. Luigi Gonzaga
  • Fundacion de Investigacion de Diego

Arms of the Study

Arm 1

Arm 2

Arm 3

Arm 4

Arm 5

Arm 6

Arm 7

Arm 8

Arm 9

Arm Type

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Experimental

Arm Label

Part A: LY3023414 Once Daily

Part A2: LY3023414 Twice Daily

Part B1 : LY3023414 + Midazolam

Part B2: LY3023414 + Fulvestrant

Part B3: LY3023414

Part B4: LY3023414 + pemetrexed/cisplatin

Part B5: LY3023414

Part B6: LY3023414

Part B7: LY3023414 + Abemaciclib + Letrozole

Arm Description

LY3023414 administered orally once daily (QD) at escalating doses for two 21 day cycles to participants with advanced/metastatic cancer (including lymphoma); participants receiving benefit may continue until disease progression or discontinuation.

LY3023414 administered orally twice daily (BID) at escalating doses for two 21 day cycles to participants with advanced/metastatic cancer (including lymphoma); participants receiving benefit may continue until disease progression or discontinuation.

LY3023414 administered orally BID for two 21 day cycles to participants with advanced/metastatic cancer; participants receiving benefit may continue until disease progression or discontinuation. Dose based on Part A. 0.2 milligrams (mg) midazolam administered orally once before LY3023414 on Day 1 and once after LY3023414 on Day 15.

LY3023414 administered orally BID for two 28 day cycles to participants with advanced/metastatic breast cancer; participants receiving benefit may continue until disease progression or discontinuation. 500 mg fulvestrant administered IM once every 28 days.

LY3023414 administered orally BID for two 21 day cycles to participants with malignant mesothelioma; participants receiving benefit may continue until disease progression or discontinuation.

LY3023414 administered orally BID for two 21 day cycles to participants with malignant mesothelioma; participants receiving benefit may continue until disease progression or discontinuation. 500 mg/m2 pemetrexed and 75 mg/m2 administered IV once every 21 days.

LY3023414 administered orally BID for two 21 day cycles to participants with indolent non-Hodgkin's lymphoma; participants receiving benefit may continue until disease progression or discontinuation.

LY3023414 administered orally BID for two 21 day cycles to participants with squamous NSCLC; participants receiving benefit may continue until disease progression or discontinuation.

LY3023414 administered orally BID with abemaciclib administered orally BID and letrozole administered orally once a day for two 28 day cycles to participants with breast cancer; participants receiving benefit may continue until disease progression or discontinuation.

Outcomes

Primary Outcome Measures

Recommended Phase 2 dose

Secondary Outcome Measures

Pharmacokinetics: Maximum concentration (Cmax)
Pharmacokinetics: Time of maximal concentration
Number of participants with tumor response
Potential of LY3023414 to inhibit CYP3A4-mediated metabolism

Full Information

First Posted
July 19, 2012
Last Updated
April 7, 2022
Sponsor
Eli Lilly and Company
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1. Study Identification

Unique Protocol Identification Number
NCT01655225
Brief Title
A Study of LY3023414 in Participants With Advanced Cancer
Official Title
A Phase 1 First-in-Human Dose Study of LY3023414 in Patients With Advanced Cancer
Study Type
Interventional

2. Study Status

Record Verification Date
April 2022
Overall Recruitment Status
Completed
Study Start Date
July 31, 2012 (Actual)
Primary Completion Date
April 4, 2019 (Actual)
Study Completion Date
February 2, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Eli Lilly and Company

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to find a recommended dose level and schedule of dosing LY3023414 that can safely be taken by participants with advanced or metastatic cancer. The study will also explore the changes to various markers in blood cells and potentially tumor cells. Finally, the study will help document any antitumor activity this drug may have. In Part A of this study, participants with advanced/metastatic cancer (including lymphoma) will receive increasing doses of LY3023414. In Part B, LY3023414 will be explored in different types of cancer, including breast and lung cancer, lymphoma and mesothelioma.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Advanced Cancer, Metastatic Cancer, Non-Hodgkin's Lymphoma, Metastatic Breast Cancer, Malignant Mesothelioma, Non-small Cell Lung Cancer
Keywords
Advanced Breast Cancer, Advanced Lung Cancer, Mesothelioma, 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
156 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Part A: LY3023414 Once Daily
Arm Type
Experimental
Arm Description
LY3023414 administered orally once daily (QD) at escalating doses for two 21 day cycles to participants with advanced/metastatic cancer (including lymphoma); participants receiving benefit may continue until disease progression or discontinuation.
Arm Title
Part A2: LY3023414 Twice Daily
Arm Type
Experimental
Arm Description
LY3023414 administered orally twice daily (BID) at escalating doses for two 21 day cycles to participants with advanced/metastatic cancer (including lymphoma); participants receiving benefit may continue until disease progression or discontinuation.
Arm Title
Part B1 : LY3023414 + Midazolam
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID for two 21 day cycles to participants with advanced/metastatic cancer; participants receiving benefit may continue until disease progression or discontinuation. Dose based on Part A. 0.2 milligrams (mg) midazolam administered orally once before LY3023414 on Day 1 and once after LY3023414 on Day 15.
Arm Title
Part B2: LY3023414 + Fulvestrant
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID for two 28 day cycles to participants with advanced/metastatic breast cancer; participants receiving benefit may continue until disease progression or discontinuation. 500 mg fulvestrant administered IM once every 28 days.
Arm Title
Part B3: LY3023414
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID for two 21 day cycles to participants with malignant mesothelioma; participants receiving benefit may continue until disease progression or discontinuation.
Arm Title
Part B4: LY3023414 + pemetrexed/cisplatin
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID for two 21 day cycles to participants with malignant mesothelioma; participants receiving benefit may continue until disease progression or discontinuation. 500 mg/m2 pemetrexed and 75 mg/m2 administered IV once every 21 days.
Arm Title
Part B5: LY3023414
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID for two 21 day cycles to participants with indolent non-Hodgkin's lymphoma; participants receiving benefit may continue until disease progression or discontinuation.
Arm Title
Part B6: LY3023414
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID for two 21 day cycles to participants with squamous NSCLC; participants receiving benefit may continue until disease progression or discontinuation.
Arm Title
Part B7: LY3023414 + Abemaciclib + Letrozole
Arm Type
Experimental
Arm Description
LY3023414 administered orally BID with abemaciclib administered orally BID and letrozole administered orally once a day for two 28 day cycles to participants with breast cancer; participants receiving benefit may continue until disease progression or discontinuation.
Intervention Type
Drug
Intervention Name(s)
LY3023414
Intervention Description
Administered orally. Dose of 20 to 600 mg, as determined in Part A.
Intervention Type
Drug
Intervention Name(s)
Midazolam
Intervention Description
0.2 mg administered orally once before LY3023414 on Day 1 and once after LY3023414 on Day 15.
Intervention Type
Drug
Intervention Name(s)
Fulvestrant
Intervention Description
500 mg administered IM on Day 1 and Day 15 in cycle 1 and Day 1 every 28 days for additional cycles.
Intervention Type
Drug
Intervention Name(s)
Pemetrexed
Other Intervention Name(s)
Alimta
Intervention Description
500 mg/m2 administered IV once on Day 1 every 21 days
Intervention Type
Drug
Intervention Name(s)
Cisplatin
Intervention Description
75 mg/m2 administered IV once on Day 1 every 21 days
Intervention Type
Drug
Intervention Name(s)
Abemaciclib
Other Intervention Name(s)
LY2835219
Intervention Description
Administered orally
Intervention Type
Drug
Intervention Name(s)
Letrozole
Intervention Description
Administered orally
Primary Outcome Measure Information:
Title
Recommended Phase 2 dose
Time Frame
Baseline to disease progression or participant discontinuation (estimated 9 weeks)
Secondary Outcome Measure Information:
Title
Pharmacokinetics: Maximum concentration (Cmax)
Time Frame
Predose up to 12 hours postdose
Title
Pharmacokinetics: Time of maximal concentration
Time Frame
Predose up to 12 hours postdose
Title
Number of participants with tumor response
Time Frame
Baseline to disease progression or participant discontinuation (estimated 9 weeks)
Title
Potential of LY3023414 to inhibit CYP3A4-mediated metabolism
Time Frame
Baseline through Cycle 1

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Parts A, A2 & B1: Participants must have pathological evidence of a diagnosis of advanced and/or metastatic cancer and must be, in the judgment of the investigator, an appropriate candidate for experimental therapy Part B2: Participants must have advanced, recurrent, or metastatic breast cancer that is refractory to aromatase inhibitors (AI) with either disease recurrence or disease progression; must be hormone receptor positive (HR+) and human epidermal growth factor receptor 2 (HER2)-negative; must be of postmenopausal status or beginning ovarian suppression with a luteinizing hormone-releasing hormone (LHRH) agonist Part B3 only: Participants must have malignant pleural or peritoneal mesothelioma Part B4 only: Participants must have malignant pleural or peritoneal mesothelioma and appropriate candidate for treatment with cisplatin/pemetrexed; no prior systemic chemotherapy Part B5 only: Participants must have histologically confirmed diagnosis of B-cell iNHL, with histological subtype; prior treatment with ≥2 prior chemotherapy- or immunotherapy-based regimens for iNHL Part B6 only: Participants must have squamous NSCLC; documented evidence of an activating molecular aberration of the PI3K/mTOR pathway Parts B2, B3 & B6 only: Must have adequate tumor tissue sample from archival biopsy available, or willingness to undergo a fresh tumor biopsy Parts B3, B4, B5 & B6: No previous treatment with any PI3K and/or mTOR inhibitor Part B7: Must have a diagnosis of HR+ and HER2- breast cancer; have locoregionally recurrent disease not amenable to resection or radiation therapy with curative intent or metastatic disease; no previous treatment or currently receiving 1 of the following treatments for locoregionally recurrent or metastatic breast cancer (chemotherapy, endocrine therapy, CDK4/6 inhibitor, and PI3K and/or mTOR inhibitor) Measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST Version 1.1), modified RECIST or Revised Response Criteria for Malignant Lymphoma Have adequate organ function, including: Absolute neutrophil count (ANC) at least 1.5 x 109/Liter (L), platelets at least 100 x 109/L, and hemoglobin at least 8 grams/deciliter (g/dL); bilirubin no more than 1.5 times upper limits of normal; alanine aminotransferase (ALT) and aspartate aminotransferase (AST) no more than 2.0 times upper limits of normal; Serum creatinine no more than 1.5 times upper limits of normal or calculated creatinine clearance >45 milliliters/minute (mL/min) Have a performance status of at least 1 on the Eastern Cooperative Oncology Group (ECOG) scale and life expectancy >6 months Have discontinued all previous cancer therapies (except nonsteroidal aromatase inhibitors for participants in Part B2), and any agents that have not received regulatory approval for any indication, for at least 21 days or 5 half lives prior to study enrollment, whichever is shorter, and recovered from the acute effects of therapy. Participants must have discontinued mitomycin-C or nitrosourea therapy for at least 42 days Are able to swallow capsules Exclusion Criteria: Have serious preexisting medical conditions Have symptomatic central nervous system (CNS) malignancy (with the exception of medulloblastoma) or metastasis (screening not required). Have known acute or chronic leukemia or current hematologic malignancies (except iNHL for patients in Part B5) that, in the judgment of the investigator and sponsor, may affect the interpretation of results Have an active fungal, bacterial, and/or known viral infection Have a second primary malignancy that in the judgment of the investigator and sponsor may affect the interpretation of results (Part B only) Part B1 only: No concomitant medications that are strong inhibitors or inducers of cytochrome P450 3A4 (CYP3A4) or midazolam Intolerance to any previous treatment with any phosphatidylinositol-3-kinase (PI3K) and/or mammalian target of rapamycin (mTOR) inhibitor. Participants with active alcohol abuse, as determined by the investigator Have a history of New York Heart Association (NYHA) Class ≥3, unstable angina, or myocardial infarction (MI) in 6 months prior to study drug administration Have QT corrected interval of >450 milliseconds (msec) on screening electrocardiogram (ECG) Have insulin-dependent diabetes mellitus or a history of gestational diabetes mellitus. Part B only: Hypersensitivity to study drugs given in combination with LY3023414
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
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)
Organizational Affiliation
Eli Lilly and Company
Official's Role
Study Director
Facility Information:
Facility Name
UCLA Medical Center
City
Los Angeles
State/Province
California
ZIP/Postal Code
90095
Country
United States
Facility Name
Memorial Sloan Kettering Cancer Center
City
New York
State/Province
New York
ZIP/Postal Code
10065
Country
United States
Facility Name
Peggy and Charles Stephenson Oklahoma Cancer Center
City
Oklahoma City
State/Province
Oklahoma
ZIP/Postal Code
73104
Country
United States
Facility Name
Penn Presbyterian Medical Center
City
Philadelphia
State/Province
Pennsylvania
ZIP/Postal Code
19104
Country
United States
Facility Name
Sarah Cannon Cancer Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Tennessee Oncology PLLC
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37203
Country
United States
Facility Name
Azienda Ospedaliero - Universitaria S. Luigi Gonzaga
City
Orbassano
State/Province
Torino
ZIP/Postal Code
10043
Country
Italy
Facility Name
Fundacion de Investigacion de Diego
City
San Juan
ZIP/Postal Code
00927
Country
Puerto Rico

12. IPD Sharing Statement

Citations:
PubMed Identifier
33660194
Citation
Zauderer MG, Alley EW, Bendell J, Capelletto E, Bauer TM, Callies S, Szpurka AM, Kang S, Willard MD, Wacheck V, Varghese AM. Phase 1 cohort expansion study of LY3023414, a dual PI3K/mTOR inhibitor, in patients with advanced mesothelioma. Invest New Drugs. 2021 Aug;39(4):1081-1088. doi: 10.1007/s10637-021-01086-6. Epub 2021 Mar 4.
Results Reference
derived
Links:
URL
https://trials.lillytrialguide.com/en-US/trial/1hEgh09hSQ64QyAaacI6my
Description
A Study of LY3023414 in Participants With Advanced Cancer

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A Study of LY3023414 in Participants With Advanced Cancer

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