| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Cancer patients for whom treatment with IV paclitaxel at 80 mg/m2 has been recommended by their oncologist, either as monotherapy or in combination with other agents |
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| E.1.1.1 | Medical condition in easily understood language |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10007050 |
| E.1.2 | Term | Cancer |
| E.1.2 | System Organ Class | 100000004864 |
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| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The primary objective of the study is to determine the safety and tolerability of Oraxol. |
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| E.2.2 | Secondary objectives of the trial |
To confirm the sustained oral bioavailability of paclitaxel following multiple dosing.
To compare the relative bioavailability of paclitaxel tablets vs paclitaxel capsules (Group B only). |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal 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/m2 has been recommended by their oncologist, either as monotherapy or in combination with other agents
4. Adequate hematologic status:
• Absolute neutrophil count (ANC) ≥1.5 x 109/L
• Platelet count ≥100 x 109/L
• Hemoglobin (Hgb) ≥90 g/L
5. Adequate liver function 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 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 1
8. Life expectancy of at least 3 months
9. Willing to fast for 8 hours before and 4 hours after Oraxol administration on all treatment days (but may have water 1 hour after completion of Oraxol dosing and as needed with other prescribed medications)
10. During the inpatient PK sampling week(s):
• Willing to abstain from alcohol consumption for 3 days before the first dose of Oraxol through the completion of protocol-specified PK sampling for that treatment week
• Willing to refrain from caffeine consumption for 12 hours before the first dose of Oraxol through the completion of protocol-specified PK sampling for that treatment week
11. 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.
12. 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. |
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| E.4 | Principal exclusion criteria |
Eligible participants must not have/be:
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)
• Strong P-gp inhibitors (eg, verapamil) or strong inducers (eg, rifampin). 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 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 toxicity 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 |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
| Treatment-emergent AEs (TEAEs) are defined as those AEs with an onset after dosing and those pre-existing AEs that worsen during the study. Verbatim terms on the eCRFs will be mapped to preferred terms (PTs) and system organ classes (SOCs) using the Medical Dictionary for Regulatory Activities (MedDRA; version 16.1 or later). The CTCAE criteria v4.03 (or later) will be used to grade the severity of the AEs. Participant incidence of AEs will be displayed by SOC. Adverse events will also be summarized by severity and relationship to the study drug. Participant incidence of SAEs will also be displayed. Laboratory parameters will be summarized using descriptive statistics at baseline and at each subsequent timepoint. Changes from baseline will also be summarized. In addition, shift tables (ie, low-normal-high at baseline versus low-normal-high at follow-up in a 3-by-3 contingency table) will be provided to assess changes in laboratory values from baseline to follow-up. For subjects in Group B, safety parameters will also be analyzed by treatment. The results of other safety assessments (concomitant medications, vital signs, physical examinations, ECGs, and ECOG performance status) will also be evaluated. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Data will be collected on an ongoing basis and at study withdrawal, disease progression or death. |
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| E.5.2 | Secondary end point(s) |
| The secondary objectives of the study include confirmation of the sustained oral bioavailability of paclitaxel following multiple dosing as well as comparison of the relative bioavailability of paclitaxel tablets vs paclitaxel capsules (Group B only). |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
All subjects: Oraxol (HM30181AK-US tablet + paclitaxel capsule) and group B subjects (HM30181AK-US tablet + paclitaxel tablet) : 0 (immediately before dosing), 1, 2, 3, 4, 6, and 8 hours after Oraxol dosing on Days 1, 2, and 3 of the inpatient treatment week (Week 4 or later).
Group B only: Oraxol (HM30181AK-US tablet + paclitaxel tablet)
Following completion of the week 5 following the administration of the paclitaxel (ie, at Week 5 or later).
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | No |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| Yes |
| E.8.4 | The trial involves multiple sites in the Member State concerned | No |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| LVLS for withdrawal or LPO for disease progression to death. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 2 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 6 |
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