Cisplatin-Pemetrexed Compared With Carboplatin-Paclitaxel-Bevacizumab in KRAS Mutated Non-small Cell Lung Cancer

Sponsor

The Netherlands Cancer Institute (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02743923

Collaborator

Dutch Society of Physicians for Pulmonology and Tuberculosis (Other)

203

Enrollment

Locations

Arms

Anticipated Duration (Months)

7.3

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Carcinoma, Non-Small Cell Lung	Drug: carboplatin Drug: paclitaxel Drug: Bevacizumab Drug: Pemetrexed Drug: cisplatin	Phase 3

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.

Study Design

Study Type:

Interventional

Actual Enrollment :

203 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

None (Open Label)

Primary Purpose:

Treatment

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

Actual Study Start Date :

Apr 1, 2016

Actual Primary Completion Date :

Sep 19, 2021

Anticipated Study Completion Date :

Apr 1, 2024

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: carboplatin-paclitaxel- 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	Drug: carboplatin AUC 6 Drug: paclitaxel 200mg/m2 Drug: Bevacizumab 15 mg/kg
Active Comparator: cisplatin-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.	Drug: Pemetrexed 500 mg/m2 Drug: cisplatin 75 mg/m2

Arm

Intervention/Treatment

Active Comparator: carboplatin-paclitaxel- 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

Drug: carboplatin

AUC 6

Drug: paclitaxel

200mg/m2

Drug: Bevacizumab

15 mg/kg

Active Comparator: cisplatin-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.

Drug: Pemetrexed

500 mg/m2

Drug: cisplatin

75 mg/m2

Outcome Measures

Primary Outcome Measures

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

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.]
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.
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]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

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.

Exclusion Criteria:

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	VUmc Medical Center	Amsterdam	Noord-Holland	Netherlands	1081HV
2	Medical spectrum Twente	Enschede	Overijssel	Netherlands	7500 KA
3	Meander Medical Center	Amersfoort	Utrecht	Netherlands	3818 ES
4	ZGT	Almelo		Netherlands	7609 PP
5	Antoni van Leeuwenhoek	Amsterdam		Netherlands	1066CX
6	OLVG	Amsterdam		Netherlands	1090 HM
7	Gelre Ziekenhuis	Apeldoorn		Netherlands
8	Amphia Hospital	Breda		Netherlands
9	Jeroen Bosch Hospital	Den Bosch		Netherlands
10	Haga	Den Haag		Netherlands	2545 CH
11	Deventer Ziekenhuis	Deventer		Netherlands
12	Albert Schweitzer ziekenhuis	Dordrecht		Netherlands
13	Ziekenhuis Gelderse Vallei	Ede		Netherlands
14	Maxima Medisch Centrum	Eindhoven		Netherlands	5631 BM
15	Groene Hart	Gouda		Netherlands
16	UMCG	Groningen		Netherlands	9713 GZ
17	Martini Ziekenhuis	Groningen		Netherlands
18	Tergooi ziekenhuizen	Hilversum		Netherlands
19	Spaarne Gasthuis	Hoofddorp		Netherlands	2130 AT
20	Medisch Centrum Leeuwarden	Leeuwarden		Netherlands
21	Maastricht University Medical Center	Maastricht		Netherlands
22	Maasstad ziekenhuis	Rotterdam		Netherlands	3007 AC
23	St. Fransicus Gasthuis	Rotterdam		Netherlands	3045 PM
24	Medical Center Haaglanden	the Hague		Netherlands
25	Diakonessenhuis Utrecht	Utrecht		Netherlands	3582 KE
26	St. Antonius ziekenhuis	Utrecht		Netherlands
27	VieCuri Medisch Centrum voor Noord-Limburg	Venlo		Netherlands
28	Isala Klinieken	Zwolle		Netherlands	8000 GK