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

Condition(s) targeted: Non Small Cell Lung Cancer

Intervention: carboplatin paclitaxel bevacizumab (Drug); Standard treatment plus nitroglycerin (Drug)

Phase: Phase 2

Status: Recruiting

Sponsored by: Dutch Society of Physicians for Pulmonology and Tuberculosis

Official(s) and/or principal investigator(s):
Anne-Marie C. Dingemans, MD PhD, Principal Investigator, Affiliation: Maastricht UMC

Overall contact:
Anne-Marie C. Dingemans, MD PhD, Phone: +31 43 3875047, Email: rsc@rsconsultancy.nl

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.

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

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

Primary outcome: progression free survival

Secondary outcome:

objective response rate

disease control rate

duration of response

safety

prediction of early response

decreased hypoxia

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.

Minimum age: 18 Years. Maximum age: N/A. Gender(s): Both.

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.

Anne-Marie C. Dingemans, MD PhD, Phone: +31 43 3875047, Email: rsc@rsconsultancy.nl

VU medisch centrum, Amsterdam, Netherlands; Recruiting
Smit, Email: ef.smit@vumc.nl
Egbert F. Smit, MD PhD, Principal Investigator

Amphia Ziekenhuis, Breda, Netherlands; Recruiting
Aerts, Email: jaerts@amphia.nl
Joachim G. Aerts, MD PhD, Principal Investigator

Jeroen Bosch Ziekenhuis, Den Bosch, Netherlands; Recruiting
Biesma, Email: b.biesma@jbz.nl
Bonne Biesma, MD PhD, Principal Investigator

Catharina-Ziekenhuis, Eindhoven, Netherlands; Recruiting
van den Borne, Email: ben.vd.borne@cze.nl
Ben E. van den Borne, MD PhD, Principal Investigator

Martini Ziekenhuis, Groningen, Netherlands; Recruiting
van Putten, Email: jwg.van.putten@mzh.nl
John W. van Putten, MD PhD, Principal Investigator

Maastricht UMC, Maastricht 6202 AZ, Netherlands; Recruiting
Anne-Marie C. Dingemans, MD PhD, Email: a.dingemans@mumc.nl
Anne-Marie C. Dingemans, MD PhD, Principal Investigator

HagaZiekenhuis, The Hague, Netherlands; Recruiting
Codrington, Email: h.codrington@hagaziekenhuis.nl
Henk E. Codrington, MD, Principal Investigator

Isala Klinieken, Zwolle, Netherlands; Recruiting
Stigt, Email: j.a.stigt@isala.nl
Jos A. Stigt, MD, Principal Investigator

Starting date: September 2010
Last updated: July 26, 2011