Clinical Trials

The James Cancer Center Columbus, OH

open for enrollment

Osimertinib and Navitoclax in Treating Patients with EGFR-Positive Previously Treated Advanced or Metastatic Non-small Cell Lung Cancer

Protocol: OSU-16155

Full 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


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.

Study Objective


I. To determine the safety and tolerability of AZD9291 (osimertinib) in combination with navitoclax in patients with EGFR-mutant non-small cell lung cancer (NSCLC) following resistance to prior EGFR-tyrosine kinase inhibitor (EGFR TKI).

II. To evaluate the feasibility of treatment with AZD9291 plus navitoclax for patients with T790M-mediated acquired resistance to EGFR TKI.


I. To study the pharmacokinetic profile of the combination of AZD9291 plus navitoclax.

II. To observe and record anti-tumor activity.


I. To study plasma genotype levels as a response biomarker in patients with EGFR-mutant lung cancer.

II. To explore tissue biomarkers of apoptosis and their association with treatment response.

OUTLINE: This is a phase Ib, dose-escalation study followed by a dose-expansion study.

Patients receive navitoclax orally (PO) once daily (QD) on days 1-28 and osimertinib PO QD on days 4-28 (days 1-28 during dose-expansion). Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days.

Are you eligible?

Inclusion Criteria:

Histologically confirmed non-squamous NSCLC, with incurable advanced or metastatic disease

Prior genotyping positive for an EGFR activating mutation (L858R, exon 19 deletion, G719X, L861Q)

Progression after prior treatment with an EGFR 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 using central genotyping (if EGFR-T790M status is unknown, patients may consent for central EGFR T790M testing as part of screening for the trial; patients who test negative for EGFR T790M by central genotyping will be ineligible), and 2) be treatment naive to T790M-directed EGFR TKI (e.g. AZD9291, rociletinib, etc)

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 =< 1 (Karnofsky >= 70%)

Patients must have the ability to swallow oral dosage forms

Life expectancy of greater than 3 months

Leukocytes >= 3,000/mcL

Absolute neutrophil count >= 1,500/mcL

Hemoglobin >= 8.0 g/dL

Platelets >= 100,000/mcL

Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 × upper limit of normal (ULN)

Total bilirubin =< 1.5 × ULN (patients with Gilbert’s syndrome may have serum bilirubin > 1.5 × ULN)

Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3.0 × institutional ULN

Creatinine =< 2.0 mg/dL

Creatinine clearance >= 50 mL/min

Women of child-bearing potential and men must agree to use adequate contraception using one of the methods listed below prior to study entry, for the duration of study participation, and up to 90 days following completion of therapy:

Total abstinence from sexual intercourse (minimum one complete menstrual cycle prior to study drug administration)

Vasectomized male subject or vasectomized partner of female subjects

Hormonal contraceptives (oral, parenteral, transdermal or vaginal ring) for at least 3 months prior to study drug administration; if the subject is currently using a hormonal contraceptive, she should also use a barrier method during this study and for 1 month after study completion

Intrauterine device (IUD)

Double-barrier method: male condom plus diaphragm or vaginal cap with spermicide (contraceptive sponge, jellies or creams)

Additionally, male subjects (including those who are vasectomized) whose partners are pregnant or might be pregnant must agree to use condoms for the duration of the study and for 90 days following completion of therapy

Women of childbearing potential must have a negative urine pregnancy test within 7 days prior to initiation of treatment; women will be considered not of childbearing potential if they are surgically sterile (bilateral oophorectomy or hysterectomy) and/or post-menopausal (amenorrheic for at least 12 months)

Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately; men treated or enrolled on this protocol must also agree to use adequate contraception prior to the study, for the duration of study participation, and 4 months after completion of study drug administration

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

Patients must have completed last chemotherapy >= 3 weeks or radiotherapy >= 2 weeks prior to receiving study drugs

Patients must have recovered from adverse events attributable to previous treatment to =< grade 1, except for alopecia and sensory neuropathy =< grade 2

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

Patients receiving anticoagulation or anti-platelet therapy are excluded; excluded agents include heparin or low molecular weight heparin, warfarin, clopidogrel, ibuprofen and other nonsteroidal anti-inflammatory drug (NSAIDS), tirofiban, and other anticoagulants, drugs, or herbal supplements that affect platelet function; administration of heparin to keep subject's infusion lines patent is allowed; low-dose anticoagulation medications that are used to maintain the patency of a central intravenous catheter are allowed; aspirin will not be allowed within 7 days prior to the first dose of navitoclax or during navitoclax administration; however, subjects who have previously received aspirin therapy for thrombosis prevention, may resume a low dose (i.e., maximum 100 mg QD) of aspirin if platelet counts are stable (>= 50,000/mm3) through 6 weeks of navitoclax administration; all decisions regarding treatment with aspirin therapy will be determined by the investigator in conjunction with the medical monitor

Patients with an underlying condition predisposing them to bleeding or currently exhibiting signs of clinically significant bleeding

Patients with a recent history of non-chemotherapy-induced thrombocytopenic-associated bleeding within 1 year prior to the first dose of study drug

Patients with a significant history of cardiovascular disease (e.g., myocardial infarction [MI], thrombotic or thromboembolic event in the last 6 months)

Any of the following cardiac criteria:

Mean resting corrected QT interval (QTc using Fredericia’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

Patients with uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, gastrointestinal disease limiting absorption of AZD9291 such as a malabsorption syndrome or inflammatory bowel disease or psychiatric illness/social situations that would limit compliance with study requirements

Pregnant women are excluded from this study; breastfeeding should be discontinued if the mother is treated with AZD9291 and navitoclax

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 are ineligible

Lung Cancers