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An Early Phase Study of Abraxane Combined With Phenelzine Sulfate in Patients With Metastatic or Advanced Breast Cancer (Epi-PRIMED)

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ClinicalTrials.gov Identifier: NCT03505528
Recruitment Status : Recruiting
First Posted : April 23, 2018
Last Update Posted : July 22, 2019
Sponsor:
Collaborators:
The Canberra Hospital
Southern Medical Day Care Centre
Liverpool Cancer Therapy Centre
Information provided by (Responsible Party):
EpiAxis Therapeutics

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.

Participants may be eligible to join this study if they are aged 18 years or above and have been diagnosed with metastatic breast cancer or inoperable locally advanced breast cancer.

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.


Condition or disease Intervention/treatment Phase
Metastatic Breast Cancer Drug: Nanoparticle albumin-bound paclitaxel Drug: Phenelzine Sulfate Phase 1

Detailed Description:

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.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 16 participants
Intervention Model: Sequential Assignment
Intervention Model Description:

An open, non-randomised, cumulative cohort group design (across 5 groups) with a target toxicity fraction of 30% and a margin of 10%. This means that a dose will be escalated between groups 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.

Masking: None (Open Label)
Primary Purpose: Treatment
Official 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
Actual Study Start Date : August 17, 2017
Estimated Primary Completion Date : December 20, 2019
Estimated Study Completion Date : April 24, 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Breast Cancer

Arm Intervention/treatment
Experimental: Cohort Group
There are five patient cohort groups. Each 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. In addition, all cohort groups will receive a constant dose of Abraxane at 100mg/m2.
Drug: Nanoparticle albumin-bound paclitaxel
Abraxane is administered intravenous at a constant dose of 100mg/m2
Other Name: Abraxane

Drug: Phenelzine Sulfate
Nardil is administered orally from a starting dose of 15mg/d to a maximum of 90mg/d
Other Name: Nardil




Primary Outcome Measures :
  1. Dose-Limiting Toxicity (DLT) events [ Time Frame: Assessed throughout the first 56 days ]

    The number of DLT events for nanoparticle albumin-bound paclitaxel and phenelzine sulfate combined, with the following events assessed using the NCI's CTCAE v4.3 toxicity criteria:

    • Grade 3 Febrile neutropenia;
    • Grade ≥2 peripheral neuropathy;
    • Any Grade 3 non-haematological toxicity except alopecia; nausea, vomiting, or diarrhoea for 72 hrs due to inadequate use of prophylaxis;
    • Grade 3 fatigue for > 7 days;
    • Non-hematologic Grade 3 or 4 laboratory AE that do not return to baseline or to Grade 1 within 7 days;
    • Grade 3 thrombocytopenia with signs of significant bleeding or platelet count Grade 4;
    • Blood bilirubin (total) Grade ≥3 for 72 hrs, AST or ALT Grade 3 for >7 consecutive days, AST or ALT Grade 4;
    • Persistent Grade 3 hypertension for >7 days & not responding to antihypertensive therapy or Grade 4 hypertension;
    • An inability to administer treatment (with >7 day delay) during Cycle 1 and Cycle 2 for toxicity reason; &
    • Any other treatment emergent SAE.


Secondary Outcome Measures :
  1. Abraxane Cmax [ Time Frame: Cmax 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. ]
    To assess maximum plasma concentration (ng/ml) of nanoparticle albumin-bound paclitaxel alone and when combined with phenelzine sulfate.

  2. Abraxane Tmax [ Time Frame: Tmax 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. ]
    To assess the time after infusion of nanoparticle albumin-bound paclitaxel alone and when combined with phenelzine sulfate to achieve peak maximum plasma concentration (minutes).

  3. Abraxane Half-life [ Time Frame: Half-life 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. ]
    To assess the terminal half-life (minutes) of nanoparticle albumin-bound paclitaxel alone and when combined with phenelzine sulfate.

  4. Abraxane AUC [ Time Frame: AUC 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. ]
    To assess the area under nanoparticle albumin-bound paclitaxel concentration time curve from 0 to infinity (ng minutes / ml) and when combined with phenelzine sulfate.

  5. Nardil Cmax [ Time Frame: Cmax will be assessed on day 57. ]
    To assess maximum plasma concentration (ng/ml) of phenelzine sulfate when combined with nanoparticle albumin-bound paclitaxel.

  6. Nardil Tmax [ Time Frame: Tmax will be assessed on day 57. ]
    To assess the time after ingestion of phenelzine sulfate, when combined with nanoparticle albumin-bound paclitaxel, to achieve peak maximum plasma concentration (minutes).

  7. Nardil Half-life [ Time Frame: Half-life will be assessed on day 57. ]
    To assess the terminal half-life (minutes) after ingestion of phenelzine sulfate, when combined with nanoparticle albumin-bound paclitaxel.

  8. Nardil AUC [ Time Frame: AUC will be assessed on day 57. ]
    To assess the area under Phenelzine Sulfate concentration time curve from 0 to infinity (ng minutes / ml) when combined with nanoparticle albumin-bound paclitaxel.

  9. Circulating Tumour Cell (CTC) burden [ Time Frame: CTC burden will assessed be at baseline and again at day 29, 57 and 85, whereas the CSC burden will assessed only at baseline and again at day 85. ]
    The CTC burden is expressed as the number of tumour cells observed per 30ml of blood.

  10. PDL1 expressing Circulating Tumour Cell (CTC) burden [ Time Frame: The PDL1 CTC expression burden will be assessed at baseline and again at day 29, 57 and 85, whereas the CSC burden will assessed only at baseline and again at day 85. ]
    The PDL1 expressing CTC burden is expressed as the number of CTC observed per 30ml of blood with PDL1 expression.

  11. HER2 expressing Circulating Tumour Cell (CTC) burden [ Time Frame: The HER2 CTC expression burden will be assessed at baseline and again at day 29, 57 and 85, whereas the CSC burden will assessed only at baseline and again at day 85. ]
    The HER2 expressing CTC burden is expressed as the number of CTC observed per 30ml of blood with PDL1 expression.

  12. FFPE Tumour cells burden [ Time Frame: Then burden will be assessed at baseline and again at day 85. ]
    The number of tumour cells observed per FFPE slide.

  13. FFPE Stoma cells burden [ Time Frame: Then burden will be assessed at baseline and again at day 85. ]
    The number of stoma cells observed per FFPE slide.

  14. FFPE Cancer Stem Cells (CSC) burden [ Time Frame: Then burden will be assessed at baseline and again at day 85. ]
    The number of CSC observed per FFPE slide.



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:   Female
Accepts Healthy Volunteers:   No
Criteria

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.

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;

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): NCT03505528


Contacts
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Contact: Jeremy S Chrisp, PhD +61 421 012 268 j.chrisp@epiaxistherapeutics.com
Contact: Sudha Rao, PhD +61 411 415 440 s.rao@epiaxitherapeutics.com

Locations
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Australia, Australian Capital Territory
Canberra Region Cancer Centre Recruiting
Canberra, Australian Capital Territory, Australia, 260
Contact: Olive Doig    +61 2 6244 3688    olive.doig@act.gov.au   
Principal Investigator: Desmond Yip, MBBS         
Principal Investigator: Laeeq Malik, MBBS         
Australia, New South Wales
Liverpool Cancer Therapy Centre Recruiting
Sydney, New South Wales, Australia, 2170
Contact: Jennifer Aung, MBBS    +61 2 8738 9163    Jennifer.Aung@health.nsw.gov.au   
Sub-Investigator: Eugene Moylan, MBBS         
Southern Medical Day Care Centre Recruiting
Wollongong, New South Wales, Australia, 2500
Contact: Sue Parker    +61 2 4228 6200    sueparker.smdcctrials@outlook.com.au   
Contact: Margaret Clingan    +61 2 4227 3733    margaret@smdcc.com.au   
Sub-Investigator: Philip Clingan, MBBS         
Sponsors and Collaborators
EpiAxis Therapeutics
The Canberra Hospital
Southern Medical Day Care Centre
Liverpool Cancer Therapy Centre
Investigators
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Principal Investigator: Desmond Yip, MBBS ACT Health
Principal Investigator: Laeeq Malik, MBBS ACT Health

Additional Information:
Publications:
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Responsible Party: EpiAxis Therapeutics
ClinicalTrials.gov Identifier: NCT03505528     History of Changes
Other Study ID Numbers: EpiAxis 001-0716
First Posted: April 23, 2018    Key Record Dates
Last Update Posted: July 22, 2019
Last Verified: July 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Plan Description: It is the sponsors intention to publish the aggregated study results after the completion of the study.

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: Yes

Keywords provided by EpiAxis Therapeutics:
Nanoparticle albumin-bound paclitaxel (Abraxane)
Phenelzine Sulfate
Cancer stem cells
epigenetics
LSD1

Additional relevant MeSH terms:
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Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Phenelzine
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action
Antidepressive Agents
Psychotropic Drugs
Monoamine Oxidase Inhibitors
Enzyme Inhibitors