A Study of LY3039478 in Participants With Advanced Cancer

Eli Lilly and Company247 enrolled

Overview

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.

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

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

247

Conditions

Neoplasms Neoplasm Metastasis Lymphoma

Interventions

LY3039478DRUG

Administered orally

PrednisoneDRUG

Administered orally

Eligibility

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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.

Locations (11)

University of Miami School of Medicine

Miami, Florida, United States

Outcomes

Primary Outcomes

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).

Time frame: 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.

Time frame: 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.

Time frame: 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).

Time frame: 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.

Data from ClinicalTrials.gov

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Secondary Outcomes

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

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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.

Time frame: 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

Time frame: 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])

Time frame: 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).

Time frame: 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.

Time frame: 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.

Time frame: Baseline to Date of Death from Any Cause (Up To 49 Months)