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Trial registered on ANZCTR


Registration number
ACTRN12615000881538
Ethics application status
Approved
Date submitted
4/08/2015
Date registered
24/08/2015
Date last updated
6/11/2018
Date data sharing statement initially provided
6/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
A Safety Study of Oraxol (HM30181 + oral paclitaxel) in Cancer Patients
Scientific title
A Safety Study of Oraxol (HM30181 + oral paclitaxel) in Cancer Patients
Secondary ID [1] 286905 0
KX-ORAX-003
Universal Trial Number (UTN)
U1111-1170-6641
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Cancer requiring treatment with IV paclitaxel 295321 0
Condition category
Condition code
Cancer 295591 295591 0 0
Any cancer

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Approximately 40 participants will be treated with a daily dosage regimen of Oraxol 205 mg/m2 on Days 1, 2, and 3 every week (i.e. a total Oraxol dose of 615mg/m2 over three days of dosing), or as adjusted in KX-ORAX-002 to achieve bioequivalence to IV paclitaxel 80 mg/m2 infused over 1 hour. Oraxol will be administered once daily for 3 consecutive days on a weekly basis as 15 mg oral HM30181AK-US tablet plus oral paclitaxel capsules. Oral paclitaxel capsules are administered one hour after the HM30181AK-US tablet. Participants must fast for 8 hours prior to administration of Oraxol and for four hours afterwards. Participants will be asked to return their daily Oraxol dose cards to check for compliance. Doses during the PK sampling week (Week 4 or later) will be administered at the study site.
A subgroup of participants (Group B) will also receive one dose of Oraxol where paclitaxel is administered as tablets rather than as capsules for one week only.
Participants may enter this study after completion of a previous study involving Oraxol (KX-ORAX-002). The study procedures are the same regardless of whether a participant was in the previous study or not; however some data (e.g. medical history) collected for the previous study would not need to be collected again for this study. The dose and administartion of Oraxol to be used in this study will be the same as the dose in the previous study that is confirmed to be equivalent to the administration of IV Paclitaxel at 80mg/m2.
Participants may continue to receive treatment with Oraxol (HM30181AK-US tablet and paclitaxel capsules) in this study until any of the following occur: death, successful completion of the course of treatment prescribed by the investigator, progression of disease, AEs not associated with progression of disease, withdrawal of consent, termination of the study by the Sponsor, or other specified reason.
If needed at any time, treatment may be delayed for up to 2 weeks to allow a participant to recover to less than or equal to Grade 1 Common Terminology Criteria for Adverse Events (CTCAE) toxicity from prior chemotherapy.
Intervention code [1] 292092 0
Treatment: Drugs
Comparator / control treatment
Nil
Control group
Uncontrolled

Outcomes
Primary outcome [1] 295303 0
Safety and tolerability as assessed by the incidence of adverse events. Treatment-emergent AEs (TEAEs) are defined as those AEs with an onset after dosing and those pre-existing AEs that worsen during the study.
AEs will include those reported by participants as well as those observed by the clinical team, or clinically significant changes in lab tests, vital signs and ECGs. Possible AEs may include gastrointestinal effects and abdominal pain but as this is an early phase clinical trial and the likely AE profile is not yet known.
Timepoint [1] 295303 0
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).
Primary outcome [2] 295304 0
Safety and tolerability as assessed by the results of routine laboratory safety tests (i.e. haematology, biochemistry and urinalysis).
Timepoint [2] 295304 0
At screening/baseline, weekly (within 72hrs prior to the start of dosing each week), and at the final visit (within 28 days after the last dose of study drug was taken, and preferably before the participant receives any additional chemotherapy). Long-term patients may have the frequency of routine laboratory safety tests reduced to every three weeks after Week 48
Primary outcome [3] 295809 0
Safety and tolerability as assessed by the severity and relationship of adverse events. Treatment-emergent AEs (TEAEs) are defined as those AEs with an onset after dosing and those pre-existing AEs that worsen during the study.
Timepoint [3] 295809 0
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).
Secondary outcome [1] 315300 0
Oraxol PK data from this study will be compared with Oraxol PK data from study KX-ORAX-002. The PK parameters to be used are AUCs, clearance, Cmax and Tmax.
Timepoint [1] 315300 0
From pre-dose until 8 hours post-dose on Days 1, 2 and 3. This time period is shorter to the time period used in the KX-ORAX-002 study, where PK blood samples are being collected until 144 hours post-dose on Day 3. PK samples will be collected during dosing for Week 4; or may be done during a later dosing week at the investigator's discretion and/or at the participant's convenience.
Secondary outcome [2] 315301 0
Safety as assessed by the use of concomitant medications, as recorded in their clinical notes and reported by participant's during their weekly contact with the study site.
Timepoint [2] 315301 0
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).
Secondary outcome [3] 315302 0
Safety as assessed by vital signs. Vital signs include pulse rate, systolic/diastolic blood pressure, respiratory rate, and temperature.
Timepoint [3] 315302 0
Vital signs are measured at Screening/Baseline, before dosing on Day 1 of every 3rd week (Weeks 1, 4, 7, 10, etc), and before dosing during the inpatient dosing week and at the Final Visit (within 28 days after the last dose of study drug was taken, and preferably before the participant receives any additional chemotherapy).
Secondary outcome [4] 315303 0
Safety as assessed by Physical Examinations. A complete PE will include an assessment of HEENT, gastrointestinal, cardiovascular, respiratory, integumentary, muscular- skeleton, neurological and endocrine/metabolism systems. Complete PEs will be performed at Screening/Baseline and at the Final Visit. All other physical examinations do not require complete examinations but will be targeted to the signs and symptoms related to Adverse Event Reporting. Additional examinations will be performed as clinically indicated to assess adverse events.
Timepoint [4] 315303 0
At screening/baseline, Weeks 1, 4, 7 10 etc, and at the final visit (within 28 days after the last dose of study drug was taken, and preferably before the participant receives any additional chemotherapy).
Secondary outcome [5] 315304 0
Safety as assessed by Eastern Co-operative Oncology Group (ECOG) performance status.
Timepoint [5] 315304 0
At screening/baseline, Weeks 1, 4, 7 10 etc, and at the final visit (within 28 days after the last dose of study drug was taken, and preferably before the participant receives any additional chemotherapy).
Secondary outcome [6] 315305 0
Safety, as assessed by ECGs.
Timepoint [6] 315305 0
At screening/baseline, Weeks 1, 4, 13 and 20, and at the final visit (within 28 days after the last dose of study drug was taken, and preferably before the participant receives any additional chemotherapy).
Secondary outcome [7] 340699 0
To compare the relative bioavailability of paclitaxel tablets vs paclitaxel capsules (Group B only)
Timepoint [7] 340699 0
Pre-dose, then hours 1, 2, 3, 4, 6 and 8 hours post-dose on Days 1, 2 and 3. This time period is shorter to the time period used in the KX-ORAX-002 study, where PK blood samples are being collected until 144 hours post-dose on Day 3. PK samples will be collected during dosing for Week 5; or may be done during a later dosing week at the investigator's discretion and/or at the participant's convenience.

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.
At Screening/Baseline, they must have
Adequate hematologic status:
- Absolute neutrophil count (ANC) greater than/equal to 1.0 x 10^9/L
- Platelet count greater than/equal to 100 x 10^9/L
- Hemoglobin greater than/equal to 90g/L
Adequate liver function as demonstrated by:
- Total bilirubin of less than/equal to 20 micromol/L or less than/equal to 30 µmol/L for participants with liver metastasis
Alanine aminotransferase (ALT) less than/equal to 3 x upper limit of normal (ULN) or less than/equal to 5 x ULN if liver metastasis is present
Alkaline phosphatase (ALP) less than/equal to 3 x ULN or less than/equal to 5 x ULN if liver or bone metastasis is present
Adequate renal function as demonstrated by serum creatinine less than/equal to 177 micromol/L or creatinine clearance greater than 50 mL/min as calculated by the Cockroft and Gault formula.
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 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. Women must be postmenopausal (more 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. 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;
- a medication known to be a P-gp inhibitor (e.g., verapamil) or inducer (rifampin) within 7 days prior to the first dose of Oraxol
- an oral medication with a narrow therapeutic index known to be a P-gp substrate (eg, digoxin or dabigatran) within 24 hours prior to the first dose of Oraxol
- a medication known to be a strong CYP3A4 strong inhibitor (e.g., ketoconazole) or strong inducer (e.g., rifampin or St. John's Wort) within 14 days prior to the first dose of Oraxol
- a medication known to be a strong inhibitor (e.g., gemfibrozil) or inducers (e.g., rifampin) of CYP2C8 within 14 days prior to the first dose of Oraxol

Other exclusions are: 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 (Participants whose allergy was due to the IV solvent (such as Cremophor [Registered Trademark]) and not paclitaxel will be eligible for this study); 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
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
This is an open label safety study (an extension of KX-ORAX-002 and for other eligible patients after the dose of Oraxol has been confirmed in KX-ORAX-002) and all participants are treated with Oraxol.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Not applicable
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety
Statistical methods / analysis
Primary endpoints: 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 CRFs 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 (version 4.03 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 time-point. 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.
Secondary endpoints: Oraxol PK data from this study will be compared with Oraxol PK data from study KX-ORAX-002.
Using the PK samples collected at designated timepoints, a population PK analysis will be explored and then used to estimate individual AUCs or clearance (CL) of paclitaxel. The effect of patient factors on paclitaxel PK will be explored that may explain interpatient variability in PK parameters. Both inter- and intra-patient variability in paclitaxel AUC will also be assessed. Paclitaxel AUC, as well as Cmax, will then be tested for association changes with toxicity endpoints, such as neutropenia or incidence of neuropathy. If an observable trend exists among changes in any of these AEs, a PK/PD model will be developed to evaluate the exposure-response relationship between the time course of paclitaxel plasma exposure (eg, AUC, Cmax) in relation to changes in neutropenia and/or neuropathy. Demographic and clinical data (ie, ethnicity, age, BSA, ECOG status, etc.) will be utilized to assess inter-patient variability in the model.
For Group B, 8 subjects will be enrolled and the geometric mean ratio (GMR) will be calculated comparing the Cmax and AUC0-8 of the tablet and capsule formulations of paclitaxel following oral administration.
The results of other safety assessments (concomitant medications, vital signs, physical examinations, ECGs, and ECOG performance status) will also be evaluated.
Safety data will be summarized using descriptive statistics (eg, n, mean, SD, median, minimum, maximum for continuous variables; n [%] for categorical variables).
A sample size of 40 patients is based on practical considerations, participant safety, and the goal of assessing the safety and tolerability of Oraxol.

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] 10353 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 22024 0
3168 - Clayton
Recruitment outside Australia
Country [1] 6975 0
New Zealand
State/province [1] 6975 0
Auckland
Country [2] 7071 0
New Zealand
State/province [2] 7071 0
Wellington
Country [3] 7072 0
New Zealand
State/province [3] 7072 0
Canterbury
Country [4] 7073 0
New Zealand
State/province [4] 7073 0
Otago
Country [5] 20874 0
United Kingdom
State/province [5] 20874 0
Manchester
Country [6] 20998 0
Taiwan, Province Of China
State/province [6] 20998 0
Taiwan

Funding & Sponsors
Funding source category [1] 291463 0
Commercial sector/Industry
Name [1] 291463 0
Kinex Pharmaceuticals Inc
Address [1] 291463 0
20 Commerce Drive
Cranford
New Jersey 07016
Country [1] 291463 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] 290143 0
Commercial sector/Industry
Name [1] 290143 0
Zenith Technology Corporation Ltd.
Address [1] 290143 0
156 Frederick Street
Dunedin 9016
Country [1] 290143 0
New Zealand

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 293012 0
Southern Health and Disability Ethics Committee
Ethics committee address [1] 293012 0
C/- Ministry of Health
Freyberg Building
20 Aitken Street
PO Box 5013
Wellington
6011
Ethics committee country [1] 293012 0
New Zealand
Date submitted for ethics approval [1] 293012 0
08/06/2015
Approval date [1] 293012 0
24/06/2015
Ethics approval number [1] 293012 0
15/STH/88

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. Initially this study is intended as an extension study of KX-Orax-002 pharmacokinetic study for patients who wish to continue Oraxol treatment and who are eligible to participate. Once the dose of Oraxol has been confirmed in the KX-ORAX-002 study, then enrolment of patients who have not participated in the KX-ORAX-002 study will be allowed. The purpose of this study is to check the safety and tolerability of Oraxol when it is administered on a weekly basis and to confirm that the blood levels of paclitaxel after several doses of Oraxol are similar to the levels expected. Participants in Group B (N=8) will receive the same weekly paclitaxel capsule treatment as the remainder of the subjects except for 1 dosing week (at least 1 week following the paclitaxel capsule PK sampling period) during which they will receive paclitaxel tablets and undergo PK assessments.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 58078 0
Dr Christopher Jackson
Address 58078 0
Department of Oncology
Dunedin Hospital
Southern District Health Board
201 Great King Street
Dunedin 9016
Country 58078 0
New Zealand
Phone 58078 0
+64 3 474 0999 ext 9698
Fax 58078 0
Email 58078 0
Christopher.jackson@southerndhb.govt.nz
Contact person for public queries
Name 58079 0
Mrs Linda Folland
Address 58079 0
Zenith Technology Corporation, Ltd. 156 Frederick Street Dunedin 9016
Country 58079 0
New Zealand
Phone 58079 0
+643 477 9669
Fax 58079 0
Email 58079 0
Linda.Folland@Zenithtechnology.co.nz
Contact person for scientific queries
Name 58080 0
Dr E. Douglas Kramer
Address 58080 0
Kinex Pharmaceuticals, Inc. 20 Commerce Drive Cranford New Jersey
07016
Country 58080 0
United States of America
Phone 58080 0
+1 908-272-0628
Fax 58080 0
Email 58080 0
dkramer@kinexpharma.com

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