A Study of LY3039478 in Participants With Advanced or Metastatic Solid Tumors

Phase 1TerminatedNCT02784795

Eli Lilly and Company94 enrolled

Overview

The main purpose of this study is to evaluate the safety of the study drug known as LY3039478 in combination with other anticancer agents in participants with advanced or metastatic solid tumors.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

Conditions

Solid Tumor Breast Cancer Colon Cancer Cholangiocarcinoma Soft Tissue Sarcoma

Interventions

LY3039478DRUG

Administered orally

TaladegibDRUG

Administered orally

AbemaciclibDRUG

Administered orally

Cisplatin

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 for all combinations: The participant must have histological or cytological evidence of cancer, either a solid tumor or a lymphoma, which is advanced or metastatic. * For Part A dose confirmation: All participants must have histological evidence of advanced or metastatic soft tissue sarcoma or breast cancer. Breast cancer participants must have prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. * For Part B dose confirmation: All participants must have histological evidence of advanced or metastatic colon cancer or soft tissue sarcoma. Colon cancer participants must have prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. * For Part C dose confirmation: All participants must have histological evidence of advanced or metastatic breast cancer and prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. * For Part D dose confirmation: All participants must have histological evidence of cholangiocarcinoma and prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. Participants must not have received \>1 line of prior systemic therapy for metastatic or resectable disease (that is, participants may have received adjuvant gemcitabine and then later gemcitabine/cisplatin for recurrent metastatic disease). * For Part E dose confirmation: All participants must have histological evidence of locally advanced or metastatic triple negative breast cancer (TNBC) and prescreened mutations, amplification, or gene/protein expression alterations related to Notch pathway. Participants must not have received \>2 lines of systemic treatment for advanced or metastatic TNBC. * Have adequate organ function. * Have a performance status of ≤1 on the Eastern Cooperative Oncology Group (ECOG) scale. * Have discontinued all previous therapies for cancer. Exclusion Criteria: * Have current acute leukemia. * Have current or recent (within 3 months of study drug administration) gastrointestinal disease with chronic or intermittent diarrhea, or disorders that increase the risk of diarrhea, such as inflammatory bowel disease.

Locations (11)

Sylvester Comprehensive Cancer Center

Miami, Florida, United States

Karmanos Cancer Institute

Detroit, Michigan, United States

Memorial Sloan Kettering Cancer Center

New York, New York, United States

Outcomes

Primary Outcomes

Number of Participants With LY3039478 Dose-Limiting Toxicities (DLT) in Part A, B, C, D and E

DLT is defined as an adverse event (AE) during Cycle 1 (28 days for Part A, B and C and 21 days for Part D, E) that was possibly related to the study drug and met 1 of the following criteria: According to the National Cancer Institute's (NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.0: ≥Grade 3 non-hematological toxicity except nausea/vomiting, diarrhea, or constipation that can be controlled with appropriate care; Grade 3 elevations of alanine aminotransferase (ALT) and/or aspartate aminotransferase (AST) lasting fewer than 8 days (without evidence of other hepatic injury); Grade 3 rash that resolves or improves to a Grade 2 or less within 7 days; CTCAE Grade 4 hematological toxicity of \>5 days duration; Grade 4 thrombocytopenia of any duration; Grade 3 thrombocytopenia with bleeding; Grade 3 febrile neutropenia.

Time frame: Baseline to toxicity (up to end of Cycle 1 [1Cycle = 28 days for Part A, B and C and 21 days for Part D, E])

Secondary Outcomes

Pharmacokinetics (PK): Area Under the Concentration-Time Curve From Time 0 to Infinity (AUC[0-∞]) of LY3039478 in Combination With Taladegib, LY3023414, Abemaciclib, Cisplatin/Gemcitabine, and Gemcitabine/Carboplatin in Part A, B, C, D and E

AUC\[0-∞\] of LY3039478 in combination with taladegib, LY3023414, abemaciclib, cisplatin/gemcitabine, and gemcitabine/carboplatin in dose escalation parts of Part A, B, C, D and E was evaluated.

Time frame: Parts A/B/C Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30 hours post-dose; Parts D/E Day 1 (Cycle 1) and 15 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6-8, 24-30 hours post-dose

PK: AUC[0-∞] of Taladegib and Its Active Metabolite LSN3185556, in Combination With LY3039478 (Part A)

AUC\[0-∞\] of taladegib and its active metabolite LSN3185556, in combination with LY3039478 (Part A) was evaluated.

Time frame: Day -3 (Lead in) : pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30, 72 hours post-dose and Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8, 24 hours post-dose

Data from ClinicalTrials.gov

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GemcitabineDRUG

Administered IV

CarboplatinDRUG

Administered IV

LY3023414DRUG

Administered orally

University of Texas MD Anderson Cancer Center

Houston, Texas, United States

Rigshospitalet

Copenhagen, København Ø, Denmark

Institut Bergonie

Bordeaux, France

Centre Leon Berard

Lyon, France

Gustave Roussy

Villejuif, France

Hospital Universitari Vall d'Hebron

Barcelona, Spain

Fundacion Jimenez Diaz

Madrid, Spain

...and 1 more locations

PK: AUC[0-∞] of LY3023414 in Combination With LY3039478 on Day -3 (Part B)

AUC\[0-∞\] of LY3023414 in combination with LY3039478 (Part B) on day -3 was evaluated.

Time frame: Day -3 (Lead in): pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30, 72 hours post-dose

PK: AUC[0-∞] of LY3023414 in Combination With LY3039478 on Day 22 (Part B)

AUC\[0-∞\] of LY3023414 in combination with LY3039478 (Part B) on day 22 was evaluated. LY3023414 PK data is summarized only for dose escalation patients in Part B with intensive PK sampling.

Time frame: Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose

PK: AUC[0-∞] of Abemaciclib and AUC From Time Zero to the Last Measured Concentration Value (AUC[0-tlast]) of Its Major Active Metabolites LSN2839567 and LSN3106726, in Combination With LY3039478 on Day -3 (Part C)

AUC\[0-∞\] of abemaciclib and AUC\[0-tlast\] of its major active metabolites LSN2839567 and LSN3106726, in combination with LY3039478 on Day 3 (Part C) was evaluated.

Time frame: Day -3 (Lead in): pre-dose, 0.5, 1, 2, 4, 6, 8, 24-30, 72 hours post-dose

AUC\[0-∞\] of abemaciclib and AUC\[0-tlast\] of its major active metabolites LSN2839567 and LSN3106726, in combination with LY3039478 on Day 22 (Part C) was evaluated.

Time frame: Day 22 (Cycle 1): pre-dose, 0.5, 1, 2, 4, 6, 8 hours post-dose

Duration of Response (DoR)

DoR was the time from the date of first evidence of complete response or partial response to the date of objective progression or the date of death due to any cause, whichever is earlier. CR and PR were defined using the RECIST v1.1. CR defined as the disappearance of all target and non-target lesions and no appearance of new lesions. PR defined as at least a 30% decrease in the sum of the LD of target lesions (taking as reference the baseline sum LD), no progression of non-target lesions, and no appearance of new lesions. If a responder was not known to have died or have objective progression as of the data inclusion cutoff date, duration of response was censored at the last adequate tumor assessment date.

Time frame: Date of Complete Response (CR) or Partial Response (PR) to Date of Objective Disease Progression (Up To 12 Months)

Progression Free Survival (PFS) Time in Part A, B, C, D and E

PFS defined as the time from the date of randomization to the first evidence of disease progression as defined by response evaluation criteria in solid tumors (RECIST) v1.1 or death from any cause. Progressive Disease (PD) was 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. If a participant does not have a complete baseline disease assessment, then the PFS time was censored at the date of randomization, regardless of whether or not objectively determined disease progression or death has been observed for the participant. If a participant was not known to have died or have objective progression as of the data inclusion cutoff date for the analysis, the PFS time was censored at the last adequate tumor assessment date. PFS time was summarized using Kaplan-Meier estimates.

Time frame: Baseline to Objective Disease Progression or Death (Up To 1.91 Months for Part A, 7.69 Months for Part B, 11.53 Months for Part C, 19.52 Months for Part D, 7.03 Months for Part E)