An Early Phase Study of Abraxane Combined With Phenelzine Sulfate in Patients With Metastatic or Advanced Breast Cancer

NCT03505528 | Completed Phase 1 FDA Drug

• 1 other identifier: EpiAxis 001-0716
• Study Type: interventional
• Target: 8
• Locations: 1 country
• Sites: 3

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.

Conditions

Metastatic Breast Cancer

Keywords

Nanoparticle albumin-bound paclitaxel (Abraxane); Phenelzine Sulfate; Cancer stem cells; epigenetics; LSD1

Outcome Measures

Primary Outcomes (1)

• Dose-Limiting Toxicity (DLT) events

  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.

  Assessed throughout the first 56 days

Secondary Outcomes (14)

• Abraxane Cmax

  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.

• Abraxane Tmax

  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.

• Abraxane Half-life

  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.

• Abraxane AUC

  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.

• Nardil Cmax

  Cmax will be assessed on day 57.

Study Arms (1)

Cohort Group

EXPERIMENTAL

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; Drug: Phenelzine Sulfate

Interventions

Nanoparticle albumin-bound paclitaxel DRUG

Abraxane is administered intravenous at a constant dose of 100mg/m2

Also known as: Abraxane

Cohort Group

Phenelzine Sulfate DRUG

Nardil is administered orally from a starting dose of 15mg/d to a maximum of 90mg/d

Also known as: Nardil

Cohort Group

Eligibility Criteria

• Age: 18 Years+
• Sex: female
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients who are 18 years or older;
• Fluent in written and spoken English and in a position to provide written informed consent to participate;
• A patient who is in a position to attend a 12-week treatment regimen and end of study visit;
• 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;
• Women with metastatic breast cancer or inoperable locally advanced breast cancer who have not received any cytotoxic therapy in the last 3 weeks;
• 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);
• ECOG Performance Status 0 or 1; and
• 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.

You may not qualify if:

• A patient who has been diagnosed as having HER2-positive metastatic breast cancer;
• A concurrent condition that may limit the decision-making capabilities of the participant during the informed consent process;
• A previous positive diagnosis of Human Immunodeficiency Virus (HIV) and/or Hepatitis C Virus (HCV) and/or Hepatitis B Virus (HBV) infection;
• Women who are pregnant or lactating;
• 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;
• Current use of monoamine oxidase inhibitors (MOAI) or use of dextromethorphan
• 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;
• Previous use of nanoparticle albumin-bound paclitaxel;
• Known allergy to phenelzine sulfate or similar MOAI; and
• Known or suspected history of alcohol abuse;

Sponsors & Collaborators

• EpiAxis Therapeutics: lead
• The Canberra Hospital: collaborator
• Southern Medical Day Care Centre: collaborator
• Liverpool Cancer Therapy Centre: collaborator

Study Sites (3)

Canberra Region Cancer Centre

Canberra, Australian Capital Territory, 260, Australia

Location

Liverpool Cancer Therapy Centre

Sydney, New South Wales, 2170, Australia

Location

Southern Medical Day Care Centre

Wollongong, New South Wales, 2500, Australia

Location

Related Publications (3)

• Boulding T, McCuaig RD, Tan A, Hardy K, Wu F, Dunn J, Kalimutho M, Sutton CR, Forwood JK, Bert AG, Goodall GJ, Malik L, Yip D, Dahlstrom JE, Zafar A, Khanna KK, Rao S. LSD1 activation promotes inducible EMT programs and modulates the tumour microenvironment in breast cancer. Sci Rep. 2018 Jan 8;8(1):73. doi: 10.1038/s41598-017-17913-x.

  PMID: 29311580 BACKGROUND

• Tan AHY, Tu W, McCuaig R, Hardy K, Donovan T, Tsimbalyuk S, Forwood JK, Rao S. Lysine-Specific Histone Demethylase 1A Regulates Macrophage Polarization and Checkpoint Molecules in the Tumor Microenvironment of Triple-Negative Breast Cancer. Front Immunol. 2019 Jun 12;10:1351. doi: 10.3389/fimmu.2019.01351. eCollection 2019.

  PMID: 31249575 BACKGROUND

• Prasanna T, Malik L, McCuaig RD, Tu WJ, Wu F, Lim PS, Tan AHY, Dahlstrom JE, Clingan P, Moylan E, Chrisp J, Fuller D, Rao S, Yip D. A Phase 1 Proof of Concept Study Evaluating the Addition of an LSD1 Inhibitor to Nab-Paclitaxel in Advanced or Metastatic Breast Cancer (EPI-PRIMED). Front Oncol. 2022 Jun 3;12:862427. doi: 10.3389/fonc.2022.862427. eCollection 2022.

  PMID: 35719960 DERIVED

Related Links

• Sponsor's website

MeSH Terms

Conditions

Breast Neoplasms

Interventions

Taxes; Albumin-Bound Paclitaxel; Phenelzine

Condition Hierarchy (Ancestors)

Neoplasms by Site; Neoplasms; Breast Diseases; Skin Diseases; Skin and Connective Tissue Diseases

Intervention Hierarchy (Ancestors)

Economics; Health Care Economics and Organizations; Paclitaxel; Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Albumins; Proteins; Amino Acids, Peptides, and Proteins; Hydrazines

Study Officials

• Desmond Yip, MBBS

  ACT Health

  PRINCIPAL INVESTIGATOR

• Laeeq Malik, MBBS

  ACT Health

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: INDUSTRY
• Responsible Party: SPONSOR

Model Details: 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.

Study Record Dates

• First Submitted: March 4, 2018
• First Posted: April 23, 2018
• Study Start: August 17, 2017
• Primary Completion: October 30, 2019
• Study Completion: October 30, 2019
• Last Updated: November 13, 2019

Record last verified: 2019-07

Data Sharing

• IPD Sharing: Will not share

Locations

AU (3)