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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

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ClinicalTrials.gov Identifier: NCT02496663
Recruitment Status : Recruiting
First Posted : July 14, 2015
Last Update Posted : October 7, 2019
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Brief Summary:
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 (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.

Condition or disease Intervention/treatment Phase
EGFR Exon 19 Deletion Mutation EGFR NP_005219.2:p.L858R EGFR NP_005219.2:p.T790M Metastatic Lung Non-Small Cell Carcinoma Recurrent Lung Non-Small Cell Carcinoma Stage IV Lung Non-Small Cell Cancer AJCC v7 Biological: Necitumumab Drug: Osimertinib Phase 1

Detailed Description:

PRIMARY OBJECTIVES:

I. To determine the safety and tolerability of osimertinib (AZD9291) in combination with necitumumab in patients with EGFR-mutant non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To observe and record anti-tumor activity in these NSCLC patients in select cohorts of patients with EGFR-activating mutations including EGFR Exon 20 insertion mutations.

TRANSLATIONAL OBJECTIVES:

I. To characterize the pharmacokinetics of AZD9291 in combination with necitumumab.

II. To explore biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors (TKIs) and with the combination by studying biopsied tumor tissue at baseline and at progression, as well as serial plasma deoxyribonucleic acid (DNA) specimens.

III. To create patient derived xenograft (PDX) models of patients with EGFR-mutant NSCLC both prior to study initiation and at acquired resistance to treatment.

OUTLINE: This is a dose-escalation study of necitumumab.

Patients receive osimertinib orally (PO) once daily (QD) on days 1-21 and necitumumab intravenously (IV) over 60 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 4 weeks, 8 weeks, every 12 weeks for 1 year, and annually thereafter.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 100 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I Trial of AZD9291 and Necitumumab in EGFR-Mutant Non-Small Cell Lung Cancer After Progression on a Previous EGFR Tyrosine Kinase Inhibitor
Actual Study Start Date : March 24, 2016
Estimated Primary Completion Date : June 30, 2020

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: Treatment (osimertinib, necitumumab)
Patients receive osimertinib PO QD on days 1-21 and necitumumab IV over 60 minutes on days 1 and 8. Cycles repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Biological: Necitumumab
Given IV
Other Names:
  • Anti-Epidermal Growth Factor Receptor Monoclonal Antibody IMC-11F8
  • IMC-11F8
  • Portrazza

Drug: Osimertinib
Given PO
Other Names:
  • AZD-9291
  • AZD9291
  • Mereletinib
  • Tagrisso




Primary Outcome Measures :
  1. Maximum tolerated dose (MTD) of necitumumab combined with osimertinib [ Time Frame: 21 days ]
    Defined as the highest dose tested in which only 0 or 1 out of 6 evaluable patients experience a dose limiting toxicity, as graded by the National Cancer Institute (NCI) Common terminology Criteria for Adverse Events (CTCAE) version 5.0. The recommended phase II dose (RP2D) will be the MTD, pending review of other safety/tolerability considerations. The RP2D will be determined based upon the MTD in the dose escalation portion as well as other considerations such as toxicities at additional courses. After completing the 4 expansion cohorts, the dose level will be re-reviewed to confirm that the RP2D is in fact well tolerated.

  2. Incidence of toxicity [ Time Frame: Up to 1 year ]
    Will be graded according to NCI CTCAE version 5.0. Grade and attribution will be summarized by dose level, cycle, organ system and type.


Secondary Outcome Measures :
  1. Objective response rate (ORR) in patients treated at the recommended phase II dose [ Time Frame: Up to 1 year ]
    Will be graded according to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. ORR will be calculated as the percent of patients in each of the expansion cohorts whose best confirmed response is complete response (CR) or partial response (PR). Point estimates and associated 90% confidence intervals will be calculated.

  2. Progression-free survival (PFS) [ Time Frame: From start of treatment to time of progression or death, whichever occurs first, assessed up to 1 year ]
    Kaplan-Meier plots will be used to summarize the progression-free survival. Medians and associated 95% confidence intervals will be calculated.

  3. Disease control rate (DCR) with combination osimertinib and necitumumab [ Time Frame: Up to 1 year ]
    DCR will be the proportion of patients in each of the expansion cohorts whose best confirmed response is CR, PR, or stable disease. Point estimates and associated 90% confidence intervals will be calculated.


Other Outcome Measures:
  1. Pharmacokinetic (PK) parameters of osimertinib in combination with necitumumab [ Time Frame: Prior to dosing on day 1 of course 2, 1, 2, 4, 6, 8, and 24 hours after dosing in course 2 (dose escalation and cohort A); prior to treatment on day 1 of course 2 for up to 4 courses (cohorts B, C, and D) ]
    The PK analyses will be descriptive and will permit comparison of the plasma levels of osimertinib and its metabolites in the presence of necitumumab (in this trial) with levels in other studies where osimertinib is given alone or combined with other drugs. We will estimate mean PK parameters as well as the between-patient variability. Results will be listed and plotted, by dose as well as by objective response, qualitative patterns will be described, and means and standard deviations will be calculated for use in planning follow-up studies.

  2. Presence of biomarkers of response and resistance to previous EGFR-tyrosine kinase inhibitors [ Time Frame: Up to 1 year ]
    Will study biopsied tumor tissue as well as serial plasma deoxyribonucleic acid specimens. For each cohort alone, Fisher's exact test, and in a stratified analysis including all cohorts, an exact logistic regression model, will be used to examine the association with objective response and a Cox proportional hazards model will be used to examine the association with PFS. Odds ratio's and hazard ratio's will be estimated and associated 90% two-sided confidence intervals will be constructed. Testing will be one-sided, at the 0.05-level.



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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

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 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 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 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, 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 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
  • 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 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 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 AZD9291 for cohorts B, C and E can continue 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 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 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 (MUGA)
  • The effects of 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 AZD9291 and necitumumab breastfeeding should be discontinued if the mother is treated with 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 AZD9291

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02496663


Locations
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United States, California
City of Hope Comprehensive Cancer Center Recruiting
Duarte, California, United States, 91010
Contact: Site Public Contact    800-826-4673    becomingapatient@coh.org   
Principal Investigator: Marianna Koczywas         
Stanford Cancer Institute Palo Alto Recruiting
Palo Alto, California, United States, 94304
Contact: Site Public Contact    650-498-7061    ccto-office@stanford.edu   
Principal Investigator: Sukhmani K. Padda         
University of California Davis Comprehensive Cancer Center Recruiting
Sacramento, California, United States, 95817
Contact: Site Public Contact    916-734-3089      
Principal Investigator: Jonathan W. Riess         
United States, Colorado
University of Colorado Hospital Recruiting
Aurora, Colorado, United States, 80045
Contact: Site Public Contact    720-848-0650      
Principal Investigator: Jose M. Pacheco         
United States, District of Columbia
MedStar Georgetown University Hospital Recruiting
Washington, District of Columbia, United States, 20007
Contact: Site Public Contact    202-444-2223      
Principal Investigator: Stephen V. Liu         
United States, Massachusetts
Massachusetts General Hospital Cancer Center Recruiting
Boston, Massachusetts, United States, 02114
Contact: Site Public Contact    877-726-5130      
Principal Investigator: Pasi A. Janne         
Brigham and Women's Hospital Recruiting
Boston, Massachusetts, United States, 02115
Contact: Site Public Contact    617-724-5200      
Principal Investigator: Pasi A. Janne         
Beth Israel Deaconess Medical Center Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    617-667-9925      
Principal Investigator: Pasi A. Janne         
Dana-Farber Cancer Institute Recruiting
Boston, Massachusetts, United States, 02215
Contact: Site Public Contact    877-442-3324      
Principal Investigator: Pasi A. Janne         
United States, North Carolina
Duke Cancer Institute Cary Active, not recruiting
Cary, North Carolina, United States, 27518
Duke University Medical Center Active, not recruiting
Durham, North Carolina, United States, 27710
Sponsors and Collaborators
National Cancer Institute (NCI)
Investigators
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Principal Investigator: Jonathan W Riess City of Hope Comprehensive Cancer Center LAO

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Responsible Party: National Cancer Institute (NCI)
ClinicalTrials.gov Identifier: NCT02496663     History of Changes
Other Study ID Numbers: NCI-2015-01053
NCI-2015-01053 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
PHI-77
9898 ( Other Identifier: City of Hope Comprehensive Cancer Center LAO )
9898 ( Other Identifier: CTEP )
UM1CA186717 ( U.S. NIH Grant/Contract )
First Posted: July 14, 2015    Key Record Dates
Last Update Posted: October 7, 2019
Last Verified: July 2019
Additional relevant MeSH terms:
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Carcinoma
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Osimertinib
Necitumumab
Antibodies, Monoclonal
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents, Immunological
Immunologic Factors
Physiological Effects of Drugs