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Trial registered on ANZCTR


Registration number
ACTRN12615000894594
Ethics application status
Approved
Date submitted
23/07/2015
Date registered
27/08/2015
Date last updated
6/11/2018
Date data sharing statement initially provided
6/11/2018
Type of registration
Retrospectively registered

Titles & IDs
Public title
Oral Paclitaxel for the Treatment of Cancer
Scientific title
A Randomized Crossover Study to Determine the Bioequivalence of Three Consecutive Daily Doses of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel
Secondary ID [1] 286900 0
KX-ORAX-002
Universal Trial Number (UTN)
U1111-1167-2526
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer requiring treatment with intravenous paclitaxel 295306 0
Condition category
Condition code
Cancer 295578 295578 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Stage 1 is a cohort of up to 6 patients (Cohort 1), to confirm the dose of Oraxol when compared with IV paclitaxel.
This is a randomised trial and therefore Oraxol may be administered in Treatment Period 1 or Treatment Period 2.
Oraxol is administered over three days (i.e. Days 1, 2 and 3 of the applicable Treatment Period). The daily dose of Oraxol is one HM30181AK-US 15mg tablet administered one hour before oral paclitaxel 205mg/m2. Oraxol will be administered at the study site on each dosing day. Patients need to fast for 8 hours before and 4 hours after Oraxol administration.
Dosing for Treatment Period 2 may start on the last day of PK sampling for Treatment Period 1, or may be delayed for up to 3 weeks, if needed, to allow the participant to recover to less than or equal to Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) or baseline toxicity from the prior study treatment or to allow the participants flexibility in scheduling inpatient treatment.
An interim analysis of pharmacokinetic (PK) data from Cohort 1 will be conducted to determine if the administered regimen would appear likely to achieve BE (AUC0-inf), if tested in a greater number of participants in Stage 2. A decision will be made by consensus of the DSMB, Kinex, Zenith Technology, and the Principal Investigator as to whether a second cohort administered a different dose is required to complete Stage1 or whether the study can proceed to Stage 2 using the dose administered in Stage 1. An additional 18 to 42 evaluable participants will be enrolled into Stage 2 based on the Stage 1 results (AUC0-inf). The study design for Stage 2 is the same as for Stage 1.
Intervention code [1] 292090 0
Treatment: Drugs
Comparator / control treatment
The control treatment for both Stage 1 and Stage 2 is one dose of intravenous paclitaxel 80mg/m2 administered over one hour. It will be administered at the study site on Day 1 of the applicable Treatment Period. There are no fasting requirements and premedication will be given as per standard local practice at the study site.
Dosing for Treatment Period 2 can begin on the last day of assessments for Treatment Period 1. However the second period of randomized treatment may be delayed for up to 2 weeks, if needed, to allow the participant to recover to less than or equal to Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) or baseline toxicity from the prior study treatment or to allow the participants flexibility in scheduling inpatient treatment.
Control group
Active

Outcomes
Primary outcome [1] 295300 0
The primary objective of the study is to compare the bioequivalence (BE) based on the AUC0-inf of orally administered paclitaxel (Oraxol) at the estimated clinical dose to that of IV paclitaxel.
Timepoint [1] 295300 0
Blood samples for assay of paclitaxel and pharmacokinetic analyses are collected from pre-dose to 96 hours post-dose for IV paclitaxel; and from pre-dose to 144 hours after the third dose of Oraxol.

After receiving IV paclitaxel PK blood samples will be obtained at the following times: Pre-dose, during infusion at 2, 5, 8, 12, 20, 40, and 60 minutes; after infusion at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, 72 and 96 hours.

After receiving Oraxol PK blood samples will be obtained at the following times:
Days 1, 2 and 3: pre-dose, after dosing at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8 and 12;
Days 4, 5, 6, 7, 8 and 9 (i.e. 24, 48, 72, 96, 120 and 144 hours after the last dose of oral paclitaxel).
Secondary outcome [1] 315291 0
* Maximum observed concentration (Cmax)
Timepoint [1] 315291 0
Blood samples for assay of paclitaxel and pharmacokinetic analyses are collected from pre-dose to 96 hours post-dose for IV paclitaxel; and from pre-dose to 144 hours after the third dose of Oraxol.
After receiving IV paclitaxel PK blood samples will be obtained at the following times: Pre-dose, during infusion at 2, 5, 8, 12, 20, 40, and 60 minutes; after infusion at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, 72 and 96 hours.

After receiving Oraxol PK blood samples will be obtained at the following times:
Days 1, 2 and 3: pre-dose, after dosing at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8 and 12;
Days 4, 5, 6, 7, 8 and 9 (i.e. 24, 48, 72, 96, 120 and 144 hours after the last dose of oral paclitaxel).
Secondary outcome [2] 315292 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of Adverse Events.
Timepoint [2] 315292 0
From screening until the final visit, which is scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later.
Secondary outcome [3] 315293 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of laboratory findings.
Safety laboratory tests will include haematology, biochemistry (i.e. electrolytes, liver and renal function tests) and other routine tests (e.g. glucose, triglycerides, cholesterol, protein) and urinalysis.
Timepoint [3] 315293 0
At Screening; daily from Baseline (Day -1) until the last visit for each PK sampling period (i.e. Day 9 for Oraxol and Day 8 for IV paclitaxel); and at the final visit (scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later).
Secondary outcome [4] 315294 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of concomitant medications.
All concomitant medications will be recorded on source documents and then entered into the eCRF.
Timepoint [4] 315294 0
From screening until the final visit, which is scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later.
Secondary outcome [5] 315295 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of vital signs.
Vital signs (pulse rate, systolic/diastolic blood pressure, respiration and temperature) will be measured at each study visit.
Timepoint [5] 315295 0
At Screening; daily from Baseline (Day -1) until the last visit for each PK sampling period (i.e. Day 9 for Oraxol and Day 8 for IV paclitaxel); and at the final visit (scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later).
Secondary outcome [6] 315296 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of physical examinations.
Physical examinations will include an assessment of general appearance; head, eyes, ears, nose, and throat; thorax (including cardiovascular and respiratory systems); abdomen; skin; musculoskeletal; extremities and neurological examination. Additional examinations will be performed as clinically indicated to assess AEs.
Timepoint [6] 315296 0
At screening, baseline (Day -1) of each Treatment Period and at the final visit, which is scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later.
Secondary outcome [7] 315297 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of ECGs.
Timepoint [7] 315297 0
At screening, Day 1 of each Treatment Period (approx. 1 hour post completion of dosing) and at the final visit, which is scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later.
Secondary outcome [8] 315298 0
The safety and tolerability of Oraxol compared with IV paclitaxel will be assessed by evaluation of ECOG performance status.
Timepoint [8] 315298 0
At screening, baseline (Day -1) of Treatment Period 2 and at the final visit, which is scheduled between the day of the last PK sample for Treatment Period 2 and 2 weeks later.
Secondary outcome [9] 316333 0
* Area under the concentration–time curve zero time to time of last quantifiable concentration (AUC0-t)
Timepoint [9] 316333 0
Blood samples for assay of paclitaxel and pharmacokinetic analyses are collected from pre-dose to 96 hours post-dose for IV paclitaxel; and from pre-dose to 144 hours after the third dose of Oraxol.

After receiving IV paclitaxel PK blood samples will be obtained at the following times: Pre-dose, during infusion at 2, 5, 8, 12, 20, 40, and 60 minutes; after infusion at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, 72 and 96 hours.

After receiving Oraxol PK blood samples will be obtained at the following times:
Days 1, 2 and 3: pre-dose, after dosing at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8 and 12;
Days 4, 5, 6, 7, 8 and 9 (i.e. 24, 48, 72, 96, 120 and 144 hours after the last dose of oral paclitaxel).
Secondary outcome [10] 316334 0
* Time at which the highest drug concentration occurs (Tmax)
Timepoint [10] 316334 0
Blood samples for assay of paclitaxel and pharmacokinetic analyses are collected from pre-dose to 96 hours post-dose for IV paclitaxel; and from pre-dose to 144 hours after the third dose of Oraxol.
After receiving IV paclitaxel PK blood samples will be obtained at the following times: Pre-dose, during infusion at 2, 5, 8, 12, 20, 40, and 60 minutes; after infusion at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, 72 and 96 hours.

After receiving Oraxol PK blood samples will be obtained at the following times:
Days 1, 2 and 3: pre-dose, after dosing at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8 and 12;
Days 4, 5, 6, 7, 8 and 9 (i.e. 24, 48, 72, 96, 120 and 144 hours after the last dose of oral paclitaxel).
Secondary outcome [11] 316335 0
* Terminal elimination phase half-life (T1/2)
Timepoint [11] 316335 0
Blood samples for assay of paclitaxel and pharmacokinetic analyses are collected from pre-dose to 96 hours post-dose for IV paclitaxel; and from pre-dose to 144 hours after the third dose of Oraxol.
After receiving IV paclitaxel PK blood samples will be obtained at the following times: Pre-dose, during infusion at 2, 5, 8, 12, 20, 40, and 60 minutes; after infusion at 0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, 72 and 96 hours.

After receiving Oraxol PK blood samples will be obtained at the following times:
Days 1, 2 and 3: pre-dose, after dosing at 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8 and 12;
Days 4, 5, 6, 7, 8 and 9 (i.e. 24, 48, 72, 96, 120 and 144 hours after the last dose of oral paclitaxel).

Eligibility
Key inclusion criteria
Eligible participants are 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. They must have adequate hematologic status and liver and renal function at Screening/Baseline; Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 1; and life expectancy of at least 3 months.
They must be willing to fast for 8 hours before and 4 hours after Oraxol administration; 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; willing to refrain from caffeine consumption for 12 hours before each treatment period through the completion of protocol-specified PK sampling for that dose. 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. 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.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Study participants must not be currently taking a prohibited concomitant medication; have unresolved toxicity from prior chemotherapy; have received investigational agents within 14 days or 5 half-lives prior to the first study dosing day, whichever is longer. Other exclusions are women of childbearing potential who are pregnant or breast feeding; uncontrolled intercurrent illness; major surgery to the upper gastrointestinal 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; known history of allergy to paclitaxel; any other condition which the investigator believes would make a subject’s participation in the study not acceptable

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Once a patient has been assessed as eligible for the study as far as can be determined at 5 days prior to dosing, the site will contact Zenith Technology where the randomisation list will be held. Zenith Technology will advise the site of the participant's randomisation number and their treatment sequence. Zenith Technology will be supplying pre-labelled PK sample collection packs and Oraxol and therefore need to randomise participants 5 working days before dosing of Treatment Period 1. This means that participants are randomised prior to the analysis and review of laboratory tests needed within 72hours prior to dosing. Therefore some participants may be randomised, found to be ineligible on the basis of these laboratory tests and not dosed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Participants will be randomized to receive either treatment Sequence A or B. Assignment to treatment sequence will be based on a computer-generated central randomization scheme that will be reviewed and approved by an independent statistician.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
This is a randomised, multicenter, open-label, 2-stage study. Both stages of the study have a two treatment periods and a crossover design. Stage 1 will consist of an initial cohort of 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. An interim analysis of pharmacokinetic data from Cohort 1 will be conducted to determine if the administered regimen would appear likely to achieve BE (AUC0-inf), 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-inf 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, a decision will be made by consensus of the DSMB, Kinex, Zenith Technology, and the Principal Investigator as to what dose should be administered in Stage 2. An additional 18 to 42 evaluable participants will be enrolled into Stage 2 based on the Stage 1 results (AUC0-inf). 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).
Phase
Phase 1
Type of endpoint(s)
Bio-equivalence
Statistical methods / analysis
A total of 24 to 48 evaluable participants receiving the selected Stage 1 dose will be evaluated for bioequivalence between Oraxol and IV paclitaxel based on a 2-sided 90% CI of log-transformed AUC0-inf between 80% and 125%.
Based on the within-subject variability of at most 30% through a comparison of the PK of Oraxol to Taxol, a sample size of 24 to 48 patients is needed to achieve BE within the 80% to 125% confidence limits with 90% statistical power.
The data from the first 6 patients dosed will be analysed with the subsequent patients given the same dose. Therefore the additional 18-42 patients data will be added to the 6 from the same dose from stage 1 to give a total of 24-48 patients. If 2 sets of 6 patients are needed in Stage 1, a total of 54 patients will be dosed, but the first 6 patients who received the different/initial dose will not be included in the PK analyses because their data will confound the BE.

Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous variables will be summarized using the mean, SD, median, minimum, and maximum. Summaries of PK parameters will also include the geometric mean and the coefficient of variation. Categorical variables will be summarized by counts and by percentage of participants in corresponding categories. All raw data obtained from the CRF/eCRF, as well as any derived data will be included in data listings.
The primary endpoint is area under the concentration–time curve zero time extrapolated to infinite time (AUC0-inf) derived for each participant by non-compartmental analysis using plasma concentration-time data for oral and IV paclitaxel.
Secondary endpoints include, but are not limited to the following PK parameters which will be derived for each participant by noncompartmental analysis using plasma concentration-time data for oral and IV paclitaxel:
* Maximum observed concentration (Cmax)
* Area under the concentration–time curve zero time to time of last quantifiable concentration (AUC0-t)
* Time at which the highest drug concentration occurs (Tmax)
* Terminal elimination phase half-life (T1/2)

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 10352 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 22023 0
3168 - Clayton
Recruitment outside Australia
Country [1] 6974 0
New Zealand
State/province [1] 6974 0
Auckland
Country [2] 7067 0
New Zealand
State/province [2] 7067 0
Wellington
Country [3] 7068 0
New Zealand
State/province [3] 7068 0
Canterbury
Country [4] 7069 0
New Zealand
State/province [4] 7069 0
Otago
Country [5] 20997 0
Taiwan, Province Of China
State/province [5] 20997 0
Taiwan

Funding & Sponsors
Funding source category [1] 291461 0
Commercial sector/Industry
Name [1] 291461 0
Kinex Pharmaceuticals Inc
Address [1] 291461 0
20 Commerce Drive
Cranford
New Jersey 07016
Country [1] 291461 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Kinex Pharmaceuticals Inc
Address
20 Commerce Drive
Cranford
New Jersey 07016

Country
United States of America
Secondary sponsor category [1] 290141 0
Commercial sector/Industry
Name [1] 290141 0
Zenith Technology Corporation Ltd.
Address [1] 290141 0
156 Frederick Street
Dunedin 9016

Country [1] 290141 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293011 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 293011 0
C/- Ministry of Health
Freyberg Building
20 Aitken Street
PO Box 5013
Wellington 6011
Ethics committee country [1] 293011 0
New Zealand
Date submitted for ethics approval [1] 293011 0
08/06/2015
Approval date [1] 293011 0
24/06/2015
Ethics approval number [1] 293011 0
15/STH/87

Summary
Brief summary
Oraxol is a combination of an oral tablet, HM30181 methanesulfonate, and capsules that contain paclitaxel. HM30181 is a drug that helps the body absorb paclitaxel, a drug used to treat cancer. The purpose of this study is to measure the levels of paclitaxel in your blood at different times when given by intravenous (IV) drip (through a vein in your arm) compared to the levels of paclitaxel at different times in your blood when given by mouth (as Oraxol).
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58038 0
Dr Christopher Jackson
Address 58038 0
Department of Oncology
Dunedin Hospital
Southern District Health Board
201 Great King Street
Dunedin 9016
Country 58038 0
New Zealand
Phone 58038 0
+64 3 474 0999 ext 9698
Fax 58038 0
Email 58038 0
Christopher.jackson@southerndhb.govt.nz
Contact person for public queries
Name 58039 0
Mrs Linda Folland
Address 58039 0
Zenith Technology Corporation, Ltd.
156 Frederick Street
Dunedin 9016
Country 58039 0
New Zealand
Phone 58039 0
+643 477 9669
Fax 58039 0
Email 58039 0
Linda.Folland@Zenithtechnology.co.nz
Contact person for scientific queries
Name 58040 0
Dr E. Douglas Kramer
Address 58040 0
Kinex Pharmaceuticals, Inc.
20 Commerce Drive
Cranford
New Jersey 07016
Country 58040 0
United States of America
Phone 58040 0
+1 908-272-0628
Fax 58040 0
Email 58040 0
dkramer@kinexpharma.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
Sponsor to decide
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable