An open-label, randomized, Phase IIIb trial evaluating the efficacy and safety of standard of care +/- continuous bevacizumab treatment beyond progression of disease (PD) in patients with advanced non-squamous non-small cell lung cancer (NSCLC) after first (1st)-line treatment with bevacizumab plus a platinum doublet-containing chemotherapy
This is a Multicenter, open-label, randomized, two-arm, phase iiib trial. Patients will be enrolled at documentation of PD1 after 4-6 cycles of 1st-line treatment with bevacizumab plus a platinum doublet-containing chemotherapy regimen and a minimum of two cycles of bevacizumab (monotherapy) maintenance treatment prior to PD1.
after confirming eligibility, and after choice of 2nd-line SoC therapy, patients will be
randomized in a 1:1 fashion to either:
* arm a: Bevacizumab 7.5 mg/kg i.v. or 15 mg/kg i.v. on Day 1 every 21 days (+/- 3 days) together with SoC treatment
* arm B: SoC treatment alone, every 21 days (+/- 3 days)
Patients with documented PD1 will be randomized (1:1) via an iW/VRS system, through a central stratified block
randomization process using the following stratification factors:
* Type of planned 2nd-line SoC treatment (erlotinib vs.
docetaxel vs. pemetrexed)
* number of cycles of bevacizumab maintenance
treatment ([Less Than] 6 vs. [Greater Than] 6)
* Smoking status (never vs. former vs. current)
1. Signed informed consent prior to initiation of any trial-specific procedure or treatment.
2. Age >= 18 years.
3. Able to comply with the protocol.
4. Histologically or cytologically (sample to be obtained by biopsy or bronchoscopy no rebiopsy is needed at PD1) confirmed non-squamous NSCLC with documented PD1 (locally recurrent or metastatic) per investigator assessment following 1st-line treatment with 4-6 cycles of bevacizumab plus a platinum doublet-containing chemotherapy regimen and a minimum of 2 cycles of
bevacizumab (monotherapy) maintenance treatment prior to PD1.
5. No treatment interruption of bevacizumab treatment greater than 42 days defined as from start of 1st-line treatment to start of Cycle 1 of 2nd line treatment.
6. Randomization within 4 weeks of PD1.
7. At least 1 unidimensionally measurable lesion meeting RECIST (v.1.1) criteria.
8. ECOG PS 0-2.
9. Life expectancy >= 16 weeks by investigator assessment.
10. Adequate hematological function:
* ANC >= 1.5 x 109/L AND
* Platelet count >= 100 x 109/L AND
* Hemoglobin >= 9 g/dL (may be transfused to maintain or exceed this level).
11. Adequate liver function:
* Total bilirubin < 1.5 x ULN AND
* AST and ALT < 2.5 x ULN in patients without liver metastases; < 5 x ULN in patients with known liver metastases.
* ALP <2.5 x ULN (<5 x ULN for patients with known liver involvement and <7 x ULN for patients with known bone involvement).
12. Adequate renal function
* Serum creatinine <= 1.25 x ULN or calculated creatinine clearance >= 50 ml/min
* Urine dipstick for proteinuria < 2+. Patients discovered to have >= 2+ proteinuria on dipstick urinalysis at baseline should undergo a 24-hour urine collection and must demonstrate < 1 g of protein in 24 hours.
13. INR <= 1.5 and aPTT <= 1.5 x ULN within 7 days prior to randomization, unless there is prophylactic use of anti-coagulation. If local standards differ, equivalent coagulation tests may be used.
14. Patients with asymptomatic treated brain metastases are eligible for trial participation. Patients must complete treatment for brain metastases (radiotherapy or stereotactic radiosurgery), including steroids, at least 14 days prior to randomization. Treatment with anticonvulsants at the time of enrollment (i.e. > 28 days) is allowed as long as the anti-convulsant is at a stable
15. Female patients must not be pregnant or breast-feeding. Female patients of childbearing potential (defined as <2 years after last menstruation or not surgically sterile) must use a highly effective contraceptive method (allowed methods of birth control, i.e. with a failure rate of less than 1 % per year, are implants,
injectables, combined oral contraceptives, IUDs [only hormonspirals], sexual abstinence or vasectomized partner) during the trial and for a period of at least 6 months following the last administration of trial drug(s). Female patients with an intact uterus (unless amenorrhoeic for the last 24 months) must have a negative serum pregnancy test within 7 days prior to randomization into the trial.
16. Fertile male patients must agree to use a highly effective contraceptive method (allowed methods of birth control, i.e. with a failure rate of less than 1 % per year, female partner using implants, injectables, combined oral contraceptives, IUDs [only hormonspirals], sexual abstinence or prior vasectomy) during the trial and for a period of at least 6 months following the last administration of trial drug(s).