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A Study to Determine the Bioequivalence of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04035473
Recruitment Status : Completed
First Posted : July 29, 2019
Results First Posted : April 13, 2022
Last Update Posted : April 13, 2022
Sponsor:
Collaborators:
PharmaEssentia
Zenith Technology Corporation Limited
Information provided by (Responsible Party):
Athenex, Inc.

Brief 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).


Condition or disease Intervention/treatment Phase
Solid Tumor Drug: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules Phase 1

Detailed Description:

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).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 42 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Randomized Crossover Study to Determine the Bioequivalence of Three Consecutive Daily Doses of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel
Actual Study Start Date : August 1, 2015
Actual Primary Completion Date : March 27, 2019
Actual Study Completion Date : March 27, 2019

Resource links provided by the National Library of Medicine

Drug Information available for: Paclitaxel

Arm Intervention/treatment
Active Comparator: Sequence A (Oraxol, IV paclitaxel)

The treatment sequences will be:

A Oraxol (paclitaxel + HM30181) on Days 1, 2, and 3 of Treatment Period 1 followed by IV paclitaxel on Day 1 of Treatment Period 2 B IV paclitaxel on Day 1 of Treatment Period 1 followed by Oraxol on Days 1, 2, and 3 of Treatment Period 2

Drug: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules

HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules

Oral paclitaxel capsules

Other Name: ORAXOL

Active Comparator: Sequence B (IV paclitaxel, Oraxol)

The treatment sequences will be:

A IV paclitaxel on Day 1 of Treatment Period 1 followed by Oraxol on Days 1, 2, and 3 of Treatment Period 2 B Oraxol (paclitaxel + HM30181) on Days 1, 2, and 3 of Treatment Period 1 followed by IV paclitaxel on Day 1 of Treatment Period 2

Drug: HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules

HM30181 methanesulfonate monohydrate plus oral paclitaxel capsules

Oral paclitaxel capsules

Other Name: ORAXOL




Primary Outcome Measures :
  1. Area Under the Concentration-Time Curve Zero Time Extrapolated to Infinite Time (AUC0-∞) [ Time Frame: Pharmacokinetic Sampling for IV Paclitaxel - Predose to 96 hours after infusion (Day 1-5). Pharmacokinetic Sampling for Oraxol- predose of Day1 to 144 hours after third dose of day 3 (Day 1-9) ]

    Paclitaxel plasma concentrations were normalized to 615 mg/m2 for Oraxol and 80 mg/m2 for IV paclitaxel.

    Pharmacokinetic and statistical analyses were based on normalized plasma concentrations. Plasma concentrations for paclitaxel were analyzed to determine AUC0-∞ by noncompartmental analysis using plasma concentration-time data for oral and IV paclitaxel



Secondary Outcome Measures :
  1. Maximum Observed Concentration (Cmax) [ Time Frame: Pharmacokinetic Sampling for IV Paclitaxel - Predose to 96 hours after infusion (Day 1-5). Pharmacokinetic Sampling for Oraxol- predose of Day1 to 144 hours after third dose of day 3 (Day 1-9) ]

    Paclitaxel plasma concentrations were normalized to 615 mg/m2 for Oraxol and 80 mg/m2 for IV paclitaxel.

    Pharmacokinetic and statistical analyses were based on normalized plasma concentrations. Plasma concentrations for paclitaxel were analyzed to determine Cmax by noncompartmental analysis using plasma concentration-time data for oral and IV paclitaxel


  2. Area Under the Concentration-time Curve From Time 0 to Time of Last Quantifiable Concentration (AUC0-t) [ Time Frame: Pharmacokinetic Sampling for IV Paclitaxel - Predose to 96 hours after infusion (Day 1-5). Pharmacokinetic Sampling for Oraxol- predose of Day1 to 144 hours after third dose of day 3 (Day 1-9) ]

    Paclitaxel plasma concentrations were normalized to 615 mg/m2 for Oraxol and 80 mg/m2 for IV paclitaxel.

    Pharmacokinetic and statistical analyses were based on normalized plasma concentrations. Plasma concentrations for paclitaxel were analyzed to determine AUC0-t by noncompartmental analysis using plasma concentration-time data for oral and IV paclitaxel


  3. Time at Which the Highest Drug Concentration Occurs (Tmax) [ Time Frame: Pharmacokinetic Sampling for IV Paclitaxel - Predose to 96 hours after infusion (Day 1-5). Pharmacokinetic Sampling for Oraxol- predose of Day1 to 144 hours after third dose of day 3 (Day 1-9) ]

    Paclitaxel plasma concentrations were normalized to 615 mg/m2 for Oraxol and 80 mg/m2 for IV paclitaxel.

    Pharmacokinetic and statistical analyses were based on normalized plasma concentrations. Plasma concentrations for paclitaxel were analyzed to determine Tmax by noncompartmental analysis using plasma concentration-time data for oral and IV paclitaxel


  4. Terminal Elimination Phase Half-life (t½) [ Time Frame: Pharmacokinetic Sampling for IV Paclitaxel - Predose to 96 hours after infusion (Day 1-5). Pharmacokinetic Sampling for Oraxol- predose of Day1 to 144 hours after third dose of day 3 (Day 1-9) ]

    Paclitaxel plasma concentrations were normalized to 615 mg/m2 for Oraxol and 80 mg/m2 for IV paclitaxel.

    Pharmacokinetic and statistical analyses were based on normalized plasma concentrations. Plasma concentrations for paclitaxel were analyzed to determine t½ by noncompartmental analysis using plasma concentration-time data for oral and IV paclitaxel


  5. Safety and Tolerability of Oraxol Compared With IV Paclitaxel [ Time Frame: From screening until final visit (within 28 days after the last dose of study drug was taken, and preferably before the participant receives any additional chemotherapy) ]
    Safety was assessed by recording all adverse events (AEs) and serious adverse events (SAEs), including CTCAE grades (version 4.03); recording concomitant medications; clinical laboratory testing (including hematology, biochemistry, and urinalysis); measurement of vital signs (pulse rate, systolic and diastolic blood pressures, respiratory rate, and body temperature), weight, and body surface area (BSA); performance of electrocardiograms (ECGs); assessment of ECOG performance status; and performance of physical examinations



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT04035473


Locations
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Australia
Monash Medical Centre
Melbourne, Australia
New Zealand
Auckland City Hospital
Auckland, New Zealand
Dunedin Hospital
Dunedin, New Zealand, 9016
Wellington Regional Hospital
Wellington, New Zealand
Taiwan
Lotung Poh-Ai Hospital
Ilan, Taiwan
Shuang Ho hospital
New Taipei City, Taiwan
Tri-Service General Hospital
Taipei, Taiwan
Sponsors and Collaborators
Athenex, Inc.
PharmaEssentia
Zenith Technology Corporation Limited
Investigators
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Study Director: David Cutler, MD Athenex, Inc.
  Study Documents (Full-Text)

Documents provided by Athenex, Inc.:
Study Protocol  [PDF] November 9, 2017
Statistical Analysis Plan  [PDF] September 17, 2019

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Responsible Party: Athenex, Inc.
ClinicalTrials.gov Identifier: NCT04035473    
Other Study ID Numbers: KX-ORAX-002
First Posted: July 29, 2019    Key Record Dates
Results First Posted: April 13, 2022
Last Update Posted: April 13, 2022
Last Verified: February 2022

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Additional relevant MeSH terms:
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Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action