Osimertinib and Bevacizumab as Treatment for EGFR-mutant Lung Cancers

Phase 1

Completed

• Conditions: EGFR-mutant Lung Cancers; Non-small Cell Lung Cancer
• Interventions: Drug: osimertinib; Drug: Bevacizumab

• Registration Number: NCT02803203
• Lead Sponsor: Memorial Sloan Kettering Cancer Center

Brief Summary

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.

Detailed Description

Not available

Study Timeline

• Study First Submitted: 2016-06-14
• Study First Submitted QC: 2016-06-14
• Study First Posted: 2016-06-16
• Study Start: 2016-06-29
• Status Verified: 2022-03
• Primary Completion: 2022-03-01
• Study Completion: 2022-03-01
• Results First Submitted: 2023-02-28
• Results First Submitted QC: 2023-08-29
• Last Update Submitted: 2023-08-29
• Results First Posted: 2023-09-22
• Last Update Posted: 2023-09-22

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 49

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

  1. Any previous venous thromboembolism > NCI CTCAE Grade 3
  2. Severe uncontrolled hypertension (systolic blood pressure ≥150 mmHg and/or diastolic blood pressure ≥ 100mmHg)
  3. 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
  4. Hemorrhagic brain metastases. Asymptomatic (not requiring escalating doses of steroids) brain metastases are acceptable.
  5. History of severe proteinuria (urine dipstick ≥ 2+ or 24 hr urine > 2gm/24hr)
  6. Prior history of hypertensive crisis or hypertensive encephalopathy
  7. History of a central nervous system disease (e.g. seizures) unrelated to cancer unless adequately treated with standard medical therapy
  8. Significant vascular disease (e.g. aortic aneurysm requiring surgical repair)≥ 6 months prior to study enrollment
  9. History of hemoptysis (≥1/2 teaspoon of bright red blood per episode) within the last 3 months
  10. Evidence of a bleeding diathesis or significant coagulopathy (in the absence of therapeutic anticoagulation)
  11. Current or recent (within 10 days of study drug start) use of aspirin (>325mg daily), clopidogrel (>75mg daily).
  12. Recent initiation of full dose oral or parental anticoagulants that have not been in place for at least 2 weeks.
  13. Tumor invading or abutting major blood vessels
  14. Tumor histology classified by squamous cell histology.
  15. 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

Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
osimertinib and bevacizumab	osimertinib	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
osimertinib and bevacizumab	Bevacizumab	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

Primary Outcome Measures

Name	Time	Method
Progression-free Survival (Phase II)	12 months	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.
Osimertinib Maximum Tolerated Dose (MTD) (Phase I)	1 year	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.
Bevacizumab Maximum Tolerated Dose (MTD) (Phase I)	1 year	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.

Trial Locations

Locations (7)

Memorial Sloan Kettering commack; 🇺🇸 Commack, New York, United States

Memorial Sloan Kettering Westchester; 🇺🇸 Harrison, New York, United States

Memorial Sloan Kettering Cancer Center; 🇺🇸 New York, New York, United States

Memorial Sloan Kettering Nassau; 🇺🇸 Uniondale, New York, United States

Memorial Sloan Kettering Bergen; 🇺🇸 Montvale, New Jersey, United States

Memoral Sloan Kettering Basking Ridge; 🇺🇸 Basking Ridge, New Jersey, United States

Memorial Sloan Kettering Monmouth; 🇺🇸 Middletown, New Jersey, United States