Clinical trial NCT02743923: Cisplatin-Pemetrexed Compared With Carboplatin-Paclitaxel-Bevacizumab in KRAS Mutated Non-small Cell Lung Cancer
Official title: Chemotherapy in KRAS Mutated Chemotherapy Naive Non-small Cell Lung Cancer Patients: a Phase III Study Comparing Cisplatin-pemetrexed With Carboplatin-paclitaxel-bevacizumab: NVALT 22
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE3
Conditions: Carcinoma, Non-Small Cell Lung
Lead sponsor: The Netherlands Cancer Institute
Sponsor class: OTHER
Collaborators: name: Dutch Society of Physicians for Pulmonology and Tuberculosis
First posted: 2016-04-19
Enrollment: 203
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Histologically or cytologically confirmed (non-squamous) NSCLC incurable locally advanced or metastatic (stage IIIB and stage IV) disease.
2. Documented KRAS mutation
3. 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.
4. At least one unidimensionally measurable lesion meeting RECIST1.1.
5. ECOG PS 0-2
6. Age ≥ 18 years
7. 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.
8. Signed informed consent
9. 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.

Exclusion Criteria:

1. Pregnant or lactating women
2. 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)
3. History of hemoptysis ≥ grade 2 (bright red blood of at least 2,5 ml in the last 3 months)
4. Evidence of tumor invading major blood vessels on imaging (i.e. superior vena cava or pulmonary artery)
5. Patients with evidence or history of bleeding diathesis
6. Non-healing wound or ulcer

Primary outcomes:
measure: progression free survival
timeFrame: 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 outcomes:
measure: disease control rate
timeFrame: 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.
measure: overall survival
timeFrame: date of randomization to the date of death from any cause, assessed up to 60 months.
measure: outcome between G12V versus G12C versus other subtypes of KRAS mutations (mutational analysis on plasma and blood platelets).
timeFrame: date of randomization to the date of death from any cause, assessed up to 60 months.
measure: response by Crabb criteria (if applicable)
timeFrame: 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
Other outcomes:
Locations:
city: Amsterdam
country: Netherlands
facility: VUmc Medical Center
state: Noord-Holland
city: Enschede
country: Netherlands
facility: Medical spectrum Twente
state: Overijssel
city: Amersfoort
country: Netherlands
facility: Meander Medical Center
state: Utrecht
city: Almelo
country: Netherlands
facility: ZGT
city: Amsterdam
country: Netherlands
facility: Antoni van Leeuwenhoek
city: Amsterdam
country: Netherlands
facility: OLVG
city: Apeldoorn
country: Netherlands
facility: Gelre Ziekenhuis
city: Breda
country: Netherlands
facility: Amphia Hospital
city: Den Bosch
country: Netherlands
facility: Jeroen Bosch Hospital
city: Den Haag
country: Netherlands
facility: Haga
city: Deventer
country: Netherlands
facility: Deventer Ziekenhuis
city: Dordrecht
country: Netherlands
facility: Albert Schweitzer ziekenhuis
city: Ede
country: Netherlands
facility: Ziekenhuis Gelderse Vallei
city: Eindhoven
country: Netherlands
facility: Maxima Medisch Centrum
city: Gouda
country: Netherlands
facility: Groene Hart
city: Groningen
country: Netherlands
facility: UMCG
city: Groningen
country: Netherlands
facility: Martini Ziekenhuis
city: Hilversum
country: Netherlands
facility: Tergooi ziekenhuizen
city: Hoofddorp
country: Netherlands
facility: Spaarne Gasthuis
city: Leeuwarden
country: Netherlands
facility: Medisch Centrum Leeuwarden
city: Maastricht
country: Netherlands
facility: Maastricht University Medical Center
city: Rotterdam
country: Netherlands
facility: Maasstad ziekenhuis
city: Rotterdam
country: Netherlands
facility: St. Fransicus Gasthuis
city: the Hague
country: Netherlands
facility: Medical Center Haaglanden
city: Utrecht
country: Netherlands
facility: Diakonessenhuis Utrecht
city: Utrecht
country: Netherlands
facility: St. Antonius ziekenhuis
city: Venlo
country: Netherlands
facility: VieCuri Medisch Centrum voor Noord-Limburg
city: Zwolle
country: Netherlands
facility: Isala Klinieken
Study officials:
affiliation: Dutch Society of Physicians for Pulmonology and Tuberculosis
name: Anne-Marie C Dingemans, MD PhD
role: PRINCIPAL_INVESTIGATOR
References: