A Study of Enzastaurin and Erlotinib in Participants With Solid Tumors and Lung Cancer

Study Overview
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Brief Summary
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Phase I: A study to see what doses of Enzastaurin and Erlotinib are best tolerated by participants with solid tumor cancer. Phase II: A study to see how long participants with non-small cell lung cancer (NSCLC) treated with Enzastaurin and Erlotinib live.

Official Title
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A Phase 1/2 Trial of Enzastaurin and Erlotinib in Patients With Advanced Solid Tumors and Non-Small Cell Lung Cancer (NSCLC) After Prior Chemotherapy

Conditions
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Non-Small Cell Lung Cancer, Malignant Solid Tumor

Intervention / Treatment
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* Drug: enzastaurin
* Drug: erlotinib


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Phase 1: Any incurable solid malignancy, with no more than 3 prior systemic treatment regimens. Phase 2: Histologic diagnosis of advanced NSCLC, Stage IIIB with malignant pleural effusion or Stage IV per American Joint Committee on Cancer Staging Criteria for NSCLC. Participants must have failed 1 or 2 prior systemic treatment regimen(s). Performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) Scale Prior chemotherapy must be completed at least 2 weeks prior to study enrollment, and the participant must have recovered from acute toxic effects (except alopecia) prior to enrollment. Prior radiotherapy is allowed to <25% of the bone marrow. Prior radiotherapy must be completed at least 2 weeks before study enrollment, and the participant must have recovered from acute toxic effects (except alopecia) prior to enrollment. Non-measurable or measurable disease as defined by Response Evaluation Criteria in Solid Tumors [RECIST, version (v) 1.0]. Exclusion Criteria: Participants who Are unable to swallow tablets. Unable to discontinue use of carbamazepine, phenobarbital, and phenytoin. Have previously been treated with an epidermal growth factor receptor (EGFR) inhibitor, including erlotinib. Are receiving concurrent administration of any other antitumor therapy. Have received treatment within the last 30 days with a drug (not including study drug) that has not received regulatory approval for any indication at the time of study entry.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Enzastaurin and erlotinib combination therapy<br>Enzastaurin: Phase 1, Dose Level 1: 500 milligram (mg) oral loading dose Day 1, 250 mg oral, daily Day 2-28, 28-day cycle until disease progression Phase 1, Dose Level 2: 1125 mg oral loading dose Day 1, 500 mg oral, daily until disease progression Phase 2: Dose determined from Phase 1, oral, daily, 28-day cycles until disease progression Erlotinib: • 150 mg, oral, daily, 28-day cycles until disease progression | Drug: enzastaurin<br>* Administered orally<br>* Other names: LY317615;Drug: erlotinib<br>* Administered orally<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Phase 2 Dose for Enzastaurin Plus Erlotinib Combination Therapy (Assess the Tolerated Dose of the Combination Erlotinib and Enzastaurin) | The recommended Phase 2 daily dose level was to be either 1 dose level below that in which 2 of 6 participants experienced dose-limiting toxicities (DLTs) in Phase 1 or the full doses of both enzastaurin and erlotinib (Phase 1, Dose Level 2) in the event that no more than 1 DLT occurred at the highest dose level (Dose Level 2). DLTs were defined as any of the following events during Phase 1, Cycle 1 that were considered by the investigator to be attributable to enzastaurin or the combination of enzastaurin with erlotinib: Grade 4 hematologic events; Grade 3 or 4 nonhematologic events except toxicities explained by a coexisting condition such as glucose disturbances in a diabetic or electrolyte imbalances from diarrhea or vomiting, and toxicities of nausea, vomiting, diarrhea, or skin rash that were tolerable with appropriate treatment. | Phase 1: Predose through end of Cycle 1 (28 days/cycle) | 
| Phase 2: Progression-Free Survival (PFS) With the Enzastaurin Plus Erlotinib Combination Regimen | PFS was defined as the time from the date of study enrollment (baseline) to the first date of progressive disease (PD) (either objectively determined or clinical progression) or death from any cause. PD was defined by Response Evaluation Criteria in Solid Tumors [RECIST, version (v) 1.0] as at least a 20% increase in the sum of the longest diameter (LD) of target lesions, taking as references the smallest sum LD recorded since the treatment started or the appearance of 1 or more new lesions. For participants not known to have died as of the data cut-off date and who did not have PD, PFS was censored at the date of the last visit with adequate assessment. For participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to disease progression or death, PFS was censored at the date of last visit with adequate assessment prior to the initiation of post discontinuation anticancer therapy. | Phase 2: Baseline to measured PD (up to 20 months) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of Participants Who Experienced Treatment-Emergent Adverse Events (TEAEs) (Safety and AE Profile for Enzastaurin/Erlotinib Combination) | A TEAE is any untoward medical occurrence that either occurred or worsened any time after treatment baseline, which did not necessarily have a causal relationship with this treatment. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | Phase 1: First dose through 30 days post last dose (up to 14 Cycles, 28 days/cycle) | 
| Phase I: Pharmacokinetic (PK) Interactions Between Enzastaurin and Erlotinib: Apparent Oral Clearance of Erlotinib Under Steady State Conditions During Multiple Dosing (CLss/F) | Clearance (CL) of a drug is a measure of the rate at which a drug is metabolized or eliminated by normal biological processes. CL obtained after an oral dose (apparent oral CL) is influenced by the fraction of the dose absorbed (F). Drug CL is a quantitative measure of the rate at which a drug substance is removed from the blood. Apparent oral CL of erlotinib over 10 hours at steady state (ss) on Day 22 was calculated. | Phase 1: Cycle 1, Day 22 [predose, 2 hours (h), 4 h, 6 h, 10 h postdose] | 
| Phase I: PK Interactions Between Enzastaurin and Erlotinib: Maximum Observed Plasma Concentration at Steady State (Cmax,ss) | Maximum observed plasma concentration at steady state (Cmax,ss) of enzastaurin, its active metabolite (LSN326020) and total analyte were reported. | Phase 1: Cycle 1, Day 22 (predose, 2 h, 4 h, 6 h, 8 h postdose) | 
| Phase I: PK Interactions Between Enzastaurin and Erlotinib: Area Under the Plasma Concentration Time Curve at Steady State [AUC(Tau,ss)] | Area under the plasma concentration time curve AUC(Tau,ss) of enzastaurin, its active metabolite (LSN326020) and total analyte were reported. | Phase 1, Cycle 1, Day 22 (predose, 2 h, 4 h, 6 h, and 8 h postdose) | 
| Phase 2: Overall Survival (OS) | OS was defined as the time from the date of study enrollment (baseline) to the date of death from any cause. For participants not known to have died as of the data cutoff date, OS was censored at the last contact date (last contact for participants in post discontinuation was equal to the last known alive date in mortality status). | Phase 2: Baseline to date of death from any cause (up to 23 months) | 
| Phase 2: Duration of Response | Duration of response: time from first objective assessment of complete response (CR) or partial response (PR) to first observation of PD. Using RECIST v1.0 criteria, CR was the disappearance of all target lesions; PR was either a ≥30% decrease in sum of LD of target lesions or a complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesion; PD was a ≥20% increase in sum of LD of target lesions, taking as references the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesion. For responding participants not known to have died and who did not have PD, duration of response was censored at date of the last visit with adequate assessment. For responding participants who received subsequent anticancer therapy (after discontinuation from study treatment) prior to PD, duration of response was censored at the date of last visit with adequate assessment prior to the initiation of post discontinuation anticancer therapy. | Phase 2: Date of first response to date of PD (up to 18 months) | 
| Phase 2: Percentage of Participants With Tumor Response | Tumor response was defined using RECIST, v1.0 criteria. CR was the disappearance of all target lesions; PR was either a ≥30% decrease in sum of LD of target lesions or a complete disappearance of target lesions, with persistence (but not worsening) of ≥1 nontarget lesion. PD was a ≥20% increase in sum of LD of target lesions, taking as references the smallest sum LD recorded since treatment started or the appearance of ≥1 new lesion. Stable Disease (SD) was defined as small changes that did not meet the above criteria. Percentage of participants with tumor response=[(number of participants with a CR, PR, SD, PD, and unknown response)/(total number of participants assessed)]*100. | Phase 2: Baseline to date of PD (up to 18 months) | 
| Phase 2: Number of Participants Who Experienced TEAEs (Safety and AE Profile) | A TEAE is any untoward medical occurrence that either occurred or worsened any time after treatment baseline, which did not necessarily have a causal relationship with this treatment. A summary of serious and other non-serious AEs, regardless of causality, is located in the Reported Adverse Events module. | Phase 2: Baseline through 30 days post last dose (up to 24 Cycles, 28 days/cycle) |