A Study to Determine the Bioequivalence of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel
Condition: Solid Tumor
Intervention: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules
Intervention description: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules
Oral paclitaxel capsules
Intervention MeSH terms: Paclitaxel
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Crossover Assignment
Masking: None (Open Label)
Enrollment: 42.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

Summary:

      This is a multicenter, open-label, 2-stage study with a 2-treatment period crossover design.
      Eligible participants are adults with cancer for whom weekly therapy with IV paclitaxel at a
      dose of 80 mg/m2 over 1 hour is indicated.

      Stage 1 will consist of an initial cohort (Cohort 1) up to 6 evaluable participants who will
      receive a dosing regimen of Oraxol consisting of a 15-mg oral HM30181AK-US tablet plus an
      oral paclitaxel dose of 205 mg/m2, both administered once daily for 3 consecutive days. The
      stages and cohorts are further described in the "Study Design - Stages and Cohorts" table
      below. An interim analysis of pharmacokinetic (PK) data from Cohort 1 will be conducted to
      determine if the administered regimen would appear likely to achieve bioequivalence(BE)
      (AUC0-∞), if tested in a greater number of participants in Stage 2. If it appears unlikely
      that the selected regimen will meet the criteria for BE based on AUC0-∞ data, a second cohort
      (Cohort 2) of up to 6 evaluable participants may be enrolled in Stage 1, and the dose of
      paclitaxel in Oraxol may be adjusted by a maximum of +/- 25%. If Cohort 2 is enrolled, a
      second interim analysis will be conducted.

      After the interim analysis/analyses (depending on the outcomes), a decision will be made by
      consensus of the Data Safety and Monitoring Board(DSMB), Kinex, Zenith Technology, and the
      Principal Investigator as to what dose should be administered in Stage 2. The DSMB will
      consist of a clinical oncologist, an ethicist, an independent statistician, and additional
      members, as deemed necessary. A DSMB charter will describe the planned evaluations and
      decision points used to determine the dose for Stage 2. An additional 18 to 42 evaluable
      participants will be enrolled into Stage 2 based on the Stage 1 results (AUC0-∞). Thus a
      total of up to 54 evaluable participants could potentially be enrolled in this study (6 each
      from Stage 1, Cohorts 1 and 2, and up to 42 participants in Stage 2).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Signed written informed consent

          2. Males and females ≥18 years of age on day of consent

          3. Cancer patients for whom treatment with IV paclitaxel at 80 mg/m2has been recommended
             by their oncologist, either as monotherapy or in combination with other agents

          4. Adequate hematologic status at Screening/Baseline:

               -  Absolute neutrophil count (ANC) ≥1.5 x 109/L

               -  Platelet count ≥100 x 109/L

               -  Hemoglobin (Hgb) ≥90 g/L

          5. Adequate liver function at Screening/Baseline as demonstrated by:

               -  Total bilirubin of ≤20 μmol/L or ≤30 μmol/L for participants with liver
                  metastasis

               -  Alanine aminotransferase (ALT) ≤3 x upper limit of normal (ULN) or ≤5 x ULN if
                  liver metastasis is present

               -  Alkaline phosphatase (ALP) ≤3 x ULN or ≤5 x ULN if liver or bone metastasis are
                  present

               -  ALP >5 x ULN if liver or bone metastasis are present and the major fraction of
                  ALP is from bone metastasis, at the discretion of the Investigator

               -  Gamma glutamyl transferase (GGT) <10 x ULN

          6. Adequate renal function at Screening/Baseline as demonstrated by serum creatinine ≤177
             μmol/L or creatinine clearance >50 mL/min as calculated by the Cockcroft and Gault
             formula

          7. Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 16

          8. Life expectancy of at least 3 months

          9. Willing to fast for 8 hours before and 4 hours after Oraxol administration

         10. Willing to abstain from alcohol consumption for 3 days before the first dose of study
             drug through the completion of protocol-specified PK sampling in Treatment Period 2

         11. Willing to refrain from caffeine consumption for 12 hours before each treatment period
             through the completion of protocol-specified PK sampling for that dose

         12. Women must be postmenopausal (>12 months without menses) or surgically sterile (ie, by
             hysterectomy and/or bilateral oophorectomy) or, if sexually active, must be using
             effective contraception (ie, oral contraceptives, intrauterine device, double barrier
             method of condom and spermicide) and agree to continue use of contraception for the
             duration of their participation in the study. Women of childbearing potential must
             agree to use contraception for 30 days after their last dose of study drug.

         13. Sexually active male participants must use a barrier method of contraception during
             the study and agree to continue the use of male contraception for at least 30 days
             after the last dose of study drug.

        Exclusion Criteria:

          1. Currently taking a prohibited concomitant medication:

               -  Strong inhibitors (eg, ketoconazole) or strong inducers (eg, rifampin or St.
                  John's Wort) of cytochrome P450 (CYP) 3A4 (within 2 weeks prior to the start of
                  dosing in the study)

               -  Strong inhibitors (eg, gemfibrozil) or strong inducers (eg, rifampin) of CYP2C8
                  (within 2 weeks prior to the start of dosing in the study)

               -  Known P-glycoprotein (P-gp) inhibitors or inducers. Participants who are taking
                  such medications but who are otherwise eligible may be enrolled if they
                  discontinue the medication ≥1 week before dosing and remain off that medication
                  through the end of PK sampling after the administration of the second study
                  treatment.

               -  An oral medication with a narrow therapeutic index known to be a P-gp substrate
                  (eg, digoxin, dabigatran) within 24 hours prior to start of dosing in the study

          2. Use of warfarin. Participants receiving warfarin who are otherwise eligible and who
             may be appropriately managed with low molecular weight heparin, in the opinion of the
             Investigator, may be enrolled in the study provided they are switched to low molecular
             weight heparin at least 7 days prior to receiving study treatment.

          3. Unresolved toxicity from prior chemotherapy (participants must have recovered all
             significant toxicity to ≤ Grade 1 CTCAE toxicity1 from previous anticancer treatments
             or previous investigational agents). This does not extend to symptoms or findings that
             are attributable to the underlying disease

          4. Received investigational agents within 14 days or 5 half-lives prior to the first
             study dosing day, whichever is longer

          5. Women of childbearing potential who are pregnant or breastfeeding

          6. Uncontrolled intercurrent illness including, but not limited to, ongoing or active
             infection, symptomatic congestive heart failure, clinically significant myocardial
             infarction within the last 6 months, unstable angina pectoris, clinically significant
             cardiac arrhythmia, bleeding disorder, chronic pulmonary disease requiring oxygen, or
             psychiatric illness/social situations that would limit compliance with study
             requirements

          7. Major surgery to the upper GI tract, or have a history of GI disease or other medical
             condition that, in the opinion of the Investigator may interfere with oral drug
             absorption

          8. A known history of allergy to paclitaxel. Participants whose allergy was due to the IV
             solvent (such as Cremophor®) and not paclitaxel will be eligible for this study.

          9. Any other condition which the Investigator believes would make a subject's
             participation in the study not acceptable