Clinical Trials /

Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases

NCT02971501

Description:

This phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Immunotherapy with monoclonal antibodies, such as bevacizumab, may induce changes in body's immune system and may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

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

Recruiting

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Osimertinib With or Without Bevacizumab in Treating Patients With EGFR Positive Non-small Cell Lung Cancer and Brain Metastases
  • Official Title: A Phase II Trial of Osimertinib With or Without Bevacizumab in Patients With EGFR Mutation Positive NSCLC and Brain Metastases

Clinical Trial IDs

  • ORG STUDY ID: NCI-2016-01733
  • SECONDARY ID: NCI-2016-01733
  • SECONDARY ID: 10042
  • SECONDARY ID: 10042
  • SECONDARY ID: 10042
  • SECONDARY ID: P30CA016359
  • SECONDARY ID: UM1CA186689
  • NCT ID: NCT02971501

Conditions

  • EGFR Activating Mutation
  • EGFR NP_005219.2:p.T790M
  • Metastatic Malignant Neoplasm in the Brain
  • Non-Small Cell Lung Carcinoma
  • Recurrent Non-Small Cell Lung Carcinoma

Interventions

DrugSynonymsArms
OsimertinibAZD-9291, AZD9291, Mereletinib, TagrissoArm I (osimertinib, bevacizumab)

Purpose

This randomized phase II trial studies how well osimertinib with or without bevacizumab works in treating patients with EGFR positive non-small cell lung cancer that has spread to the brain. Osimertinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies, such as bevacizumab, may interfere with the ability of tumor cells to grow and spread. Giving osimertinib with or without bevacizumab may work better in treating patients with non-small cell lung cancer.

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the progression-free survival with osimertinib plus bevacizumab compared to osimertinib alone.

SECONDARY OBJECTIVES:

I. To assess the safety and tolerability of the combination of osimertinib and bevacizumab.

II. To evaluate the time to progression in the central nervous system (CNS) with osimertinib plus bevacizumab versus single-agent osimertinib.

III. To determine the overall response rate and the intracranial response rate to the combination versus single agent.

IV. To assess the overall survival in patients receiving osimertinib plus bevacizumab compared to osimertinib alone.

TERTIARY OBJECTIVES:

I. To investigate mechanisms of sensitivity and resistance to combination osimertinib plus bevacizumab versus osimertinib by molecularly characterizing tumor samples including T790M status.

II. To assess whether circulating tumor deoxyribonucleic acid (DNA) in plasma can be used as an indicator of sensitivity and resistance to treatment.

III. To determine whether an angiogenic signature using a multiplex panel array is associated with benefit from the combination of osimertinib plus bevacizumab.

IV. To investigate angiogenesis, immune and signaling pathway markers in tumor samples to determine biomarkers predictive of benefit from combination therapy.

OUTLINE: Patients are randomized to 1 of 2 arms.

ARM I: Patients receive osimertinib orally (PO) once daily (QD) on days 1-12 and bevacizumab intravenously (IV) over 30-90 minutes on day 1.

ARM II: Patients receive osimertinib PO QD on days 1-12.

In both arms, courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up for a minimum of 4 weeks.

Trial Arms

NameTypeDescriptionInterventions
Arm I (osimertinib, bevacizumab)ExperimentalPatients receive osimertinib PO QD on days 1-12 and bevacizumab IV over 30-90 minutes on day 1. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
      • Osimertinib
Arm II (osimertinib)ExperimentalPatients receive osimertinib PO QD on days 1-12. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
      • Osimertinib

Eligibility Criteria

Inclusion Criteria:

- Biopsy proven non-small cell lung cancer (NSCLC) with an activating EGFR mutation (exon 19 deletion, L858R point mutation, or any other mutation known to be associated with EGFR TKI sensitivity); plasma testing for EGFR is a suitable alternative to tissue testing if performed in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory; AND

- The presence of an EGFR T790M mutation from biopsy from any site of disease (intra- or extra-cranial) after progression on a first- or second-generation EGFR TKI; plasma testing for EGFR T790M is a suitable alternative to tissue testing if performed in a CLIA-certified laboratory; for patients who have disease progression in the CNS only (with otherwise stable disease systemically), T790M positivity is not required

- Patients must have measurable disease, defined as one or more of the following:

- At least one systemic (i.e. non-CNS) lesion that can be accurately measured in at least one dimension (longest diameter to be recorded for non-nodal lesions and short axis for nodal lesions) as >= 20 mm (>= 2 cm) with conventional techniques or as >= 10 mm (>= 1 cm) with spiral computed tomography (CT) scan, magnetic resonance imaging (MRI), or calipers by clinical exam; and/or

- At least one brain lesion that can be accurately measured in at least one dimension (longest diameter to be recorded) as >= 5 mm (>= 0.5 cm) with brain MRI; if the lesion is 5-10 mm in size and is the only measurable disease, MRI imaging must be performed with 1.5 mm slice thickness or less

- Disease progression on a first- or second-generation EGFR TKI (i.e. erlotinib, gefitinib, or afatinib); patient may have also received prior chemotherapy or immunotherapy but this is not required

- The presence of at least one untreated cerebral metastasis that is at least 5 mm but less than 20 mm, that is asymptomatic, and does not require local therapy at the time of enrollment; a history of previously treated brain metastases is allowed, however any lesion present at the time of whole brain radiotherapy or included in the stereotactic radiotherapy field (or within 2 mm of the treated lesion) will NOT be considered "untreated" unless it is new or documented to have progressed unequivocally since treatment

- Eastern Cooperative Oncology Group (ECOG) performance status =< 2

- Life expectancy of greater than 3 months

- Absolute neutrophil count >= 1,500/mcL

- Platelets >= 75,000/mcL

- Total bilirubin =< 1.5 x institutional upper limit of normal if no demonstrable liver metastases or =< 3 x institutional upper limit of normal in the presence of liver metastases or Gilbert's syndrome (unconjugated hyperbilirubinemia)

- Aspartate aminotransferases (AST) (serum glutamic-oxaloacetic transaminase [SGOT])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 2.5 x institutional upper limit of normal if no demonstrable liver metastases or =< 5 x institutional upper limit of normal in the presence of liver metastases

- Creatinine =< 1.5 x institutional upper limit of normal OR creatinine clearance >= 50 mL/min/1.73 m^2 for patients with creatinine levels above institutional normal

- The use of anti-convulsants in allowed, as long as the patient is on a stable dose with no seizure activity for at least 2 weeks prior to initiating trial therapy

- Fertile men and women must agree to use adequate contraceptive measures during study therapy and for at least 6 months after the completion of bevacizumab therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, the patient should inform the treating physician immediately

- Ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria:

- Symptomatic brain metastases

- Patients with brain metastases for whom complete surgical resection is clinically appropriate

- Prior treatment with a third-generation EGFR TKI (i.e. rociletinib)

- The use of corticosteroids to control cerebral edema or treat neurologic symptoms will not be allowed, and patients who previously required corticosteroids for symptom control must be off steroids for at least 3 days without recurrence of symptoms prior to starting trial therapy; corticosteroids for other indications is allowed

- Presence of leptomeningeal disease

- Patients may not be receiving any other investigational agents and may not have participated in a study of an investigational agent or using an investigational device within 2 weeks of the first dose of treatment

- Treatment with an EGFR TKI (i.e. erlotinib, gefitinib or afatinib) within 8 days or approximately 5 x half-life, whichever is longer, of the first dose of study treatment

- Any unresolved toxicities from prior therapy greater than Common Terminology Criteria for Adverse Events (CTCAE) grade 1 at the time of starting study treatment with the exception of alopecia and grade 2 platinum-therapy related neuropathy

- Concurrent, active malignancies in addition to that being studied (other than cutaneous squamous cell carcinoma or basal cell carcinoma)

- Any contraindication to MRI (i.e. patients with pacemakers or other metal implanted medical devices)

- History of clinically significant interstitial lung disease (ILD) (including drug-induced ILD), radiation pneumonitis requiring steroid treatment, or any evidence of clinically active ILD

- History of allergic reactions attributed to compounds of similar chemical or biologic composition to osimertinib or bevacizumab

- Urine protein should be screened by urine analysis; if protein is 2+ or higher, 24-hour urine protein should be obtained; patients with 24-hour urine protein >= 1000 mg are excluded

- Serious or non-healing wound, ulcer or bone fracture

- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months prior to day 1

- Invasive procedures defined as follows:

- Major surgical procedure, open biopsy or significant traumatic injury within 28 days prior to day 1 therapy

- Anticipation of need for major surgical procedures during the course of the study

- Core biopsy within 7 days prior to day 1 (D1) therapy

- Significant vascular disease (e.g., aortic aneurysm, requiring surgical repair or recent peripheral arterial thrombosis) within 6 months prior to day 1

- Patients with clinically significant cardiovascular disease are excluded.

- Inadequately controlled hypertension (HTN) (systolic blood pressure [SBP] > 160 mmHg and/or diastolic blood pressure [DBP] > 90 mmHg despite antihypertensive medication)

- History of cerebrovascular accident (CVA) within 6 months (see additional requirement for adjuvant protocols)

- Myocardial infarction or unstable angina within 6 months (see additional requirement for adjuvant protocols)

- New York heart association grade II or greater congestive heart failure

- Serious and inadequately controlled cardiac arrhythmia

- Significant vascular disease (e.g. aortic aneurysm, history of aortic dissection)

- Clinically significant peripheral vascular disease

- Any of the following cardiac criteria:

- Mean resting corrected QT interval (Fridericia's correction formula [QTcF]) > 470 ms using Fredericia's formula

- 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 corrected QT (QTc) prolongation or risk of arrhythmic events

- Evidence of bleeding diathesis or coagulopathy (including clinically significant hemoptysis)

- Patients with known hypersensitivity to Chinese hamster ovary cell products or other recombinant human antibodies

- 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 inhibitors of CYP3A4 (at least 1 week prior) and potent inducers of CYP3A4 (at least 3 week prior)

- Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements

- Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy

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

Primary Outcome Measures

Measure:Progression free survival (PFS)
Time Frame:From start of treatment to time of progression (in CNS or non-CNS disease) or death, whichever occurs first, assessed up to 2 years
Safety Issue:
Description:The two study arms will be compared for PFS with Kaplan-Meier estimates and log-rank tests. The Rothman confidence interval (CI), and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the PFS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.

Secondary Outcome Measures

Measure:Brain metastasis response rate
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Incidence of adverse events assessed by CTCAE
Time Frame:Up to 2 years
Safety Issue:
Description:Adverse medical events will be tabulated. National Cancer Institute toxicity grade 1 to grade 4 laboratory abnormalities will be listed.
Measure:Intracranial response assessed by Response Assessment in Neuro-Oncology Criteria-Glioblastoma Multiforme
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:Intracranial response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
Measure:Objective response defined as a complete or partial response assessed by Response Evaluation Criteria in Solid Tumors version 1.1
Time Frame:Up to 2 years
Safety Issue:
Description:
Measure:OS rate
Time Frame:At 12 months
Safety Issue:
Description:The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:Overall response rate
Time Frame:Up to 2 years
Safety Issue:
Description:Will be estimated using the 95% confidence CI based on Wilson's method. The Wilcoxon rank sum test and Fisher's exact test will be applied to study the association between the response status and the continuous and categorical variables respectively.
Measure:Overall survival (OS)
Time Frame:From start of treatment to death, assessed up to 2 years
Safety Issue:
Description:The two study arms will be compared for OS with Kaplan-Meier estimates and log-rank tests. The Rothman CI, and the simultaneous confidence bands will be reported. In addition, the possible risk factors will be compared for survival with log-rank test. For multivariate analysis, the proportional hazards Cox model will be applied to investigate potential prognostic factors, such as age and stage of disease of the OS data. The adjusted p-values of the hazard ratios and the adjusted 95% confidence interval will be reported.
Measure:Time to CNS progression
Time Frame:From start of treatment to time of progression in the CNS, assessed up to 2 years
Safety Issue:
Description:
Measure:Time to intracranial progression
Time Frame:Up to 2 years
Safety Issue:
Description:

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Not yet recruiting
Lead Sponsor:National Cancer Institute (NCI)

Trial Keywords

    Last Updated

    December 16, 2016