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

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])

Population: All participants who receive at least one dose of study drug in Part A, B, C, D and E.

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)

Population: Duration of Response was not calculated for any participant as the study was terminated prior to data collection.

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

Population: All participants who received at least one dose of study drug with intensive PK sampling in the dose escalation cohorts of Part A, B, C, D and E. PK data was interpreted by combining Part B (25 mg LY3039478 + 150/200 mg LY3023414; Cohorts 1 and 3) and Part C (25 mg LY3039478 + 100/150 mg abemaciclib; Cohorts 1 and 3) reporting arms as all participants received same dose of 50 mg LY3039478 (Part B and C Cohorts 1 and 2) and to increase the sample size for interpretability.

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

Population: All randomized participants who received at least one dose of study drug with evaluable PK data in 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

Population: All randomized participants who received at least one dose of study drug with evaluable PK data in Part C. Day -3 Cohort 1 and 2 results for Parts B were combined as Part C: 100 mg Abemaciclib (Cohort 1 and Cohort 2) since they are from same dose and were collected in the absence of LY3039478 co-administration.

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

Population: All participants who received at least one dose of study drug with intensive PK sampling in the dose escalation cohort of 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

Population: All randomized participants who received at least one dose of study drug with evaluable PK data in Part B. Day -3 Cohort 1 and 2 results for Parts B were combined as 'Part B:150 mg LY3023414 (Cohort 1 and Cohort 2)' since they are from same dose and were collected in the absence of LY3039478 co-administration. Part B Cohort 4 participants had sparse PK sampling limited to day 22 so day -3 PK results are not available/reported.

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

Population: All randomized participants who received at least one dose of study drug with evaluable PK data in Part A.

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)

Population: All randomized participants in Part A, B, C, D and E. Censored participants: Part A= 2, Part B = 0, 4, 2 and 7, Part C = 0, 6 and 5, Part D = 2, 3, Part E = 3, 7.