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PAKT: AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer (PAKT)

This study is ongoing, but not recruiting participants.
Sponsor:
ClinicalTrials.gov Identifier:
NCT02423603
First Posted: April 22, 2015
Last Update Posted: August 30, 2017
The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
Collaborators:
AstraZeneca
Cancer Research UK
Information provided by (Responsible Party):
Queen Mary University of London
  Purpose

Normally, cells in human body divide in an orderly way. However in cancer cells, some important proteins, which help control cell growth, start to behave abnormally resulting in faster growth and multiplication. In this study, we are looking at a protein called AKT that helps the cancer cells to develop. Blocking the action of AKT with a drug like AZD5363 may slow down or stop the cancer growing. The development of AZD5363 is intended to provide a new treatment option for patients with cancer. The standard chemotherapy agent, Paclitaxel, is given to destroy cancer cells. AZD5363 may also make the cancer more sensitive to Paclitaxel and so make this agent more effective.

A gene called PIK3CA has an important relationship with AKT. In tumours where this gene has been altered, or said to have 'mutated', the response to AZD5363 may be better. PIK3CA mutations are found commonly in breast cancers, and we will test for the presence of these mutations in both blood and tumour tissue samples that we ask you to provide. This study will also look at the relationship between tumours with PIK3CA mutations and the effect of the treatment.


Condition Intervention Phase
Metastatic Breast Cancer Drug: Paclitaxel Drug: AZD5363 Drug: Placebo Phase 2

Study Type: Interventional
Study Design: Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: A Phase II, Double-blind, Randomised, Placebo-controlled Study of the AKT Inhibitor AZD5363 in Combination With Paclitaxel in Triple-Negative Advanced or Metastatic Breast Cancer (PAKT).

Resource links provided by NLM:


Further study details as provided by Queen Mary University of London:

Primary Outcome Measures:
  • Progression-free survival [ Time Frame: Date of randomisation to date of first tumour progression or death (this can range on average between 3 weeks and 32 weeks). ]
    Progression-free survival, defined as the time from the date of randomisation to the date of first documented tumour progression (using RECIST 1.1) or death from any cause, whichever occurs first.


Enrollment: 140
Study Start Date: May 2014
Estimated Study Completion Date: December 2018
Estimated Primary Completion Date: December 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Active Comparator: Paclitaxel + AZD5363

Patients receive Paclitaxel on Day 1, Day 8 and Day 15 plus AZD5363/Placebo on Days 2-5, Days 9-12, and Days 16-19.

Upon Paclitaxel withdrawal,

Patient receive AZD5363/Placebo on Days 2-5, Days 9-12, Days 16-19 and Days 23-27.

Drug: Paclitaxel
Patient receive Once a week for three weeks - with one week off treatment
Other Name: Taxol
Drug: AZD5363
Patients receive AZD5363/Placebo in an intermittent treatment schedule. Please see study arms for full information.
Placebo Comparator: Paclitaxel + Placebo

Patients receive Paclitaxel on Day 1, Day 8 and Day 15. plus AZD5363/Placebo on Days 2-5, Days 9-12, and Days 16-19.

Upon Paclitaxel withdrawal,

Patient receive AZD5363/Placebo on Days 2-5, Days 9-12, Days 16-19 and Days 23-27.

Drug: Paclitaxel
Patient receive Once a week for three weeks - with one week off treatment
Other Name: Taxol
Drug: Placebo
Patients receive AZD5363/Placebo in an intermittent treatment schedule. Please see study arms for full information.

Detailed Description:

The term triple-negative breast cancer (TNBC) is generally used to define tumours that do not express oestrogen receptors (ER), progesterone receptors (PR) and HER2 receptors. This subtype comprises 10-15% of all breast cancers.

TNBC has an aggressive clinical course, shares features with basal-like tumours, and has a poorer outcome compared with other subtypes. Clinically, TNBC's are a challenge to treat because there is no role for endocrine or HER2-directed therapy. Chemotherapy is effective, but neo-adjuvant studies have shown that despite initial chemo-sensitivity, TNBC's still had a worse outcome, particularly in women in whom a pathologically confirmed complete response was not achieved. Consequently, there is a clear need to develop specific treatment strategies for the subgroup of TNBC's both in the early and advanced disease setting.

AZD5363 is a potent, selective inhibitor of the kinase activity of the serine/threonine AKT/PKB (protein kinase B) that is being developed as a potential treatment for solid and haematological malignancies. AKT is part of the AGC family of kinases. Mammalian cells express three closely related AKT isoforms: AKT1 (PKBa), AKT2 (PKBß) and AKT3 (PKBgamma), all encoded by different genes.

This is a placebo-controlled, multi-centre, 2-arm randomised phase II trial of Paclitaxel + AZD5363 versus Paclitaxel + placebo in patients with triple-negative (ER-negative, PR-negative/unknown, HER2-negative) advanced or metastatic breast cancer.

Patients will be randomised into either of the Arms Paclitaxel + Placebo OR Paclitaxel + AZD5363.

Randomisation will be stratified by the following criteria:

  • Number of metastatic sites (<3, =3)
  • (Neo)Adjuvant chemotherapy (end of (neo)adjuvant chemotherapy =12 months ago, end of (neo)adjuvant chemotherapy >12 months or no prior (neo)adjuvant chemotherapy).
  Eligibility

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.


Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   Female
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  1. Written informed consent prior to admission to this study
  2. Women, age > 18 years
  3. Histologically confirmed breast cancer
  4. Metastatic or locally recurrent disease; locally recurrent disease must not be amenable to resection with curative intent (patients who are considered suitable for surgical or ablative techniques following potential down-staging with study treatment are not eligible)
  5. Patient must have

    • At least one lesion, not previously irradiated, that can be measured accurately at baseline as ≥ 10mm in the longest diameter (except lymph nodes which must have short axis ≥15mm) with CT, or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements, OR
    • lytic or mixed bone lesions in the absence of measurable disease as defined above; patients with sclerotic/osteoblastic bone lesions only in the absence of measurable disease are not eligible.
  6. Radiological or clinical evidence of recurrence or progression
  7. Triple-negative disease, defined as tumour cells being

    • Negative for ER with <1% of tumour cells positive for ER on IHC or IHC score of ≥2
    • Negative for PR with <1% of tumour cells positive for PR on IHC or IHC score of ≥2 or PR unknown
    • Negative for HER2 with 0, 1+ or 2+ intensity on IHC and no evidence of amplification on ISH
  8. Formalin fixed paraffin embedded tumour sample from the primary or recurrent cancer must be available for central testing
  9. Patients must be able to swallow and retain oral medication
  10. Haematologic and biochemical indices within protocol specified ranges
  11. ECOG performance status 0-2
  12. Non-childbearing potential. If patient is of childbearing potential, she must have a negative serum pregnancy test and agree to use adequate contraception
  13. Willing and able to provide written informed consent

Exclusion Criteria:

  1. Patients with confirm brain metastases or a history of primary central nervous system tumours or who have signs/symptoms attributable to brain metastases and have not been assessed with radiologic imaging to rule out the presence of brain metastases.
  2. Prior chemotherapy for metastatic breast cancer
  3. Radiotherapy with a wide field of radiation within 4 weeks before the first dose of study medication
  4. Prior treatment with PI3K inhibitors, AKT inhibitors or mTOR inhibitors
  5. Prior treatment with paclitaxel or docetaxel in the (neo)adjuvant setting within 12 months from inclusion into this study
  6. Pre-existing sensory or motor polyneuropathy ≥ Grade 2 according to CTCAE
  7. Malabsorption syndrome or other condition that would interfere with enteral absorption
  8. Clinically significant pulmonary dysfunction
  9. Prolongation defined as a QTc interval >470msecs or other significant abnormalities in rhythm, conduction or morphology of resting ECG including 2nd degree (Type II) or 3rd degree AV block or bradycardia (ventricular rate <50 beats/min)
  10. Any factors that increase risk of QTc prolongation or risk of arrythmic events
  11. Experience of any of the following procedures or conditions in the preceding 6 months: coronary artery bypass graft, angioplasty, vascular stent, myocardial infarction, angina pectoris, congestive heart failure NYHA Grade ≥2, or cardiac ejection fraction outside institutional range of normal or <50%
  12. Clinically significant abnormalities of glucose metabolism
  13. Patients with proteinuria or creatine >1.5xULN concurrent with creatinine clearance <50mL/min
  14. Exposure to potent inhibitors or inducers or substrates of CYP3A4 or substrates of CYP2D6 within 2 weeks before the first dose of study treatment
  15. Concurrent treatment with other experimental drugs or participation in another clinical trial with any investigational drug within 30 days prior to study entry
  16. Psychological, familial, sociological or geographical conditions that do not permit compliance with the study protocol.
  17. Detained persons or prisoners
  18. Pregnant or nursing women
  Contacts and Locations
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): NCT02423603


  Show 46 Study Locations
Sponsors and Collaborators
Queen Mary University of London
AstraZeneca
Cancer Research UK
Investigators
Study Chair: Peter Schmid Queen Mary University London
Principal Investigator: Nicholas Turner Royal Marsden Hospital NHS- Institute of Cancer Research
  More Information

Responsible Party: Queen Mary University of London
ClinicalTrials.gov Identifier: NCT02423603     History of Changes
Other Study ID Numbers: 009246QM
2013-001521-43 ( EudraCT Number )
First Submitted: July 11, 2014
First Posted: April 22, 2015
Last Update Posted: August 30, 2017
Last Verified: August 2017

Keywords provided by Queen Mary University of London:
Triple Negative Breast Cancer
Metastatic
AKT Inhibitor
Advanced
AZD5363
Paclitaxel
PAKT

Additional relevant MeSH terms:
Breast Neoplasms
Neoplasms by Site
Neoplasms
Breast Diseases
Skin Diseases
Paclitaxel
Albumin-Bound Paclitaxel
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action