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

Phase 1

Terminated

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

Interventions: Drug: LY2584702
Drug: Erlotinib
Drug: Everolimus

Registration Number: NCT01115803

Lead Sponsor: Eli Lilly and Company

Brief Summary: 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: 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.

Recruitment & Eligibility

Status: TERMINATED

Sex: All

Target Recruitment: 29

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:
1. Arm A: advanced or metastatic non-small cell lung cancer after failure of at least one prior chemotherapy regimen.
2. 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.
1. Dose Escalation portion (Part 1): participants may have measurable or nonmeasurable disease.
2. Dose Confirmation portion (Part 2): participants must have measurable disease.
Have adequate organ function including:
1. 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).
2. 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.
3. 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.

Study & Design

Study Type: INTERVENTIONAL

Study Design: SEQUENTIAL

Arm && Interventions

Group	Intervention	Description
Arm B: LY2584702 + Everolimus	LY2584702	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.
Arm A: LY2584702 + Erlotinib	LY2584702	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.
Arm A: LY2584702 + Erlotinib	Erlotinib	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.
Arm B: LY2584702 + Everolimus	Everolimus	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.

Primary Outcome Measures

Name	Time	Method
Recommended Dose for Phase 2 Studies	Baseline up to 6 cycles of 28 days	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.

Secondary Outcome Measures

Name	Time	Method
Percentage of Participants Achieving Complete Response (CR) or Partial Response (PR) [Response Rate (RR)]	Baseline to disease progression or death or up to 6 cycles of 28 days	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.
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
Number of Participants With Complete Response (CR), Partial Response (PR) or Stable Disease (SD) [Best Overall Response (BOR) (CR+PR+SD)]	Baseline up to 112 Days	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.
Progression-Free Survival (PFS)	Baseline to disease progression or death or up to 166 days postbaseline	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.
Clinically Significant Effects (Number of Participants With Adverse Events)	Baseline up to 7 months	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.
Pharmacokinetics, Area Under the Concentration Time Curve (AUC)	Cycle 1 Days 1 (C1 D1) and Cycle 1 Day 8 (C1 D8) of 28-day cycle	AUC from time 0 to 8 hours (AUC0-8) and AUC from time 0 to infinity (AUC0-∞).

Trial Locations

Locations (1): For additional information regarding investigative sites for this trial, contact 1-877-CTLILLY (1-877-285-4559, 1-317-615-4559) Mon - Fri from 9 AM to 5 PM Eastern Time (UTC/GMT - 5 hours, EST), or speak with your personal physician.
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Villejuif, France