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

Metastatic Breast Cancer Clinical Trial

— Epi-PRIMED  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT03505528
• Other study ID #: EpiAxis 001-0716
• Status: Completed
• Phase: Phase 1
• Start date: August 17, 2017
• Est. completion date: October 30, 2019

Study information

• Verified date: July 2019
• Source: EpiAxis Therapeutics
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 8
• Est. completion date: October 30, 2019
• Est. primary completion date: October 30, 2019
• Accepts healthy volunteers: No
• Gender: Female
• Age group: 18 Years and older

Eligibility

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;

Related Conditions & MeSH terms

• Breast Neoplasms
• Metastatic Breast Cancer

Intervention

Drug:
• Nanoparticle albumin-bound paclitaxel
Abraxane is administered intravenous at a constant dose of 100mg/m2
• Phenelzine Sulfate
Nardil is administered orally from a starting dose of 15mg/d to a maximum of 90mg/d

Locations

Country	Name	City	State
Australia	Canberra Region Cancer Centre	Canberra	Australian Capital Territory
Australia	Liverpool Cancer Therapy Centre	Sydney	New South Wales
Australia	Southern Medical Day Care Centre	Wollongong	New South Wales

Sponsors (4)

Lead Sponsor	Collaborator
EpiAxis Therapeutics	Liverpool Cancer Therapy Centre, Southern Medical Day Care Centre, The Canberra Hospital

Country where clinical trial is conducted

Australia, 

References & Publications (2)

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. — View 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. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	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	Abraxane Cmax	To assess maximum plasma concentration (ng/ml) of nanoparticle albumin-bound paclitaxel alone and when combined with phenelzine sulfate.	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.
Secondary	Abraxane Tmax	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).	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.
Secondary	Abraxane Half-life	To assess the terminal half-life (minutes) of nanoparticle albumin-bound paclitaxel alone and when combined with phenelzine sulfate.	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.
Secondary	Abraxane AUC	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.	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.
Secondary	Nardil Cmax	To assess maximum plasma concentration (ng/ml) of phenelzine sulfate when combined with nanoparticle albumin-bound paclitaxel.	Cmax will be assessed on day 57.
Secondary	Nardil Tmax	To assess the time after ingestion of phenelzine sulfate, when combined with nanoparticle albumin-bound paclitaxel, to achieve peak maximum plasma concentration (minutes).	Tmax will be assessed on day 57.
Secondary	Nardil Half-life	To assess the terminal half-life (minutes) after ingestion of phenelzine sulfate, when combined with nanoparticle albumin-bound paclitaxel.	Half-life will be assessed on day 57.
Secondary	Nardil AUC	To assess the area under Phenelzine Sulfate concentration time curve from 0 to infinity (ng minutes / ml) when combined with nanoparticle albumin-bound paclitaxel.	AUC will be assessed on day 57.
Secondary	Circulating Tumour Cell (CTC) burden	The CTC burden is expressed as the number of tumour cells observed per 30ml of blood.	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.
Secondary	PDL1 expressing Circulating Tumour Cell (CTC) burden	The PDL1 expressing CTC burden is expressed as the number of CTC observed per 30ml of blood with PDL1 expression.	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.
Secondary	HER2 expressing Circulating Tumour Cell (CTC) burden	The HER2 expressing CTC burden is expressed as the number of CTC observed per 30ml of blood with PDL1 expression.	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.
Secondary	FFPE Tumour cells burden	The number of tumour cells observed per FFPE slide.	Then burden will be assessed at baseline and again at day 85.
Secondary	FFPE Stoma cells burden	The number of stoma cells observed per FFPE slide.	Then burden will be assessed at baseline and again at day 85.
Secondary	FFPE Cancer Stem Cells (CSC) burden	The number of CSC observed per FFPE slide.	Then burden will be assessed at baseline and again at day 85.

External Links

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