A Study of LY2584702 With Erlotinib or Everolimus in Participants With Solid Tumors

Study Overview
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Brief Summary
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Study I3G-MC-JGCB (JGCB) is a multicenter, nonrandomized, open-label, dose-escalation Phase 1b study of LY2584702 in combination with either erlotinib or everolimus.

Detailed Description
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Study JGCB will consist of the following parts: Part 1 - Dose Escalation to maximum tolerated dose in each arm. Arm A - LY2584702 + Erlotinib in participants with advanced or metastatic cancer. Arm B - LY2584702 + Everolimus in participants with advanced or metastatic cancer. Part 2 - Dose Confirmation of maximum tolerated dose from each arm in Part 1. Arm A - LY2584702 + Erlotinib in participants with advanced or metastatic non-small cell lung cancer. Arm B - LY2584702 + Everolimus in participants with advanced renal cell carcinoma after treatment failure with sunitinib or sorafenib, or advanced neuroendocrine tumors.

Official Title
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A Phase 1b Trial of LY2584702 in Combination With Erlotinib or Everolimus in Patients With Solid Tumors

Conditions
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Metastases, Neoplasm, Carcinoma, Non-small Cell Lung, Renal Cell Carcinoma, Neuroendocrine Tumors

Intervention / Treatment
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* Drug: LY2584702
* Drug: Erlotinib
* Drug: Everolimus


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Dose Escalation portion (Part 1): have histological or cytological evidence of a diagnosis of cancer that is advanced and/or metastatic disease (including Non-Hodgkin's Lymphoma) for which no proven effective therapy exists. Dose Confirmation portion (Part 2): have histological or cytological evidence of: Arm A: advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen. Arm B: advanced renal cell carcinoma after failure of treatment with sunitinib or sorafenib, or advanced neuroendocrine tumors. Have the presence of measurable or nonmeasurable disease as defined by the Response Evaluation Criteria in Solid Tumors (RECIST 1.1) or the Revised Response Criteria for Malignant Lymphoma. Dose Escalation portion (Part 1): participants may have measurable or nonmeasurable disease. Dose Confirmation portion (Part 2): participants must have measurable disease. Have adequate organ function including: Hematologic: absolute neutrophil count (ANC) greater than or equal to 1.5 x 10⁹/liters (L), platelets greater than or equal to 100 x 10⁹/L, and hemoglobin greater than or equal to 8 grams/deciliter (g/dL). Hepatic: bilirubin less than or equal to 1.5 times upper limits of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) less than or equal to 2.5 times ULN. If the liver has tumor involvement, AST and ALT equaling less than or equal to 5 times ULN are acceptable. Participants with bone metastases may enter with alkaline phosphatase values less than or equal to 5 times ULN, as long as other hepatic parameters meet inclusion criteria. Renal: Serum creatinine less than or equal to 1.5 times ULN or calculated creatinine clearance >45 milliliter/minute (ml/mn). Have a performance status of less than or equal to 1 on the Eastern Cooperative Oncology Group (ECOG) scale. Have discontinued all previous therapies for cancer, including chemotherapy, radiotherapy, cancer-related hormonal therapy, or other investigational therapy for at least 2 weeks (3 weeks for myelosuppressive agents) prior to study enrollment, and have recovered from the acute effects of therapy. At the discretion of the investigator, participants with prostate cancers progressing under luteinizing hormone-releasing hormone (LHRH) agonists therapy, and participants with adrenal carcinomas using mitotane, may have that treatment continued while receiving study drug. Exclusion Criteria: Have received treatment with a drug that has not received regulatory approval for any indication within 14 or 21 days of the initial dose of study drug for a nonmyelosuppressive or myelosuppressive agent, respectively. Have serious preexisting medical conditions that, in the opinion of the investigator, would preclude participation in this study. Have symptomatic central nervous system (CNS) malignancy or metastasis. Participants with treated CNS metastases are eligible provided their disease is radiographically stable and asymptomatic, and they are not currently receiving corticosteroids and/or anticonvulsants. Screening of asymptomatic participants without history of CNS metastasis is not required. Concomitant treatment by strong cytochrome P450 (CYP) 3A4 inhibitors or CYP3A4 inducers. Have an acute or chronic leukemia. Have received an autologous or allogeneic stem-cell transplant within 75 days of the initial dose of study drug. In addition, recipients of an allogeneic stem-cell transplant must have discontinued immunosuppressive therapy at least 24 hours before study drug administration with no more than Grade 1 acute graft-versus-host disease. For Dose Confirmation portion (Part 2): have previously received erlotinib for Arm A or everolimus for Arm B.

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
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Arm A: LY2584702 + Erlotinib<br>Participants received 50 mg LY2584702 once daily (QD )+ 150 mg Erlotinib QD, 50 mg LY2584702 twice daily (BID) + 150 mg Erlotinib QD, 100 mg LY2584702 BID + 150 mg Erlotinib QD and 75 mg LY2584702 BID + 150 mg Erlotinib QD. | Drug: LY2584702<br>* Supplied as 25 milligrams (mg) and 100 mg capsules, administered orally for two 28-day cycles.<br>Drug: Erlotinib<br>* Supplied as 25 mg, 100 mg, or 150 mg tablets, administered orally, daily for two 28-day cycles. Starting dose is 150mg. Doses may be decreased in 50mg increments if necessary due to toxicity.<br>|
| Experimental: Arm B: LY2584702 + Everolimus<br>Participants received 50 mg LY2584702 QD + 10 mg Everolimus QD, 100 mg LY2584702 QD + 10 mg Everolimus QD and 50 mg LY2584702 BID + 10 mg Everolimus QD. | Drug: LY2584702<br>* Supplied as 25 milligrams (mg) and 100 mg capsules, administered orally for two 28-day cycles.<br>Drug: Everolimus<br>* Supplied as 5 mg or 10 mg tablets, administered orally, daily for two 28-day cycles.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Recommended Dose for Phase 2 Studies | The recommended dose for the Phase 2 (Dose Confirmation Phase) study was determined by safety assessment. Doses were escalated following the assessment for toxicity based on Common Terminology Criteria for Adverse Events (CTCAE v4.0). Any adverse events (AE) that were possibly related to LY2584702 were considered toxicities. The Phase 2 dose of LY2584702 was not determined due to unacceptable toxicities of LY2584702 in combination with erlotinib or everolimus in Phase 1 of the study. | Baseline up to 6 cycles of 28 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Clinically Significant Effects (Number of Participants With Adverse Events) | Clinically significant events were defined as serious adverse events (SAEs) and other non-SAEs regardless of causality. A summary of serious and other non SAEs regardless of causality is located in the Reported Adverse Event module. | Baseline up to 7 months | 
| Progression-Free Survival (PFS) | PFS was defined as the time from the date of enrollment to the date of objectively determined progressive disease (PD) or death whichever comes first. Censoring of PFS was defined as participants not known to have died as of the data cut-off date and who did not have objective PD, PFS was censored at the date of the last objective assessment; for participants who received subsequent systematic anticancer therapy (after discontinuation from study treatment) prior to objectively determined disease progression, PFS was censored at the date of the last objective progression-free disease assessment prior to post discontinuation of therapy. PFS was not analyzed due to different tumor types and different doses. | Baseline to disease progression or death or up to 166 days postbaseline | 
| Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) [Response Rate (RR)] | Response was determined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeters (mm) and normalization of tumor marker level of non-target lesions; PR was defined as at least a 30% decrease in sum of longest diameter of target lesions. | Baseline to disease progression or death or up to 6 cycles of 28 days | 
| Pharmacokinetics, Maximum Observed Plasma Concentration (Cmax) of LY2584702 |  | Cycle 1 Day 1 (C1 D1): predose, 0.5, 1, 2, 3, 5, 8 hours postdose and Cycle 1 Day 8 (C1 D8): predose, 0.5, 1, 2, 3, 5, and 8 hours postdose of 28-day cycle | 
| Pharmacokinetics, Area Under the Concentration Time Curve (AUC) | AUC from time 0 to 8 hours (AUC0-8) and AUC from time 0 to infinity (AUC0-∞). | Cycle 1 Days 1 (C1 D1) and Cycle 1 Day 8 (C1 D8) of 28-day cycle | 
| Number of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) [Best Overall Response (BOR) (CR+PR+SD)] | BOR was determined using Response Evaluation Criteria In Solid Tumors (RECIST v1.1) criteria. CR was defined as the disappearance of all target and non-target lesions and any pathological lymph nodes (whether target or non-target) must have reduction in short axis to <10 millimeters (mm) and normalization of tumor marker level of non-target lesions; PR was defined as at least a 30% decrease in sum of longest diameter (LD) of target lesions; Progressive Disease (PD) was defined as at least 20% increase in sum of LD of target lesions and minimum 5 mm increase over nadir. SD was defined as small changes that did not meet above criteria. | Baseline up to 112 Days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Advanced Cancer, Metastatic Cancer, Non-Small Cell Lung Cancer, Renal Cell Carcinoma, Neuroendocrine Tumors