Patient case: 60-year-old female with gastric cancer; genetic feature: EGFR

Clinical trial: AZD9291 in Combination With Ascending Doses of Novel Therapeutics

Summary: 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 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: (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.

Relevance to patient case: not relevant