Clinical Trial 19339

Cancer Type:
Interventions:AZD9291 (Osimertinib); Avastin (Bevacizumab); Bevacizumab

Study Type: Treatment
Phase of Study: Phase II
Investigators:

  • Peter Forsyth

Overview

Study Title

A Phase II Trial of AZD9291 (Osimertinib) with or without Bevacizumab in Patients with EGFR Mutation Positive NSCLC and Brain Metastases

Summary

The purpose of this study is to see how well osimertinib, with or without bevacizumab works in treating patients with epidermal growth factor receptor(EGFR) positive non-small cell lung cancer (NSCLC) that has spread to the brain.

Objective

Primary Objectives: To determine the progression-free survival with AZD9291 (osimertinib) plus bevacizumab compared to AZD9291 (osimertinib) alone. Secondary Objectives: To assess the safety and tolerability of the combination of AZD9291(osimertinib) and bevacizumab. To evaluate the time to progression in the CNS with AZD9291 (osimertinib) plus bevacizumab versus single-agent osimertinib. To determine the overall response rate and the intracranial response rate to the combination versus single agent. To assess the overall survival in patients receiving AZD9291 (osimertinib) plus bevacizumab compared to AZD9291 (osimertinib) alone.

Inclusion Criteria

  • Non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); presence of an activating EGFR mutation may be documented in tumor tissue or by plasma testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory; AND
  • The presence of an EGFR T790M mutation after progression on a first- or second-generation EGFR TKI; presence of an EGFR T790M mutation may be documented from biopsy material from any site of disease (intra- or extra-cranial) or from plasma testing if performed in a CLIA-certified laboratory; for patients who have disease progression in the central nervous system (CNS) only (with otherwise stable disease systemically), T790M positivity is not required
  • Disease progression on a first- or second-generation EGFR TKI (i.e., erlotinib, gefitinib, or afatinib); patient may have also received prior chemotherapy or immunotherapy but this is not required
  • Must have at least one measurable CNS lesion that is asymptomatic, untreated, and does not require local therapy at the time of enrollment; measurable CNS disease is defined as a brain metastasis that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain MRI; if the lesion is 5-10 mm in size and is the only measurable disease, magnetic resonance imaging (MRI) imaging must be performed with 1.5 mm slice thickness or less; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment
  • Participants are not required to have measurable systemic (i.e., non-CNS) disease; if present, measurable systemic disease must be able to be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, MRI, or calipers by clinical exam
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 2
  • Life expectancy of greater than 3 months
  • Adequate organ and marrow function
  • The use of anti-convulsants in allowed, as long as the patient is on a stable dose with no seizure activity for at least 2 weeks prior to initiating trial therapy
  • Fertile men must agree to use adequate contraceptive measures during and for 4 months after AZD9291 (osimertinib), and fertile women must agree to use adequate contraceptive measures during and for 6 weeks after AZD9291 (osimertinib
  • Ability to understand and the willingness to sign a written informed consent document

  • Exclusion Criteria

  • Symptomatic brain metastases
  • Patients with brain metastases for whom complete surgical resection is clinically appropriate
  • Prior treatment with a third-generation EGFR TKI
  • Prior treatment with agents targeting the VEGF pathway, including bevacizumab
  • Use of corticosteroids to control cerebral edema or treat neurologic symptoms, patients who previously required corticosteroids for symptom control must be off steroids for at least 3 days without recurrence of symptoms prior to starting trial therapy; corticosteroids for other indications is allowed
  • Leptomeningeal disease
  • Receiving any other investigational agents or participated in a study of an investigational agent or using an investigational device within 5 half-lives or 3 months , whichever greater
  • Treatment with an EGFR TKI within 8 days or approximately 5 x half-life, whichever is longer, of the first dose of study treatment
  • Any unresolved toxicities from prior therapy greater than CTCAE grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 platinum-therapy related neuropathy
  • Concurrent, active malignancies in addition to that being studied (except cutaneous squamous cell carcinoma or basal cell carcinoma)
  • Any contraindication to MRI (pacemakers, other metal implanted medical devices)
  • Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease> History of allergic reactions attributed to compounds of similar chemical or biologic composition to osimertinib or bevacizumab
  • If urine protein is 2+ or higher, 24-hour urine protein should be obtained; patients with 24-hour urine protein >= 1000 mg are excluded
  • Serious or non-healing wound, ulcer or bone fracture
  • History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1
  • Invasive procedures: major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to day 1 therapy; Anticipation of need for major surgical procedures during the course of the study; Core biopsy within 7 days prior to day 1 (D1) therapy
  • Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1
  • Clinically significant cardiovascular disease
  • Evidence of bleeding diathesis or coagulopathy
  • Known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies