Osimertinib and Bevacizumab as Treatment for EGFR-mutant Lung Cancers

Study Overview
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Brief Summary
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The purpose of this study is to test the safety of combining the drugs osimertinib and bevacizumab at different dose levels. The investigators want to find out what effects, good and/or bad, taking osimertinib and bevacizumab has on the patient and lung cancer. This study will try to find the best dose of osimertinib and bevacizumab given together that does not cause significant side effects. Once the investigators determine that combining osimertinib and bevacizumab is safe, they want to see if the combination is effective in treating lung cancers with the EGFR mutation.

Official Title
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A Phase 1/2 Study of Combination Osimertinib and Bevacizumab as Treatment for Patients With EGFR-mutant Lung Cancers

Conditions
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Non-small Cell Lung Cancer, EGFR-mutant Lung Cancers

Intervention / Treatment
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* Drug: osimertinib
* Drug: Bevacizumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Written informed consent Advanced biopsy-proven metastatic non-small cell lung cancer Somatic activating mutation in EGFR No prior treatment with an EGFR TKI No prior treatment with a VEGF inhibitor Measurable (RECIST 1.1) indicator lesion not previously irradiated Karnofsky performance status (KPS) ≥ 70% Age >18 years old Adequate organ function AST, ALT ≤ 3 x ULN Total bilirubin ≤ 1.5x ULN Creatinine ≤ 1.5x ULN OR calculated creatinine clearance > 60ml/min Absolute neutrophil count (ANC) ≥ 1000 cells/mm3 Hemoglobin≥8.0 g/dL Platelets ≥100,000/mm3 Exclusion Criteria: Any contra-indications to bevacizumab which include but are not limited to recent Any previous venous thromboembolism > NCI CTCAE Grade 3 Severe uncontrolled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥ 100mmHg) Cardiovascular disease including stroke of myocardial infarction <6 months prior to study enrollment, New York Heart Association Grade 2 or greater congestive heart failure, serious cardiac arrythmia uncontrolled by medication Hemorrhagic brain metastases. Asymptomatic (not requiring escalating doses of steroids) brain metastases are acceptable. History of severe proteinuria (urine dipstick ≥ 2+ or 24 hr urine > 2gm/24hr) Prior history of hypertensive crisis or hypertensive encephalopathy History of a central nervous system disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy Significant vascular disease (e.g. aortic aneurysm requiring surgical repair)≥ 6 months prior to study enrollment History of hemoptysis (≥1/2 teaspoon of bright red blood per episode) within the last 3 months Evidence of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation) Current or recent (within 10 days of study drug start) use of aspirin (>325mg daily), clopidogrel (>75mg daily). Recent initiation of full dose oral or parental anticoagulants that have not been in place for at least 2 weeks. Tumor invading or abutting major blood vessels Tumor histology classified by squamous cell histology. Any history of abdominal fistula or GI perforation within 6 months of study enrollment Pregnant or lactating women Any type of systemic anticancer therapy (chemotherapy or experimental drugs) within 2 weeks of starting treatment on protocol Any radiotherapy within 1 week of starting treatment on protocol Any major surgery within 4 weeks of starting treatment on protocol Any evidence of clinically significant interstitial lung disease Known hypersensitivity to any component of bevacizumab and osimertinib

Ages Eligible for Study
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Minimum Age: 19 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: osimertinib and bevacizumab<br>Phase 1: 3+3 dose escalation design 2 dose levels Dose level -1: Osimertinib 40mg daily Maximum accrual = 12 Bevacizumab 15mg/kg q3 weeks Dose level 1: Osimertinib 80mg daily Bevacizumab 15mg/kg q3 Weeks Phase 2: Use MTD determined during phase 1 | Drug: osimertinib<br> <br> * Other names: AZD9291;Drug: Bevacizumab<br> <br> |

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Osimertinib Maximum Tolerated Dose (MTD) (Phase I) | The MTD (maximum tolerated dose)/recommended phase 2 dose will be the highest dose level at which <1 DLT is detected in the first cycle for 6 treated patients. If only 3 patients are treated at a dose level being considered for the MTD, an additional 3 patients will be enrolled. | 1 year | 
| Bevacizumab Maximum Tolerated Dose (MTD) (Phase I) | The MTD (maximum tolerated dose)/recommended phase 2 dose will be the highest dose level at which <1 DLT is detected in the first cycle for 6 treated patients. If only 3 patients are treated at a dose level being considered for the MTD, an additional 3 patients will be enrolled. | 1 year | 
| Progression-free Survival (Phase II) | Tumor response will be assessed using RECIST 1.1. A CT chest/abdomen/pelvis will be performed to demonstrate all known areas of measurable disease. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Overall Response (OR) = CR + PR. | 12 months | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Osimertinib, bevacizumab, metastatic, 16-033