A Study of LY3405105 in Participants With Advanced Cancer

Phase 1

Terminated

Conditions: Solid Tumor

Interventions: Drug: LY3405105

Registration Number: NCT03770494

Lead Sponsor: Eli Lilly and Company

Brief Summary: The main purpose of this study is to investigate the safety of LY3405105 in participants with advanced cancer. The study has two parts phase 1a and phase 1b. Participants will only enroll in one part.

Detailed Description: Not available

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 54

Inclusion Criteria

Phase 1 a:

Have histological or cytological evidence of a diagnosis of a solid tumor cancer that is advanced and/or metastatic
Have available archived tissue for exploratory biomarker analysis
Have adequate organ function
Have discontinued all previous treatments for cancer and recovered from their side effects
Are able to swallow capsules/tablets

Phase 1 b:

Cohort 1: Triple-negative breast cancer (TNBC).
Cohort 2: Clear cell ovarian cancer, endometrioid ovarian cancer, or endometrioid endometrial carcinoma with a LOF mutation in one or more of the following genes: ARID1A, KMT2C (MLL3), KMT2D (MLL2), or KDM6A (UTX).
Cohort 3: Soft tissue sarcoma or sarcomatoid/rhabdoid malignancy with loss of expression of INI1, BRG1, or BRM by immunohistochemistry or a LOF mutation in one or more of the following genes: ARID1A, SMARCA2, SMARCA4, or SMARCB1. Participants aged ≥ 12 years with a body weight of ≥ 40 kilogram (kg) are acceptable for Cohorts 3. Participants with synovial sarcoma and a confirmed SS18-SSX gene fusion are also eligible.
Cohort 4: Epithelioid sarcoma with INI1 loss of expression by immunohistochemistry or SMARCB1 LOF mutation. Participants aged ≥ 12 years with a body weight of ≥ 40 kilogram (kg) are acceptable for Cohorts 4.
Cohort 5: Bladder cancer with a LOF mutation in one or more of the following genes: ARID1A, KMT2C (MLL3), KMT2D (MLL2), or KDM6A (UTX).

Exclusion Criteria

Have symptomatic central nervous system (CNS) malignancy or metastasis
Have symptomatic human immunodeficiency virus (HIV), Hepatitis A, B, or C
Have congestive heart failure
Are breastfeeding

Study & Design

Study Type: INTERVENTIONAL

Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
LY3405105	LY3405105	This study was designed to be conducted in two phases: Phase 1a: This is a dose-escalation phase with a starting dose of LY3405105 1 milligram (mg) once daily (Part A1) or 2 mg three times per week (Part A2) on a 28-day cycle until confirmed progressive disease, unacceptable toxicity, or discontinuation for any other reason. Each dose-level will be determined and will have participants enrolled to it based on dose-limiting toxicity rate observed at previous dose-level. Intermediate, alternate, or higher dose levels will be explored if deemed necessary. Phase 1b: This is a dose-expansion phase designed to explore the anti-tumor activity of recommended LY3405105 dose and dosing schedule determined in phase 1a, in participants with multiple tumor types. \[Phase 1b was planned but not initiated based on the sponsor's decision and limited efficacy observed in phase 1a\]

Primary Outcome Measures

Name	Time	Method
Phase 1a: Number of Participants With Dose Limiting Toxicities (DLTs)	Cycle 1 (Up To 28 Days)	A DLT is a clinically significant adverse event that is possibly related to the study drug and fulfils any one of the following criteria using the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE) v4.0: 1\) Nonhematologic Grade ≥3 toxicity, except nausea, constipation, diarrhoea, vomiting or electrolyte disturbance lasting for \<72 hours and can be controlled with treatment, fatigue/anorexia lasting for \<5 days, transient grade 3 elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST), without evidence of other hepatic injury; 2) Total bilirubin \>2×upper limit of normal (ULN) with ALT/AST \>3×ULN in the absence of cholestasis (alkaline phosphatase \<2×ULN); 3) Grade 4 neutropenia \>5 days duration, Any febrile neutropenia, Grade 4 thrombocytopenia of any duration, Grade 3 thrombocytopenia with clinically significant bleeding, Grade 3/4 anemia or any other significant toxicity deemed to be dose limiting by investigators.
Phase 1b: Objective Response Rate (ORR): Percentage of Participants With a Confirmed Complete Response (CR) or Partial Response (PR)	Baseline through Measured Progressive Disease (Estimated up to 6 Months)	ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions.

Secondary Outcome Measures

Name	Time	Method
Phase 1a (Part A1): Pharmacokinetics (PK): Area Under the Concentration Versus Time Curve From Time Zero to 24 Hours [AUC(0-24)] of LY3405105	Cycle 1 Day 1 (Predose, 1, 2, 4, 6, 8, 24 hours post-dose)	AUC(0-24) of LY3405105
Phase 1a (Part A1): PK: Area Under the Concentration Versus Time Curve During One Dosing Interval [AUC(Tau)] of LY3405105	Cycle 1 Day 15 (Predose, 1, 2, 4, 6, 8, 24 hours post-dose)	AUC of LY3405105 during one dosing interval of 24 hours \[tau = 24 hours\].
Phase 1a (Part A2): PK: Area Under the Concentration Versus Time Curve From Time Zero to Infinity [AUC(0-∞)] of LY3405105	Cycle 1 Day 1 (Predose, 1, 2, 4, 6, 8, 24, 48 hours post-dose)	AUC(0-∞) of LY3405105.
Phase 1a (Part A2): PK: Area Under the Concentration Versus Time Curve During One Dosing Interval [AUC(Tau)] of LY3405105	Cycle 1 Day 15 (Predose, 1, 2, 4, 6, 8, 24, 48 hours post-dose)	AUC of LY3405105 during one dosing interval of 48 hours \[tau = 48 hours\].
Phase 1a: Objective Response Rate (ORR): Percentage of Participants With a Confirmed Complete Response (CR) or Partial Response (PR)	Baseline through Measured Progressive Disease (Up To 349 Days)	ORR is the best overall tumor response of complete response (CR) or partial response (PR) as classified by the investigator according to the Response Evaluation Criteria In Solid Tumors (RECIST v1.1). CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions.
Phase 1a: Disease Control Rate (DCR): Percentage of Participants Who Exhibit Stable Disease (SD), Confirmed CR or PR	Baseline through Measured Progressive Disease (Up To 349 Days)	DCR is the percentage of participants with a best overall response of CR, PR or SD as defined by RECIST v1.1. CR is defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR is defined as at least a 30% decrease in the sum of the longest diameter (LD) of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. SD is neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD) for target lesions, no progression of non-target lesions, and no appearance of new lesions. PD is defined as at least a 20% increase in the sum of the diameters of target lesions, with reference being the smallest sum on study and an absolute increase of at least 5 mm, or unequivocal progression of non-target lesions, or 1 or more new lesions.
Phase 1a: Duration of Response (DOR)	Date of Confirmed CR or PR to Date of Objective Progression or Death Due to Any Cause (Estimated up to 12 Months)	DoR will be calculated only for responders. It is measured from the date of first evidence of a confirmed CR or PR response to the date of first progression of disease or the date of death due to any cause, whichever is earlier.
Phase 1a: Time to Response (TTR)	Baseline to Date of Confirmed CR or PR (Estimated up to 6 Months)	TTR is defined as the time from the date of start of treatment to the date measurement criteria for confirmed CR or PR (whichever is first recorded) are first met.
Phase 1b: Progression Free Survival (PFS)	Baseline to Objective Progression or Death Due to Any Cause (Estimated up to 12 Months)	PFS is defined as the time from the date of start of treatment to the first date of radiologically documented progressive disease or the date of death due to any cause, whichever occurs first.
Phase 1b: Overall Survival (OS)	Baseline to Date of Death from Any Cause (Estimated up to 12 Months)	OS is defined as the time from the date of start of treatment to the date of death due to any cause.

Trial Locations

Locations (17): Highlands Oncology Group
🇺🇸
Fayetteville, Arkansas, United States
Smilow Cancer Hospital at Yale-New Haven
🇺🇸
New Haven, Connecticut, United States
Columbia University Medical Center
🇺🇸
New York, New York, United States
Memorial Sloan Kettering Cancer Center
🇺🇸
New York, New York, United States
Duke University Medical Center
🇺🇸
Durham, North Carolina, United States
University of Pennsylvania Hospital
🇺🇸
Philadelphia, Pennsylvania, United States
University of Texas MD Anderson Cancer Center
🇺🇸
Houston, Texas, United States
Princess Margaret Hospital
🇨🇦
Toronto, Ontario, Canada
Institut Bergonie
🇫🇷
Bordeaux, France
Institut Curie
🇫🇷
Paris, France
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Highlands Oncology Group
🇺🇸Fayetteville, Arkansas, United States