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A Phase III, Double-Blind, Randomised Study to Assess the Efficacy and Safety of AZD9291 versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First-Line Treatment in Patients with Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung CancerD5160C00007

PHRR150319-000990

D5160C00007

2014-CT0267

A Phase III, Double-Blind, Randomised Study to Assess the Efficacy and Safety of AZD9291 versus a Standard of Care Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitor as First-Line Treatment in Patients with Epidermal Growth Factor Receptor Mutation Positive, Locally Advanced or Metastatic Non-Small Cell Lung CancerD5160C00007

This is a Phase III, double-blind, randomised study assessing the efficacy and safety of AZD9291 (80 mg orally, once daily) versus a standard of care (SoC) Epidermal Growth Factor Receptor (EGFR)
Tyrosine Kinase Inhibitor (TKI) (either gefitinib [250 mg orally, once daily] or erlotinib [150 mg orally, once daily]) in patients with locally advanced or metastatic EGFR sensitising mutation (EGFRm+) Non-small Cell Lung Cancer (NSCLC) who are treatment-naïve and eligible for first-line treatment with an EGFR-TKI.

Regime Classification Priority
2010 - 2016 Health Technology Development Drug Discovery and Development
Start Date Duration in Months Target Completion Date Actual Completion Date
2015-03-15 36 2018-03-15 2019-12-12

Completed

Institution Classification Region LTO #
AstraZeneca AB Private Business Sweden N/A
Institution Classification Region LTO #
PAREXEL Clinical Research (Philippines) Ltd. Corp. Private Business NCR CDRR-NCR-CRO-4
Institution Region
AstraZeneca AB Sweden
Name E-Mail Institution and Institution Address
Wylenn Ferrer Wylenn.Ferrer@PAREXEL.com 15th Floor Philamlife Tower, 8767 Paseo de Roxas, Makati City
Name E-Mail Institution and Institution Address
Maaliddin Biruar Maaliddin.Biruar@parexel.com 15th Floor Philamlife Tower, 8767 Paseo de Roxas, Makati City
Name Expertise Affiliation
Guia Elena Imelda R. Ladrera, MD Principal Investigator Lung Center of the Philippines
Jemela Anne Osorio-Sanchez, MD Principal Investigator Perpetual Succour Hospital
Marie Cherry Lynn Samson-Fernando, MD Principal Investigator Manila Doctors Hospital
Project Location Institutional Ethics Review Board
Lung Center of the Philippines Lung Center of the Philippines Ethics Review Committee
Perpetual Succour Hospital Perpetual Succour Hospital Institutional Ethics and Review Board
Manila Doctors Hospital Manila Doctors Hospital Institutional Review Board

Non-Small Cell Lung Cancer

To assess the efficacy of single agent AZD9291 compared with SoC EGFR-TKI therapy as measured by progression free survival (PFS).

To assess the efficacy of AZD9291 compared with SoC EGFR-TKI therapy by assessment of PFS in patients with:
- Positive (or negative) pre-treatment T790M (amino acid substitution at position 790 in EGFR, from a threonine to a methionine) mutation.
- EGFR Ex19del or L858R mutation.
- EGFRm+ Ex19del or L858R detectable in plasma-derived circulating tumour deoxyribonucleic acid (ctDNA).
To further assess the efficacy of AZD9291 compared with SoC EGFR-TKI therapy.
To further assess the efficacy of AZD9291 compared with SoC EGFR-TKI therapy.
To characterise the pharmacokinetics (PK) of AZD9291 and its metabolites (AZ5104 and AZ7550).
To assess the impact of AZD9291 compared to SoC EGFR-TKI therapy on patients’ disease-related symptoms and Health Related
Quality of Life (HRQoL).
To assess patient satisfaction with treatment when receiving AZD9291 compared with SoC EGFR-TKI therapy.

Completed

  • Australia
  • Belgium
  • Brazil
  • Bulgaria
  • Canada
  • China
  • Czech Republic
  • France
  • Germany
  • Hong Kong
  • Hungary
  • Israel
  • Italy
  • Japan
  • Philippines
  • Poland
  • Romania
  • Russia
  • South Korea
  • Spain
  • Sweden
  • Taiwan
  • Thailand
  • United Kingdom
  • United States

Clinical Trial

D5160C00007

20141016151740 and 20150105154013

2015-01-29

0000-00-00

30

9

Unspecified

15 Mar 2015

Each patient should meet all of the inclusion criteria and none of the exclusion criteria for this study. Under no circumstances can there be exceptions to this rule.
Inclusion criteria
For inclusion in the study, patients must fulfil all of the following criteria:
1. Provision of informed consent prior to any study specific procedures, sampling, and analyses.
2. Male or female, aged at least 18 years. Patients from Japan aged at least 20 years.
3. Pathologically confirmed adenocarcinoma of the lung (e.g., this may occur as systemic recurrence after prior surgery  for early stage disease or patients may be newly diagnosed with Stage IIIB/IV disease). Patients with mixed histology are eligible if adenocarcinoma is the predominant histology.
4. Locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.
5. The tumour harbours one of the 2 common EGFR mutations known to be associated with EGFR-TKI sensitivity (Ex19del, L858R), either alone or in combination with other EGFR mutations, assessed by a CLIA-certified (USA sites) or an accredited (outside of the USA) local laboratory or by central testing.
6. Mandatory provision of an unstained, archived tumour tissue sample in a quantity sufficient to allow for central analysis of EGFR mutation status. Please refer to the Laboratory Manual for details.
7. Patients must be treatment- naïve for advanced NSCLC and eligible to receive first-line treatment with gefitinib or erlotinib as selected by the participating centre.
8. World Health Organization Performance Status of 0 to 1 with no clinically significant deterioration over the previous 2 weeks and a minimum life expectancy of 12 weeks.
9. At least one lesion, not previously irradiated and not chosen for biopsy during the study Screening period, that can be accurately measured at baseline as =10 mm in the longest diameter (except lymph nodes which must have a short axis of =15 mm) with computerised tomography (CT) or magnetic resonance imaging (MRI), and which is suitable for accurate repeated measurements.
10. Female patients should be using adequate contraceptive measures, should not be breast feeding, and must have a
negative pregnancy test prior to first dose of study drug; or female patients must have an evidence of non-child-bearing potential by fulfilling one of the following criteria at screening:
• Post-menopausal defined as aged more than 50 years and amenorrheic for at least 12 months following cessation of all
exogenous hormonal treatments.
• Women under 50 years old would be consider postmenopausal if they have been amenorrheic for 12 months or more following
cessation of exogenous hormonal treatments and with luteinizing hormone (LH) and follicle-stimulating hormone (FSH) levels in the post-menopausal range for the institution.
• Documentation of irreversible surgical sterilisation by hysterectomy, bilateral oophorectomy, or bilateral salpingectomy but not tubal ligation.
11. Male patients should be willing to use barrier contraception, i.e., condoms.
12. For inclusion in the optional genetics research study, patients must provide informed consent for genetic research. If a patient declines to participate in any voluntary exploratory research and/or genetic component of the study, there will be no penalty or loss of benefit to the patient and he/she will not be excluded from other aspects of the study.

Exclusion criteria
Patients must not enter the study if any of the following exclusion criteria are fulfilled:
1. Involvement in the planning and/or conduct of the study (applies to both AstraZeneca staff and/or staff at the study site).
2. Treatment with any of the following:
• Prior treatment with any systemic anti-cancer therapy for advanced NSCLC including standard chemotherapy, biologic therapy, immunotherapy, or any investigational drug.
• Prior treatment with an EGFR-TKI.
• Major surgery (excluding placement of vascular access) within 4 weeks of the first dose of study drug.
• Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug.
• Patients currently receiving (or unable to stop use at least 1 week prior to receiving the first dose of study drug)  medications or herbal supplements known to be potent inhibitors or inducers of cytochrome P450 (CYP) 3A4 (Appendix B).
• Treatment with an investigational drug within five half-lives of the compound or any of its related material, if known.
3. Any concurrent and/or other active malignancy that has required systemic treatment within 2 years of first dose of study drug.
4. Any unresolved toxicities from prior systemic therapy (e.g., adjuvant chemotherapy) greater than CTCAE grade 1 at the
time of starting study drug with the exception of alopecia and grade 2, prior platinum-therapy related neuropathy.
5. Spinal cord compression, symptomatic and unstable brain metastases, requiring steroids over the last 4 weeks prior to
randomisation in this study (asymptomatic or symptomatic brain metastases stable for at least 4 weeks and off steroids are allowed).
6. Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the Investigator’s opinion makes it undesirable for the patient to participate in the trial or which would jeopardise compliance with the protocol; or active infection including hepatitis B, hepatitis C and human immunodeficiency virus (HIV). Screening for chronic conditions is not required.
7. Refractory nausea and vomiting, chronic gastrointestinal diseases, inability to swallow the formulated product, or previous significant bowel resection that would preclude adequate absorption of AZD9291.
8. Any of the following cardiac criteria:
• Mean resting corrected QT interval (QTc) >470 msec, obtained from 3 ECGs, using the screening clinic ECG machine-derived QTc value.
• Any clinically important abnormalities in rhythm, conduction, or morphology of resting ECG, e.g., complete left bundle branch block, third-degree heart block, second-degree heart block, PR interval >250 msec.
• Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, congenital long QT syndrome, family history of long QT syndrome, or unexplained sudden death under 40 years of age in first-degree relatives or any concomitant medication known to prolong the QT interval.
9. Past medical history of ILD, drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
10. Inadequate bone marrow reserve or organ function as demonstrated by any of the following laboratory values.
• Absolute neutrophil count • Platelet count • Haemoglobin • Alanine aminotransferase (ALT) >2.5x the upper limit of normal (ULN) if no demonstrable liver metastases or >5xULN in the presence of liver metastases.
• Aspartate aminotransferase (AST) >2.5xULN if no demonstrable liver metastases or >5xULN in the presence of liver metastases.
• Total bilirubin >1.5xULN if no liver metastases or >3xULN in the presence of documented Gilbert’s Syndrome (unconjugated hyperbilirubinaemia) or liver metastases.
• Creatinine >1.5xULN concurrent with creatinine clearance 1.5xULN.
11. Women who are breast feeding.
12. History of hypersensitivity to active or inactive excipients of AZD9291 or drugs with a similar chemical structure or class to AZD9291.
13. Judgment by the Investigator that the patient should not participate in the study if the patient is unlikely to comply with study procedures, restrictions, and requirements.
14. In addition, the following are considered criteria for exclusion from the exploratory genetic research:
• Prior allogeneic bone marrow transplant.
• Non-leukocyte depleted whole blood transfusion within 120 days of genetic sample collection.

Interventional

AZD9291

AZD9291 is an oral, potent, selective, irreversible inhibitor of both EGFR-TKI sensitising and resistance mutations in NSCLC with a significant selectivity margin over wild-type EGFR. AZD9291 (80 mg orally, once daily) or matching placebo, in accordance with the randomisation schedule, will be administered. A cycle of treatment is defined as 21 days of once daily AZD9291 treatment.

Date Amendment Classification Reason
2015-11-02 Amendments related to the protocol Statistical analysis
2015-07-09 Amendments related to the protocol Informed consent
2016-06-07 Amendments related to the protocol

Randomized

Double Blind

This is a Phase III, double-blind, randomised study to assess the efficacy and safety of AZD9291 (80 mg orally, once daily) versus SoC, EGFR-TKI (either gefitinib [250 mg orally, once daily] or erlotinib [150 mg orally, once daily]), as first-line treatment in patients with locally or centrally confirmed EGFRm+, locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.

Unspecified

To assess the efficacy and safety of AZD9291 (80 mg orally, once daily) versus SoC, EGFR-TKI (either gefitinib [250 mg orally, once daily] or erlotinib [150 mg orally, once daily]), as first-line treatment in patients with locally or centrally confirmed EGFRm+, locally advanced or metastatic NSCLC, not amenable to curative surgery or radiotherapy.

Phase III

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