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Clinical Trial 19642

Cancer Type:
Interventions:ABT-263 (Navitoclax); AZD9291 (Osimertinib); Navitoclax

Study Type: Treatment
Phase of Study: Phase I
Investigators:

  • Eric Haura

Overview

Study Title

A Phase 1B Study of AZD9291 in Combination with Navitoclax in EGFR-mutant Non-Small Cell Lung Cancer Following Resistance to Initial EGFR Kinase Inhibitor

Summary

This phase Ib trial studies the side effects and best dose of osimertinib and navitoclax when given together and to see how well they work in treating patients with previously treated epidermal growth factor receptor (EGFR)-positive non-small cell lung cancer that has spread to other places in the body or has not responded to previous treatment with initial EGFR kinase inhibitor. Osimertinib and navitoclax may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving with osimertinib together with navitoclax may work better in treating EGFR-positive non-small cell lung cancer.

Objective

Primary Objectives: To determine the safety and tolerability of AZD9291 in combination with navitoclax in patients with EGFR-mutant NSCLC following resistance to prior EGFR TKI. To evaluate the feasibility of treatment with AZD9291 plus navitoclax for patients with T790M-mediated acquired resistance to EGFR TKI.

Inclusion Criteria

  • Histologically confirmed non-squamous non-small cell lung cancer (NSCLC), with incurable advanced or metastatic disease
  • Prior genotyping positive for an estimated glomerular filtration rate (EGFR) activating mutation (L858R, exon 19 deletion, G719X, L861Q)
  • Progression after prior treatment with an EGFR tyrosine kinase inhibitor (TKI); in addition to this one prior line of therapy, any additional prior lines of therapy are permitted; prior treatment with a third-generation EGFR TKI is allowed for the dose escalation phase, but is not permitted for the expansion cohort
  • Adequate archival tissue from a biopsy performed after progression of disease on previous EGFR TKI; or willing to undergo a new tumor biopsy prior to registration (for the dose escalation portion only this requirement can be waived if T790M status has already been determined using a local assay)
  • For the dose expansion portion only, patient must: 1) have a tumor which is EGFR-T790M positive and 2) be treatment naive to T790M-directed EGFR TKI (e.g., AZD9291, rociletinib, etc.); T790M testing may be done locally or centrally on study, but if done locally, tissue must be available for central confirmation
  • Measurable disease per Response Evaluation Criteria in Solid Tumors (RECIST 1.1)
  • Any number of prior therapies are allowed
  • Eastern Cooperative Oncology Group (ECOG) performance status less than or equal to 1 (Karnofsky >= 70%)
  • Participants must have the ability to swallow oral dosage forms
  • Life expectancy of greater than 3 months
  • Leukocytes >= 3,000/mcL
  • Absolute neutrophil count (ANC) >= 1,500/mcL
  • Hemoglobin >= 8.0 g/dL
  • Platelets >= 100,000/mcL
  • Activated partial thromboplastin time (aPTT), prothrombin time (PT) less than or equal to 1.2 x upper limit of normal (ULN)
  • Total bilirubin less than or equal to 1.5 x ULN (patients with Gilbert's syndrome may have serum bilirubin > 1.5 x ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) less than or equal to 3.0 x institutional ULN
  • Creatinine less than or equal to 2.0 mg/dL Creatinine clearance >= 50 mL/min Women of child-bearing potential and men must agree to use adequate contraception as outlined in the study protocol.
  • Patients with a prior history of brain metastases are eligible provided: The brain metastases have been treated; The patient is asymptomatic from the brain metastases; Corticosteroids prescribed for the management of brain metastases have been discontinued at least 7 days prior to registration; The brain metastases are stable on pre-registration imaging.
  • Must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs
  • Must have recovered from adverse events attributable to previous treatment to => Ability to understand and the willingness to sign a written informed consent document

  • Exclusion Criteria

  • Major surgery within 21 days of starting protocol treatment
  • Patients must discontinue previous EGFR-TKI at least 7 days prior to study enrollment
  • Patients who are receiving any other investigational agents
  • Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis requiring steroid treatment, or any evidence of clinically active interstitial lung disease
  • Patients currently receiving (or unable to stop use at least 1 week prior to receiving the 1st dose of AZD9291) medications or herbal supplements known to be potent inhibitors of cytochrome P450, family 2, subfamily C, polypeptide 8 (CYP2C8) and potent inhibitors or inducers of cytochrome P450, family 3, subfamily A, polypeptide 4 (CYP3A4) are ineligible; patients are eligible if they stop use of these compounds at least 1 week prior to receiving any treatment on this protocol
  • Receiving anticoagulation or anti-platelet therapy
  • Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding
  • A recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug
  • Significant history of cardiovascular disease
  • Mean resting corrected QT interval (QTc using Frederica's formula [QTcF]) > 470 msec
  • Any clinically important abnormalities in rhythm, conduction or morphology of resting electrocardiogram (ECG) (e.g., complete left bundle branch block, third degree heart block, second degree heart block)
  • Congenital long QT syndrome or family history of long QT syndrome
  • Patients with active malignancies other than NSCLC or prior curatively treated malignancy at high risk of relapse during the study period with the exception of localized squamous or basal cell skin cancers
  • Uncontrolled intercurrent illness
  • Pregnant or breastfeeding
  • History of hypersensitivity to AZD9291 (or drugs with a similar chemical structure or class to AZD9291) or any excipients of these agents
  • Patients with human immunodeficiency virus (HIV) on antiretroviral therapy
  • Additional criteria may apply