Clinical Trials /

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

NCT03433469

Description:

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.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib in Treating Participants With Stage I-IIIA EGFR-mutant Non-small Cell Lung Cancer Before Surgery
  • Official Title: A Phase II Study to Evaluate Neoadjuvant Osimertinib Therapy in Patients With Surgically Resectable, EGFR-Mutant Non-Small Cell Lung Cancer

Clinical Trial IDs

  • ORG STUDY ID: 17658
  • SECONDARY ID: NCI-2018-00019
  • SECONDARY ID: 17-23309
  • SECONDARY ID: 17658
  • NCT ID: NCT03433469

Conditions

  • EGFR (Epidermal Growth Factor Receptor) Exon 19 Deletion Mutation
  • EGFR NP_005219.2:p.L858R
  • EGFR NP_005219.2:p.T790M
  • Stage I Non-Small Cell Lung Cancer AJCC (American Joint Committee on Cancer) v7
  • Stage IA Non-Small Cell Lung Carcinoma AJCC v7
  • Stage IB Non-Small Cell Lung Carcinoma AJCC v7
  • Stage II Non-Small Cell Lung Cancer AJCC v7
  • Stage IIA Non-Small Cell Lung Carcinoma AJCC v7
  • Stage IIB Non-Small Cell Lung Carcinoma AJCC v7
  • Stage IIIA Non-Small Cell Lung Cancer AJCC v7

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, TagrissoTreatment (osimertinib)

Purpose

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.

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.
    

Trial Arms

NameTypeDescriptionInterventions
Treatment (osimertinib)ExperimentalParticipants 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.
  • Osimertinib

Eligibility 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

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

Primary Outcome Measures

Measure:Major pathological response rate (MPR) defined as =< 10% viable tumor present histologically in the resected tumor specimen
Time Frame:Up to 1 year
Safety Issue:
Description: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

Measure: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
Safety Issue:
Description:The Kaplan-Meier analysis will be used to calculate the mean DFS with 95% confidence interval.
Measure:1 year overall survival (OS)
Time Frame:From surgical resection to death due to any cause, assessed up to 1 year
Safety Issue:
Description:The Kaplan-Meier analysis will be used to calculate the mean OS with 95% confidence interval.
Measure: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
Safety Issue:
Description:Depth of response will be summarized using descriptive statistics and correlated with patient outcomes using hazard ratios via the Cox proportional hazards model.
Measure: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
Safety Issue:
Description: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.
Measure: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
Safety Issue:
Description:
Measure:Rate of inability to undergo surgical resection
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure:Rate of surgical complications occurring prior to the end of treatment visit
Time Frame:Up to 1 year
Safety Issue:
Description:Rate of surgical complications occurring prior to the end of treatment visit will be recorded.
Measure:Treatment-emergent adverse events (AEs), laboratory abnormalities and electrocardiogram (ECG) abnormalities
Time Frame:Up to 1 year
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:University of California, San Francisco

Last Updated

April 27, 2018