Paclitaxel-Carboplatin-Bevacizumab +/- Nitroglycerin in Metastatic Non-Squamous-Non-Small Cell Lung Cancer (NVALT12)

This study is currently recruiting participants. (see Contacts and Locations)
Verified July 2011 by Dutch Society of Physicians for Pulmonology and Tuberculosis
Sponsor:
Information provided by:
Dutch Society of Physicians for Pulmonology and Tuberculosis
ClinicalTrials.gov Identifier:
NCT01171170
First received: July 23, 2010
Last updated: July 26, 2011
Last verified: July 2011
  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

Resource links provided by NLM:


Further study details as provided by Dutch Society of Physicians for Pulmonology and Tuberculosis:

Primary Outcome Measures:
  • progression free survival [ Time Frame: every 6 weeks during chemotherapy ] [ Designated as safety issue: No ]
    Imaging


Secondary Outcome Measures:
  • 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:
  • Taxol
  • Avastin
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:
  • Taxol
  • Avastin

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
Criteria

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
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01171170

Contacts
Contact: Anne-Marie C. Dingemans, MD PhD +31 43 3875047 rsc@rsconsultancy.nl
Contact: Raymond J. Schmidt, MD +31 575 441001 rsc@rsconsultancy.nl

Locations
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         
Sponsors and Collaborators
Dutch Society of Physicians for Pulmonology and Tuberculosis
Investigators
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 July 23, 2014