Paclitaxel-Carboplatin-Bevacizumab +/- Nitroglycerin in Metastatic Non-Squamous-Non-Small Cell Lung Cancer (NVALT12)
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Purpose
This study is designed to assess the effects of adding nitroglycerin (NTG) patches, delivery 25 mg NTG per 24 h, to the standard first line treatment of metastatic non-squamous non-small cell lung cancer (NSCLC), i.e. 4 cycles of carboplatin-paclitaxel-bevacizumab, followed by bevacizumab alone until disease progression. Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker, related to treatment resistance. Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia related drug resistance. NTG is a NO donating drug. NTG increases tumor blood flow and thereby augments antitumor drug delivery to the tumor.
A randomized phase II has shown an increase in the response rate from 42% to 72%, when NTG patches (25 mg/day, day -2 to +3) were added to vinorelbine/cisplatin in patients with advanced NSCLC. In addition, the time to progression increased from 185 to 327 days.
The hypothesis of the present study is that adding NTG transdermal patches to bevacizumab containing chemotherapy improves progression free survival, response rate and overall survival in patients with metastatic non-squamous NSCLC.
| Condition | Intervention | Phase |
|---|---|---|
|
Non Small Cell Lung Cancer |
Drug: carboplatin paclitaxel bevacizumab Drug: Standard treatment plus nitroglycerin |
Phase 2 |
| Study Type: | Interventional |
| Study Design: | Allocation: Randomized Endpoint Classification: Efficacy Study Intervention Model: Parallel Assignment Masking: Open Label Primary Purpose: Treatment |
| Official Title: | A Randomized Phase II Study of Paclitaxel-carboplatin-bevacizumab With or Without Nitroglycerin Patches in Patients With Stage IV Non-squamous-non-small Cell Lung Cancer: NVALT12 |
- progression free survival [ Time Frame: every 6 weeks during chemotherapy ] [ Designated as safety issue: No ]Imaging
- objective response rate [ Time Frame: every 6 weeks during chemotherapy ] [ Designated as safety issue: No ]Imaging
- disease control rate [ Time Frame: every 6 weeks during chemotherapy ] [ Designated as safety issue: No ]
- duration of response [ Time Frame: every 6 weeks during chemotherapy ] [ Designated as safety issue: No ]Imaging
- safety [ Time Frame: every 3 weeks during chemotherapy ] [ Designated as safety issue: Yes ]adverse events, hematology, chemistry, physial examination
- prediction of early response [ Time Frame: after 3 weeks ] [ Designated as safety issue: No ]FDG PET scan (exploratory objective)
- decreased hypoxia [ Time Frame: after 6 weeks ] [ Designated as safety issue: No ]FAZA scan (exploratory objective)
| Estimated Enrollment: | 222 |
| Study Start Date: | September 2010 |
| Estimated Study Completion Date: | August 2014 |
| Estimated Primary Completion Date: | August 2014 (Final data collection date for primary outcome measure) |
| Arms | Assigned Interventions |
|---|---|
|
Active Comparator: carboplatin-paclitaxel-bevacizumab
paclitaxel 200 mg/m2 d1 - carboplatin area under the curve (AUC) 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression
|
Drug: carboplatin paclitaxel bevacizumab
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression
Other Names:
|
|
Experimental: standard treatment plus nitroglycerin
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression. Plus nitroglycerin transdermal patches 25 mg per day from day -3 till +2 of First combination cycle till the last bevacizumab monotherapy cycle
|
Drug: Standard treatment plus nitroglycerin
paclitaxel 200 mg/m2 d1 - carboplatin AUC 6 d1 - bevacizumab 15 mg/kg d1. Cycles every 3 weeks. Paclitaxel and carboplatin 4 cycles. Bevacizumab till progression. Plus nitroglycerin transdermal patches 25 mg per day from day -3 till +2 of First combination cycle till the last bevacizumab monotherapy cycle
Other Names:
|
Detailed Description:
Standard treatment for non-small cell lung cancer (NSCLC) consists of platinum-containing chemotherapy. It has been shown that the addition of bevacizumab to standard chemotherapy improves progression-free survival (PFS) and overall survival (OS) in patients with non-squamous NSCLC. There is a need for improved PFS and OS and response rates to chemotherapy are only 25-35%.
Tumor hypoxia is a common phenomenon in lung cancer; it is a known poor prognostic marker, related to treatment resistance. Hypoxia Inducible Factor (HIF) -1α is the major factor regulating the response to hypoxia.
HIF directly activates vascular endothelial growth factor (VEGF) and VEGF-receptor. Bevacizumab interacts with this pathway by blocking VEGF.
Pre-clinical studies have shown that nitric oxide (NO) donating drugs may decrease hypoxia related drug resistance. Nitroglycerin (NTG) is a NO donating drug. NTG increases tumor blood flow and thereby augments antitumor drug delivery to the tumor and inhibits HIF-1α.
Interestingly, it has recently been shown in mouse models that the addition of HIF-1α inhibitors to bevacizumab significantly inhibits tumor growth by inducing apoptosis.
A randomized phase II has shown an increase in the response rate from 42% to 72%, when NTG patches (25 mg/day, day -2 to +3) were added to vinorelbine/cisplatin in patients with advanced NSCLC. In addition, the time to progression increased from 185 to 327 days.
The hypothesis of the present study is that adding NTG transdermal patches to bevacizumab containing chemotherapy improves PFS, response rate and OS in patients with metastatic non-squamous NSCLC.
Eligibility| Ages Eligible for Study: | 18 Years and older |
| Genders Eligible for Study: | Both |
| Accepts Healthy Volunteers: | No |
Inclusion Criteria:
- Histologically/cytologically proven stage IV non-squamous NSCLC (according to IASLC staging 7.0)
- No prior chemotherapy or therapy with systemic anti-tumor therapy (e.g., monoclonal antibody therapy) or prior exposure to agents directed at the HER axis (e.g. epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKI), Herceptin). Prior surgery and/or localized palliative irradiation is permitted provided that the irradiated lesion is not the only measurable lesion. Prior adjuvant chemotherapy > 1 year ago and prior treatment with an EGFR-TKI for patients with an activating EGFR mutation is allowed.
- Age ≥ 18 years.
- ECOG Performance Status of 0 - 2.
- Life expectancy of at least 12 weeks.
- Subjects with at least one uni-dimensional(for RECIST) measurable lesion.
- Adequate bone marrow, liver and renal function.
- Adequate non-hormonal contraception for females of childbearing potential during the study and in the 6 months thereafter.
- Adequate contraception for male participants (or their partners) during the study and in the 6 months thereafter.
Exclusion Criteria:
- 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).
- Symptomatic hypotension.
- History of hemoptysis at least 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).
- History of HIV infection or chronic hepatitis B or C.
- Active clinically serious infection
- Symptomatic metastatic brain or meningeal tumors. Patients with brain metastasis may be included the patient is treated with brain radiotherapy and asymptomatic.
- History of organ allograft.
- Patients with evidence or history of bleeding diathesis.
- Non-healing wound or ulcer.
- History of abdominal fistula, gastrointestinal perforation or intra-abdominal abscess within 6 months of enrolment
- Anticancer chemotherapy or immunotherapy during the study or within 4 weeks of study entry
- Radiotherapy within 4 weeks of start of study drug. Palliative radiotherapy for bone lesions is allowed > 14 days of start of chemotherapy. Major surgery within 4 weeks of start of study.
- Use of vasodilators (including 5-phosphodiesterase inhibitors, calcium antagonists or nitrates)
- Autologous bone marrow transplant or stem cell rescue within 4 months of study
- Investigational drug therapy outside of this trial during or within 4 weeks of study entry
- Pregnancy or lactation.
Contacts and Locations| Contact: Anne-Marie C. Dingemans, MD PhD | +31 43 3875047 | rsc@rsconsultancy.nl |
| Contact: Raymond J. Schmidt, MD | +31 575 441001 | rsc@rsconsultancy.nl |
| Netherlands | |
| VU medisch centrum | Recruiting |
| Amsterdam, Netherlands | |
| Contact: Smit ef.smit@vumc.nl | |
| Principal Investigator: Egbert F. Smit, MD PhD | |
| Amphia Ziekenhuis | Recruiting |
| Breda, Netherlands | |
| Contact: Aerts jaerts@amphia.nl | |
| Principal Investigator: Joachim G. Aerts, MD PhD | |
| Jeroen Bosch Ziekenhuis | Recruiting |
| Den Bosch, Netherlands | |
| Contact: Biesma b.biesma@jbz.nl | |
| Principal Investigator: Bonne Biesma, MD PhD | |
| Catharina-Ziekenhuis | Recruiting |
| Eindhoven, Netherlands | |
| Contact: van den Borne ben.vd.borne@cze.nl | |
| Principal Investigator: Ben E. van den Borne, MD PhD | |
| Martini Ziekenhuis | Recruiting |
| Groningen, Netherlands | |
| Contact: van Putten jwg.van.putten@mzh.nl | |
| Principal Investigator: John W. van Putten, MD PhD | |
| Maastricht UMC | Recruiting |
| Maastricht, Netherlands, 6202 AZ | |
| Contact: Anne-Marie C. Dingemans, MD PhD a.dingemans@mumc.nl | |
| Principal Investigator: Anne-Marie C. Dingemans, MD PhD | |
| HagaZiekenhuis | Recruiting |
| The Hague, Netherlands | |
| Contact: Codrington h.codrington@hagaziekenhuis.nl | |
| Principal Investigator: Henk E. Codrington, MD | |
| Isala Klinieken | Recruiting |
| Zwolle, Netherlands | |
| Contact: Stigt j.a.stigt@isala.nl | |
| Principal Investigator: Jos A. Stigt, MD | |
| Principal Investigator: | Anne-Marie C. Dingemans, MD PhD | Maastricht UMC |
More Information
Additional Information:
No publications provided
| Responsible Party: | Anne-Marie C. Dingemans, MD PhD, Maastricht UMC |
| ClinicalTrials.gov Identifier: | NCT01171170 History of Changes |
| Other Study ID Numbers: | NVALT12 |
| Study First Received: | July 23, 2010 |
| Last Updated: | July 26, 2011 |
| Health Authority: | Netherlands: The Central Committee on Research Involving Human Subjects (CCMO) |
Keywords provided by Dutch Society of Physicians for Pulmonology and Tuberculosis:
|
non small cell lung cancer stage IV nitroglycerin |
carboplatin paclitaxel bevacizumab |
Additional relevant MeSH terms:
|
Carcinoma, Non-Small-Cell Lung Lung Neoplasms Carcinoma, Bronchogenic Bronchial Neoplasms Respiratory Tract Neoplasms Thoracic Neoplasms Neoplasms by Site Neoplasms Lung Diseases Respiratory Tract Diseases Nitroglycerin Bevacizumab Carboplatin Paclitaxel Vasodilator Agents |
Cardiovascular Agents Therapeutic Uses Pharmacologic Actions Antineoplastic Agents Tubulin Modulators Antimitotic Agents Mitosis Modulators Molecular Mechanisms of Pharmacological Action Antineoplastic Agents, Phytogenic Angiogenesis Inhibitors Angiogenesis Modulating Agents Growth Substances Physiological Effects of Drugs Growth Inhibitors |
ClinicalTrials.gov processed this record on October 17, 2012
