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Osimertinib in Treating Participants With Stage I-IIIA EGFR-mutant Non-small Cell Lung Cancer Before Surgery

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ClinicalTrials.gov Identifier: NCT03433469
Recruitment Status : Recruiting
First Posted : February 14, 2018
Last Update Posted : May 14, 2019
Sponsor:
Collaborator:
AstraZeneca
Information provided by (Responsible Party):
University of California, San Francisco

Brief Summary:
This phase II trial studies how well osimertinib works in treating participants with stage I-IIIA Epithelial Growth Factor Receptor (EGFR) -mutant non-small cell lung cancer before surgery. Osimertinib may stop the growth of tumor cells by blocking mutant EGFR signaling in cancer cells.

Condition or disease Intervention/treatment Phase
Stage I Non-Small Cell Lung Cancer Stage IA Non-Small Cell Lung Cancer Stage IB Non-Small Cell Lung Cancer Stage II Non-Small Cell Lung Cancer Stage IIA Non-Small Cell Lung Cancer Stage IIB Non-Small Cell Lung Cancer Stage IIIA Non-Small Cell Lung Cancer Other: Laboratory Biomarker Analysis Drug: Osimertinib Procedure: Therapeutic Conventional Surgery Phase 2

Detailed Description:

PRIMARY OBJECTIVES:

I. To evaluate the efficacy of osimertinib as neoadjuvant therapy in patients with surgically resectable EGFR-mutant non-small cell lung cancer (NSCLC).

SECONDARY OBJECTIVES:

I. To evaluate the safety of osimertinib given as neoadjuvant therapy in early stage EGFR-mutant NSCLC participants.

II. To evaluate whether neoadjuvant osimertinib treatment increases the frequency of tumors that are unresectable due to adverse events or disease progression.

III. To evaluate secondary measures of clinical efficacy in early stage EGFR-mutant NSCLC patients treated with osimertinib induction therapy.

TERTIARY OBJECTIVES:

I. To evaluate long-term measures of efficacy in patients treated with osimertinib neoadjuvant therapy.

II. To explore tissue and cell-free biomarkers that may be predictive of response or primary resistance to osimertinib neoadjuvant therapy.

OUTLINE:

Participants receive osimertinib orally (PO) once daily (QD) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection of their cancer.

After completion of study treatment, participants are followed up at 30 days then every 3 months for up to 1 year.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 27 participants
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase II Study to Evaluate Neoadjuvant Osimertinib Therapy in Patients With Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer
Actual Study Start Date : July 31, 2018
Estimated Primary Completion Date : May 31, 2021
Estimated Study Completion Date : May 31, 2022

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lung Cancer
Drug Information available for: Osimertinib

Arm Intervention/treatment
Experimental: Treatment (osimertinib)
Participants receive osimertinib orally, once a day (PO QD) on days 1-28. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. Patients then undergo surgical resection of their cancer.
Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Osimertinib
Given PO (orally)
Other Names:
  • AZD-9291
  • Tagrisso

Procedure: Therapeutic Conventional Surgery
Undergo surgery




Primary Outcome Measures :
  1. Major pathological response rate (MPR) defined as =< 10% viable tumor present histologically in the resected tumor specimen [ Time Frame: Up to 1 year ]
    Tumors that exhibit =< 10% viable tumor will meet the criteria for a major pathological response. The major pathological response rate will be reported with 95% confidence intervals.


Secondary Outcome Measures :
  1. 1 year disease-free survival (DFS) [ Time Frame: From date of surgical resection to documented radiographic relapse/progression or death due to any cause, assessed up to 1 year ]
    The Kaplan-Meier analysis will be used to calculate the mean DFS with 95% confidence interval.

  2. 1 year overall survival (OS) [ Time Frame: From surgical resection to death due to any cause, assessed up to 1 year ]
    The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.

  3. Depth of response (DpR) defined as the percentage change in tumor burden by RECIST criteria at best response versus baseline imaging [ Time Frame: Baseline up to 1 year ]
    Depth of response will be summarized using descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox proportional hazards model.

  4. Objective Response Rate (ORR) determined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria by investigator's assessment [ Time Frame: From start of treatment until time of surgery ]
    The frequency and percentages of patients with a best overall response rate of complete response (CR), partial response (PR), stable disease (SD), or progressive disease (PD) will be determined. The ORR will be reported with 95% confidence intervals.

  5. Pathologic complete response rate (pCR) defined as absence of (0%) viable tumor present histologically in the resected tumor specimen [ Time Frame: Up to 1 year ]
  6. Rate of inability to undergo surgical resection [ Time Frame: Up to 1 year ]
    Rate of conversion from operable to non-operative will be recorded as rate of patients initially assessed as surgically resectable, who are subsequently unable to undergo surgical resection due to either treatment-related adverse events (AEs) or disease progression.

  7. Rate of surgical complications occurring prior to the end of treatment visit [ Time Frame: Up to 1 year ]
    Rate of surgical complications occurring prior to the end of treatment visit will be recorded.

  8. Treatment-emergent adverse events (AEs), laboratory abnormalities and electrocardiogram (ECG) abnormalities [ Time Frame: Up to 1 year ]
    AE terms recorded on the case report forms (CRFs) will be mapped to preferred terms using the Medical Dictionary for Regulatory Activities (MedDRA). Seriousness, severity grade and relationship to study treatment will be assessed by the investigator. Severity grade will be defined by the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 4.03.


Other Outcome Measures:
  1. Adverse pathologic outcomes [ Time Frame: Up to 1 year ]
    Rates of adverse pathologic features including rates of positive margins, lymphovascular invasion (LVI), and pathologic upstaging (e.g. by T or N status) as compared to clinical staging based on pre-operative scans, for comparison to historical controls will be recorded.

  2. Changes in circulating tumor deoxyribonucleic acid (ctDNA) [ Time Frame: Baseline up to 1 year ]
    Descriptive statistics and graphical methods will be used to analyze the data.

  3. Changes in immune cell infiltration [ Time Frame: Baseline up to 1 year ]
  4. Calculation of z-score to describe genomic and transcriptional changes within cancer cell populations after treatment [ Time Frame: Baseline up to 1 year ]
    Performance of RNA sequencing and whole exome sequencing analysis on isolated cancer cell populations from pre-treatment tumor biopsy specimens, as well as tumor tissue acquired at the time of surgical resection. Changes of expression levels to baseline will described by calculating z-score

  5. Concentration of ctDNA in peripheral blood samples [ Time Frame: Up to 1 year ]
    Peripheral blood and plasma samples will be stored for the assessment of variant allele frequencies



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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:

  • Histologically or cytologically confirmed non-small cell lung cancer, performed on a biopsy that occurred within the last 60 days
  • Documented activating EGFR mutation (Exon 19 deletion, T790M, or L858R) on tumor samples by Food and Drug Administration (FDA)-approved test
  • Positron emission tomography (PET)-computed tomography (CT) within the last 60 days showing radiographic stage I to IIIa lung cancer (mediastinal staging biopsy is allowed but not required)
  • Brain magnetic resonance imaging (MRI) (or CT if contraindication to MRI) within the last 60 days showing no evidence of metastatic disease
  • Documentation that the patient is a candidate for surgical resection of their lung cancer by an American Board of Thoracic Surgery certified surgeon
  • Measurable disease defined by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria
  • The patient must have a tumor size >=1 centimeter (cm) in its longest diameter.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) of 0-1
  • Resolution of all acute toxic effects of prior chemotherapy, radiotherapy or surgical procedures to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.03 grade 1
  • Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 2.5 x upper limit of normal (ULN)
  • Bilirubin =< 1.5 x ULN, (Patients with documented Gilbert?s syndrome and conjugated bilirubin within the normal range may be allowed into the study; in this event, it will be documented that the patient was eligible based on conjugated bilirubin levels)
  • Potassium and magnesium within normal range, patients may receive supplements to meet this requirement
  • Leukocytes > 3,000/microliter (mcL)
  • Hemoglobin >= 9 g/dL, with no blood transfusions in the 28 days prior to study entry
  • Absolute neutrophil count > 1,500/mcL
  • Platelets > 100,000/mcL
  • Creatinine =< 1.5 x upper limit of normal (ULN) OR creatinine clearance > 50 mL/min/1.73 m2 for patients with creatinine levels =< 1.5 x upper limit above institutional normal
  • Ability to swallow oral medications
  • Women of childbearing potential (WoCBP) must have a negative serum pregnancy test within 3 days prior to the first dose of study treatment and agree to use highly effective contraception, during the study and for 90 days following the last dose of osimertinib

    • Women of childbearing potential (WoCBP): women between menarche and menopause who have not been permanently or surgically sterilized and are capable of procreation
    • Women NOT of childbearing potential: women who are permanently or surgically sterilized or postmenopausal

      • Permanent sterilization includes hysterectomy and/or bilateral oophorectomy and/or bilateral salpingectomy but excludes bilateral tubal occlusion; tubal occlusion is considered a highly effective method of birth control but does not absolutely exclude possibility of pregnancy; (the term occlusion refers to both occluding and ligating techniques that do not physically remove the oviducts)
    • Women who have undergone tubal occlusion should be managed on trials as if they are of WoCBP (e.g. undergo pregnancy testing etc., as required by the study protocol)
    • Women will be considered postmenopausal if they are amenorrhoeic for 12 months without an alternative medical cause; the following age-specific requirements apply:

      • Women under 50 years old will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and with luteinizing hormone and follicle-stimulating hormone levels in the postmenopausal range
      • Women over 50 years of age will be considered postmenopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments
    • Acceptable contraception methods are:

      • Total sexual abstinence (abstinence must be for the total duration of the trial and the follow-up period)
      • Vasectomized sexual partner plus male condom (with participant assurance that partner received post-vasectomy confirmation of azoospermia)
      • Tubal occlusion plus male condom
      • Intra-uterine device - provided coils are copper-banded, plus male condom
      • Intra-uterine system (IUS) levonorgestrel IUS (e.g., Mirena), plus male condom
      • Medroxyprogesterone injections (Depo-Provera) plus male condom
      • Etonogestrel implants (e.g., Implanon, Norplan) plus male condom
      • Normal and low dose combined oral contraceptive pills, plus male condom
      • Norelgestromin / ethinylestradiol transdermal system plus male condom
      • Intravaginal device (e.g., ethinylestradiol and etonogestrel) plus male condom
      • Cerazette (desogestrel) plus male condom (Cerazette is currently the only highly efficacious progesterone based pill)
    • Unacceptable Contraception Methods The following methods are considered not to be highly effective and are therefore not acceptable contraceptive methods:

      • Triphasic combined oral contraceptives
      • All progesterone only pills except, Cerazette
      • All barrier methods, if intended to be used alone
      • Non-copper containing intra-uterine devices
      • Fertility awareness methods
      • Coitus interruptus
  • Men with a female partner of childbearing potential must have either had a prior vasectomy agree to use effective contraception as described in the full protocol for at least 14 days prior to administration of the first dose of study treatment, during the study, and for 90 days following the last dose of osimertinib

Exclusion Criteria:

  • Leptomeningeal carcinomatosis or other central nervous system (CNS) metastases
  • Stage IIIB, or distant metastases (including malignant pleural effusion) identified on PET-CT scan or biopsy (PET abnormalities that are negative for malignancy on biopsy will be considered on a case by case basis
  • Past medical history of interstitial lung disease, drug-induced interstitial lung disease, radiation pneumonitis which required steroid treatment, or any evidence of clinically active interstitial lung disease
  • History of confirmed, corneal ulceration
  • Patients who are known to be serologically positive for human immunodeficiency virus (HIV)
  • Active second malignancy, i.e. patient known to have potentially fatal cancer present for which he/she may be (but not necessarily) currently receiving treatment; patients with a history of malignancy that has been completely treated, with no evidence of that cancer currently, are permitted to enroll in the trial provided all chemotherapy for prior malignancy was completed > 12 months prior and/or bone marrow transplant > 2 years prior
  • Patients who are currently receiving treatment with contraindicated corrected QT interval (QTc) prolonging medications or potent CYP3A4 inducers, if that treatment cannot be either discontinued or switched to a different medication prior to first day of study treatment
  • Any of the following cardiac abnormalities or history:

    • Mean resting corrected QT interval (QTc) > 470 msec, obtained from 3 electrocardiograms (ECGs), using the screening clinic ECG machine derived QTc value
    • Any clinically important abnormalities in rhythm, conduction or morphology of resting ECG e.g. complete left bundle branch block, third degree heart block and second degree heart block
    • Any factors that increase the risk of QTc prolongation or risk of arrhythmic events such as heart failure, hypokalaemia, 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
  • Treatment with prohibited medications (concurrent anticancer therapy including chemotherapy, radiation, hormonal treatment [except corticosteroids and megesterolacetate], or immunotherapy) =< 14 days prior to treatment with osimertinib
  • Prior treatment with osimertinib or other drugs that target EGFR mutant non-small cell lung cancer (including erlotinib, afatinib, gefitinib, rocelitinib)
  • Any evidence of severe or uncontrolled systemic diseases, including uncontrolled hypertension and active bleeding diatheses, which in the investigator?s opinion makes it undesirable for the patient to participate in the trial or which would jeopardize compliance with the protocol, or known active infection including chronic active hepatitis B, hepatitis C and human immunodeficiency virus (HIV); screening for chronic conditions is not required; patients with chronic hepatitis B virus (HBV) with negative HBV viral load on appropriate antiviral therapy will be permitted, if able to continue appropriate antiviral therapy throughout treatment period
  • Active tuberculosis
  • Signs or symptoms of infection within 2 weeks prior to first day of study
  • Therapeutic oral or intravenous (IV) antibiotics within 2 weeks prior to first day of study treatment:

    • Patients receiving prophylactic antibiotics (eg, to prevent a urinary tract infection or chronic obstructive pulmonary disease exacerbation) are eligible
  • Class II to IV heart failure as defined by the New York Heart Association functional classification system
  • Patients with known coronary artery disease, congestive heart failure not meeting the above criteria, or left ventricular ejection fraction (LVEF) < 50% must be on a stable medical regimen that is optimized in the opinion of the treating physician, in consultation with a cardiologist if appropriate, to be eligible
  • Patients who have experienced untreated and/or uncontrolled cardiovascular conditions and/or have symptomatic cardiac dysfunction (unstable angina, congestive heart failure, myocardial infarction within the previous 3 months; coronary angioplasty, or stenting or bypass grafting within the past 6 months; cardiac ventricular arrhythmias requiring medication; any history of second (2nd) or third (3rd) degree atrioventricular conduction defects)
  • Females who are pregnant or breastfeeding
  • Presence of active gastrointestinal (GI) disease (including GI bleeding or ulceration) or other condition that could affect GI absorption (e.g. malabsorption syndrome, history of biliary tract disease), including refractory nausea or vomiting, or chronic GI disease which may affect absorption or tolerance to oral medications
  • History of hypersensitivity to active or inactive excipients of osimertinib or drugs with a similar chemical structure or class to osimertinib
  • Involvement in the planning and/or conduct of the study (applies to both investigator staff and/or staff at the study site)
  • Participation in another clinical study with an investigational product during the last 2 months or within five half-lives of the compound, whichever is longer
  • Uncontrolled medical, psychological, familial, sociological, or geographical conditions that interfere with the patient?s safety, ability to provide informed consent, or ability to comply with the protocol

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): NCT03433469


Locations
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United States, California
University of California, San Francisco Recruiting
San Francisco, California, United States, 94115
Contact: Collin M. Blakely, M.D.    877-827-3222    cancertrials@ucsf.edu   
Principal Investigator: Collin M. Blakely, M.D.         
United States, Colorado
University of Colorado Not yet recruiting
Denver, Colorado, United States, 80217-3364
Contact: Robert C. Doebele    303-724-2980    robert.doebele@ucdenver.edu   
Contact: Paula Fisk    720-848-0676    Paula.Fisk@ucdenver.edu   
Principal Investigator: Robert C. Doebele         
Sponsors and Collaborators
University of California, San Francisco
AstraZeneca
Investigators
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Principal Investigator: Collin Blakely University of California, San Francisco

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Responsible Party: University of California, San Francisco
ClinicalTrials.gov Identifier: NCT03433469     History of Changes
Other Study ID Numbers: 17658
NCI-2018-00019 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
17658 ( Other Identifier: University of California, San Francisco )
First Posted: February 14, 2018    Key Record Dates
Last Update Posted: May 14, 2019
Last Verified: May 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Product Manufactured in and Exported from the U.S.: No

Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Osimertinib
Antineoplastic Agents
Protein Kinase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action