An Open-Label, Multicenter, Phase 1/2 Study of Poly(ADP-Ribose) Polymerase (PARP) Inhibitor E7449 as Single Agent in Subjects With Advanced Solid Tumors or With B-cell Malignancies and in Combination With Temozolomide (TMZ) or With Carboplatin and Paclitaxel in Subjects With Advanced Solid Tumors

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2014 by Eisai Inc.
Sponsor:
Information provided by (Responsible Party):
Eisai Inc. ( Eisai Limited )
ClinicalTrials.gov Identifier:
NCT01618136
First received: May 14, 2012
Last updated: April 2, 2014
Last verified: April 2014
  Purpose

Overall Design: This is a multicenter, open-label, Phase 1/2 study which will be conducted in three arms (as described below). Each arm will be conducted in two parts: a Phase 1 part which will include dose escalation and a Phase 2 part which will include four cohorts in specific disease indications. Phase 1 will also include a food effect study of E7449 as a single agent. Once the MTD in the Phase 1 single agent arm and the Phase 1 combination arms of this study has been achieved, the sponsor will submit the relevant safety information and recommended Phase 2 dose to the IRB/Health Authorities. Arm 1: E7449 will be administered as a single agent. Arm 2: E7449 will be administered in combination with TMZ. Arm 3: E7449 will be administered in combination with carboplatin and paclitaxel


Condition Intervention Phase
Malignant Solid Tumour
Ovarian Cancer
Triple Negative Breast Cancer
Advanced Melanoma
B-cell Malignancy, Low-grade
Drug: E7449 alone
Drug: E7449 plus TMZ
Drug: E7449 plus carboplatin and paclitaxel
Phase 1
Phase 2

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety/Efficacy Study
Intervention Model: Single Group Assignment
Masking: Open Label
Primary Purpose: Treatment
Official Title: An Open-Label, Multicenter, Phase 1/2 Study of Poly(ADP-Ribose) Polymerase (PARP) Inhibitor E7449 as Single Agent in Subjects With Advanced Solid Tumors or With B-cell Malignancies and in Combination With Temozolomide (TMZ) or With Carboplatin and Paclitaxel in Subjects With Advanced Solid Tumors

Resource links provided by NLM:


Further study details as provided by Eisai Inc.:

Primary Outcome Measures:
  • Phase 1 To determine the maximum tolerated dose of E7449 as a single agent [ Time Frame: Baseline to 24 months. ] [ Designated as safety issue: No ]
  • Phase 1 To determine the maximum tolerated dose of E7449 and in combination with TMZ [ Time Frame: Baseline to 24 months. ] [ Designated as safety issue: No ]
  • Phase 1 To determine the maximum tolerated dose of E7449 and in combination with carboplatin and paclitaxel [ Time Frame: Baseline to 24 months. ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Phase 2 to assess the objective response rate of E7449 as a single agent in subjects with platinum sensitive recurrent high-grade serious ovarian cancer and subjects with relapsed and/or refractory ATM- deficient B-cell malignancies [ Time Frame: Baseline to 20 months. ] [ Designated as safety issue: No ]
  • Phase 2 to assess the objective response rate of E7447 in combination with TMZ in subjects with advanced melanoma [ Time Frame: Baseline to 20 months. ] [ Designated as safety issue: No ]
  • Phase 2 to assess the objective response rate of E7449 in combination with carboplatin and paclitaxel in subjects with metastatic triple negative breast cancer [ Time Frame: Baseline to 20 months. ] [ Designated as safety issue: No ]

Estimated Enrollment: 198
Study Start Date: December 2011
Estimated Primary Completion Date: November 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: E7449 Drug: E7449 alone
Will be administered as single agent orally, once daily (QD) continuously in 28-day cycles to determine the MTD. In these subjects, a food-effect component will be conducted under fed/fasted conditions to determine the effect of food on the bioavailability of E7449 administered orally QD.
Active Comparator: E7449 plus TMZ Drug: E7449 plus TMZ
Dose escalation,will be administered orally, once daily for 7 consecutive days along with 150 mg/m2/d TMZ administered orally, once daily for 5 consecutive days in 28-day cycles to determine the MTD of E7449 in combination with TMZ.
Active Comparator: E7449 plus carboplatin and paclitaxel Drug: E7449 plus carboplatin and paclitaxel
Dose escalation, E7449 will be administered orally, once daily continuously in 21-day cycles along with carboplatin and paclitaxel, which will be administered via i.v. infusion on Day 1 of the cycle only, to determine the MTD of E7449 in combination with carboplatin and paclitaxel.

  Eligibility

Ages Eligible for Study:   18 Years and older
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

All subjects:

  1. Subjects with measurable or non-measurable disease following the Response Evaluation Criteria in Solid Tumors (RECIST 1.1, Appendix 1) for Phase 1 part of the study. (Only subjects with measurable disease are allowed to enter at the MTD during the expanded cohort of Phase 1)
  2. Histologically and/or cytologically confirmed advanced or metastatic solid tumor or Bcell malignancies which have progressed after treatment with approved therapies or for which there are no standard therapies available (Phase 1).
  3. Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix 2).
  4. Life expectancy ≥3 months after starting E7449.
  5. Subjects with known brain metastases will be eligible under the following conditions (see Exclusion Criterion #2):

    • has undergone complete surgical excision and are more than 1 month post surgery with no radiographic evidence of brain disease recurrence Or
    • has undergone stereotactic radio surgery (gamma knife procedure) and are more than 1 month post procedure and with no radiographic evidence of brain disease progression And
    • is asymptomatic And
    • discontinued corticosteroid treatment at least 30 days prior to C1D1.
  6. Adequate renal function defined as Serum Creatinine <1.5xULN, or use SI units or calculated creatinine clearance ≥ 50 mL/min per the Cockroft-Gault formula (Appendix 3).
  7. Adequate bone marrow function:

    • Absolute neutrophil count (ANC) ≥1500/mm3 (≥ 1.5 x 103/mL);
    • Platelets ≥ 100,000/mm3 (≥100 x 109/L);
    • Hemoglobin ≥10.0 g/dL.
  8. Adequate liver function:

    • Bilirubin ≤ 1.5 x the upper limit of normal (ULN) except for unconjugated hyperbilirubinemia of Gilbert's syndrome;
    • Alkaline phosphatase (in the absence of bone disease), alanine aminotransferase (ALT), and aspartate aminotransferase (AST) ≤ 3 x ULN (≤ 5 x ULN if subject has liver metastasis).
  9. Left ventricular ejection fraction (LVEF) > 50% on echocardiography or multiple-gated acquisition (MUGA) scanning
  10. Males or females age ≥18 years at the time of informed consent.
  11. Females must not be lactating or pregnant at Screening or Baseline (as documented by a negative beta-human chorionic gonadotropin [ß-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of ß-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 (at least 12 months consecutive amenorrheic, 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.
  12. Male subjects must have had a successful vasectomy (confirmed azoospermia) or they and their female partner 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).
  13. Voluntary agreement to provide written informed consent and the willingness and ability to comply with all aspects of the protocol.

    For the Phase 2 Cohort 1 (Platinum-sensitive recurrent high-grade serous ovarian cancer) only:

  14. Histologically confirmed platinum-sensitive recurrent high grade serous ovarian cancer locally advanced or metastatic with disease progression after standard treatments. (Exclude platinum refractory/resistant defined as progression on platinum or relapse within six months of prior platinum.
  15. At least one lesion of ≥ 1.0 cm in the longest diameter for a non-lymph node or ≥ 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) or photography. If there is only one target lesion, it should have a longest diameter of ≥ 1.5 cm (for a non-lymph node) or ≥ 1.5 cm in the short-axis diameter (for a lymph node).

    For the Phase 2 Cohort 2 (B-cell malignancies) Only:

  16. Subjects with one of the following relapsed and/or refractory B-cell malignancies with disease progression following up to three prior systemic treatment regimens:

    • Mantle cell, Marginal zone, Follicular, Diffuse large B-cell, B-cell chronic lymphocytic leukemia (B-CLL).
    • ATM-deficient.

    For the Phase 2 Cohort 3 (Melanoma) only:

  17. Histopathologically confirmed advanced melanoma (except melanoma of intraocular origin) with disease progression following up to two systemic treatment regimens
  18. At least one lesion of ≥ 1.0 cm in the longest diameter for a non-lymph node or ≥ 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) or photography. If there is only one target lesion, it should have a longest diameter of ≥ 1.5 cm (for a non-lymph node) or ≥ 1.5 cm in the short-axis diameter (for a lymph node).
  19. No previous treatment with dacarbazine (DTIC) or TMZ containing regimens

    For the Phase 2 Cohort 4 (mTNBC) only:

  20. Histologically confirmed metastatic triple-negative breast cancer. Estrogen receptor (ER)-negative, Progesterone Receptor (PR)-negative, Human Epidermal Growth Factor 2 (HER2)-negative (mTNBC) with disease progression after one standard treatment.
  21. At least one lesion of ≥ 1.0 cm in the longest diameter for a non-lymph node or ≥ 1.5 cm in the short-axis diameter for a lymph node which is serially measurable according to RECIST 1.1 using computerized tomography/magnetic resonance imaging (CT/MRI) or photography. If there is only one target lesion, it should have a longest diameter of ≥ 1.5 cm (for a non-lymph node) or ≥ 1.5 cm in the short-axis diameter (for a lymph node).
  22. No previous treatment with carboplatin and/or paclitaxel

Exclusion Criteria:

All subjects

  1. Prior exposure to E7449.
  2. Leptomeningeal metastases or brain metastases (except as for Inclusion Criterion #5).
  3. Prior treatment with a PARP inhibitor (Phase 2 only).
  4. Subjects taking medications which are either strong CYP inhibitors or inducers.
  5. Subjects with active malignancies other than advanced ovarian cancer (Cohort 1 only), ATM-deficient B-cell malignancies (Cohort 2 only), advanced melanoma (Cohort 3 only), and mTNBC (Cohort 4 only), will be excluded from Phase 2.
  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 malabsorption 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 stroke 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. Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks prior to study drug administration.
  14. 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 (e.g., cirrhosis, active chronic hepatitis).
    • Significant non-neoplastic renal disease.
    • Immunocompromised patients, including patients known to be infected with human immunodeficiency virus (HIV).
    • Uncontrolled endocrine diseases (e.g., diabetes mellitus, hypothyroidism or hyperthyroidism, adrenal disorder) i.e., requiring relevant changes in medication within the last month or hospital admission within the last three months.
    • Tumor bleeding
  15. Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study
  16. Females who are pregnant or breastfeeding.

    For Phase 1 Arm 2 and Phase 2 Arm 2 (E7449 in combination with TMZ) only:

  17. Known intolerance or known hypersensitivity to any of the study drugs or any of the Excipients (E7449 and/or TMZ) For Phase 1 Arm 3 and Phase 2 Arm 3 (E7449 in combination with carboplatin and paclitaxel) only:
  18. Known intolerance or known hypersensitivity reactions to E7449, carboplatin or other platinum containing compounds, paclitaxel, macrogolglycerol ricinoleate (poloxyl castor oil) or any of the excipients
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01618136

Contacts
Contact: Ruth Plummer, Prof +441912464414

Locations
United Kingdom
King's College London Guy's Hospital Campus Recruiting
London, United Kingdom, SE1 9RT
Contact: Debashis Sarker       debastis.sarker@kcl.ac.uk   
Newcastle Upon Tyne NHS Foundation Trust Recruiting
Newcastle Upon Tyne and Wear, United Kingdom, NE7 7DN
Contact: Ruth Plummer    0044 (0) 1912138444    ruth.plummer@newcasstle.ac.uk   
Sponsors and Collaborators
Eisai Limited
  More Information

No publications provided

Responsible Party: Eisai Inc. ( Eisai Limited )
ClinicalTrials.gov Identifier: NCT01618136     History of Changes
Other Study ID Numbers: E7449-E044-101
Study First Received: May 14, 2012
Last Updated: April 2, 2014
Health Authority: United Kingdom: Medicines and Healthcare Products Regulatory Agency

Keywords provided by Eisai Inc.:
PARP inhibitors
Malignant Solid Tumour
ovarian cancer
triple negative breast cancer
advanced melanoma

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms
Leukemia, Lymphocytic, Chronic, B-Cell
Melanoma
Ovarian Neoplasms
Triple Negative Breast Neoplasms
Neoplasms by Site
Breast Diseases
Skin Diseases
Leukemia, B-Cell
Leukemia, Lymphoid
Leukemia
Neoplasms by Histologic Type
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases
Neuroendocrine Tumors
Neuroectodermal Tumors
Neoplasms, Germ Cell and Embryonal
Neoplasms, Nerve Tissue
Nevi and Melanomas
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders

ClinicalTrials.gov processed this record on August 28, 2014