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

NCT01171170 | Completed Phase 2

• 1 other identifier: NVALT12
• Study Type: interventional
• Target: 223
• Locations: 1 country
• Sites: 8

Brief Summary

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.

Conditions

Non Small Cell Lung Cancer

Keywords

non small cell lung cancer; stage IV; nitroglycerin; carboplatin; paclitaxel; bevacizumab

Outcome Measures

Primary Outcomes (1)

• progression free survival

  Imaging

  every 6 weeks during chemotherapy

Secondary Outcomes (6)

• objective response rate

  every 6 weeks during chemotherapy

• disease control rate

  every 6 weeks during chemotherapy

• duration of response

  every 6 weeks during chemotherapy

• safety of the treatment

  every 3 weeks during chemotherapy

• prediction of early response

  after 3 weeks

Study Arms (2)

carboplatin-paclitaxel-bevacizumab

ACTIVE COMPARATOR

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

standard treatment plus nitroglycerin

EXPERIMENTAL

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

Interventions

carboplatin paclitaxel bevacizumab DRUG

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

Also known as: Taxol, Avastin

carboplatin-paclitaxel-bevacizumab

Standard treatment plus nitroglycerin DRUG

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

Also known as: Taxol, Avastin

standard treatment plus nitroglycerin

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Dutch Society of Physicians for Pulmonology and Tuberculosis: lead

Study Sites (8)

Jeroen Bosch Ziekenhuis

's-Hertogenbosch, Netherlands

Location

VU medisch centrum

Amsterdam, Netherlands

Location

Amphia Ziekenhuis

Breda, Netherlands

Location

Catharina-Ziekenhuis

Eindhoven, Netherlands

Location

Martini Ziekenhuis

Groningen, Netherlands

Location

Maastricht UMC

Maastricht, 6202 AZ, Netherlands

Location

HagaZiekenhuis

The Hague, Netherlands

Location

Isala Klinieken

Zwolle, Netherlands

Location

Related Publications (5)

• Dingemans AM, Groen HJ, Herder GJ, Stigt JA, Smit EF, Bahce I, Burgers JA, van den Borne BE, Biesma B, Vincent A, van der Noort V, Aerts JG; NVALT study group. A randomized phase II study comparing paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches in patients with stage IV nonsquamous nonsmall-cell lung cancer: NVALT12 (NCT01171170)dagger. Ann Oncol. 2015 Nov;26(11):2286-93. doi: 10.1093/annonc/mdv370. Epub 2015 Sep 7.

  PMID: 26347109 RESULT

• de Jong EE, van Elmpt W, Leijenaar RT, Hoekstra OS, Groen HJ, Smit EF, Boellaard R, van der Noort V, Troost EG, Lambin P, Dingemans AC. [18F]FDG PET/CT-based response assessment of stage IV non-small cell lung cancer treated with paclitaxel-carboplatin-bevacizumab with or without nitroglycerin patches. Eur J Nucl Med Mol Imaging. 2017 Jan;44(1):8-16. doi: 10.1007/s00259-016-3498-y. Epub 2016 Sep 6.

  PMID: 27600280 RESULT

• Degens JHRJ, Sanders KJC, de Jong EEC, Groen HJM, Smit EF, Aerts JG, Schols AMWJ, Dingemans AC. The prognostic value of early onset, CT derived loss of muscle and adipose tissue during chemotherapy in metastatic non-small cell lung cancer. Lung Cancer. 2019 Jul;133:130-135. doi: 10.1016/j.lungcan.2019.05.021. Epub 2019 May 20.

  PMID: 31200819 RESULT

• de Goeje PL, Poncin M, Bezemer K, Kaijen-Lambers MEH, Groen HJM, Smit EF, Dingemans AC, Kunert A, Hendriks RW, Aerts JGJV. Induction of Peripheral Effector CD8 T-cell Proliferation by Combination of Paclitaxel, Carboplatin, and Bevacizumab in Non-small Cell Lung Cancer Patients. Clin Cancer Res. 2019 Apr 1;25(7):2219-2227. doi: 10.1158/1078-0432.CCR-18-2243. Epub 2019 Jan 14.

  PMID: 30642911 RESULT

• de Jong EEC, Hendriks LEL, van Elmpt W, Gietema HA, Hofman PAM, De Ruysscher DKM, Dingemans AC. What you see is (not) what you get: tools for a non-radiologist to evaluate image quality in lung cancer. Lung Cancer. 2018 Sep;123:112-115. doi: 10.1016/j.lungcan.2018.07.014. Epub 2018 Jul 18.

  PMID: 30089580 DERIVED

Related Links

• Related Info

MeSH Terms

Conditions

Carcinoma, Non-Small-Cell Lung

Interventions

Paclitaxel; Bevacizumab; Nitroglycerin

Condition Hierarchy (Ancestors)

Carcinoma, Bronchogenic; Bronchial Neoplasms; Lung Neoplasms; Respiratory Tract Neoplasms; Thoracic Neoplasms; Neoplasms by Site; Neoplasms; Lung Diseases; Respiratory Tract Diseases

Intervention Hierarchy (Ancestors)

Taxoids; Cyclodecanes; Cycloparaffins; Hydrocarbons, Alicyclic; Hydrocarbons, Cyclic; Hydrocarbons; Organic Chemicals; Diterpenes; Terpenes; Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Nitro Compounds

Study Officials

• Anne-Marie C. Dingemans, MD PhD

  Maastricht UMC

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: July 23, 2010
• First Posted: July 28, 2010
• Study Start: January 1, 2011
• Primary Completion: June 1, 2014
• Study Completion: August 1, 2020
• Last Updated: September 28, 2020

Record last verified: 2020-09

Locations

NL (8)