Study of E7046 in Subjects With Selected Advanced Malignancies

An Open-Label Multicenter Phase 1 Study of E7046 in Subjects With Selected Advanced Malignancies

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.

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.

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