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

NCT02520778 | Completed Phase 1

• 4 other identifiers: NCI-2015-0127016-7149903UM1CA186709
• Study Type: interventional
• Target: 27
• Locations: 1 country
• Sites: 18

Brief 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 (metastatic) 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.

Conditions

Advanced Lung Non-Squamous Non-Small Cell Carcinoma; Metastatic Lung Non-Squamous Non-Small Cell Carcinoma; Stage III Lung Non-Small Cell Cancer AJCC v7; Stage IIIA Lung Non-Small Cell Cancer AJCC v7; Stage IIIB Lung Non-Small Cell Cancer AJCC v7; Stage IV Lung Non-Small Cell Cancer AJCC v7

Outcome Measures

Primary Outcomes (2)

• Incidence of toxicity (dose escalation)

  Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 4.03. Frequency and severity of adverse events will be tabulated using counts and proportions detailing frequently occurring, serious and severe events of interest. Adverse events will be summarized using all adverse events experienced, although a sub-analysis may be conducted including only those adverse events in which the treating physician deems possibly, probably or definitely attributable to one or both study treatments.

  Up to 2 years

• Feasibility of the combination therapy in T790M+ lung cancer (dose expansion)

  Will be measured as at least 50% of patients achieving the expected dose duration and intensity. The proportion of patients completing 3 courses of therapy with \> 75% of total dose of each drug will be quantified. The combination dosing will be considered potentially feasible if at least 50% of patients achieve the expected dose duration and intensity (95% confidence interval 30%-70%).

  Up to 12 weeks (3 cycles of treatment)

Secondary Outcomes (4)

• Pharmacokinetics parameters (maximum observed plasma drug concentration, area-under-the concentration-time-curve, trough drug concentration at steady state, and half-life) of osimertinib in combination with navitoclax

  Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 3 of cycle 1 and day 1 of cycle 2)

• Objective response rate

  Baseline up to 30 days after completion of study drug

• Change in plasma concentration of EGFR T790M and other EGFR mutations

  Baseline to up to 2 years

• Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue

  Baseline

Study Arms (1)

Treatment (navitoclax, osimertinib)

EXPERIMENTAL

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

Drug: Navitoclax; Drug: Osimertinib

Interventions

Navitoclax DRUG

Given PO

Also known as: A-855071.0, ABT-263, BcI-2 Family Protein Inhibitor ABT-263

Treatment (navitoclax, osimertinib)

Osimertinib DRUG

Given PO

Also known as: AZD 9291, AZD-9291, AZD9291, Mereletinib

Treatment (navitoclax, osimertinib)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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 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
• Age \>= 18 years. NSCLC is exceedingly rare in patients \< 18 years of age. Because no dosing or adverse event data are currently available on the use of AZD9291 in combination with navitoclax in patients \< 18 years of age, children are excluded from this study
• 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

You may not qualify if:

• 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 due to the risk of thrombocytopenia with navitoclax; 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/mm\^3) 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 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 patients with 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

Sponsors & Collaborators

• National Cancer Institute (NCI): lead

Study Sites (18)

University of California Davis Comprehensive Cancer Center

Sacramento, California, 95817, United States

Location

UCHealth University of Colorado Hospital

Aurora, Colorado, 80045, United States

Location

Moffitt Cancer Center-International Plaza

Tampa, Florida, 33607, United States

Location

Moffitt Cancer Center

Tampa, Florida, 33612, United States

Location

Emory University Hospital/Winship Cancer Institute

Atlanta, Georgia, 30322, United States

Location

University of Kentucky/Markey Cancer Center

Lexington, Kentucky, 40536, United States

Location

Johns Hopkins University/Sidney Kimmel Cancer Center

Baltimore, Maryland, 21287, United States

Location

Massachusetts General Hospital Cancer Center

Boston, Massachusetts, 02114, United States

Location

Brigham and Women's Hospital

Boston, Massachusetts, 02115, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

Rutgers Cancer Institute of New Jersey-Robert Wood Johnson University Hospital

New Brunswick, New Jersey, 08903, United States

Location

Rutgers Cancer Institute of New Jersey

New Brunswick, New Jersey, 08903, United States

Location

UNC Lineberger Comprehensive Cancer Center

Chapel Hill, North Carolina, 27599, United States

Location

Duke University Medical Center

Durham, North Carolina, 27710, United States

Location

Duke Raleigh Hospital

Raleigh, North Carolina, 27609, United States

Location

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

University of Pittsburgh Cancer Institute (UPCI)

Pittsburgh, Pennsylvania, 15232, United States

Location

University of Virginia Cancer Center

Charlottesville, Virginia, 22908, United States

Location

MeSH Terms

Interventions

navitoclax; osimertinib

Study Officials

• Pasi A Janne

  Dana-Farber - Harvard Cancer Center LAO

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NIH
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: August 10, 2015
• First Posted: August 13, 2015
• Study Start: August 30, 2016
• Primary Completion: October 26, 2022
• Study Completion: December 4, 2023
• Last Updated: August 21, 2024

Record last verified: 2024-08

Locations

US (18)