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

NCT01618136 | Completed Phase 1

• 1 other identifier: E7449-E044-101
• Study Type: interventional
• Target: 41
• Locations: 1 country
• Sites: 2

Brief Summary

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

Conditions

Malignant Solid Tumour; Ovarian Cancer; Triple Negative Breast Cancer; Advanced Melanoma; B-cell Malignancy, Low-grade

Keywords

PARP inhibitors; Malignant Solid Tumour; ovarian cancer; triple negative breast cancer; advanced melanoma

Outcome Measures

Primary Outcomes (3)

• Phase 1 To determine the maximum tolerated dose of E7449 as a single agent

  Baseline to 24 months.

• Phase 1 To determine the maximum tolerated dose of E7449 and in combination with TMZ

  Baseline to 24 months.

• Phase 1 To determine the maximum tolerated dose of E7449 and in combination with carboplatin and paclitaxel

  Baseline to 24 months.

Secondary Outcomes (3)

• 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

  Baseline to 20 months.

• Phase 2 to assess the objective response rate of E7447 in combination with TMZ in subjects with advanced melanoma

  Baseline to 20 months.

• Phase 2 to assess the objective response rate of E7449 in combination with carboplatin and paclitaxel in subjects with metastatic triple negative breast cancer

  Baseline to 20 months.

Study Arms (3)

E7449

EXPERIMENTAL

Drug: E7449 alone

E7449 plus TMZ

ACTIVE COMPARATOR

Drug: E7449 plus TMZ

E7449 plus carboplatin and paclitaxel

ACTIVE COMPARATOR

Drug: E7449 plus carboplatin and paclitaxel

Interventions

E7449 alone DRUG

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.

E7449

E7449 plus TMZ DRUG

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.

E7449 plus TMZ

E7449 plus carboplatin and paclitaxel DRUG

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.

E7449 plus carboplatin and paclitaxel

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• All subjects:
• 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)
• 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).
• Eastern Cooperative Oncology Group (ECOG) performance status of 0-2 (Appendix 2).
• Life expectancy greater than or equal to 3 months after starting E7449.
• 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.
• Adequate renal function defined as Serum Creatinine less than 1.5 x ULN, or use SI units or calculated creatinine clearance greater than or equal to 50 mL/min per the Cockroft-Gault formula (Appendix 3).
• Adequate bone marrow function:
• Absolute neutrophil count (ANC) greater than or equal to1500/mm3 (greater than or equal to 1.5 x 10\^3/mL);
• Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 x 10\^9/L);
• Hemoglobin greater than or equal to 10.0 g/dL.
• Adequate liver function:

You may not qualify if:

• All subjects
• Prior exposure to E7449.
• Prior treatment with a PARP inhibitor (Phase 2 only).
• Subjects taking medications which are either strong CYP inhibitors or inducers.
• 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.
• 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.
• Major surgery within 4 weeks prior to the first dose of study drug.
• 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.
• 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.
• Prolongation of QTc interval to greater than 480 msec when electrolytes balance is normal.
• Active infection requiring systemic therapy.
• Known hypersensitivity to any component of E7449
• Achlorhydria or use of antacids, proton-pump inhibitors, or other drugs known to raise gastric pH within 2 weeks prior to study drug administration.
• Other relevant disease or adverse clinical conditions such as:
• History of significant neurological (no neuropathy greater than Grade 2) or psychiatric disorders.

Sponsors & Collaborators

• Eisai Limited: lead

Study Sites (2)

King's College London Guy's Hospital Campus

London, SE1 9RT, United Kingdom

Location

Newcastle Upon Tyne NHS Foundation Trust

Newcastle Upon Tyne and Wear, NE7 7DN, United Kingdom

Location

Related Publications (1)

• Plummer R, Dua D, Cresti N, Drew Y, Stephens P, Foegh M, Knudsen S, Sachdev P, Mistry BM, Dixit V, McGonigle S, Hall N, Matijevic M, McGrath S, Sarker D. First-in-human study of the PARP/tankyrase inhibitor E7449 in patients with advanced solid tumours and evaluation of a novel drug-response predictor. Br J Cancer. 2020 Aug;123(4):525-533. doi: 10.1038/s41416-020-0916-5. Epub 2020 Jun 11.

  PMID: 32523090 DERIVED

MeSH Terms

Conditions

Ovarian Neoplasms; Triple Negative Breast Neoplasms; Leukemia, Lymphocytic, Chronic, B-Cell

Interventions

stenoparib; Temozolomide; Carboplatin; Paclitaxel

Condition Hierarchy (Ancestors)

Endocrine Gland Neoplasms; Neoplasms by Site; Neoplasms; Ovarian Diseases; Adnexal Diseases; Genital Diseases, Female; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Urogenital Diseases; Genital Neoplasms, Female; Urogenital Neoplasms; Genital Diseases; Endocrine System Diseases; Gonadal Disorders; Breast Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases; Leukemia, B-Cell; Leukemia, Lymphoid; Leukemia; Neoplasms by Histologic Type; Hematologic Diseases; Hemic and Lymphatic Diseases; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Chronic Disease; Disease Attributes; Pathologic Processes; Pathological Conditions, Signs and Symptoms

Intervention Hierarchy (Ancestors)

Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Coordination Complexes; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Diterpenes; Terpenes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NON RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: May 14, 2012
• First Posted: June 13, 2012
• Study Start: January 1, 2012
• Primary Completion: July 1, 2015
• Study Completion: July 1, 2015
• Last Updated: June 18, 2023

Record last verified: 2016-10

Locations

GB (2)