Clinical trial NCT03505528: An Early Phase Study of Abraxane Combined With Phenelzine Sulfate in Patients With Metastatic or Advanced Breast Cancer
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Breast Cancer
Keywords: Nanoparticle albumin-bound paclitaxel (Abraxane)
Phenelzine Sulfate
Cancer stem cells
epigenetics
LSD1
Lead sponsor: EpiAxis Therapeutics
Sponsor class: INDUSTRY
Collaborators: name: The Canberra Hospital
name: Southern Medical Day Care Centre
name: Liverpool Cancer Therapy Centre
First posted: 2018-04-23
Enrollment: 8
Sex: FEMALE
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Intervention model: SEQUENTIAL
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.
Primary purpose: TREATMENT

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.

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.

Eligibility 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;

Primary outcomes:
measure: Dose-Limiting Toxicity (DLT) events
timeFrame: Assessed throughout the first 56 days
Secondary outcomes:
measure: Abraxane Cmax
timeFrame: 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.
measure: Abraxane Tmax
timeFrame: 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.
measure: Abraxane Half-life
timeFrame: 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.
measure: Abraxane AUC
timeFrame: 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.
measure: Nardil Cmax
timeFrame: Cmax will be assessed on day 57.
measure: Nardil Tmax
timeFrame: Tmax will be assessed on day 57.
measure: Nardil Half-life
timeFrame: Half-life will be assessed on day 57.
measure: Nardil AUC
timeFrame: AUC will be assessed on day 57.
measure: Circulating Tumour Cell (CTC) burden
timeFrame: 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.
measure: PDL1 expressing Circulating Tumour Cell (CTC) burden
timeFrame: 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.
measure: HER2 expressing Circulating Tumour Cell (CTC) burden
timeFrame: 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.
measure: FFPE Tumour cells burden
timeFrame: Then burden will be assessed at baseline and again at day 85.
measure: FFPE Stoma cells burden
timeFrame: Then burden will be assessed at baseline and again at day 85.
measure: FFPE Cancer Stem Cells (CSC) burden
timeFrame: Then burden will be assessed at baseline and again at day 85.
Other outcomes:
Locations:
city: Canberra
country: Australia
facility: Canberra Region Cancer Centre
state: Australian Capital Territory
city: Sydney
country: Australia
facility: Liverpool Cancer Therapy Centre
state: New South Wales
city: Wollongong
country: Australia
facility: Southern Medical Day Care Centre
state: New South Wales
Study officials:
affiliation: ACT Health
name: Desmond Yip, MBBS
role: PRINCIPAL_INVESTIGATOR
affiliation: ACT Health
name: Laeeq Malik, MBBS
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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.
citation: 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.