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Trial registered on ANZCTR


Registration number
ACTRN12614000365662
Ethics application status
Approved
Date submitted
25/03/2014
Date registered
7/04/2014
Date last updated
26/09/2014
Type of registration
Prospectively registered

Titles & IDs
Public title
An Open-label, Randomized Cross-over, Pharmacokinetic Study to Determine the Bioavailability, Safety, and Tolerability of Two Consecutive Daily Doses of Oraxol in Cancer Patients Treated With Intravenous Paclitaxel Amendment 1
Scientific title
Patients with cancer for whom IV paclitaxel (at a dose of 80 mg/m2 IV over 1 hour) is indicated will be treated with intravenous paclitaxel and Oraxol (Paclitaxel + HM30181AK-US) to evaluate bioavailability, safety and tolerability of Oraxol.
Secondary ID [1] 284318 0
Nil
Universal Trial Number (UTN)
U1111-1152-5696
Trial acronym
Nil
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer 291489 0
Condition category
Condition code
Cancer 291854 291854 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Crossover Design:

Study treatments will be administered on consecutive weeks with 1 week between each treatment administration.

There are two sequences; IV paclitaxel followed by 15 mg oral HM30181 methanesulfonate monohydrate plus 270 mg oral paclitaxel and,
HM30181 methanesulfonate monohydrate plus 270 mg oral paclitaxel followed by IV paclitaxel.

Treatment details:
80 mg/m2 IV paclitaxel (as Taxol registered trademark or generic) infused over 1 hour (Day 1 or Day 8) plus premedication per standard local practice, or

15 mg oral HM30181 methanesulfonate monohydrate plus 270 mg oral paclitaxel (Days 1 and 2 or Days 8 and 9). HM30181AK-US tablet will be administered 1 hour before oral paclitaxel; no premedication is allowed during this treatment sequence.

Qualified staff will administer IV paclitaxel treatment and monitor the subject for safety. Subjects will remain at the study site for at least the first 24 hours after dosing of IV paclitaxel for PK blood sample collection.

Qualified staff will administer HM30181 methanesulfonate monohydrate plus 270 mg oral paclitaxel. Subjects will remain at the study site for the first 48 hours after dosing of Oraxol for PK blood sample collection.

Subjects may leave the site and return for PK blood sample collections after 24 hours for IV paclitaxel or 48 hours of Oraxol PK blood collections have been completed and will return to the study site for the remaining PK blood collections. If more convenient, at the discretion of the investigator, the subjects may be discharged to a local motel or remain housed at the study site for the entirety of the PK blood collection periods for both IV paclitaxel and Oraxol.

The second week of randomized treatment may be delayed for up to 2 weeks, if needed, to allow the subject to recover to less than or equal to Grade 1 CTCAE toxicity from the prior study treatment.
Intervention code [1] 289054 0
Treatment: Drugs
Comparator / control treatment
The bioavailability, safety, and tolerability of 15 mg oral HM30181 methanesulfonate monohydrate plus 548mg mg oral paclitaxel over two days will be compared with 80 mg/m2 IV paclitaxel (as Taxol registered trademark or generic) infused over 1 hour
Control group
Active

Outcomes
Primary outcome [1] 291766 0
The absolute bioavailabilty of Oraxol will be determined by comparing the ratio of the dose-adjusted AUC0-inf of Oraxol to that of IV paclitaxel.
Timepoint [1] 291766 0
Pharmacokinetic sampling times:
IV paclitaxel – predose, during infusion (2, 5, 8, 12, 20, 40, and 60 minutes), after infusion (0.25, 0.5, 0.75, 1, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56 and 72 hours) on Days 1 to 4 or Days 8 to 11

Lower-dose Paclitaxel (270 mg per day for 2 consecutive days)
Oraxol (paclitaxel and HM30181AK-US) Day 1 or 8 - predose, and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, and 18 hours after the first dose (Days 1 or 8)

Day 2 to Day 5 or Day 9 to Day 12- predose, and at 0.25, 0.5,
0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, and 72
hours after the second dose (Days 2 to 5 or 9 to 12)

Higher-dose Paclitaxel (548 mg/m2 per day for 2 consecutive days)

Oraxol (paclitaxel and HM30181AK-US) Day 1 or 8 - predose, and at 0.25, 0.5, 0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, and 18 hours after the first dose (Days 1 or 8)

Day 2 to Day 5 or Day 9 to Day 12- predose, and at 0.25, 0.5,
0.75, 1, 1.25, 1.5, 2, 3, 4, 6, 8, 12, 18, 24, 32, 48, 56, 72, 96,
120, 144, and 168 hours after the second dose (Days 2 to 5
or 9 to 12)
Secondary outcome [1] 307471 0
Safety assessments will consist of determining and recording all AEs including all CTCAE grades (for both increasing and decreasing severity) and SAEs.
Timepoint [1] 307471 0
Safety assessments will be done from screening, (Day -28 to Day -1), enrollment and follow up (Day 1 to two weeks after the last pharmacokinetic blood sample collection or Day 26, which ever is sooner).

Eligibility
Key inclusion criteria
1. Signed written informed consent
2. 18 years of age and older
3. Cancer patients for which treatment with paclitaxel at 80 mg/m2 has been recommended by their oncologist, either as monotherapy or in combination with other agents.
4. Adequate bone marrow reserve as demonstrated by:
Absolute neutrophil count (ANC) 1.0 109/L
Platelet count 100 109/L
Haemoglobin (Hgb) 9 g/L
5. Adequate liver function as demonstrated by:
Total bilirubin of 20 micro mol/L or 30 micro mol/L for subjects with liver metastasis
Alanine aminotransferase (ALT) 3 times upper limit of normal (ULN) or 5 times ULN if liver metastasis is present
Alkaline phosphatase (ALP) 3 times ULN or 5 times ULN if bone metastasis is present
6. Adequate renal function as demonstrated by serum creatinine 177 micro mol/L or creatinine clearance greater than 50 mL/min as calculated by the Cockroft 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.
10. Willing to abstain from alcohol consumption for 3 days prior to the first dose of study drug through the completion of protocol-specified PK sampling on Day 12
11. Willing to refrain from caffeine consumption for 12 hours prior to each dose of study drug through the completion of protocol-specified PK sampling for that dose on Day 5 or Day 12. Women must be postmenopausal (greater than 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 subjects 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
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Eligible subjects must not have/be:
1. Currently taking a prohibited concomitant medication:
Strong inhibitors or inducers of CYP3A4.
Clinically significant inhibitors (gemfibrozil) or inducers (rifampin) of CYP2C8
Known P-gp inhibitors or inducers
2. 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
3. Received investigational agents within 14 days or 5 half-lives of the first study dosing day, whichever is longer.
4. Women of childbearing potential who are pregnant or breast feeding.
5. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, myocardial infarction within the last 6 months, unstable angina pectoris, clinically significant cardiac arrhythmia, chronic pulmonary disease requiring oxygen, known bleeding disorders, or psychiatric illness/social situations that would limit compliance with study requirements
6. Significant or uncontrolled cardiovascular disease or bleeding disorder
7. Major surgery to the upper gastrointestinal (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. Subjects whose allergy was due to the IV solvent (such as Cremophorregister trademark) and not paclitaxel will be eligible for this study.

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)
Subjects will be screened within 28 days of the first dose of study drug and all safety evaluations, will be performed after the subject provides informed consent and eligibility criteria are met. Eligible subjects are adults with cancer for whom therapy with IV paclitaxel at a dose of 80 mg/m2 is indicated.

Sequence dosing will be explained to subjects at the time of obtaining the informed consent. On Day -1, after all eligibility criteria have been met, the subject will be notified of their assigned sequence. This is an open-label study, unblinded study. The sequence will be generated by the statistician and the Investigator will assign sequences in chronological order. Allocation is not concealed.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
This is an open-label study. Subjects will be randomly assigned to a treatment sequence. A simple randomization table created by computer software (i.e. computerized sequence generation) will be used to generate sequence assignment.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Crossover
Other design features
Phase
Phase 1
Type of endpoint/s
Bio-availability
Statistical methods / analysis
Methods:
Statistical analyses will be reported using summary tables, graphs, and data listings. Continuous variables will be summarized using the mean, standard deviation, 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 subjects in corresponding categories. All raw data obtained from the case report forms as well as any derived data will be included in data listings.
Analysis:
Pharmacokinetic:
Plasma concentrations for paclitaxel only will be analyzed to determine the following PK parameters: Cmax, AUC0-t, AUC0-inf, Tmax, and t1/2 will be determined for each formulation.
Absolute bioavailability of Oraxol will be determined by comparing the ratio of the dose-adjusted AUC0-inf of Oraxol to that of IV paclitaxel.
Pharmacodynamic: Not applicable.
Pharmacokinetic-Pharmacodynamic: Not applicable.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
21/04/2014
Actual
28/04/2014
Date of last participant enrolment
Anticipated
14/11/2014
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
8
Accrual to date
Final
Recruitment outside Australia
Country [1] 5925 0
New Zealand
State/province [1] 5925 0
Dunedin

Funding & Sponsors
Funding source category [1] 288969 0
Commercial sector/Industry
Name [1] 288969 0
Kinex Pharmaceuticals, Inc.
Country [1] 288969 0
United States of America
Primary sponsor type
Commercial sector/Industry
Name
Kinex Pharmaceuticals, Inc.
Address
701 Ellicott Street
Buffalo, NY 14203
Country
United States of America
Secondary sponsor category [1] 287650 0
None
Name [1] 287650 0
Address [1] 287650 0
Country [1] 287650 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 290780 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 290780 0
Ethics committee country [1] 290780 0
Date submitted for ethics approval [1] 290780 0
Approval date [1] 290780 0
21/02/2014
Ethics approval number [1] 290780 0
14/STH/12

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 47198 0
Dr Christopher Jackson
Address 47198 0
Southern blood and Cancer Service
Southern District Health Board
Dunedin Hospital
201 Great King Street
Dunedin, 9016
Country 47198 0
New Zealand
Phone 47198 0
+64 3 474 0999 ext 9698
Fax 47198 0
+64 3 477 9605
Email 47198 0
Christopher.Jackson@southerndhb.govt.nz
Contact person for public queries
Name 47199 0
Linda Zenith
Address 47199 0
Zenith Technology Corporation Ltd
156 Frederick Street
PO Box 1777
Dunedin, 9016
Country 47199 0
New Zealand
Phone 47199 0
+64 3 477 9669
Fax 47199 0
+64 3 477 9605
Email 47199 0
linda.folland@zenithtechnology.co.nz
Contact person for scientific queries
Name 47200 0
Christopher Jackson
Address 47200 0
Southern blood and Cancer Service
Southern District Health Board
Dunedin Hospital
201 Great King Street
Dunedin, 9016
Country 47200 0
New Zealand
Phone 47200 0
+64 3 474 0999 ext 9698
Fax 47200 0
+64 3 477 9605
Email 47200 0
Christopher.Jackson@southerndhb.govt.nz

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Results publications and other study-related documents

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