| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Locally advanced or metastatic estrogen receptor positive breast cancer |
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| E.1.1.1 | Medical condition in easily understood language |
| Breast cancer that is locally advanced or has spread to other parts of the body. |
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| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The amended primary objectives for parts A and B are to investigate the safety and tolerability of the combination of AZD2014 and palbociclib on a background of fulvestrant in patients with locally advanced/metastatic ER+ve breast cancer and to define the combination dose(s)/schedule(s) for further clinical evaluation. |
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| E.2.2 | Secondary objectives of the trial |
PART A: To assess the anti-tumour activity of the triplet by evaluation of tumour response (best objective response, objective response rate, clinical benefit rate and change in tumor size) using RECIST version 1.1
PART B: To assess anti-tumour activity and efficacy of the triplet by evaluation of PFS, tumour response (BOR, ORR, DoR, CBR PFS and change in tumor size) by RECIST version 1.1 & overall survival.
PART A: To characterise the single dose and multiple dose PK of AZD2014 and palbociclib administered as the triplet combination.
PART B: To characterise the multiple dose PK of AZD2014 and palbociclib administered as the triplet combination.
PARTS A & B: To obtain preliminary assessment of the triplet activity in tumour by evaluation of PD biomarker changes including pS6 & pAKT. |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed and dated written informed consent prior to any mandatory study specific procedures, sampling and analyses.
2. Signed and dated written informed consent for mandatory tumour biopsies. If the tumour is found not to be safely accessible the biopsies will not be taken. Accessible lesions are defined as those which are biopsiable and amenable to repeat biopsies, unless clinically contraindicated. In this case the patient will remain in the study and there will be no penalty or loss of benefit to the patient and they will not be excluded from other aspects of the study.
3. Postmenopausal women aged >= 18 years
4. Negative pregnancy test prior to dosing and willing to use a highly effective method of contraception for the duration of the study and for 90 days after the last dose of IP if they are under 50 unless they have medically confirmed irreversible premature ovarian failure, bilateral oophorectomy, bilateral salpinectomy, or complete or partial hysterectomy.
Highly effective methods of contraception are:
• Use of oral, injected or implanted hormonal methods of contraception which inhibit ovulation, either estrogen and progestogen containing intravaginal, transdermal) or only progesterone containing (oral, injectable, implantable)
• Placement of an intrauterine device (IUD or intrauterine system (IUS)
• True abstinence
•Bilateral tubal ligation
• Vasectomised partner
5. World Health Organisation/Eastern Cooperative Oncology Group (ECOG) performance status of patient is 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks.
6. Histologically or cytologically proven diagnosis of breast cancer with evidence of locally advanced or metastatic disease, not amenable to resection or radiation therapy with curative intent.
7. Documentation of estrogen receptor positive (ER+) breast cancer based on most recent tumour biopsy (unless bone-only disease).
8. Documented human epidermal growth factor receptor 2 negative (HER2-) tumor on most recent tumor biopsy.
9. Where regionally permitted, all patients must agree to provide if available a formalin-fixed paraffin embedded (FFPE) tissue biopsy sample taken at the time of presentation with recurrent or metastatic disease.
10. At least one lesion (measurable and/or non measurable) that can be accurately assessed at baseline with computerised tomography (CT) or magnetic resonance imaging (MRI) which is suitable for accurate repeated measurements.
11. Meet the following study part specific criteria related to previous therapy for breast cancer:
For Part A: Postmenopausal patient suitable for fulvestrant. Patient is allowed to have a maximum of 3 prior lines of chemotherapy. Previous treatment with CDK4/6 inhibitors is allowed
For Part B: Postmenopausal patient with locally advanced or metastatic ER+ve breast cancer and refractory to AIs defined as:
• Disease recurrence while on, or within 12 months of end of adjuvant treatment with letrozole, anastrozole, or exemestane, or
• Disease progression while on, or within one month of end of letrozole, anastrozole or exemestane treatment for locally advanced or metastatic breast cancer
- Letrozole or anastrozole do not have to be the last treatment prior to starting the treatment.
- Patients who received one prior chemotherapy line for advanced/metastatic breast cancer are allowed.
Previous treatment with fulvestrant (or letrozole) is allowed. Other prior anticancer therapy (e.g. tamoxifen) are also allowed.
For inclusion in the optional research component:
1. Genetic research: Provision of signed and dated written consent for genetic research sampling and analyses. If a patient declines to participate in genetic component of the study, there will be no penalty or loss of benefit to the patient. The patient will not be excluded from other aspects of the study described in this Clinical Study Protocol, so long as they consent to the main study.
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| E.4 | Principal exclusion criteria |
1. Prior chemotherapy, biological, radiation, or immunotherapy, androgens, thalidomide, other anticancer agents, investigational drug or corticosteroids <14 days. Patients who received prior radiotherapy to >= 25% of bone marrow are not eligible. Patients are not eligible if there are unresolved toxicities from prior therapy > CTCAE grade 1 with the exception of alopecia.
2. Exposure to potent or moderate inhibitors or inducers of CYP3A4/5, Pgp (MDR1) or BCRP within stated washout periods.
3. Exposure to sensitive or narrow therapeutic range substrates of drug transporters OATP1B1, OATP1B3, MATE1 and MATE2K within wash-out period (5 x elimination half-life).
4. Exposure to PPIs within wash-out period (5 x elimination half-life).
5. Previous AZD2014, AZD8055 or other dual mTORC1/2 inhibitor
- In Part B only: Prior treatment with CDK4/6, or everolimus or any PI3K-mTOR pathway
- In Part C only: Prior treatment with fulvestrant, or with everolimus, or any agent whose mechanism of action is to inhibit the PI3K-mTOR pathway.
6. Active uncontrolled or symptomatic CNS metastases, carcinomatous meningitis, or leptomeningeal disease. Patients with CNS metastases or cord compression are eligible if definitively treated and clinically stable and off anticonvulsants & steroids for >4 weeks. Patients are not eligible if there is spinal cord compression and/or brain metastases, unless asymptomatic or treated and stable and off steroids for at >4 weeks.
7. Evidence of severe or uncontrolled systemic diseases such as: Severe hepatic impairment; interstitial lung disease (bilateral, diffuse, parenchymal lung disease); current unstable or uncompensated respiratory or cardiac conditions; uncontrolled hypertension; active bleeding diatheses; any active infection.
8. Other malignancy within 3 years, except adequately treated basal cell or squamous cell skin cancer, or carcinoma in situ of the cervix.
9. Experienced any of the following currently or in the last 12 months:
Coronary/peripheral artery bypass graft; angioplasty; vascular stent; myocardial infarction; angina pectoris; congestive heart failure NYHA Grade ≥2; ventricular arrhythmias requiring continuous therapy; supraventricular arrhythmias including atrial fibrillation of any grade; symptomatic pulmonary embolism; haemorrhagic or thrombotic stroke.
10. Abnormal ECHO or MUGA at baseline (LVEF <50%).
11. Mean resting QTc >470 msec, family or personal history of long or short QT syndrome, Brugada syndrome or known history of QTc prolongation or Torsade de Pointes within 12 months.
12. Clinically important abnormalities in rhythm, conduction or morphology of resting ECG.
13. Hepatitis B (HBV), Hepatitis C (HCV) or Human Immunodeficiency virus (HIV).
14. Concomitant medications known to predispose to Torsade de Pointes, or factors that increase the risk of QT prolongation or risk of arrhythmic events such as: Heart failure; hypokalaemia; congenital long QT syndrome; family history of long QT syndrome; family history of unexplained sudden death under 40 years-of-age.
15. Inadequate bone marrow reserve or organ function as demonstrated by: ANC <1.5 x 10^9/L
• In Part A only - Cohorts of patients with specific baseline ANC range to be enrolled defined as follows: I) Low ANC patients: >= 1.5 x 10^9/L < 3.0 x 10^9/L; ii) High ANC patients >= 3.0 x 10^9/L
• Platelets <100 x 10^9/L
• Haemoglobin <90 g/L
• ALT >2.5 x ULN or > 5 x ULN in the presence of liver mets
• AST >2.5 x ULN or > 5 x ULN in the presence of liver mets
• Total bilirubin >1.5 x ULN. Total bilirubin >3 x ULN in patients with documented Gilbert's Syndrome
• Serum creatinine >1.5 x ULN concurrent with creatinine clearance ≤50 mL/min
16. Pre-existing renal disease including glomerulonephritis, nephritic syndrome, Fanconi Syndrome or Renal tubular acidosis.
17. Refractory nausea/vomiting, chronic GI diseases, inability to swallow product or previous significant bowel resection.
18. Hypersensitivity to excipients of AZD2014, Palbociclib or Fulvestrant or drugs with a similar structure.
19. Diabetes Type I or uncontrolled Type II, as defined in WHO 2006 (fasting serum glucose of > 7.0 mmol/L [126 mg/dL]).
20. Patient with advanced/metastatic, symptomatic, visceral spread, that are at risk of life-threatening complications in the short term including patients with massive uncontrolled effusions (pleural, pericardial, peritoneal), pulmonary lymphangitis, and over 50% of liver involvement in metastases
21. Prior hematopoietic stem cell or bone marrow transplant
22. Regular coumadin therapy. Low-molecular-weight heparin therapy or oral Factor Xa antagonists are allowed.
23. Known abnormalities in coagulation e.g. bleeding diathesis.
24. Hematopoietic growth factors (erythropoietin, granulocyte colony stimulating factor [G-CSF], granulocyte macrophage colony stimulating factor [GM-CSF]) < 2 weeks prior. Primary prophylactic use of G-CSF is not permitted. |
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| E.5 End points |
| E.5.1 | Primary end point(s) |
1. Primary Endpoints for Parts A and B: The incidence of Dose Limiting Toxicities (DLTs), and the occurrence of adverse events, and changes in vital signs, clinical chemistry and haematology, coagulation parameters, and ECGs.
2. Primary Endpoint for Part C: Progression Free Survival (PFS) according to RECIST v 1.1. |
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
1. AEs/vitals every visit until 28 days after last AZD2014/Palbo dose. SAEs until 250 days after last Fulvestrant dose. Blood collected Day 1, (2), 8, 15, 22 in Cycles 1 and 2; Day 1 and 15 of Cycles 3 and 4; Day 1 of each cycle thereafter to assess changes in clinical chemistry, haematology, coagulation, 12-lead ECGs on Days 1, 8, 15 (or other specified day), 22 of Cycle 1 and Day 1 of each Cycle thereafter.
2. Assessed at baseline and Day 1 Cycle 3 and every 8 weeks until objective progression |
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| E.5.2 | Secondary end point(s) |
1. Part A: Anti-tumour activity of the triplet according to investigator assessment of BOR, ORR, CBR, and percentage change in tumour size.
2. Part B: Anti-tumour activity and efficacy of the triplet according to RECIST v1.1 by investigator assessment of BOR, ORR, DoR, CBR, percentage change in tumour size, and PFS and OS.
3. Parts A: Plasma AZD2014 and palbociclib single dose concentrations and derived PK parameters
4. Parts A and B: Plasma AZD2014 and palbociclib multiple dose concentrations and derived PK parameters
5. Parts A and B: Evaluation of pharmacodynamic biomarker changes including pS6 and pAKT by determining percentage change from baseline in H score. |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Every 8 wks
2. Every 8 wks. CBR will be assessed at 24 weeks. Survival will be assessed every 12 wks.
3. Samples for single-dose PK will be collected at prespecified times on PK days for AZD2014 and palbociclib.
4. Samples for multiple-dose PK will be collected at prespecified times on PK days for AZD2014 and palbociclib at steady state.
5. Biomarker analysis will be done every 4 weeks. |
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| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Parts A and B are open-label and non-controlled. |
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| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| United Kingdom |
| United States |
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| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
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