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

Non Small Cell Lung Cancer Clinical Trial

— NVALT12  

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01171170
• Other study ID #: NVALT12
• Status: Completed
• Phase: Phase 2
• Start date: January 2011
• Est. completion date: August 2020

Study information

• Verified date: September 2020
• Source: Dutch Society of Physicians for Pulmonology and Tuberculosis
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial 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.

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.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 223
• Est. completion date: August 2020
• Est. primary completion date: June 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years and older

Eligibility

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.

Related Conditions & MeSH terms

• Carcinoma, Non-Small-Cell Lung
• Lung Neoplasms
• Non Small Cell Lung Cancer

Intervention

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
• 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

Locations

Country	Name	City	State
Netherlands	VU medisch centrum	Amsterdam
Netherlands	Amphia Ziekenhuis	Breda
Netherlands	Jeroen Bosch Ziekenhuis	Den Bosch
Netherlands	Catharina-Ziekenhuis	Eindhoven
Netherlands	Martini Ziekenhuis	Groningen
Netherlands	Maastricht UMC	Maastricht
Netherlands	HagaZiekenhuis	The Hague
Netherlands	Isala Klinieken	Zwolle

Sponsors (1)

Lead Sponsor	Collaborator
Dutch Society of Physicians for Pulmonology and Tuberculosis

Country where clinical trial is conducted

Netherlands, 

References & Publications (4)

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 Ce — View Citation

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-be — View Citation

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. 20 — View Citation

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 nitrog — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	progression free survival	Imaging	every 6 weeks during chemotherapy
Secondary	objective response rate	Imaging	every 6 weeks during chemotherapy
Secondary	disease control rate	Imaging	every 6 weeks during chemotherapy
Secondary	duration of response	Imaging	every 6 weeks during chemotherapy
Secondary	safety of the treatment	adverse events, hematology, chemistry, physial examination	every 3 weeks during chemotherapy
Secondary	prediction of early response	FDG PET scan (exploratory objective)	after 3 weeks
Secondary	decreased hypoxia	FAZA scan (exploratory objective)	after 6 weeks

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