Study of E7046 in Subjects With Selected Advanced Malignancies
Condition: Tumors
MeSH terms: Neoplasms
Intervention: E7046
Intervention description: 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.
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 31.0
Sex: All
Minimum age: 18 Years
Maximum age: 99 Years
Healthy volunteers: No
Keywords: E7046; Advanced malignancies; malignancies

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.
    

Eligibility criteria:

        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