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Advanced Lung Non-Squamous Non-Small Cell CarcinomaPhase 1NCT02520778

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

A Phase 1 study testing Navitoclax and Osimertinib in people with Advanced Lung Non-Squamous Non-Small Cell Carcinoma and Metastatic Lung Non-Squamous Non-Small Cell Carcinoma, run by National Cancer Institute (NCI) at 18 sites in United States.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
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Trial 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… Read more about this study

Who is it for?
Ages 18 years and older
What is being tested?
Navitoclax and Osimertinib
Could I receive a placebo?
No, everyone receives an active treatment
How many people
27 participants
Where
18 sitesUnited States
Study dates
30 Aug 2016to 4 Dec 2023
Phase
Phase 1
Are there results?
None posted in the registry

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • 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)
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  • 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
  • Activated partial thromboplastin time (aPTT), prothrombin time (PT) =< 1.2 x upper limit of normal (ULN)
  • Total bilirubin =< 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]) =< 3.0 x institutional ULN
  • Creatinine =< 2.0 mg/dL OR
  • Creatinine clearance >= 50 mL/min
  • The effects of AZD9291 and navitoclax on the developing human fetus are unknown; for this reason, 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 for 3 months for women and 6 months for men following the date of the last dose of AZD9291 and/or navitoclax:
  • 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 3 months 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 6 months 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
  • 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

Who cannot join

  • 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
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  • 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
  • Pregnant women are excluded from this study because AZD9291 and navitoclax have the potential for teratogenic or abortifacient effects; because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with AZD9291 and navitoclax, 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 because of the potential for pharmacokinetic interactions with AZD9291

Trial locations and contacts

18 sites in 1 country.

18 sites in 1 country

United States18 sites

  • Emory University Hospital/Winship Cancer Institute

    Atlanta, Georgia, 30322

  • UCHealth University of Colorado Hospital

    Aurora, Colorado, 80045

  • Johns Hopkins University/Sidney Kimmel Cancer Center

    Baltimore, Maryland, 21287

  • Massachusetts General Hospital Cancer Center

    Boston, Massachusetts, 02114

  • Brigham and Women's Hospital

    Boston, Massachusetts, 02115

  • Dana-Farber Cancer Institute

    Boston, Massachusetts, 02215

  • UNC Lineberger Comprehensive Cancer Center

    Chapel Hill, North Carolina, 27599

  • University of Virginia Cancer Center

    Charlottesville, Virginia, 22908

  • Ohio State University Comprehensive Cancer Center

    Columbus, Ohio, 43210

  • Duke University Medical Center

    Durham, North Carolina, 27710

  • University of Kentucky/Markey Cancer Center

    Lexington, Kentucky, 40536

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

    New Brunswick, New Jersey, 08903

  • Rutgers Cancer Institute of New Jersey

    New Brunswick, New Jersey, 08903

  • University of Pittsburgh Cancer Institute (UPCI)

    Pittsburgh, Pennsylvania, 15232

  • Duke Raleigh Hospital

    Raleigh, North Carolina, 27609

  • University of California Davis Comprehensive Cancer Center

    Sacramento, California, 95817

  • Moffitt Cancer Center-International Plaza

    Tampa, Florida, 33607

  • Moffitt Cancer Center

    Tampa, Florida, 33612

Other trials in United States

About this study

Official 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 (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.

Read the detailed description

PRIMARY OBJECTIVES:

  1. To determine the safety and tolerability of osimertinib (AZD9291) 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.

SECONDARY OBJECTIVES:

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

II. To observe and record anti-tumor activity.

CORRELATIVE OBJECTIVES:

  1. 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). Cycles 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.

Being tested
Navitoclax, Osimertinib

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • NavitoclaxDrug

    Also called A-855071.0, ABT-263, BcI-2 Family Protein Inhibitor ABT-263

    Given PO

  • OsimertinibDrug

    Also called AZD 9291, AZD-9291, AZD9291, Mereletinib

    Given PO

Study groups in NCT02520778
Study groupRoleWhat they receive
Treatment (navitoclax, osimertinib)ExperimentalPatients 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
Receives: Drug: Navitoclax; Drug: Osimertinib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Up to 2 years

  2. 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%).

    Measured: Up to 12 weeks (3 cycles of treatment)

Secondary outcomes (4)

  1. 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

    Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.

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

  2. Objective response rate

    Will be assessed by Response Evaluation Criteria in Solid Tumors (RECIST). Calculated in the 20 patient expansion cohort and compared to the expected response rate of 61% in T790M+ lung cancer.

    Measured: Baseline up to 30 days after completion of study drug

  3. Change in plasma concentration of EGFR T790M and other EGFR mutations

    Change in plasma concentration of EGFR T790M and other EGFR mutations will be studied in an exploratory fashion and compared to tumor response on imaging.

    Measured: Baseline to up to 2 years

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

    Biomarkers of apoptosis such as BCL-XL and BIM levels will be measured in tumor tissue and correlated with response in an exploratory fashion, under the hypothesis that navitoclax will have greater activity in cancers with high BCL-XL levels and inadequate apoptotic response.

    Measured: Baseline

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted13 Aug 2015 (estimated)
  2. Study start30 Aug 2016
  3. Primary completion26 Oct 2022
  4. Study completion4 Dec 2023

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
27 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02520778
Sponsor's protocol ID
NCI-2015-01270
Other IDs
NCI-2015-01270, 16-714, 9903, 9903, UM1CA186709
Status last verified
Aug 2024
First submitted
10 Aug 2015
Last updated
21 Aug 2024
Results posted
No
Data monitoring committee
No

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing Navitoclax and Osimertinib in people with Advanced Lung Non-Squamous Non-Small Cell Carcinoma and Metastatic Lung Non-Squamous Non-Small Cell Carcinoma, run by National Cancer Institute (NCI) at 18 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 37 inclusion and 18 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 21 Aug 2024. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 18 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

The study is completed, but results are not available in the source record. That does not mean the treatment did or did not work.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Incidence of toxicity (dose escalation) (time frame: Up to 2 years). The study lists 2 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02520778.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2024.

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