Cisplatin-Pemetrexed Compared With Carboplatin-Paclitaxel-Bevacizumab in KRAS Mutated Non-small Cell Lung Cancer
- Conditions
- Carcinoma, Non-Small Cell Lung
- Interventions
- Registration Number
- NCT02743923
- Lead Sponsor
- The Netherlands Cancer Institute
- Brief Summary
The purpose of this study is to determine whether carboplatin-paclitaxel-bevacizumab results in a prolonged progression free survival compared to cisplatin-pemetrexed as first line treatment in patients with KRAS mutated non-small cell lung cancer.
- Detailed Description
KRAS mutations occur in 30% of patients with non-small cell lung cancer, especially adenocarcinoma. For long time KRAS mutation has been related with poor prognosis and poor response to chemotherapy. Recent data however show that this is both not true. It seems that response, progression free survival and overall survival is similar in KRAS mutated. Until now no specific targeted therapy is available for KRAS mutated NSCLC patients. Optimization of treatment in advanced NSCLC patients with a KRAS mutation could also be achieved by selecting the best available chemotherapy treatment.
Two standard chemotherapy schemes are frequently used and FDA and EMA approved as first line treatment for patients with adenocarcinoma: cisplatin-pemetrexed and carboplatin-paclitaxel-bevacizumab.
The aim of this randomized phase III study is to compare two standard treatment regimens in patients with KRAS mutated, advanced stage NSCLC and the hypothesis is that bevacizumab with chemotherapy improves outcomes compared to chemotherapy alone as first line treatment. Furthermore the outcome for the different KRAS mutations will be studied.
Treatment with one of the two following chemotherapy combinations according to the label: carboplatin-paclitaxel-bevacizumab or cisplatin-pemetrexed q3wks for up to six cycles. Continuation maintenance with bevacizumab and pemetrexed is allowed until progression. Blood and archival tissue will be optionally collected for translational research. This may help to identify subgroups of patients who are likely better treated with a specific treatment regimen.
Recruitment & Eligibility
- Status
- UNKNOWN
- Sex
- All
- Target Recruitment
- 203
-
Histologically or cytologically confirmed (non-squamous) NSCLC incurable locally advanced or metastatic (stage IIIB and stage IV) disease.
-
Documented KRAS mutation
-
Chemotherapy-naive NSCLC patients. Adjuvant chemotherapy or chemoradiotherapy is allowed when given > 1 year for study entry. Previous anti-PD(L1) therapy for advanced disease is allowed.
-
At least one unidimensionally measurable lesion meeting RECIST1.1.
-
ECOG PS 0-2
-
Age ≥ 18 years
-
Adequate organ function, including:
- Adequate bone marrow reserve: ANC ≥ 1.5 x 109/L, platelets ≥ 100 x 109/L.
- Hepatic: bilirubin ≤1.5 x ULN, AP, ALT, AST ≤ 3.0 x ULN AP, ALT, and AST ≤5 xULN is acceptable if the liver has tumor involvement
- Renal: calculated creatinine clearance ≥ 60 ml/min based on the Cockroft-Gault formula.
- Urine protein (dip-stick) < 2 +; when ≥ 2 +: 24 hours urine protein ≤ 1 gr.
-
Signed informed consent
-
Male and female patients with reproductive potential must use an approved contraceptive method, if appropriate. Female patients with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.
- Pregnant or lactating women
- Clinically significant (i.e. active) cardiovascular disease: congestive heart failure >NYHA class 2; CVA or myocardial infarction < 6 months prior to study entry; uncontrolled hypertension (blood pressure systolic > 150 mmHg and/or diastolic > 100 mmHg)
- History of hemoptysis ≥ grade 2 (bright red blood of at least 2,5 ml in the last 3 months)
- Evidence of tumor invading major blood vessels on imaging (i.e. superior vena cava or pulmonary artery)
- Patients with evidence or history of bleeding diathesis
- Non-healing wound or ulcer
Study & Design
- Study Type
- INTERVENTIONAL
- Study Design
- PARALLEL
- Arm && Interventions
Group Intervention Description carboplatin-paclitaxel- bevacizumab carboplatin carboplatin AUC 6, paclitaxel 200 mg/m2, bevacizumab 15 mg/kg all administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by bevacizumab maintenance every 3 weeks until progression carboplatin-paclitaxel- bevacizumab paclitaxel carboplatin AUC 6, paclitaxel 200 mg/m2, bevacizumab 15 mg/kg all administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by bevacizumab maintenance every 3 weeks until progression carboplatin-paclitaxel- bevacizumab Bevacizumab carboplatin AUC 6, paclitaxel 200 mg/m2, bevacizumab 15 mg/kg all administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by bevacizumab maintenance every 3 weeks until progression cisplatin-pemetrexed Pemetrexed pemetrexed 500 mg/m2 administered intravenously on day 1 and cisplatin 75 mg/m2 administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by maintenance pemetrexed every 3 weeks until progression. cisplatin-pemetrexed cisplatin pemetrexed 500 mg/m2 administered intravenously on day 1 and cisplatin 75 mg/m2 administered intravenously on day 1 every 3 weeks for 4-6 cycles, followed by maintenance pemetrexed every 3 weeks until progression.
- Primary Outcome Measures
Name Time Method progression free survival Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months
- Secondary Outcome Measures
Name Time Method response by Crabb criteria (if applicable) Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months overall survival date of randomization to the date of death from any cause, assessed up to 60 months. Stratification for KRAS mutation (G12V versus G12C versus other)
outcome between G12V versus G12C versus other subtypes of KRAS mutations (mutational analysis on plasma and blood platelets). date of randomization to the date of death from any cause, assessed up to 60 months. The two most common KRAS types are G12C in about 40% of cases, G12V in 18% and G12D in 15% of cases. Subgroup analyses are planned to explore treatment effect in these different KRAS mutations groups. At baseline the metastatic patterns of these subgroups will be described. KRAS mutations in NSCLC occur mainly in codon 12 and 13.
Stratification for KRAS mutation (G12V versus G12C versus other) at randomization.disease control rate Every 6 weeks, from date of randomization until the date of progression of disease or of death from any cause, assessed up to 60 months.
Trial Locations
- Locations (28)
Haga
🇳🇱Den Haag, Netherlands
Spaarne Gasthuis
🇳🇱Hoofddorp, Netherlands
Medisch Centrum Leeuwarden
🇳🇱Leeuwarden, Netherlands
Meander Medical Center
🇳🇱Amersfoort, Utrecht, Netherlands
Medical spectrum Twente
🇳🇱Enschede, Overijssel, Netherlands
VUmc Medical Center
🇳🇱Amsterdam, Noord-Holland, Netherlands
Gelre Ziekenhuis
🇳🇱Apeldoorn, Netherlands
Deventer Ziekenhuis
🇳🇱Deventer, Netherlands
Medical Center Haaglanden
🇳🇱the Hague, Netherlands
ZGT
🇳🇱Almelo, Netherlands
Antoni van Leeuwenhoek
🇳🇱Amsterdam, Netherlands
OLVG
🇳🇱Amsterdam, Netherlands
Amphia Hospital
🇳🇱Breda, Netherlands
Albert Schweitzer ziekenhuis
🇳🇱Dordrecht, Netherlands
St. Antonius ziekenhuis
🇳🇱Utrecht, Netherlands
Jeroen Bosch Hospital
🇳🇱Den Bosch, Netherlands
Maxima Medisch Centrum
🇳🇱Eindhoven, Netherlands
Ziekenhuis Gelderse Vallei
🇳🇱Ede, Netherlands
Groene Hart
🇳🇱Gouda, Netherlands
UMCG
🇳🇱Groningen, Netherlands
Tergooi ziekenhuizen
🇳🇱Hilversum, Netherlands
Martini Ziekenhuis
🇳🇱Groningen, Netherlands
Maastricht University Medical Center
🇳🇱Maastricht, Netherlands
Maasstad ziekenhuis
🇳🇱Rotterdam, Netherlands
St. Fransicus Gasthuis
🇳🇱Rotterdam, Netherlands
Diakonessenhuis Utrecht
🇳🇱Utrecht, Netherlands
VieCuri Medisch Centrum voor Noord-Limburg
🇳🇱Venlo, Netherlands
Isala Klinieken
🇳🇱Zwolle, Netherlands