A Study of LY3023414 in Participants With Advanced Cancer

Sponsor

Eli Lilly and Company (Industry)

Overall Status

Completed

CT.gov ID

NCT01655225

Collaborator

(none)

156

Enrollment

Locations

Arms

114.1

Actual Duration (Months)

19.5

Patients Per Site

0.2

Patients Per Site Per Month

Study Details

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.

Condition or Disease	Intervention/Treatment	Phase
Advanced Cancer Metastatic Cancer Non-Hodgkin's Lymphoma Metastatic Breast Cancer Malignant Mesothelioma Non-small Cell Lung Cancer	Drug: LY3023414 Drug: Midazolam Drug: Fulvestrant Drug: Pemetrexed Drug: Cisplatin Drug: Abemaciclib Drug: Letrozole	Phase 1

Study Design

Study Type:

Interventional

Actual Enrollment :

156 participants

Allocation:

Non-Randomized

Intervention Model:

Single Group Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

Official Title:

A Phase 1 First-in-Human Dose Study of LY3023414 in Patients With Advanced Cancer

Actual Study Start Date :

Jul 31, 2012

Actual Primary Completion Date :

Apr 4, 2019

Actual Study Completion Date :

Feb 2, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part A: LY3023414 Once Daily 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A.
Experimental: Part A2: LY3023414 Twice Daily 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A.
Experimental: Part B1 : LY3023414 + Midazolam 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A. Drug: Midazolam 0.2 mg administered orally once before LY3023414 on Day 1 and once after LY3023414 on Day 15.
Experimental: Part B2: LY3023414 + Fulvestrant 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A. Drug: Fulvestrant 500 mg administered IM on Day 1 and Day 15 in cycle 1 and Day 1 every 28 days for additional cycles.
Experimental: Part B3: LY3023414 LY3023414 administered orally BID for two 21 day cycles to participants with malignant mesothelioma; participants receiving benefit may continue until disease progression or discontinuation.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A.
Experimental: Part B4: LY3023414 + pemetrexed/cisplatin 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A. Drug: Pemetrexed 500 mg/m2 administered IV once on Day 1 every 21 days Other Names: Alimta Drug: Cisplatin 75 mg/m2 administered IV once on Day 1 every 21 days
Experimental: Part B5: LY3023414 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A.
Experimental: Part B6: LY3023414 LY3023414 administered orally BID for two 21 day cycles to participants with squamous NSCLC; participants receiving benefit may continue until disease progression or discontinuation.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A.
Experimental: Part B7: LY3023414 + Abemaciclib + Letrozole 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.	Drug: LY3023414 Administered orally. Dose of 20 to 600 mg, as determined in Part A. Drug: Abemaciclib Administered orally Other Names: LY2835219 Drug: Letrozole Administered orally

Outcome Measures

Primary Outcome Measures

Recommended Phase 2 dose [Baseline to disease progression or participant discontinuation (estimated 9 weeks)]

Secondary Outcome Measures

Pharmacokinetics: Maximum concentration (Cmax) [Predose up to 12 hours postdose]
Pharmacokinetics: Time of maximal concentration [Predose up to 12 hours postdose]
Number of participants with tumor response [Baseline to disease progression or participant discontinuation (estimated 9 weeks)]
Potential of LY3023414 to inhibit CYP3A4-mediated metabolism [Baseline through Cycle 1]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts 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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	UCLA Medical Center	Los Angeles	California	United States	90095
2	Memorial Sloan Kettering Cancer Center	New York	New York	United States	10065
3	Peggy and Charles Stephenson Oklahoma Cancer Center	Oklahoma City	Oklahoma	United States	73104
4	Penn Presbyterian Medical Center	Philadelphia	Pennsylvania	United States	19104
5	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
6	Tennessee Oncology PLLC	Nashville	Tennessee	United States	37203
7	Azienda Ospedaliero - Universitaria S. Luigi Gonzaga	Orbassano	Torino	Italy	10043
8	Fundacion de Investigacion de Diego	San Juan		Puerto Rico	00927

Sponsors and Collaborators

Eli Lilly and Company

Investigators

Study Director: 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), Eli Lilly and Company