EGFR-mutant Lung Cancers, Non-small Cell Lung Cancer
Conditions
Keywords
Osimertinib, bevacizumab, metastatic, 16-033
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.
Interventions
DRUGosimertinib
DRUGBevacizumab
Sponsors
AstraZeneca
Genentech, Inc.
Memorial Sloan Kettering Cancer Center
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
19 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Osimertinib and Bevacizumab Phases 1+2: Osimertinib + Bevacizumab 80 mg Osimertinib PO QD and 15 mg/kg Bevacizumab IV Q3W
This section accurately reflects the flow of participants as all participants were enrolled into the same dosing cohort. This protocol utilized a dose de-escalation model where the initial dose was continued for Phase 2. | 49 |
| Total | 49 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | Adverse Event | 4 |
| Overall Study | Complete resection of target disease | 2 |
| Overall Study | Death | 4 |
| Overall Study | Participant moved away | 1 |
| Overall Study | Progressive disease | 29 |
| Overall Study | Switched to commercial Osi | 1 |
| Overall Study | Withdrawal by Subject | 8 |
Baseline characteristics
| Characteristic | Osimertinib and Bevacizumab |
|---|---|
| Age, Continuous | 60 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 2 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 46 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 1 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 14 Participants |
| Race (NIH/OMB) Black or African American | 1 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 3 Participants |
| Race (NIH/OMB) White | 31 Participants |
| Region of Enrollment United States | 49 Participants |
| Sex: Female, Male Female | 34 Participants |
| Sex: Female, Male Male | 15 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 37 / 49 |
| other Total, other adverse events | 49 / 49 |
| serious Total, serious adverse events | 26 / 49 |
Outcome results
Primary
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib and Bevacizumab | Bevacizumab Maximum Tolerated Dose (MTD) (Phase I) | 15 mg/kg |
Primary
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.
Time frame: 1 year
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Osimertinib and Bevacizumab | Osimertinib Maximum Tolerated Dose (MTD) (Phase I) | 80 mg |
Primary
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.
Time frame: 12 months
| Arm | Measure | Category | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Osimertinib and Bevacizumab | Progression-free Survival (Phase II) | Unconfirmed Partial Response/PR | 5 Participants |
| Osimertinib and Bevacizumab | Progression-free Survival (Phase II) | Stable Disease/SD | 9 Participants |
| Osimertinib and Bevacizumab | Progression-free Survival (Phase II) | Not Evaluable/NE | 1 Participants |
| Osimertinib and Bevacizumab | Progression-free Survival (Phase II) | Confirmed Partial Response/PR | 34 Participants |