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AZD9291 in Combination With Ascending Doses of Novel Therapeutics

This study is currently recruiting participants. (see Contacts and Locations)
Verified April 2017 by AstraZeneca
Sponsor:
Information provided by (Responsible Party):
AstraZeneca
ClinicalTrials.gov Identifier:
NCT02143466
First received: May 9, 2014
Last updated: April 25, 2017
Last verified: April 2017
  Purpose
The purpose of this study is to determine the safety, tolerability and preliminary anti-tumour activity of AZD9291 when given together with AZD6094 or selumetinib in patients with EGFR mutation positive advanced lung cancer.

Condition Intervention Phase
Advanced Non Small Cell Lung Cancer
Drug: Part A - AZD9291 in combination with AZD6094
Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)
Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)
Drug: Part A - AZD9291 in combination with intermittent selumetinib
Drug: Part A - AZD9291 in combination with MEDI4736
Drug: Part B - AZD9291 in combination with AZD6094
Drug: Part B - AZD9291 in combination with selumetinib
Drug: Part B - AZD9291 in combination with MEDI4736
Drug: Part C - AZD6094 monotherapy (Japan only)
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: No masking
Primary Purpose: Treatment
Official Title: A Multi-arm, Phase Ib, Open-Label, Multicentre Study to Assess the Safety,Tolerability, Pharmacokinetics and Preliminary Anti-tumour Activity of AZD9291 in Combination With Ascending Doses of Novel Therapeutics in Patients With EGFRm+ Advanced NSCLC Who Have Progressed Following Therapy With an EGFR TKI (TATTON).

Resource links provided by NLM:


Further study details as provided by AstraZeneca:

Primary Outcome Measures:
  • Number of participants with Adverse Events and/or Dose Limiting Toxicities as a Measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib [ Time Frame: Adverse events will be collected from baseline until 28 days after the last dose in the AZD6094 or selumetinib arms. ]
    Part A: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib who have progressed following prior therapy with an EGFR TKI agent, and define the combination dose(s) for further clinical evaluation.

  • Number of participants with Adverse Events as a measure of Safety and Tolerability of AZD9291 when given in combination with AZD6094 or selumetinib [ Time Frame: Adverse events: baseline until 28 days after the last dose in the AZD6094 or selumetinib arms. ]
    Part B: To investigate the safety and tolerability of AZD9291 when given in combination with AZD6094 or selumetinib in patients with locally advanced or metastatic NSCLC, who have progressed on prior therapy with an EGFR TKI agent.


Secondary Outcome Measures:
  • Cmax after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Tmax after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • AUC after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • AUC0-t after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • AUC0-24 after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Terminal half life after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • CL/f after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Volume of distribution after single dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Cssmax after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Tssmax after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Cssmin after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times for the duration of treatment. ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • AUCss after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • CLss/f after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 2 day 1 up to 24 hours ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Rac after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1 ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Time dependency of PK after multiple dosing [ Time Frame: Blood samples will be collected from each subject at pre-specified times on cycle 1 day 1 and cycle 2 day 1 ]
    To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when given orally to patients with EGFRm+ NSCLC in combination with AZD9291, AZD6094 or selumetinib through plasma concentrations.

  • Objective response rate [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]
    To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

  • Disease control rate [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]
    To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

  • Duration of response [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]
    To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

  • Percentage change in tumour size [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]
    To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1

  • Progression free survival [ Time Frame: At baseline and every 6 weeks until disease progression or withdrawal from study. ]
    To obtain a preliminary assessment of the anti-tumour activity of the combination of AZD9291 and AZD6094 or selumetinib by evaluation of tumour response (objective response rate, duration of response, change in tumour size) and progression free survival using RECIST version 1.1 Expansion phase only


Estimated Enrollment: 298
Actual Study Start Date: August 5, 2014
Estimated Study Completion Date: December 28, 2018
Estimated Primary Completion Date: December 28, 2018 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: AZD6094
AZD9291 in combination with AZD6094
Drug: Part A - AZD9291 in combination with AZD6094
Part A - AZD9291 and AZD6094 administered in different doses to investigate the safety and tolerability of this combination and define the combination dose for further clinical evaluation in Part B.
Other Name: Osimertinib & Savolitinib/Volitinib
Drug: Part B - AZD9291 in combination with AZD6094
Part B - AZD9291 and AZD6094 administered in the dose identified in Part A (AZD9291 80mg OD + AZD6094 600mg OD) to further investigate the safety and tolerability of this combination.
Other Name: Osimertinib & Savolitinib/Volitinib
Experimental: Selumetinib
AZD9291 in combination with selumetinib
Drug: Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)
Part A - AZD9291 and selumetinib (continuous treatment) administered in different doses to investigate the safety and tolerability of this combination in Asian subjects and to define the combination dose for further clinical evaluation in Part B.
Other Name: Osimertinib & ARRY-142886
Drug: Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)
Part A - AZD9291 and selumetinib (continuous treatment) administered in different doses to investigate the safety and tolerability of this combination in non-Asian subjects and to define the combination dose for further clinical evaluation in Part B.
Other Name: Osimertinib & ARRY-142886
Drug: Part A - AZD9291 in combination with intermittent selumetinib
Part A - AZD9291 and selumetinib (intermittent treatment) administered in different doses to investigate the safety and tolerability of this combination and to define the combination dose for further clinical evaluation in Part B.
Other Name: Osimertinib & ARRY-142886
Drug: Part B - AZD9291 in combination with selumetinib
Part B - AZD9291 and selumetinib administered in the dose identified in Part A (AZD9291 80mg OD + selumetinib 75 mg BD intermittent [4 days on/3 days off]) to further investigate the safety and tolerability of this combination.
Other Name: Osimertinib & ARRY-142886
Experimental: MEDI4736
AZD9291 in combination with MEDI4736 (no patients still receiving this combination in this study due to an increased incidence of ILD-like events).
Drug: Part A - AZD9291 in combination with MEDI4736

Part A - AZD9291 and MEDI4736 administered in different doses to investigate the safety and tolerability of this combination and to define the combination dose for further clinical evaluation in Part B.

Note: combination terminated and no longer being evaluated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis).

Other Name: Osimertinib & Durvalumab
Drug: Part B - AZD9291 in combination with MEDI4736

Part A - AZD9291 and MEDI4736 administered in the dose identified in Part A to further investigate the safety and tolerability of this combination.

Note: combination terminated and no longer being evaluated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis).

Other Name: Osimertinib & Durvalumab
Experimental: AZD6094 (monotherapy)
AZD6094 in monotherapy (for Japan only)
Drug: Part C - AZD6094 monotherapy (Japan only)
Part C - AZD6094 monotherapy to assess the safety, tolerability and pharmacokinetics of the monotherapy of AZD6094 in Japanese patients with advanced NSCLC with the purpose of conducting further dose expansion (Part B) in Japan.
Other Name: Savolitinib/Volitinib

Detailed Description:

This is a Phase Ib, open-label, multicentre study of AZD9291 administered orally in combination with novel therapeutics (AZD6094 or selumetinib (AZD6244, ARRY142886)) to patients with EGFRm+ advanced NSCLC. The study has been designed to allow an investigation of the optimal combination dose and schedule whilst ensuring the safety of patients with intensive safety monitoring. There are two parts to this study. Part A, Combination dose finding and Part B, Dose expansion.

AZD9291 (osimertinib) is a potent irreversible inhibitor of both the single epidermal growth factor receptor sensitising mutation positive (EGFRm+) (tyrosine kinase inhibitor [TKI] sensitivity-conferring mutation) and dual EGFRm+/T790M+ (TKI resistance-conferring mutation) receptor forms of EGFR. AZD9291 therefore has the potential to provide clinical benefit to patients with advanced non-small cell lung cancer (NSCLC) harbouring both the single sensitivity mutations and the resistance mutation following prior therapy with an EGFR TKI. AZD9291 (osimertinib) was awarded FDA accelerated approval in November 2015, followed by conditional approval in the EU, full approval in Japan and additional markets in 2016, for the treatment of patients with EGFR T790M+ NSCLC who have progressed on or after EGFR TKI therapy.

Enrolment into the patient cohort that evaluated AZD9291 treatment in combination with MEDI4736 as 1st line treatment has been terminated due to an increased incidence of ILD-like events (interstitial lung disease/pneumonitis), and is no longer being evaluated in this study.

The combination dose of AZD9291 + AZD6094 has not been conducted in Japan since there were no clinical data about Japanese patients who took AZD6094 monotherapy. Therefore, an Amendment to the Protocol added a Part C applicable for Japan only, to assess the safety, tolerability and pharmacokinetics of the monotherapy of AZD6094 in Japanese patients with advanced NSCLC with the purpose of conducting further dose expansion (Part B) in Japan.

  Eligibility

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

(summarized due to limitation of characters)

Inclusion Criteria:

  1. Written informed consent
  2. Aged at least 18 years (20 years for Japan)
  3. Histological or cytological confirmation diagnosis of EGFRm+ NSCLC. Confirmation from a previous archival sample that the tumour harbours an EGFRm+ known to be associated with EGFR TKI sensitivity.
  4. Radiological documentation of disease progression while on a previous continuous treatment with an EGFR TKI (on the last treatment administered prior to enrolling in the study)

    Part B cMET+ve patients:

    • No prior treatment with a 3rd generation TKI: at least one prior line of therapy with 1st or 2nd generation EGFR TKI, but not a 3rd generation (T790M-directed) EGFR TKI.
    • Prior treatment with a 3rd generation TKI: at least one prior line of therapy with a 3rd generation (T790M-directed) EGFR TKI for EGFRm or T790M+ NSCLC.

    Part B cMET-ve patients:

    • T790M directed EGFR TKI patients only: their immediate prior therapy before entry into this study must be a T790M directed EGFR TKI.
    • ≥2nd line cohort: patients must have progressed while on treatment with an EGFR TKI (T790M directed EGFR TKIs are permitted). Other prior lines of therapy may have been given.
  5. cMET status: Prior to study entry, local confirmation of tumour cMET status is acceptable, a central result will be confirmed retrospectively. If a local test is not available, central confirmation of tumour cMET status must be obtained prior to study entry.

    T790M status: Local confirmation of tumour T790M status is acceptable, a central result will be confirmed retrospectively. If local testing is performed with the Cobas® EGFR Mutation Test v.2, the central confirmation is not required.

  6. At least one lesion, not previously irradiated, not biopsied during the screening period, that can be accurately measured at baseline as ≥10 mm in the longest diameter (except lymph nodes which must have short axis ≥15 mm) with CT or MRI which is suitable for accurate repeated measurements
  7. WHO performance status 0-1 with no deterioration over the previous 2 weeks and minimum life expectancy of 12 weeks
  8. Females should be using adequate contraceptive measures, must not be breast feeding and must have a negative pregnancy test prior to start of dosing if of child-bearing potential or must have evidence of non-child-bearing potential.

Exclusion Criteria (summary):

  • Treatment with an EGFR TKI within approximately 5x half-life of the first dose of study treatment. Any cytotoxic chemotherapy, investigational agents or other anticancer drugs for the treatment of advanced NSCLC from a previous treatment regimen or clinical study within 14 days of the first dose of study treatment. Patients currently receiving (or unable to stop use) medications or herbal supplements known to be potent inducers of CYP3A4 (at least 3 weeks prior). For AZD6094 patients currently receiving (or unable to stop use at least 2 weeks) prior to receiving the first dose, medications known to be strong inhibitors of CYP1A2. Prior AZD9291 dosing in the present study. Prior or current treatment with AZD6094 or another cMET inhibitor (if allocated to AZD9291 + AZD6094). Radiotherapy with a limited field of radiation for palliation within 1 week of the first dose of study treatment, with the exception of patients receiving radiation to more than 30% of the bone marrow or with a wide field of radiation which must be completed within ≥4 weeks of the first dose of study treatment. Major (or anticipated major) surgical procedure (excluding placement of vascular access) or significant traumatic injury within 4 weeks of the first dose of study treatment. Currently receiving treatment with warfarin sodium.
  • With the exception of alopecia and Grade 2, prior platinum-therapy related neuropathy, any unresolved toxicities from prior therapy and/or pre-study biopsies greater than CTCAE Grade 1 at the time of starting study treatment.
  • Spinal cord compression or brain metastases unless asymptomatic, stable and not requiring steroids for at least 2 weeks prior to start of study treatment.
  • Severe or uncontrolled systemic diseases; known serious active infection; active hepatitis B or C; cardiac disease; inadequate bone marrow reserve or organ function or coagulation parameters; inadequate liver or renal function; GI events that would preclude adequate absorption, distribution, metabolism or excretion of AZD9291, AZD6094 or selumetinib; hipersensitivity to IP or similar drugs
  • Past medical history of interstitial lung disease (ILD), drug-induced ILD, radiation pneumonitis which required steroid treatment, or any evidence of clinically active ILD.
  Contacts and Locations
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, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT02143466

Contacts
Contact: AstraZeneca Clinical Study Information Center 1-877-240-9479 information.center@astrazeneca.com
Contact: Cancer Study Locator 877 400 4656 AstraZeneca@emergingmed.com

Locations
United States, Georgia
Research Site Recruiting
Atlanta, Georgia, United States
United States, Massachusetts
Research Site Recruiting
Boston, Massachusetts, United States
United States, New York
Research Site Recruiting
New York, New York, United States
United States, Tennessee
Research Site Recruiting
Nashville, Tennessee, United States
United States, Texas
Research Site Withdrawn
Houston, Texas, United States
Canada, Alberta
Research Site Not yet recruiting
Calgary, Alberta, Canada
Research Site Not yet recruiting
Edmonton, Alberta, Canada
Canada, New Brunswick
Research Site Not yet recruiting
Moncton, New Brunswick, Canada
Canada, Ontario
Research Site Not yet recruiting
London, Ontario, Canada
Research Site Not yet recruiting
Ottawa, Ontario, Canada
Japan
Research Site Recruiting
Chuo-ku, Japan
Research Site Recruiting
Habikino-shi, Japan
Research Site Recruiting
Hirakata-shi, Japan
Research Site Recruiting
Kashiwa-shi, Japan
Research Site Recruiting
Nagoya-shi, Japan
Korea, Republic of
Research Site Recruiting
Cheongju-si, Korea, Republic of
Research Site Recruiting
Goyang-si, Korea, Republic of
Research Site Recruiting
Seongnam-si, Korea, Republic of
Research Site Recruiting
Seoul, Korea, Republic of
Russian Federation
Research Site Not yet recruiting
Moscow, Russian Federation
Research Site Not yet recruiting
Saint Petersburg,, Russian Federation
Research Site Not yet recruiting
St. Petersburg, Russian Federation
Taiwan
Research Site Not yet recruiting
Kaohsiung, Taiwan
Research Site Recruiting
Tainan, Taiwan
Research Site Recruiting
Taipei, Taiwan
Research Site Not yet recruiting
Taipei, Taiwan
Sponsors and Collaborators
AstraZeneca
Investigators
Study Director: Jenny Yang AstraZeneca
  More Information

Responsible Party: AstraZeneca
ClinicalTrials.gov Identifier: NCT02143466     History of Changes
Other Study ID Numbers: D5160C00006
Study First Received: May 9, 2014
Last Updated: April 25, 2017

Keywords provided by AstraZeneca:
Phase I
Safety
Tolerability
Efficacy
Anti-tumour
AZD9291
AZD6094
MEDI4736
Osimertinib
Savolitinib
Selumetinib
Durvalumab
Ascending Doses
Expansion cohorts
EGFR
Advanced Non-Small Cell Lung Cancer
Tyrosine Kinase Inhibitors

Additional relevant MeSH terms:
Carcinoma, Non-Small-Cell Lung
Carcinoma, Bronchogenic
Bronchial Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Coal Tar
Antibodies, Monoclonal
Osimertinib
Keratolytic Agents
Dermatologic Agents
Immunologic Factors
Physiological Effects of Drugs
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action

ClinicalTrials.gov processed this record on April 28, 2017