Clinical Trials /

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

NCT02520778

Description:

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.

Related Conditions:
  • Non-Small Cell Lung Carcinoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

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

Clinical Trial IDs

  • ORG STUDY ID: NCI-2015-01270
  • SECONDARY ID: NCI-2015-01270
  • SECONDARY ID: 16-714
  • SECONDARY ID: 9903
  • SECONDARY ID: 9903
  • SECONDARY ID: UM1CA186709
  • NCT ID: NCT02520778

Conditions

  • Advanced Lung Non-Squamous Non-Small Cell Carcinoma
  • EGFR Activating Mutation
  • EGFR Exon 19 Deletion Mutation
  • EGFR NP_005219.2:p.G719X
  • EGFR NP_005219.2:p.L858R
  • EGFR NP_005219.2:p.L861Q
  • EGFR NP_005219.2:p.T790M
  • Metastatic Lung Non-Squamous Non-Small Cell Carcinoma
  • Stage III Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7
  • Stage IIIB Lung Non-Small Cell Cancer AJCC v7
  • Stage IV Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
NavitoclaxA-855071.0, ABT-263, BcI-2 Family Protein Inhibitor ABT-263Treatment (navitoclax, osimertinib)
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoTreatment (navitoclax, osimertinib)

Purpose

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.

Detailed Description

      PRIMARY OBJECTIVES:

      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.

      SECONDARY OBJECTIVES:

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

      II. To observe and record anti-tumor activity.

      CORRELATIVE OBJECTIVES:

      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). 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.
    

Trial Arms

NameTypeDescriptionInterventions
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
  • Navitoclax
  • Osimertinib

Eligibility Criteria

        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 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 =< 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

          -  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

        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 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 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Incidence of toxicity (Dose escalation)
Time Frame:Up to 2 years
Safety Issue:
Description:Incidence of toxicity will be graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events version 5

Secondary Outcome Measures

Measure: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
Time Frame:Pre-dose, 1, 2, 4, 6, and 8 hours after navitoclax administration (day 1 of courses 1 and 2)
Safety Issue:
Description:Pharmacokinetic calculations will incorporate consideration of the dosing change in navitoclax between the two measurement days.
Measure:Objective response rate
Time Frame:Baseline up to 30 days after completion of study drug
Safety Issue:
Description: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.
Measure:Change in plasma concentration of EGFR T790M and other EGFR mutations
Time Frame:Baseline to up to 2 years
Safety Issue:
Description: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.
Measure:Biomarkers of apoptosis such as BCL2-like 1 (BCL-XL) and BCL2-like 11 (apoptosis facilitator) (BIM) levels in tumor tissue
Time Frame:Baseline
Safety Issue:
Description: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.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:National Cancer Institute (NCI)

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