Clinical Trials /

Phase II Study of AZD9291 in Advanced Stage NSCLC With EGFR and T790M Mutations Detected in Plasma Ct-DNA

NCT02811354

Description:

Circulating tumor DNA (ctDNA) is a highly specific and effective biomarker for the detection of EGFR mutation status. We hypothesise AZD9291 is efficacious in patients with EGFR sensitizing mutations and T790M detected in plasma ctDNA. This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. Approximately 106 subjects will be enrolled. All patients must have documented radiological progression on EGFR-TKI treatment and on the last treatment administered prior to enrolling in the study.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Phase II Study of AZD9291 in Advanced Stage NSCLC With EGFR and T790M Mutations Detected in Plasma Ct-DNA
  • Official Title: Phase II Study of AZD9291 in Patients With Advanced Stage Non-small Cell Lung Cancer Following Prior EGFR TKI Therapy With EGFR and T790M Mutations Detected in Plasma Circulating Tumor DNA (PLASMA)

Clinical Trial IDs

  • ORG STUDY ID: ESR-15-10932
  • SECONDARY ID: 2015/01069
  • NCT ID: NCT02811354

Conditions

  • Carcinoma, Non-Small-Cell Lung

Interventions

DrugSynonymsArms
AZD9291OsimertinibAZD9291

Purpose

Circulating tumor DNA (ctDNA) is a highly specific and effective biomarker for the detection of EGFR mutation status. We hypothesise AZD9291 is efficacious in patients with EGFR sensitizing mutations and T790M detected in plasma ctDNA. This is a prospective, open label, multi-centre single arm phase II study assessing the efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring sensitising EGFR mutation (exon 19 deletions or exon 21 L858R substitution mutations) and T790M who have progressed following prior treatment with an approved EGFR TKI. Approximately 106 subjects will be enrolled. All patients must have documented radiological progression on EGFR-TKI treatment and on the last treatment administered prior to enrolling in the study.

Detailed Description

      As T790M is the most common mechanism of acquired resistance to EGFR TKI, EGFR TKIs targeting
      T790M has been developed.

      AZD9291 is an oral, potent, irreversible EGFR-TKI selective for sensitizing (EGFRm) and T790M
      resistance mutation with a significant selectivity margin against wild-type EGFR. As a
      result, AZD9291 can effectively block EGFR signaling both in EGFR single mutant cells with
      activating EGFR mutations and in double mutant cells bearing the resistance T790M mutation.

      This is a prospective, open label, multi-centre single arm phase II study assessing the
      efficacy and safety of AZD9291 monotherapy in patients with stage IIIB or IV harboring
      sensitising EGFR mutation (exon 19 deletions and exon 21 L858R substitution mutations) and
      T790M who have progressed following prior treatment with an approved EGFR TKI. Approximately
      108 subjects will be enrolled.

      All patients must have documented radiological progression on EGFR-TKI treatment and on the
      last treatment administered prior to enrolling in the study.

      Target patient population:

      Patients will be > 18 years of age, with a diagnosis of locally advanced/metastatic NSCLC not
      amenable to curative surgery or radiotherapy with documented activating EGFR mutations (exon
      19 deletions and exon 21 L858R substitution mutations) at the time of initial diagnosis, have
      radiological disease progression following either 1st line EGFR TKI treatment OR following
      prior therapy with an EGFR TKI and a platinum-based doublet chemotherapy. Plasma sample must
      harbour an EGFR mutation known to be associated with EGFR TKI sensitivity (exon 19 deletion,
      L858R as well as presence of T790M by central lab testing from a plasma sample taken after
      confirmation of disease progression on the most recent treatment regimen. Patients must have
      normal organ and bone marrow function and ECOG PS 0-2.

      Treatment and regimens:

      Patient will be treated with AZD9291 at a starting dose of 80mg once a day until the patient
      completes the study, withdraws from the study or closure of the study. A cycle of treatment
      is defined as 28 days of once daily AZD9291 treatment. Patients may continue to receive
      AZD9291 until objective disease progression (determined by RECIST 1.1) or if the subject is
      no longer receiving clinical benefit in the Investigator's opinion.
    

Trial Arms

NameTypeDescriptionInterventions
AZD9291ExperimentalPatient will be treated with AZD9291 at a starting dose of 80mg once a day until the patient completes the study, withdraws from the study or closure of the study. A cycle of treatment is defined as 28 days of once daily AZD9291 treatment. Patients may continue to receive AZD9291 until objective disease progression (determined by RECIST 1.1) or if the subject is no longer receiving clinical benefit in the Investigator's opinion.
  • AZD9291

Eligibility Criteria

        Inclusion Criteria:

          1. Provision of informed consent prior to any study specific procedures

          2. Patients must be >= 21 years of age.

          3. Locally advanced/metastatic NSCLC not amenable to curative surgery or radiotherapy

          4. Documentation of activating EGFR mutations (exon 19 deletions or exon 21 L858R
             substitution mutations) at the time of initial diagnosis

          5. Radiological documentation of disease progression: following 1st line EGFR TKI
             treatment but who have not received further treatment OR following prior therapy with
             an EGFR TKI and a platinum-based doublet chemotherapy. All patients must have
             documented radiological progression on the last treatment administered prior to
             enrolling in the study.

          6. Patient may receive up to two lines of therapies (including EGFR TKI).

          7. Plasma sample must harbour an EGFR mutation known to be associated with EGFR TKI
             sensitivity (exon 19 deletion, L858R). Confirmation of T790M status by central lab
             testing from a plasma sample taken after confirmation of disease progression on the
             most recent treatment regimen.

          8. Patients must have normal organ and bone marrow function measured within 28 days prior
             to administration of study treatment as defined below:

               -  Haemoglobin >= 10.0 g/dL and no blood transfusions in the 28 days prior to entry

               -  Absolute neutrophil count (ANC) >= 1.5 x 109/L

               -  No features suggestive of MDS/AML on peripheral blood smear

               -  White blood cells (WBC) > 3x109/L

               -  Platelet count >= 100 x 109/L

               -  Total bilirubin <= 1.5 x institutional upper limit of normal (ULN)

               -  AST (SGOT)/ALT (SGPT) <= 2.5 x institutional upper limit of normal unless liver
                  metastases are present in which case it must be <= 5x ULN

               -  Serum creatinine <= 1.5 x institutional upper limit of normal (ULN)

               -  ECOG performance status 0-2

          9. Patients must have a life expectancy >= 12 weeks.

         10. Females should be using adequate contraceptive measures, should 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 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 LH and 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 (see Restrictions,
             Section 5.1)

         12. Patient is willing and able to comply with the protocol for the duration of the study
             including undergoing treatment and scheduled visits and examinations including follow
             up.

         13. At least one lesion, not previously irradiated, 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 computed tomography (CT) or magnetic resonance imaging (MRI) and
             which is suitable for accurate repeated measurements

        Exclusion Criteria:

          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 an EGFR-TKI within 8 days of study entry; any cytotoxic chemotherapy,
             or other anticancer drugs within 21 days of study entry

          3. Treatment with an investigational drug within five half-lives of the compound

          4. Prior treatment with an immune checkpoint inhibitor

          5. Previous treatment with AZD9291 (or 3rd generation EGFR TKIs)

          6. Patients with second primary cancer, except: adequately treated non-melanoma skin
             cancer, curatively treated in-situ cancer of the cervix, or other solid tumours
             curatively treated with no evidence of disease for >= 5 years

          7. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of
             radiation within 4 weeks

          8. The patient may receive bisphosphonates for the treatment of bone metastases.

          9. Any unresolved toxicities from prior therapy greater than Common Terminology Criteria
             for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the
             exception of alopecia and grade 2, prior platinum-therapy related neuropathy.

         10. Unstable spinal cord compression/brain metastases unless asymptomatic, stable and not
             requiring steroids for at least 2 weeks prior to start of study treatment.

         11. Major surgery within 4 weeks of starting study treatment and patients must have
             recovered from any effects of any major surgery.

         12. Patients currently receiving (or unable to stop use prior to receiving the first dose
             of study treatment) medications or herbal supplements known to be potent inhibitors of
             CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior)
             (Appendix A). All patients must try to avoid concomitant use of any medications,
             herbal supplements and/or ingestion of foods with known inducer/inhibitory effects on
             CYP3A4.

         13. 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.

         14. Past medical history of ILD, drug-induced ILD, radiation pneumonitis requiring steroid
             treatment, or any evidence of clinically active ILD

         15. Any of the following cardiac criteria:

               1. Mean resting corrected QT interval (QTc using Fredericia's formula) > 470 msec

               2. 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)

               3. Any factors that increase the risk of QTc prolongation or risk of arrhythmic
                  events such as heart failure, hypokalemia, 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

         16. 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

         17. History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or
             class to AZD9291) or any excipients of these agents

         18. Males and females of reproductive potential who are not using an effective method of
             birth control and females who are pregnant or breastfeeding or have a positive serum
             pregnancy test prior to study entry

         19. 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

         20. Previous allogeneic bone marrow transplant.

         21. Non-leukocyte depleted whole blood transfusion within 120 days of the date of the
             genetic sample collection.
      
Maximum Eligible Age:99 Years
Minimum Eligible Age:21 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Objective response rate (ORR)
Time Frame:From the time of their first treatment with daily AZD9291 till 28 days after discontinuation
Safety Issue:
Description:

Secondary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From the time of their first treatment with daily AZD9291 till 28 days after discontinuation
Safety Issue:
Description:
Measure:Duration of response (DoR)
Time Frame:From the time of their first treatment with daily AZD9291 till 28 days after discontinuation
Safety Issue:
Description:
Measure:Disease control rate (DCR)
Time Frame:From the time of their first treatment with daily AZD9291 till 28 days after discontinuation
Safety Issue:
Description:
Measure:Tumour shrinkage
Time Frame:From the time of their first treatment with daily AZD9291 till 28 days after discontinuation
Safety Issue:
Description:
Measure:Overall survival (OS)
Time Frame:From the time of their first treatment with daily AZD9291 till 28 days after discontinuation
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National University Hospital, Singapore

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