Clinical Trials /

AZD9291 in Combination With Ascending Doses of Novel Therapeutics

NCT02143466

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Active, not recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: AZD9291 in Combination With Ascending Doses of Novel Therapeutics
  • 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).

Clinical Trial IDs

  • ORG STUDY ID: D5160C00006
  • NCT ID: NCT02143466

Conditions

  • Advanced Non Small Cell Lung Cancer

Interventions

DrugSynonymsArms
Part A - AZD9291 in combination with AZD6094Osimertinib & Savolitinib/VolitinibAZD6094
Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)Osimertinib & ARRY-142886Selumetinib
Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)Osimertinib & ARRY-142886Selumetinib
Part A - AZD9291 in combination with intermittent selumetinibOsimertinib & ARRY-142886Selumetinib
Part A - AZD9291 in combination with MEDI4736Osimertinib & DurvalumabMEDI4736
Part B - AZD9291 in combination with AZD6094Osimertinib & Savolitinib/VolitinibAZD6094
Part B - AZD9291 in combination with selumetinibOsimertinib & ARRY-142886Selumetinib
Part B - AZD9291 in combination with MEDI4736Osimertinib & DurvalumabMEDI4736
Part C - AZD6094 monotherapy (Japan only)Savolitinib/VolitinibAZD6094 (monotherapy)
Part C - AZD9291 in combination with AZD6094 (Japan only)Osimertinib & Savolitinib/VolitinibAZD6094
Part D - AZD9291 in combination with AZD6094Osimertinib & Savolitinib/VolitinibAZD6094

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.

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 three main parts to this study; Part A, Combination
      dose finding and Parts B and D, Dose expansion. Part C, AZD6094 dose finding sub-study in
      advanced solid tumour patients is ongoing in Japan.

      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.
    

Trial Arms

NameTypeDescriptionInterventions
AZD6094ExperimentalAZD9291 in combination with AZD6094
  • Part A - AZD9291 in combination with AZD6094
  • Part B - AZD9291 in combination with AZD6094
  • Part C - AZD9291 in combination with AZD6094 (Japan only)
  • Part D - AZD9291 in combination with AZD6094
SelumetinibExperimentalAZD9291 in combination with selumetinib
  • Part A - AZD9291 in combination with continuous selumetinib (Asian subjects)
  • Part A - AZD9291 in combination with continuous selumetinib (non-Asian subjects)
  • Part A - AZD9291 in combination with intermittent selumetinib
  • Part B - AZD9291 in combination with selumetinib
MEDI4736ExperimentalAZD9291 in combination with MEDI4736. 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.
  • Part A - AZD9291 in combination with MEDI4736
  • Part B - AZD9291 in combination with MEDI4736
AZD6094 (monotherapy)ExperimentalAZD6094 in monotherapy (for Japan only)
  • Part C - AZD6094 monotherapy (Japan only)

Eligibility 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.

             Part D cMET-ve patients:

             No prior treatment with a 3rd generation TKI, T790M negative:

             Patients must have received at least one prior line of therapy with 1st or 2nd
             generation EGFR TKI, but not a 3rd generation (T790M directed) EGFR TKI.

          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, 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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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.
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure:Cssmin after multiple dosing
Time Frame:Blood samples will be collected from each subject at pre-specified times for the duration of treatment.
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure: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
Safety Issue:
Description:To characterise the pharmacokinetics of AZD9291, AZD6094 or selumetinib and metabolites after single dosing and at steady state after multiple dosing when AZD9291 is given orally in combination with AZD6094 or selumetinib (or, in case of Part C monotherapy for Japanese subjects, when AZD6094 is given alone) to patients with EGFRm+ NSCLC through plasma concentrations.
Measure:Objective response rate
Time Frame:At baseline and every 6 weeks until disease progression or withdrawal from study.
Safety Issue:
Description: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.
Measure:Disease control rate
Time Frame:At baseline and every 6 weeks until disease progression or withdrawal from study.
Safety Issue:
Description: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
Measure:Duration of response
Time Frame:At baseline and every 6 weeks until disease progression or withdrawal from study.
Safety Issue:
Description: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
Measure:Percentage change in tumour size
Time Frame:At baseline and every 6 weeks until disease progression or withdrawal from study.
Safety Issue:
Description: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
Measure:Progression free survival
Time Frame:At baseline and every 6 weeks until disease progression or withdrawal from study.
Safety Issue:
Description: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
Measure:Overall survival
Time Frame:Confirmed during the FUP period and at least every 12 weeks until the data cut-off for the primary analysis and determination that no further OS collection is needed, approximately 5 years, death, or full withdrawal of consent, whichever comes first.
Safety Issue:
Description:To obtain a preliminary assessment of overall survival in the AZD9291+AZD6094 combination arms of the study for Parts B and D.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:AstraZeneca

Trial Keywords

  • 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

Last Updated

February 2, 2018