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

NCT03505528

Description:

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.

Related Conditions:
  • Breast Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: 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

Clinical Trial IDs

  • ORG STUDY ID: EpiAxis 001-0716
  • NCT ID: NCT03505528

Conditions

  • Metastatic Breast Cancer

Interventions

DrugSynonymsArms
Nanoparticle albumin-bound paclitaxelAbraxaneCohort Group
Phenelzine SulfateNardilCohort Group

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Cohort GroupExperimentalThere 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.
  • Nanoparticle albumin-bound paclitaxel
  • Phenelzine Sulfate

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;
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:Female
Healthy Volunteers:No

Primary Outcome Measures

Measure:Dose-Limiting Toxicity (DLT) events
Time Frame:Assessed throughout the first 56 days
Safety Issue:
Description: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

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

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:EpiAxis Therapeutics

Trial Keywords

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

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