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Trial registered on ANZCTR


Registration number
ACTRN12617000943347
Ethics application status
Approved
Date submitted
21/06/2017
Date registered
30/06/2017
Date last updated
8/11/2018
Date data sharing statement initially provided
8/11/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
An early phase study of Abraxane combined with Phenelzine Sulfate in patients with metastatic or advanced breast cancer
Scientific title
A Phase Ib Safety and Pharmacokinetics (PK)/ Pharmacodynamics (PD) Study to Determine the Dosage of Abraxane in Combination with Phenelzine Sulfate in Metastatic or Inoperable Locally Advanced Breast Cancer
Secondary ID [1] 292138 0
None
Universal Trial Number (UTN)
U1111-1197-5518
Trial acronym
Epi-PRIMED

EpiAxis Therapeutics' Prolonging Remission in Metastatic Disease
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Metastatic breast cancer 303566 0
Inoperable locally advanced breast cancer
303571 0
Condition category
Condition code
Cancer 302977 302977 0 0
Breast

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Nanoparticle albumin-bound paclitaxel (Abraxane) will be administered intravenously over 3 cycles at a fixed dosage of 100mg/m2 to each study participant. This dose will be administered weekly for the first 3 consecutive weeks, over the 4 week cycle, before commencing the second and third cycles.

In addition to the fixed dose of nanoparticle albumin-bound paclitaxel, all patients will receive a continuous daily oral dose of phenelzine sulfate across all three cycles,

Each of the five patient cohort groups will receive a progressively higher starting dose of phenelzine sulfate, consecutively. Cohort A will start at 15mg/day and will be increased to 30mg/d by week 2 and further increased to 45mg/d for week 3, which will be maintained throughout the study. Cohort B will start at 45mg/d and will be held constant throughout the Study. Similarly, Cohort C, D & E will start at 60, 75 and 90mg/d, respectively, and will also be held on this dose throughout the study. The decision to escalate the dose for the next cohort will be made on the basis of the number of dose limiting toxicity (DLT) events observed during the first 8 weeks in the preceding cohort group.

Phenelzine sulfate compliance will be monitored weekly based on drug tablet returns.


Intervention code [1] 298285 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 302440 0
To determine the safety of the therapeutic combination of nanoparticle albumin-bound paclitaxel and phenelzine sulfate. Safety will be assessed by an evaluation of all adverse events, concomitant illnesses and medications, physical exam findings, vital signs, clinical haematology reports, ECG results and CT imaging data.
Timepoint [1] 302440 0
Assessed weekly over the 3 cycles, with the first 56 consecutive dosing days representing the DLT window for dose escalation consideration.
Primary outcome [2] 302529 0
To determine the maximum tolerated dose (MTD) of the therapeutic combination of nanoparticle albumin-bound paclitaxel and phenelzine sulfate. This will be assessed in relation to the number of DLT events, using the National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) version 4.03.
Timepoint [2] 302529 0
Assessed weekly over the 3 cycles.
Secondary outcome [1] 336013 0
To assess the pharmacokinetic parameters of Cmax: Ctrough; Tmax; Ke; T1/2; AUCo-t; AUCt-8; and AUC0-8 for nanoparticle albumin-bound paclitaxel alone and later in combination with phenelzine sulfate.
Timepoint [1] 336013 0
The pharmacokinetics will be assessed on two separate occasions, The first is at day 1 and is for the effect of nanoparticle albumin-bound paclitaxel alone. The second is at day 57 and is for the combined effect with phenelzine sulfate.
Secondary outcome [2] 336014 0
To identify relationships between pharmacokinetic characteristics of the treatment and the circulating tumor cell (CTC) / cancer stem cell (CSC) burden. A flow cytometric method will be used to assess the CTC and CSC burden from a blood and solid tissue biopsy sample, respectively. This method will be deployed using a DepArray machine. The relationships will be assessed with nanoparticle albumin-bound paclitaxel alone and later in combination with phenelzine sulfate.
Timepoint [2] 336014 0
The pharmacokinetic relationships will be assessed on two separate occasions, The first is at day 1 and is for the effect of nanoparticle albumin-bound paclitaxel alone. The second is at day 57 and is for the combined effect with phenelzine sulfate.

In addition, the CTC and CSC burdens will be assessed on two further occasions, at day 29 and day 85, but not in relation to the pharmacokinetics of either drug.
Secondary outcome [3] 336015 0
To identify relationships between pharmacokinetic characteristics of the treatment and the composite expression of epithelial growth factor receptor (EGRF), cytokeratin and phosphorylated LSD1 with the CTC/CSC burden. Theses relationships will be assessed with nanoparticle albumin-bound paclitaxel alone and later in combination with phenelzine sulfate.
Timepoint [3] 336015 0
The pharmacokinetic relationships will be assessed on two separate occasions, The first is at day 1 and is for the effect of nanoparticle albumin-bound paclitaxel alone. The second is at day 57 and is for the combined effect with phenelzine sulfate.

In addition, EGRF, cytokeratin and phosphorylated LSD1 will be assessed on two further occasions, at day 29 and day 85, in relation to the CTC/ CSC burden, but not in relation to the pharmacokinetics of either drug.
Secondary outcome [4] 336315 0
To assess the pharmacodynamic parameters for the treatment, which will include change over the course of the study in the CTC/CSC burden; immune response parameters; LSD1 and PKC-theta gene and protein expression, and in T cell cytokine profiles. These changes will be assessed with nanoparticle albumin-bound paclitaxel alone and later in combination with phenelzine sulfate.
Timepoint [4] 336315 0
The pharmacodynamic parameters will be assessed on four separate occasions. The first is at day 1 and is for the effect of nanoparticle albumin-bound paclitaxel alone. The second, third and fourth assessments are at day 29, 57 and 85, respectively, and are for the combined effect with phenelzine sulfate.

Eligibility
Key inclusion criteria
1. Patients who are 18 years or older;
2. Fluent in written and spoken English and in a position to provide written informed consent to participate;
3. A patient who is in a position to attend a 12-week treatment regimen and end of study visit;
4. Metastatic Breast Cancer (MBC) or inoperable locally advanced breast cancer diagnosis based on pre-existing documented histopathology and medical imaging results, either Triple Negative Metastatic Breast Cancer (TNBC) or not;
5. Women with metastatic breast cancer or inoperable locally advanced breast cancer who have not received any cytotoxic therapy in the last 3 weeks;
6. Volunteers of child-bearing potential must have a negative serum pregnancy test (serum beta-human chorionic gonadotropin or ß-hCG) and have agreed to practice an effective, reliable contraceptive regimen for the duration of this clinical trial, such as an intrauterine device (IUD) or intrauterine system (IUS) with a failure rate of <1% stated on the product label or a male partner who is has been sterilised (vasectomy with documented azoospermia);
7. ECOG Performance Status 0 or 1; and
8. Adequate liver function as evidenced by bilirubin of <1.5 times upper limit of normal (ULN) and ALT/AST <2 times of ULN. However, AST and ALT of <5 times ULN if liver metastases are present
Minimum age
18 Years
Maximum age
No limit
Gender
Females
Can healthy volunteers participate?
No
Key exclusion criteria
1. A patient who has been diagnosed as having HER2-positive metastatic breast cancer;
2. A concurrent condition that may limit the decision-making capabilities of the participant during the informed consent process;
3. A previous positive diagnosis of Human Immunodeficiency Virus (HIV) and/or Hepatitis C Virus (HCV) and/or Hepatitis B Virus (HBV) infection;
4. Women who are pregnant or lactating;
5. Uncontrolled, untreated intra-cranial metastases. However, controlled intra-cranial metastases are allowed, i.e. stable patients with more than a month after the completion of whole brain radiotherapy and not currently on steroids or anticonvulsants;
6. Current use of monoamine oxidase inhibitors (MOAI) or use of dextromethorphan
7. Current use of CNS depressants such as selective serotonin re-uptake inhibitors as well as specific medication for pain management including pethidine, tramadol, dextromethorphan, fentanyl and/or methadone. This includes the concurrent use of any serotoninergic agents or buspirone hydrochloride during the week preceding phenelzine sulfate administration, the active study treatment phase and the washout period at the end of study. Serotoninergic drugs may include but are not limited to the following: dexfenfluramine, fluoxetine, fluvoxamine, paroxetine, sertraline, citalopram and venlafaxine;
8. Previous use of nanoparticle albumin-bound paclitaxel;
9. Known allergy to phenelzine sulfate or similar MOAI; and
10. Known or suspected history of alcohol abuse;

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)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Other
Other design features
Cumulative Cohort group design with a target toxicity fraction of 30% and a margin of 10%. This means that a dose will be escalated when the observed toxicity rate is < 20%, de-escalated when > 40% and maintained otherwise.

The toxicity fraction is the number of participants receiving that dose who experience a DLT.
Phase
Phase 1
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
In general, industry standards for phase I development or proof of concept/principle (PoC/PoP) research were applied, which suggested a sample size of between 10-20 participants assuming that there will be an attrition rate of between 10-15%.

All statistical analyses will be performed using data collected from the Intent-to-Treat population, which comprises all study participants who are allocated to treatment and receive at least one dose of the study medication.

All statistical calculations will be performed using a validated installation of the R language (Version 3.3.0).

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)
ACT,NSW
Recruitment hospital [1] 8380 0
The Canberra Hospital - Garran
Recruitment hospital [2] 10241 0
Southern Medical Day Care Centre - Wollongong
Recruitment hospital [3] 12376 0
Liverpool Hospital - Liverpool
Recruitment postcode(s) [1] 16448 0
2605 - Garran
Recruitment postcode(s) [2] 21906 0
2500 - Wollongong
Recruitment postcode(s) [3] 24641 0
2170 - Liverpool

Funding & Sponsors
Funding source category [1] 296676 0
Commercial sector/Industry
Name [1] 296676 0
EpiAxis Therapeutics Pty Ltd
Address [1] 296676 0
Building 1, Room 1D131, Kirinari Street, Bruce, ACT 2617
Country [1] 296676 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
EpiAxis Therapeutics Pty Ltd
Address
Building 1, Room 1D131, Kirinari Street, Bruce, ACT 2617
Country
Australia
Secondary sponsor category [1] 295635 0
None
Name [1] 295635 0
Address [1] 295635 0
Country [1] 295635 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 297902 0
The ACT Health Human Research Ethics Committee
Ethics committee address [1] 297902 0
PO Box 11, Woden, ACT 2606
Ethics committee country [1] 297902 0
Australia
Date submitted for ethics approval [1] 297902 0
09/10/2016
Approval date [1] 297902 0
03/03/2017
Ethics approval number [1] 297902 0
ETH.10.16.218

Summary
Brief summary
This phase 1b study will determine the safety and efficacy of combined treatment of Abraxane and phenelzine sulfate (Nardil) for metastatic or locally advanced breast cancer.

Who is it for?
You may be eligible to join this study if you are aged 18 years or above and have been diagnosed with metastatic breast cancer or inoperable locally advanced breast cancer.

Study details
All participants will receive a combination of intravenous Abraxane and an oral dose of phenelzine sulfate. Abraxane will be administered weekly for the first 3 weeks of a 4-week cycle for 3 consecutive cycles. Phenelzine sulfate will be taken daily for the duration of the 3 cycles. Five patient cohort groups will receive a progressively increasing dose of phenelzine sulfate. Safety and efficacy will be assessed weekly over the 3 cycles of treatment.

Although both drugs have been used in clinical care for more than a decade, they have not been intentionally combined together in a cancer therapy setting. This means that the combined effect of these two drugs has not been documented. This is being addressed in this study.
Trial website
www.epiaxistherapeutics.com
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 75414 0
Prof Desmond Yip
Address 75414 0
Clinical Director
Department of Medical Oncology
The Canberra Hospital
Yamba Drive
Garran
ACT 2606 Australia
Country 75414 0
Australia
Phone 75414 0
+61 420 946 624
Fax 75414 0
+61 2 6244 4266
Email 75414 0
Desmond.Yip@act.gov.au
Contact person for public queries
Name 75415 0
Dr Jeremy Chrisp
Address 75415 0
EpiAxis Therapeutics, c/- Building 1, Room 1D131, Kirinari Street, Bruce, ACT 2617
Country 75415 0
Australia
Phone 75415 0
+61 421 012 268
Fax 75415 0
Email 75415 0
j.chrisp@epiaxistherapeutics.com
Contact person for scientific queries
Name 75416 0
Prof Sudha Rao
Address 75416 0
EpiAxis Therapeutics, c/- Building 1, Room 1D131, Kirinari Street, Bruce, ACT 2617
Country 75416 0
Australia
Phone 75416 0
+61 411 415 440
Fax 75416 0
Email 75416 0
s.rao@epiaxistherapeutics.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Undecided
No/undecided IPD sharing reason/comment
This will need to be discussed with PI's
What supporting documents are/will be available?
No other documents available
Summary results
Not applicable