Osimertinib and Necitumumab in Treating Patients With EGFR-Mutant Stage IV or Recurrent Non-small Cell Lung Cancer Who Have Progressed on a Previous EGFR Tyrosine Kinase Inhibitor

Not Recruiting

Trial ID: NCT02496663


This phase I trial studies the side effects and best dose of necitumumab when given together with osimertinib in treating patients with EGFR-mutant non-small cell lung cancer that is stage IV or has come back after a period of improvement (recurrent) and who have progressed on a previous EGFR tyrosine kinase inhibitor. Immunotherapy with monoclonal antibodies, such as necitumumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Giving necitumumab with osimertinib may be a better treatment for EGFR-mutant non-small cell lung cancer.

Official Title

A Phase I Trial of Osimertinib (AZD9291) and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor

Stanford Investigator(s)

Heather Wakelee
Heather Wakelee

Winston Chen and Phyllis Huang Professor and Professor of Medicine (Oncology)

Joel Neal, MD, PhD
Joel Neal, MD, PhD

Associate Professor of Medicine (Oncology)

Kavitha Ramchandran
Kavitha Ramchandran

Clinical Professor, Medicine - Oncology

Millie Das
Millie Das

Clinical Professor, Medicine - Oncology


Inclusion Criteria:

   - Patients with stage IV or recurrent/metastatic histologically confirmed non-small cell
   lung cancer (NSCLC)

   - NSCLC must harbor at least one of the following EGFR activating mutations: Exon 21
   L858R, Exon 19 deletion, Exon 18 G719X, Exon 21 L861Q or for EGFR Exon 20 insertion
   expansion cohort D, NSCLC must harbor an EGFR Exon 20 insertion performed by a
   Clinical Laboratory Improvement Act (CLIA) certified test

   - For Dose escalation cohort - progressive disease on at least one prior EGFR-TKI
   (previous treatment with 3rd generation EGFR-TKI including osimertinib (AZD9291)
   allowed for dose escalation)

   - For Dose Expansion Cohort A: patient must 1) have progression of disease on erlotinib,
   gefitinib or afatinib as last previous systemic treatment, 2) have biopsy of tumor
   taken after progression on erlotinib, gefitinib or afatinib which must be EGFR-T790M
   negative confirmed by central testing prior to treatment (if EGFR-T790M status is
   unknown, patients may consent for trial and for biopsy and testing for EGFR T790M will
   be performed as part of initial biopsy for trial), and 3) be treatment naive to 3rd
   generation EGFR-TKI (rociletinib, EGFR inhibitor HM61713 [HM61713] and osimertinib
   [AZD9291]) and EGFR monoclonal antibodies

   - For Dose Expansion Cohort B (closed to accrual as of 8/30/18): patient must 1) have
   progression of disease on a 3rd generation EGFR-TKI such as AZD9291, rociletinib,
   HM61713, 2) be treatment naive to an EGFR monoclonal antibody, and 3) have a biopsy of
   tumor taken after progression on last EGFR-TKI that indicates loss of EGFR-T790M
   (EGFR-T790M negative) confirmed by central testing prior to treatment (if EGFR-T790M
   status is unknown, patients may consent for trial and for biopsy, and testing for EGFR
   T790M will be performed as part of initial biopsy for trial)

   - For Dose Expansion Cohort C: patient must 1) have progression of disease on a 3rd
   generation EGFR-TKI such as osimertinib (AZD9291), rociletinib, HM61713, 2) be
   treatment naive to an EGFR monoclonal antibody, 3) have a biopsy of tumor taken after
   progression on last EGFR-TKI that indicates preservation of EGFR-T790M
   post-progression on 3rd generation EGFR-TKI with biopsy confirmation by central
   testing prior to treatment (if EGFR-T790M status is unknown, patients may consent for
   trial and for biopsy, and testing for EGFR T790M will be performed as part of initial
   biopsy for trial)

   - For Dose Expansion Cohort D: patient must 1) tumor that harbors an EGFR Exon 20
   insertion by a CLIA certified test, and 2) have progressive disease on or after
   platinum based chemotherapy, and 3) be treatment naïve to 3rd generation and beyond
   EGFR-TKI (i.e., osimertinib [AZD9291], poziotinib, TAK-778) and EGFR monoclonal
   antibody; patient who received 1st or 2nd generation EGFR-TKI (such as erlotinib,
   gefitinib, afatinib) are eligible provided that they did not achieve a response to
   treatment or they did not have a duration of treatment on EGFR-TKI of 6 months or more

   - For Dose Expansion Cohort E: patient must have progressive disease on osimertinib
   (AZD9291) as first-line EGFR-TKI treatment for metastatic NSCLC; patients must also be
   treatment naive to EGFR-monoclonal antibody

   - Adequate archival tissue from a biopsy performed after progression of disease on
   previous EGFR-TKI or willing to consent for a fresh tumor biopsy; (mandatory for
   Cohorts A, B, C; optional for dose escalation and Cohort D, and Cohort E)

   - Patients must have measurable disease by Response Evaluation Criteria in Solid Tumors
   (RECIST) 1.1, defined as at least one lesion that can be accurately measured in at
   least one dimension >= 10 mm (>= 1 cm) by computed tomography (CT) imaging or magnetic
   resonance imaging (MRI) within 42 days prior to registration; the CT from a combined
   positron emission tomography (PET)/CT may be used only if it is of diagnostic;
   laboratory parameters are not acceptable as the only evidence of disease

   - Any number of prior therapies is 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 and necitumumab in
   patients < 18 years of age, children are excluded from this study

   - Eastern Cooperative Oncology Group (ECOG) performance status =< 1

   - Patients must have the ability to swallow tablets

   - Life expectancy of greater 3 months

   - Absolute neutrophil count >= 1,500/mcL

   - Platelets >= 100,000/mcL

   - Total bilirubin =< 1.5 x upper limit of normal (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 x institutional upper limit of normal

   - Creatinine =< 1.5 x ULN OR

   - Creatinine clearance >= 50 mL/min

   - The effects of osimertinib (AZD9291) and necitumumab 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 osimertinib (AZD9291) and/or necitumumab:

      - 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) 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, for all methods above (except for abstinence), male subjects
      (including those who are vasectomized) whose partners are pregnant or might be
      pregnant must use condoms for the duration of the study and for 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 untreated brain metastases are allowed provided that the patient is
   clinically asymptomatic and stable; patients with a prior history of symptomatic brain
   metastases are eligible provided:

      - The brain metastases have been treated

      - The patient is asymptomatic from the brain metastases at enrollment

      - 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
   with the exception that patients on osimertinib (AZD9291) for cohorts B, C and E can
   continue osimertinib (AZD9291) and need not discontinue prior to enrollment

   - Patients who are receiving any other investigational agents; patients must have
   discontinued any other investigational agents for at least 5 half-lives or 3 months,
   whichever is greater, prior to initiation of osimertinib (AZD9291) in an
   investigational setting

   - 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 prior to receiving the first dose
   of study treatment) medications or herbal supplements known to be potent inducers of
   CYP3A4 (at least 3 weeks prior); all patients must try to avoid concomitant use of any
   medications, herbal supplements and/or ingestion of foods with known inducer effects
   of CYP3A4

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

   - Mean resting corrected QT interval (QTc using Fridericia's formula [QTcF]) > 470 msec

   - Any clinically important abnormalities in rhythm, conduction or morphology of resting
   electrocardiography (ECG) (e.g., complete left bundle branch block, third degree heart
   block, second degree heart block)

   - Any factors that increase the risk of QTc prolongation or risk of arrhythmic events
   such as heart failure, hypokalemia, congenital long QT syndrome, family history of
   long QT syndrome or unexplained sudden death under 40 years of age in first degree
   relatives or any concomitant medication known to prolong the QT interval and cause
   torsades de pointes

   - Left ventricular ejection fraction < 50% on echocardiogram or multi-gated acquisition

   - The effects of osimertinib (AZD9291) and necitumumab on the developing human fetus are
   unknown; for this reason and because EGFR inhibitors are known to be teratogenic,
   pregnant women are excluded from this study; because there is an unknown but potential
   risk for adverse events in nursing infants secondary to treatment of the mother
   osimertinib (AZD9291) and necitumumab breastfeeding should be discontinued if the
   mother is treated with osimertinib (AZD9291) and necitumumab; these potential risks
   may also apply to other agents used in this study

   - Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral
   therapy are ineligible because of the potential for pharmacokinetic interactions with
   osimertinib (AZD9291)


biological: Necitumumab

drug: Osimertinib

procedure: Biospecimen Collection

procedure: Computed Tomography

procedure: Magnetic Resonance Elastography

Not Recruiting

Contact Information

Stanford University
School of Medicine
300 Pasteur Drive
Stanford, CA 94305
Brianna Velazquez

New Trial Alerts

Receive email alerts when trials open to patients.