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Study of E7046 in Subjects With Selected Advanced Malignancies

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ClinicalTrials.gov Identifier: NCT02540291
Recruitment Status : Terminated (Terminated due to, licensing agreement granting exclusive rights of research, development, manufacture and marketing of Eisai's E7046 to Adlai Nortye Biopharma.)
First Posted : September 3, 2015
Results First Posted : February 17, 2020
Last Update Posted : February 17, 2020
Sponsor:
Information provided by (Responsible Party):
Eisai Inc.

Tracking Information
First Submitted Date  ICMJE August 25, 2015
First Posted Date  ICMJE September 3, 2015
Results First Submitted Date  ICMJE February 27, 2019
Results First Posted Date  ICMJE February 17, 2020
Last Update Posted Date February 17, 2020
Actual Study Start Date  ICMJE July 30, 2015
Actual Primary Completion Date February 27, 2018   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 4, 2020)
  • Number of Participants With Treatment-emergent Adverse Events (TEAEs) and Serious Adverse Events (SAEs) [ Time Frame: From the first dose of study drug up to 30 days after the last dose of study drug (approximately up to 2 years) ]
  • Maximum Tolerated Dose (MTD) of E7046 [ Time Frame: Cycle 1 (21 days) ]
  • Recommended Phase 2 Dose (RP2D) of E7046 [ Time Frame: Cycle 1 (21 days) ]
    Two RP2Ds were planned to be evaluated.
Original Primary Outcome Measures  ICMJE
 (submitted: September 2, 2015)
  • Safety/tolerability profile of E7046 by measuring treatment-emergent adverse events (TEAEs) and serious adverse event (SAEs) [ Time Frame: From the first dose of study drug till 30 days after the last dose, or up to approximately 3 years ]
  • Maximum tolerated dose (MTD) [ Time Frame: Cycle 1 (21 days) ]
  • Recommended Phase 2 dose (RP2D) [ Time Frame: Cycle 1 (21 days) ]
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 4, 2020)
  • Objective Response Rate (ORR) [ Time Frame: From first dose date until disease progression/recurrence (approximately up to 2 years) ]
    The ORR is the percentage of participants achieving a best overall response of confirmed immune-related partial response (irPR) + immune-related complete response (irCR), according to immune-related Response Evaluation Criteria In Solid Tumors (irRECIST) v1.1, from first dose date until disease progression/recurrence.
  • Progression-free Survival (PFS) [ Time Frame: From first dose date to the date of the first documentation of confirmed disease progression or death (approximately up to 2 years) ]
    PFS is defined as the time from first dose date to the date of the first documentation of confirmed disease progression or death, whichever occurs first, according to irRECIST v1.1. PFS was calculated using Kaplan-Meier product-limit method and Greenwood Formula.
  • Duration of Response (DOR) [ Time Frame: From the date of first documented confirmed irCR/irPR until the first documentation of confirmed disease progression or death (approximately up to 2 years) ]
    The DOR is defined as the time from the date of first documented confirmed irCR/irPR, according to irRECIST v1.1 until the first documentation of confirmed disease progression or death, whichever came first.
  • Disease Control Rate (DCR) [ Time Frame: From the first dose date until disease progression/recurrence (approximately up to 2 years) ]
    The DCR is percentage of participants achieving best overall response of confirmed irCR, irPR, or immune-related stable disease (irSD) (lasting at least 5 weeks), according to irRECIST v1.1 from the first dose date until disease progression/recurrence.
  • Clinical Benefit Rate (CBR) [ Time Frame: From first dose date until disease progression/recurrence (approximately up to 2 years) ]
    The CBR is the percentage of participants achieving irPR + irCR + irSD (lasting at least 24 weeks), according to irRECIST v1.1 from first dose date until disease progression/recurrence.
Original Secondary Outcome Measures  ICMJE
 (submitted: September 2, 2015)
  • Objective Response Rate (ORR) [ Time Frame: From date of Randomization (Day 1) until disease progression/recurrence, or up to approximately 3 years ]
  • Progression-free survival [ Time Frame: From date of randomization (Day 1) until date of first documentation of disease progression or death from any cause (whichever occurs first), or up to approximately 3 years ]
  • Duration of Response (DOR) [ Time Frame: From date of Randomization (Day 1) until disease progression/recurrence, or up to approximately 3 years ]
  • Disease control rate [ Time Frame: From date of randomization (Day 1) until date of first documentation of disease progression or death from any cause (whichever occurs first), or up to approximately 3 years ]
  • Clinical benefit rate [ Time Frame: From date of randomization (Day 1) until date of first documentation of disease progression or death from any cause (whichever occurs first), or up to approximately 3 years ]
  • Maximum concentration (Cmax) [ Time Frame: Cycle 1 on Day 1 and Day 8 ]
  • Time to maximum concentration (Tmax) [ Time Frame: Cycle 1 on Day 1 and Day 8 ]
  • Area under the curve (AUC) [ Time Frame: Cycle 1 on Day 1 and Day 8 ]
  • Half life (t1/2) [ Time Frame: Cycle 1 on Day 1 and Day 8 ]
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Study of E7046 in Subjects With Selected Advanced Malignancies
Official Title  ICMJE An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With Selected Advanced Malignancies
Brief Summary This is an open label, multicenter, Phase 1 study of E7046 to assess the safety and tolerability of E7046 and to determine the maximum tolerated dose (MTD) and/or the recommended Phase 2 dose (RP2D) of E7046.
Detailed Description The study will be conducted in 2 parts: a dose escalation part to determine the MTD and/or RP2D of E7046, and a cohort expansion part with 6 to 16 participants to better characterize safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) at the RP2D. In the dose escalation part, increasing doses of E7046 will be administered to cohorts of 6 participants, at dose levels ranging from 125 mg to 750 mg.
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE Tumors
Intervention  ICMJE Drug: E7046
E7046 will be administered as a single agent orally once daily (QD) continuously in 21-day cycles. In the dose escalation part, increasing doses of E7046 ranging from 125 mg to 750 mg will be administered to cohorts of 6 participants. In the cohort expansion part, participants will be treated at the RP2D.
Study Arms  ICMJE Experimental: E7046
Participants with tumor types that harbor high levels of myeloid infiltrate based on the Cancer Genome Atlas (TCGA).
Intervention: Drug: E7046
Publications * Hong DS, Parikh A, Shapiro GI, Varga A, Naing A, Meric-Bernstam F, Ataman Ö, Reyderman L, Binder TA, Ren M, Liu M, Dayal S, Siu AY, Sachdev P, Xu L, Bhagawati-Prasad V, Tchakov I, Ooi CE, Bao X, Marabelle A. First-in-human phase I study of immunomodulatory E7046, an antagonist of PGE(2)-receptor E-type 4 (EP4), in patients with advanced cancers. J Immunother Cancer. 2020 Jun;8(1). pii: e000222. doi: 10.1136/jitc-2019-000222.

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: September 5, 2018)
31
Original Estimated Enrollment  ICMJE
 (submitted: September 2, 2015)
40
Actual Study Completion Date  ICMJE February 27, 2018
Actual Primary Completion Date February 27, 2018   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age greater than or equal to 18 years
  2. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1
  3. Life expectancy greater than or equal to 12 weeks
  4. Participants must have any of the following tumor types, confirmed by available pathology records or current biopsy, that is advanced, nonresectable, or recurrent and progressing since last antitumor therapy, and for which no alternative standard therapy exists: pancreatic adenocarcinoma, renal clear cell carcinoma, SCCHN (squamous cell carcinoma of head and neck), NSCLC (non-small cell lung cancer), colorectal cancer (CRC), hepatocellular carcinoma (HCC), ovarian serous epithelial cancer, bladder transitional cancer, cervical cancer, and triple-negative breast cancer
  5. Prior chemotherapy or immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) must have been completed at least 4 weeks before study drug administration, and all adverse events (AEs) have either returned to baseline or stabilized
  6. Prior definitive radiation therapy must have been completed at least 6 weeks before study drug administration and the irradiated lesions should show evidence of progression if they are intended to be considered target lesions. Prior palliative radiotherapy must be completed at least 2 weeks before study drug administration. The radiotherapy-related side effects must have resolved before the study entry. No radiopharmaceuticals (strontium, samarium) will be allowed within 8 weeks before study drug administration.
  7. Participants must have accessible tumors and consent to repeated biopsy for performance of correlative tissue studies
  8. Must have at least one measurable lesion per irRECIST (immune-related Response Evaluation Criteria Criteria in Solid Tumors):

    • At least 1 lesion of greater than or equal to 10 mm in the longest diameter for a non-lymph node or greater than or equal to 15 mm in the short-axis diameter for a lymph node that is serially measurable according to irRECIST using computerized tomography/magnetic resonance imaging (CT/MRI)
    • Lesions that have had definitive external beam radiotherapy or locoregional therapies such as radiofrequency (RF) ablation or brachytherapy must show evidence of progressive disease to be deemed a target lesion
  9. Prior treated brain or meningeal metastases must be without evidence of progression (confirmed by MRI) for at least 8 weeks and off immunosuppressive doses of systemic steroids (greater than 10 mg/day prednisone or equivalent) for at least 4 weeks before study drug administration
  10. Immunosuppressive doses of systemic medications, such as steroids or absorbed topical steroids (doses greater than 7.5 to 10 mg/day prednisone or equivalent) must be discontinued at least 2 weeks before study drug administration.
  11. Participants with prior Hepatitis B or C are eligible on the condition that participants have adequate liver function as defined by Inclusion Criterion number 16 and Exclusion Criterion number 5
  12. Left ventricular ejection fraction (LVEF) greater than 50% on echocardiography or multiple gated acquisition (MUGA) scan
  13. Adequate renal function defined as serum creatinine less than 1.5 X ULN (upper limit of normal) or use SI units or calculated creatinine clearance greater than or equal to 50 mL/min per the Cockcroft and Gault formula
  14. Adequate bone marrow function:

    • Absolute neutrophil count (ANC) greater than or equal to 1500/mm3 (greater than or equal to 1.5 X 103/ul)
    • Platelets greater than or equal to 100,000/mm3 (greater than or equal to 100 X 109/L)
    • Hemoglobin greater than or equal to 9.0 g/dL
  15. Adequate liver function:

    • Total bilirubin less than or equal to 1.5 X ULN except for unconjugated hyperbilirubinemia of Gilbert's syndrome
    • Alkaline phosphatase, alanine aminotransferase (ALT), and aspartate aminotransferase (AST) less than or equal to 3 X ULN (less than or equal to 5 X ULN if participant has liver metastases). If 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 the participant 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 total alkaline phosphatase
  16. Adequate blood coagulation function as evidenced by an International Normalized Ratio (INR) less than or equal to 1.5
  17. Willing and able to comply with all aspects of the protocol
  18. Provide written informed consent prior to any study-specific screening procedures
  19. Females must not be lactating or pregnant at screening or baseline (as documented by a negative beta-human chorionic gonadotropin [B-hCG] test with a minimum sensitivity of 25 IU/L or equivalent units of B-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 (ie, 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, from the last menstrual period prior to initiation of treatment, during Treatment Cycles, and for 30 days after the final dose of study treatment, and have a male partner who uses a condom. Highly effective contraception includes:

    • Double barrier methods of contraception such as condom plus diaphragm or cervical/vault cap with spermicide
    • Placement of an intrauterine device
    • Established hormonal contraceptive methods: oral, injectable, or implant. 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. Female participants exempt from this requirement are participants who practice total abstinence or have a male partner who is vasectomized with confirmed azoospermia. If currently abstinent, the participant must agree to use a double barrier method as described above if they become sexually active during the Treatment Cycles, and for 30 days after study drug discontinuation
  20. Male participants must have had a successful vasectomy (confirmed azoospermia) or they and their female partners must meet the criteria above (ie, not of childbearing potential or practicing highly effective contraception and use a condom throughout the study period and for 90 days after study drug discontinuation)

Exclusion Criteria:

  1. Other malignancy active within the previous 2 years except for basal or squamous cell skin cancer, superficial bladder cancer or carcinoma in situ of the cervix or breast that has completed curative therapy
  2. Participants with any active autoimmune disease (Appendix 2) or a documented history of autoimmune disease, poorly controlled asthma or history of syndrome that required systemic steroids or immunosuppressive medications, except for participants with vitiligo or resolved childhood asthma/atopy. Participants with asthma who require intermittent use of bronchodilators (such as albuterol) will not be excluded from this study.
  3. Participants with inflammatory bowel disease
  4. Known human immunodeficiency virus (HIV) infection
  5. Active infection requiring therapy, including known positive tests for Hepatitis B surface antigen and hepatitis C virus (HCV) RNA
  6. Major surgery within 4 weeks before the first dose of study drug
  7. Concurrent medical condition requiring the use of immunosuppressive medications, or immunosuppressive doses of systemic or absorbable topical corticosteroids except inhaled or intranasal corticosteroids (with minimal systemic absorption)
  8. Inability to take oral medication, or malabsorption syndrome or any other uncontrolled gastrointestinal condition (eg, nausea, diarrhea, or vomiting) that might impair the bioavailability of E7046
  9. Any other major illness that, in the investigator's judgment, will substantially increase the risk associated with the participant's participation in this study
  10. Use of other investigational drugs within 28 days or at least 5 half-lives (whichever is shorter) before study drug administration
  11. Prior exposure to drugs that are antagonists of colony stimulating factor-1 receptor (CSF1R) like but not limited to emactuzumab (RG7155) (Roche), PLX3397 (Plexicon), and JNJ40346627 (J & J)
  12. Use of any live vaccines (eg, intranasal influenza, measles, mumps, rubella, oral polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines) within 28 days
  13. Prolongation of corrected QT [QTcF (Fridericia's corrected QT interval)] interval to greater than 480 msec when electrolytes balance is normal
  14. 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 (including oral anticoagulation)
  15. Females who are pregnant (positive urine test) or breastfeeding
  16. Any history of a medical condition or a concomitant medical condition that, in the opinion of the investigator, would compromise the subject's ability to safely complete the study
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years to 99 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE France,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02540291
Other Study ID Numbers  ICMJE E7046-G000-101
2014-004823-37 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Eisai Inc.
Study Sponsor  ICMJE Eisai Inc.
Collaborators  ICMJE Not Provided
Investigators  ICMJE Not Provided
PRS Account Eisai Inc.
Verification Date July 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP