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Malignant Solid TumourPhase 1/2NCT01618136

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

A Phase 1/2 study testing E7449 alone, E7449 plus TMZ and E7449 plus carboplatin and paclitaxel in people with Malignant Solid Tumour and Ovarian Cancer, run by Eisai Limited at 2 sites in United Kingdom.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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. Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
E7449 alone, E7449 plus TMZ and E7449 plus carboplatin and paclitaxel
Could I receive a placebo?
No, everyone receives an active treatment
How many people
41 participants
Where
2 sitesUnited Kingdom
Study dates
Jan 2012to Jul 2015
Phase
Phase 1/2
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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.
  • Subjects with known brain metastases will be eligible under the following conditions (see Exclusion Criterion #2):
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  • 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:
  • Bilirubin less than or equal to 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) less than or equal to 3 x ULN (less than or equal to 5 x ULN if subject has liver metastasis).
  • Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple-gated acquisition (MUGA) scanning
  • Males or females age greater than or equal to 18 years at the time of informed consent.
  • 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 (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.
  • 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).
  • 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:
  • 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.
  • At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a non-lymph node or greater than or equal to 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 greater than or equal to 1.5 cm (for a non-lymph node) or greater than or equal to 1.5 cm in the short-axis diameter (for a lymph node).
  • For the Phase 2 Cohort 2 (B-cell malignancies) Only:
  • 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:
  • Histopathologically confirmed advanced melanoma (except melanoma of intraocular origin) with disease progression following up to two systemic treatment regimens
  • At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a non-lymph node or greater than or equal to 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 greater than or equal to 1.5 cm (for a non-lymph node) or greater than or equal to 1.5 cm in the short-axis diameter (for a lymph node).
  • No previous treatment with dacarbazine (DTIC) or TMZ containing regimens
  • For the Phase 2 Cohort 4 (mTNBC) only:
  • 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.
  • At least one lesion of greater than or equal to 1.0 cm in the longest diameter for a non-lymph node or greater than or equal to 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 greater than or equal to 1.5 cm (for a non-lymph node) or greater than or equal to 1.5 cm in the short-axis diameter (for a lymph node).
  • No previous treatment with carboplatin and/or paclitaxel.

Who cannot join

  • All subjects
  • Prior exposure to E7449.
  • Leptomeningeal metastases or brain metastases (except as for Inclusion Criterion #5).
  • 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.
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  • 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.
  • 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
  • Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the subject's participation in this study
  • Females who are pregnant or breastfeeding.
  • For Phase 1 Arm 2 and Phase 2 Arm 2 (E7449 in combination with TMZ) only:
  • 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:
  • 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

Trial locations and contacts

2 sites in 1 country.

United Kingdom2 sites

  • King's College London Guy's Hospital Campus

    London, SE1 9RT

  • Newcastle Upon Tyne NHS Foundation Trust

    Newcastle Upon Tyne and Wear, NE7 7DN

Other trials in United Kingdom

About this study

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

Being tested
E7449 alone, E7449 plus TMZ, E7449 plus carboplatin and paclitaxel
Keywords
PARP inhibitors, Malignant Solid Tumour, ovarian cancer, triple negative breast cancer, advanced melanoma
Medical subject headings
Ovarian Neoplasms, Triple Negative Breast Neoplasms, Leukemia, Lymphocytic, Chronic, B-Cell

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • E7449 aloneDrug

    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 plus TMZDrug

    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 carboplatin and paclitaxelDrug

    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.

Study groups in NCT01618136
Study groupRoleWhat they receive
E7449ExperimentalNot described
Receives: Drug: E7449 alone
E7449 plus TMZActive comparatorNot described
Receives: Drug: E7449 plus TMZ
E7449 plus carboplatin and paclitaxelActive comparatorNot described
Receives: Drug: E7449 plus carboplatin and paclitaxel

What is being measured

The primary outcome is the main question the study is designed to answer.

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

    Measured: Baseline to 24 months.

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

    Measured: Baseline to 24 months.

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

    Measured: Baseline to 24 months.

Secondary outcomes (3)

  1. 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

    Measured: Baseline to 20 months.

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

    Measured: Baseline to 20 months.

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

    Measured: Baseline to 20 months.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Jun 2012 (estimated)
  2. Study startJan 2012
  3. Primary completionJul 2015
  4. Study completionJul 2015

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1/2
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Single group
Masking
None (open label)
Enrolment
41 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT01618136
Sponsor's protocol ID
E7449-E044-101
Status last verified
Oct 2016
First submitted
14 May 2012
Last updated
18 Jun 2023
Results posted
No
Data monitoring committee
No

Publications

  • 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.

    PubMed 32523090

Questions about this trial

What is this clinical trial studying?

A Phase 1/2 study testing E7449 alone, E7449 plus TMZ and E7449 plus carboplatin and paclitaxel in people with Malignant Solid Tumour and Ovarian Cancer, run by Eisai Limited at 2 sites in United Kingdom.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 38 inclusion and 26 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 18 Jun 2023. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 2 sites in United Kingdom. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this combined phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Phase 1 To determine the maximum tolerated dose of E7449 as a single agent (time frame: Baseline to 24 months.). The study lists 3 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT01618136, which also lists 1 linked publication.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 18 Jun 2023.

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