A Dose-Finding Study of E7389 in Combination With Carboplatin in Patients With Solid Tumors

Study Overview
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Brief Summary
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The purpose of this study is to determine the maximum tolerated dose (MTD) and to explore the safety and anti-tumor activity of E7389 in combination with carboplatin in patients with advanced solid tumors.

Detailed Description
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This is a Phase Ib open-label, two-arm, dose-finding study of E7389 in combination with carboplatin in patients with solid tumors.

Official Title
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A Phase Ib Open-Label, Two-Arm, Dose-Finding Study of E7389 in Combination With Carboplatin in Patients With Solid Tumors

Conditions
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Cancer

Intervention / Treatment
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* Drug: E7389 + carboplatin AUC 5
* Drug: E7389 + carboplatin AUC 6
* Drug: E7389+carboplatin AUC 6


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients ≥ 18 years of age. Patients with an Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or 1. Patients with a life expectancy of ≥ three months. Patients with adequate renal function as evidenced by serum creatinine ≤ 2.0 mg/dL or calculated creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula. Patients with adequate bone marrow function as evidenced by absolute neutrophil count (ANC) ≥ 1.5 × 10^9/L, hemoglobin ≥ 10.0 g/dL (this may have been corrected by transfusion or growth factors) and platelet count ≥ 100 × 10^9/L. Patients with adequate liver function as evidenced by bilirubin ≤ 1.5 mg/dL and alkaline phosphatase (ALP), alanine transaminase (ALT) and aspartate aminotransferase (AST) ≤ 3 times the upper limits of normal (ULN) (in the case of liver metastases ≤ 5 x ULN), unless there are bone metastases, in which case liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. to assess the liver function instead of the total alkaline phosphatase. Patients willing and able to comply with the study protocol for the duration of the study. Written informed consent prior to any study-specific screening procedures with the understanding that the patient may withdraw consent at any time without prejudice. For patients in the dose finding phase, the following additional inclusion criteria must be fulfilled: Patients with pathologically diagnosed, histologically or cytologically confirmed advanced solid tumor, that has progressed following standard therapy or for which no standard therapy exists (including surgery or radiation therapy). Patients with disease progression despite standard therapy or have disease for which no standard therapy exists. Patients with ≤ Grade 2 chemotherapy or radiation-related toxicities except alopecia. For NSCLC patients at the MTD, the following additional inclusion criteria must be fulfilled: Patients with pathologically diagnosed, histologically or cytologically confirmed advanced NSCLC (Stage IIIB or IV) with measurable disease, not amenable to surgical or radiation treatment. Patients with no prior chemotherapy for NSCLC including neoadjuvant or adjuvant treatment. Exclusion Criteria: Patients are excluded if they have received any of the following within three weeks prior to first study treatment: investigational drugs, immunotherapy, gene therapy, hormone therapy (except leuprolide, and megestrol acetate for appetite stimulation), other biological therapy, chemotherapy or radiation. Patients with major surgery without full recovery or major surgery within 3 weeks prior to first study treatment are also excluded. Patients must have recovered from any previous major therapy-related toxicity (Grade 3 or 4) to < Grade 2 at study entry (except for neuropathy). Patients who have received radiation ≤ 3 weeks prior to study enrollment, whose marrow exposure has exceeded 30% or who have not recovered from the toxic effects of the treatment prior to study enrollment (except for alopecia). Patients who have received prior high dose chemotherapy with hematopoietic stem cell rescue or stem cell or bone marrow transplant in the past two years. Patients with pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen Patients with active symptomatic brain metastases. Patients with central nervous system (CNS) metastases are considered eligible if they have had adequately treated brain metastases, ie, have completed treatment (tapered off steroids) at least four weeks before starting treatment with E7389. Patients who have no evidence that the metastases are symptomatic or actively growing (no evidence of midline shift on computed tomography scan or magnetic resonance imaging) may be enrolled without initiation of local therapy for the CNS metastases. In this case, a repeat scan must be performed within four weeks of the original scan to ensure that disease progression is not occurring. It is not the intention of this study to treat patients with active brain metastases. Patients with meningeal carcinomatosis. Patients who require therapeutic anti-coagulant therapy with warfarin or related compounds. Women who are pregnant or breast-feeding. Women of childbearing potential with either a positive pregnancy test at Screening or no pregnancy test. Women of childbearing potential unless (1) surgically sterile or (2) using adequate measures of contraception in the opinion of the investigator (e.g., using 2 forms of contraception including a barrier method). Perimenopausal women must be amenorrheic for at least 12 months to be considered of non-childbearing potential. Fertile men who are not willing to use contraception or fertile men with a female partner who is not willing to use contraception. Patients with severe/uncontrolled intercurrent illness or infection. Patients with significant cardiovascular impairment (history of congestive heart failure > New York Heart Association Grade II, unstable angina or myocardial infarction within the past six months, or serious cardiac arrhythmia). Patients with organ allografts. Patients who have a history of positive testing for HIV and/or have active hepatitis B or active hepatitis C at study entry. Patients with pre-existing neuropathy > Grade 2. Patients with a hypersensitivity to halichondrin B and/or to a halichondrin B chemical derivative. Patients who participated in a prior E7389 clinical trial. Patients with other significant disease or disorders that, in the investigator's opinion, would exclude the patient from the study. For NSCLC patients at the MTD, the following additional exclusion criterion must be fulfilled: 1. Patients who have had a prior malignancy, other than carcinoma in situ of the cervix, or non-melanoma skin cancer, unless the prior malignancy was diagnosed and definitively treated ≥ five years previously with no subsequent evidence of recurrence.

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: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: 1<br> | Drug: E7389 + carboplatin AUC 5<br>* Patients will receive E7389 before (Schedule A) or after (Schedule B) carboplatin AUC 5 infusion. E7389 will be administered as a 2-5 minute intravenous (IV) bolus infusion at a starting dose of 0.7 mg/m^2 on Days 1 and 8 every 21 days. Carboplatin 5 AUC will be administered as a 30-minute IV infusion on Day 1 every 21 days. Dose escalation will be performed in cohorts of three patients per dose level per schedule.<br>|
| Experimental: 2<br> | Drug: E7389 + carboplatin AUC 6<br>* After MTD is reached with carboplatin AUC 5, dose escalation of E7389 in combination with carboplatin at AUC 6 will begin at one dose level below MTD, using the preferred schedule (A or B). If carboplatin AUC 6 with E7389 is tolerated, the MTD reached will be used to enroll 20 additional patients with Stage IIIB or IV non-small cell lung cancer (NSCLC). If carboplatin AUC 6 is not tolerated, these patients will be enrolled at the MTD determined with the combination of E7389 and carboplatin AUC 5.<br>|
| Experimental: 3<br> | Drug: E7389+carboplatin AUC 6<br>* In a population of patients who had generally received multiple prior chemotherapies, the eribulin MTD has been determined to be 1.1 mg/m2 in combination with carboplatin at an AUC of 6. The first-line NSCLC patients in the extension arm may tolerate a higher dose of eribulin, because they have not been exposed to the toxicity of other chemotherapies. To investigate this possibility, the dose of eribulin will be increased to 1.4 mg/m2 for subsequent patients, if the first six of these patients do not experience a DLT during their first cycle of eribulin at 1.1 mg/m2 and carboplatin at AUC 6 combination therapy. If no more than one of the first six patients experience a DLT during the first cycle with the 1.4 mg/m2 dose of eribulin, then the 1.4 mg/m2 dose will be considered the recommended dose for front-line NSCLC therapy and the remaining patients will be treated using this dose.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Eribulin Mesylate of E7389 in Combination With Carboplatin in Subjects With Advanced Solid Tumors. | MTD was established by summarizing the number and percent of subject with dose- limiting toxicities (DLTs) for the first cycle. | 21 days (first cycle) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Safety of Eribulin Mesylate in Combination With Carboplatin as Measured by the Number of Subjects With Treatment Emergent Adverse Events. | Adverse events were considered treatment emergent if they started on or after the date of administration of the first dose of study drug, or if they were present prior to the administration of the first dose of study drug and increased in severity during the study. | Throughout the entire study | 
| Percent of Subjects With Best Overall Response as Measured by Response Evaluation Criteria in Solid Tumors (RECIST) Criteria. | Objective response measured by Response Evaluation Criteria In Solid Tumors (RECIST) criteria and is Complete Response (disappearance of all target lesions) plus Partial Response (at least 30% decrease in sum of longest diameter [LD] of target lesions compared baseline sum of LD). | From start of eribulin treatment until disease progression or death |