Advanced solid tumors (including ovarian cancer, triple negative breast cancer, and advanced melanoma) and B-cell lymphomas MedDRA version: 14.1 Level: LLT Classification code 10033130 Term: Ovarian cancer NOS System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 14.1 Level: LLT Classification code 10027475
Conditions
Interventions
Product Name: E7449
Product Code: PACT
Pharmaceutical Form: Capsule
INN or Proposed INN: PACT (no current proposed INN/ INN)
Current Spo
Sponsors
Eisai Limited
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1- Subjects with measurable or non-measurable disease following the Response Evaluation Critieria in Solid Tumours for Phase 1 part of the study. 2 - Histologically and/ or cytologically confirmed advanced or metastatic solid tumor or B-cell lymphomas which have progressed after treatment with approved therapies or for which there are no standard therapies available. 3 - Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 4 - Life expectancy of >= 3 months after starting E7449 5 - Subjects with known brain metastases will be eligible under the following conditions: a) have undergone complete surgical excision and are more than 1 month post surgery with no radiographic evidence of brain disease recurrence or b) have undergone stereotactic radio surgery (gamma knife procedure) or radiotherapy and are more than 1 month post procedure and with no radiographic evidence of brain disease progression and are asymptomatic and discontinued corticosteroid treatment at least 30 days prior to C1D1. 6- Adequate renal function defined as Serum Creatinine = 50mL/min per the Cockcroft-Gault formula 7- Adequate bone marrow function (as defined in protocol) 8 - Adequate liver function (as defined in protocol) 9 - Left ventricular ejection fraction (LVEF) >50% on echocardiography or multiple-gated acquision (MUGA) scanning 10 - Males or females >= 18 years at the time of informed consent 11 - Females must not be lactating or pregnant. All females will be considered to be of childbearing potential unless they are postmenopausal or have been sterilized surgically. Females of child bearing 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 12- Male subjects must have had a succesful vasetomy (confirmed azoospermia) or they and their female partner must meet the criteria above. Those with partners using hormonal contraception must also be using an additional approved method of contraception, as described previously. 13 - Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 150 F.1.3 Elderly (>=65 years) yes F.1.3.1 Number of subjects for this age range 48
Exclusion criteria
Exclusion criteria: 1 - Prior exposure to E7449 2 - Leptomeningeal metastases or brain metastases (except as for Inclusion Criteria #5) 3 - Prior treatment with a PARP inhibitor (Phase 2 only) 4 - Subjects taking medications with are either strong CYP inhibitors or inducers 5 - Subjects with a history of malignancies other than advanced ovarian cancer (Cohort 1 only), ATM-deficient B-cell lymphomas (Cohort 2 only), advanced melanoma (Cohort 3 only) or mTNBC (Cohort 4 only), will be excluded from Phase 2 unless the subject has been disease free from that additional malignancy for 5 years or the cancer was a squamous cell carcinoma of the skin, carcinoma in situ of the cervix, adequately treated Stage I or Stage II cancer from which the subject is currently in complete remission. 6 - Subjects who have received any anticancer treatment within 4 weeks or any investigational agent within 30 days prior to the first dose of study drug or who have not recovered from any acute toxicity greater than Grade 0 or 1 related to previous anticancer treatment 7 - Major surgery within 4 weeks prior to the first dose of study drug 8 - Inability to take oral medication, or malabsoption syndrome or any other uncontrolled gastrointestinal condition (e.g., nausea, diarrhea, or vomiting) that might impair the bioavailability of E7449 9 - Significant cardiovascular impairment: history of congestive heart failure greater than New York Heart Association (NYHA) Class II, uncontrolled arterial hypertension, unstable angina, myocardial infarction or storke within 6 months of the first dose of study drug; or cardiac arrhythmia requiring medical treatment 10 - Prolongation of QTc interval to >480 msec when electrolytes balance is normal 11 - Active infection requiring systemic therapy 12 - Known hypersensitivity to any component of E7449 13 - Other relevant disease or adverse clinical conditions such as: history of significant neurological(no neuropathy> Grade 2) or psychiatric disorders, significant non-neoplastic liver disease, significant non-neoplastic renal disease, immunocompromised patients, including patients known to be infected with HIV, uncontrolled endocrine diseases i.e. requiring relevant changes in medication with the last month or hospital admission within the last three months, tumor bleeding 14 - Any other major illness that, in the investigator's judgement, will substantially increase the risk associated with the subject's participation in this study 15 - Females who are pregnant or breast feeding
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objective: - Determine maximum tolerated dose (MTD) as single agent, once daily (QD) continuously in 28-day cycles - Determine MTD of E7449, QD for 7 consecutive days in combination with TMZ, QD for 5 consecutive days in 28-day cycles - Determine the MTD of E7449, QD continuously in 21-day cycles in combination with carboplatin and paclitaxel administered via intravenous (i.V.) infusion on Day 1 of each cycle - Assess the objective response rate of E7449 as single agent in subjects with platinum-sensitive recurrent high grade serous ovarian cancer (Cohort 1) and in subjects with relapsed and/or refractory ataxia telangiectasia mutated (ATM)-deficient B-cell lymphoma (Cohort 2) - Assess the ORR of E7449 in combination with TMZ in subjects with advanced melanoma (Cohort 3) - To assess the ORR of E7449 in combination with carboplatin and paclitaxel in subjects with metastatic triple-negative breast cancer (mTNBC) (Cohort 4) ; Secondary Objective: To assess the following parameters of E7449 when administered as a single agent and in combination with TMZ or in combination with carboplatin and paclitaxel: - safety and tolerability - PK profiles - PD activity including inhibition of PARP and effect on DNA damage - PK and PD relationship - Preliminary antitumor activity - Assess PFS, disease control rate, and clinical benefit rate - Identify and investigate biomarkers and their correlation with biological activity Additionally, to: - Determine the effect of a high fat meal on the bioavailability of E7449 administered as single agent orally, QD relative to fasting conditions - Explore E7449 administered as a BID dose and evaluate the PK and tolerability of BID dosing. | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): The secondary efficacy endpoints for each cohort are: - DCR defined as CR + PR + stable disease(SD). For subjects who do not have target lesions (e.g., some subjects in dose escalation may have non-target disease only), the response category Non-CR/Non-PD (NN) will be used instead of SD - CBR defined as the proportion of subjects who have BOR of CR or PR, or durable SD (duration of SD>=23 weeks) - Durable SD rate defined as the proportion of subjects whose BOR is SD and the duration of SD>= 23 weeks - Progression-free Survival (PFS) defined as the time from the date of first dosing to the date of first documentation or disease progression or death (whichever occurs first) ;Timepoint(s) of evaluation of this end point: After end of trial database lock | — |
Countries
United Kingdom
Contacts
Public ContactMedical Information
Eisai Limited
Outcome results
None listed