An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820 to Determine the Maximum Tolerated Dose Following Twice Daily Oral Administration in Subjects With Unresectable Solid Tumors

Study Overview
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Brief Summary
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This study consists of two Parts. Part A (Food Effect Study) and Part B (Determination of Maximum Tolerated Dose [MTD] for twice daily [BID] Dosing).Part A will be initiated first, and Part B will be initiated after the PK results of Part A have been evaluated.

Official Title
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An Open-label, Dose Escalation, Pharmacodynamic, Pharmacokinetic, and Effect of Food Phase 1 Study of E7820, to Determine the Maximum Tolerated Dose Following Twice Daily Oral Administration in Subjects With Unresectable Solid Tumors

Conditions
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Advanced Solid Tumors

Intervention / Treatment
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* Drug: E7820
* Drug: E7820


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 years or older. Histological or cytological evidence of an unresectable or refractory solid tumor. Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2 Subjects with known brain metastases will be eligible under the following conditions A. Have undergone complete surgical excision and are more then 1 month post surgery with no radiographic evidence of brain disease recurrence or B. Have undergone stereotactic radio surgery (gamma knife procedure) and are more then 1 month post procedure and with no radiographic evidence of brain disease progression and C. Are asymptomatic and D. Discontinued corticosteroid treatment at least 30 days prior to Cycle 1, Day 1 Adequate liver function as evidenced by bilirubin less than or equal to 1.5 times the upper limits of normal (ULN) and alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 x ULN (in the case of liver metastases less than or equal to 5 x ULN) In case alkaline phosphatase is greater than 3 x ULN (in absence of liver metastases) or greater than 5 x ULN (in presence of liver metastases) AND subject also is known to have bone metastases, the liver specific alkaline phosphatase must be separated from the total and used to assess the liver function instead of the total alkaline phosphatase. Adequate renal function as evidenced by serum creatinine less than or equal to 2.0 mg/dL (177 micro-mol/L) or calculated creatinine clearance greater than or equal to 40 mL/min per the Cockcroft and Gault formula Provide written informed consent. Are willing and able to comply with all aspects of the protocol. Adequate bone marrow function as evidenced by absolute neutrophil count (ANC) greater than or equal to 1.5 x 109/L, hemoglobin greater than or equal to 9 g/dL (5.5 mmol/L) and platelet count greater than or equal to 100 x 109/L. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [beta-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of beta-hCG). A separate baseline assessment is required if a negative screening pregnancy test was obtained more than 72 hours before the first dose of study drug. All females will be considered to be of childbearing potential unless they are postmenopausal (amenorrheic for at least 12 consecutive months, in the appropriate age group, and without other known or suspected cause) or have been sterilized surgically (i.e., bilateral tubal ligation, total hysterectomy, or bilateral oophorectomy, all with surgery at least 1 month before dosing). Females of childbearing potential must not have had unprotected sexual intercourse within 30 days prior to study entry and must agree to use a highly effective method of contraception (e.g., total abstinence, an intrauterine device, a double-barrier method [such as condom plus diaphragm with spermicide], a contraceptive implant, an oral contraceptive or have a vasectomized partner with confirmed azoospermia) throughout the entire study period and for 30 days after study drug discontinuation. If currently abstinent, the subject must agree to use a double-barrier method as described above if she becomes sexually active during the study period or for 30 days after study drug discontinuation. Females who are using hormonal contraceptives must have been on a stable dose of the same hormonal contraceptive product for at least 4 weeks prior to dosing and must continue to use the same contraceptive during the study and for 30 days after study drug discontinuation. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (i.e., not of childbearing potential or practicing highly effective contraception throughout the study period and for 30 days after study drug discontinuation). No sperm donation is allowed during the study period and for 30 days after study drug discontinuation. Exclusion Criteria: Leptomeningeal metastases or brain metastases (except as for inclusion criteria #4). Active hemoptysis (at least 2.5 mL [0.5 teaspoon] bright red blood) within 3 weeks prior to the first dose of study drug. Hypersensitivity to sulfonamide derivatives. Subjects who have had radiation to greater than or equal to 30% of their bone marrow. Subjects who require therapeutic anti-coagulant therapy with warfarin or related vitamin K antagonists. Prophylactic doses of heparin or low molecular weight heparin or thrombin inhibitors may be used in place of warfarin. Left ventricular ejection fraction less than 50% on echocardiography or MUGA scanning. Anticancer therapies that have not been completed at least 28 days (42 days in the case of mitomycin C or nitrosoureas) prior to treatment with E7820 (other than surgery or treatment with a protein kinase inhibitor which must have been completed no less than one week prior to treatment with E7820). Incomplete recovery from previous radiotherapy, chemotherapy, or surgery other than residual cutaneous effects or stable less than Grade 2 gastrointestinal toxicity. History of an ischemic cardiac event, myocardial infarction or unstable cardiac disease within 3 months before study entry. A clinically significant electrocardiogram (ECG) abnormality, including a marked baseline prolongation of QTc interval greater than 480 msec. Evidence of clinically significant disease (e.g., cardiac, respiratory, gastrointestinal, renal disease) that in the opinion of the investigator(s) could affect the subject's safety or study conduct. Concurrent treatment with CYP3A4 inhibitors such as verapamil, cyclosporin, quinidine, erythromycin, mibefradil, clarithramycin and azoles. Concurrent treatment with drugs known to be extensively metabolized by CYP2C9 and/or CYP2C19. Chronic treatment with known inducers of CYP3A4 within four weeks of receiving treatment with E7820 other than corticosteroids (Appendix 6). Subjects who have a positive test result for human immunodeficiency virus (HIV), hepatitis A, hepatitis B or hepatitis C. Psychotic disorder(s) or unstable recurrent affective disorder(s) evident by use of antipsychotics or prior suicide attempt(s) within approximately the last 2 years. History of drug or alcohol dependency or abuse within approximately the last 2 years. Presence of a progressive central nervous system (CNS) disease, including degenerative CNS diseases and progressive tumors. Pulmonary lymphangitic involvement that results in pulmonary dysfunction requiring active treatment, including the use of oxygen. Use of illegal recreational drugs. Any medical or other condition that, in the opinion of the investigator, would preclude the subject's participation in a study.

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: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Part A<br> | Drug: E7820<br>* FOOD EFFECT STUDY: Each subject (a minimum of 12 subjects) will be assigned according to a randomization code to receive a single 50 mg dose of E7820 on Day 1, either after fasting for 10 hours, or immediately after consuming a high fat breakfast. Following a 7-day washout period, the subjects will crossover and a second 50 mg dose of E7820 will be administered on Day 8.<br>|
| Experimental: Part B<br> | Drug: E7820<br>* MTD DETERMINATION FOR BID DOSING SCHEDULE The initial dose of E7820 will be 50 mg BID. If allowed by the rules for dose escalation, the dose escalations will be to 60 mg BID, 80 mg BID, and 100 mg BID.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Treatment Phase Part A: AUC(0-inf): Area Under the Plasma Concentration-time Curve From Time 0 to Infinity for E7820 |  | Day 1 or 8: 0.5-48 hours | 
| Treatment Phase Part A: AUC(0-t): Area Under the Plasma Concentration- Time Curve From Time 0 to t for E7820 |  | Day 1 or 8: 0.5-48 hours | 
| Treatment Phase Part A: Cmax: Maximum Observed Plasma Concentration for E7820 |  | Day 1 or 8: 0.5-48 hours | 
| Treatment Phase Part B: Maximum Tolerated Dose (MTD) of E7820 BID Dosing Schedule | MTD defined as the highest dose level at which no more than 1 of 6 participants experienced a dose-limiting toxicity(DLT), with the next higher dose having at least 2 of 3 or 2 of 6 participants experiencing DLTs. DLTs were defined using National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events(CTCAE) Version 4.03 as: Neutropenia less than(<) 0.5*10^9/liter(L) for greater than(>) 5 days; neutropenia <1*10^9/L with fever; thrombocytopenia <25*10^9/L accompanied by bleeding or thrombocytopenia <10*10^9/L; any Grade 3 or 4 nonhematological toxicity for which the study drug could not be excluded as a cause (other than nausea, vomiting or diarrhea in the absence of appropriate prophylaxis) with the following clarification: Grade 3 or 4 nonhematological laboratory abnormalities for which there was no expected clinical correlation would not be considered DLTs; treatment delay of >14 days required to recover from E7820-related toxicities. | Up to Cycle 6 (Cycle length =28 days) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Extension Phase Part A, and Treatment and Extension Phase Part B: Number of Participants With Best Overall Response (BOR) | BOR based on RECIST 1.1 for target and non-target lesions is complete response (CR) or partial response (PR) for >4 weeks or stable disease (SD) for >5 weeks from first dose. CR: disappearance of target and non-target lesions, normalization of tumor marker level, all lymph nodes must be non- pathological in size (<10 millimeter [mm] short axis). PR: at least 30% decrease in sum of diameters (SOD) of target lesions, taking as reference the baseline SOD persistence of one or more non- target lesions and/or maintenance of tumor marker level above the normal limits. SD: neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease (PD), taking as reference the smallest SOD. PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions, taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From first dose of study drug (Baseline) up to approximately 6.6 years | 
| Extension Phase Part A, and Treatment and Extension Phase Part B: Duration of Response | Duration of response based on RECIST 1.1 for target and non-target lesions is the time from the date of first documented confirmed CR/PR until the first documentation of confirmed progressive disease (PD) or death, whichever came first. CR: disappearance of target and non-target lesions,normalization of tumor marker level,all lymph nodes must be non-pathological in size(<10 mm short axis). PR: at least 30% decrease in SOD of target lesions,taking as reference the baseline SOD persistence of one or more non- target lesions and/or maintenance of tumor marker level above the normal limits. PD:at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions,taking as reference the smallest sum and/or unequivocal progression of existing non-target lesions and/or appearance of 1 or more new lesions. | From date of first documented confirmed CR/PR until date of first documentation of PD or death (approximately up to 6.6 years) | 
| Extension Phase Part A, and Treatment and Extension Phase Part B: Number of Participants With Death and Progressive Disease (PD) | PD: at least 20% increase (including an absolute increase of at least 5 mm) in the SOD of target lesions. For PD: participants with best response of PD have been reported. For Death: participants with death known to have died at any point have been reported. | From first dose date to the date of the first documentation of confirmed PD or death (approximately up to 6.6 years) | 
| Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) | Safety assessments consisted of monitoring and recording all AEs and SAEs; regular monitoring of hematology, clinical chemistry, and urine values; physical examinations; and regular measurement of vital signs, ECG, and multiple-gated acquisition (MUGA) scans or echocardiograms. | From the first dose of study drug up to 30 days after the last dose of study drug (approximately up to 6.6 years) |