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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

Phase 2
18 Years
Open (Enrolling)
Non Small Cell Lung Cancer

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Trial Information

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

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.

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

- 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

- 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

- 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

- Pregnancy or lactation.

Type of Study:


Study Design:

Allocation: Randomized, Endpoint Classification: Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Outcome Measure:

progression free survival

Outcome Description:


Outcome Time Frame:

every 6 weeks during chemotherapy

Safety Issue:


Principal Investigator

Anne-Marie C. Dingemans, MD PhD

Investigator Role:

Principal Investigator

Investigator Affiliation:

Maastricht UMC


Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Study ID:




Start Date:

September 2010

Completion Date:

August 2014

Related Keywords:

  • Non Small Cell Lung Cancer
  • non small cell lung cancer
  • stage IV
  • nitroglycerin
  • carboplatin
  • paclitaxel
  • bevacizumab
  • Carcinoma, Non-Small-Cell Lung
  • Lung Neoplasms