Nitroglycerin Plus Intracranial Radiotherapy for Brain Metastases in NSCLC Patients

NCT04338867 | Completed Phase 2 DMC

• 1 other identifier: 014/034/ICI
• Study Type: interventional
• Target: 96
• Locations: 1 country
• Sites: 1

Brief Summary

Background: Whole-brain radiotherapy (WBRT) is the standard treatment for multiple brain metastases (BM), in NSCLC patients who are not candidates for treatment with stereotactic radiation body therapy. Hypoxia has been associated with chemo-radioresistance secondary to Vascular Endothelial Growth Factor Receptor (VEGFR) induced by Hypoxia Induced Factor (HIF). Nitroglycerin (NTG) can reduce HIF-1 alfa in tissues, and this may have anti-angiogenic, pro-apoptotic and anti-efflux effects. In this phase II study, we evaluated the effect of transdermal nitroglycerin (TN) on intracranial progression-free survival (ICPFS), objective response rate (ORR) and overall survival (OS) of NSCLC patients with BM. Material and methods: We performed an open-label, phase II clinical trial among ninety-six histologically confirmed NSCLC patients with BM. Patients were randomized 1:1 to receive NTG plus WBRT or WBRT alone. ORR and ICPFS were evaluated by MRI by two independent, blinded radio-oncologists.

Conditions

Phase II Clinical Trial; Ninety-six Histologically Confirmed NSCLC Patients With BM; Randomized 1:1 to Received TN Plus WBR or Only WBR; ICPFS Evaluated by Two Blinded and Independent Radio-oncologist With MRI

Keywords

nitroglycerin; whole intracranial radiotherapy; brain metastases; non-small cell cancer; lung cancer; hypoxia

Outcome Measures

Primary Outcomes (1)

• itroglycerin Plus Intracranial Radiotherapy for Brain Metastases in NSCLC Patients

  The concurrent administration of nitroglycerin plus chemotherapy and radiotherapy could increases the therapeutic response (ORR, PFS) and OS in patients with NSCLC and cerebral metastases.

  1 year

Study Arms (2)

Therapeutic arm

ACTIVE COMPARATOR

Patients who received WBRT and the addition 36 mg of transdermal nitroglycerin (TN) with the release of 10 mg in 24 hours, for 24 hours with a 12-hour rest interval (to avoid saturation of receptors)

Radiation: Whole-brain radiotherapy

Control arm

ACTIVE COMPARATOR

Patients who received whole-brain radiotherapy (WBRT) (30 Gy in 10 fractions, in 10 days of treatment)

Radiation: Whole-brain radiotherapy

Interventions

Whole-brain radiotherapy RADIATION

Patients were randomized 1:1 and allocated to either the control arm who received whole-brain radiotherapy (WBRT) or the experimental arm who received WBRT and the addition 36 mg of transdermal nitroglycerin (TN)

Also known as: Any other intervention names

Control arm; Therapeutic arm

Eligibility Criteria

• Age: 18 Years - 90 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients with histologically confirmed NSCLC with documented BM (defined as the presence of one or more intra-axial enhancing lesions on gadolinium-enhanced brain magnetic resonance imaging (MRI)

You may not qualify if:

• Candidate patients who underwent radiosurgery or surgery resection

Sponsors & Collaborators

• Instituto Nacional de Cancerologia de Mexico: lead

Study Sites (1)

National Cancer Institute of Mexico

Mexico City, Mexico City, 14080, Mexico

Location

Related Publications (16)

• Gondi V, Pugh SL, Tome WA, Caine C, Corn B, Kanner A, Rowley H, Kundapur V, DeNittis A, Greenspoon JN, Konski AA, Bauman GS, Shah S, Shi W, Wendland M, Kachnic L, Mehta MP. Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol. 2014 Dec 1;32(34):3810-6. doi: 10.1200/JCO.2014.57.2909. Epub 2014 Oct 27.

  PMID: 25349290 BACKGROUND

• Andrews DW, Scott CB, Sperduto PW, Flanders AE, Gaspar LE, Schell MC, Werner-Wasik M, Demas W, Ryu J, Bahary JP, Souhami L, Rotman M, Mehta MP, Curran WJ Jr. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet. 2004 May 22;363(9422):1665-72. doi: 10.1016/S0140-6736(04)16250-8.

  PMID: 15158627 BACKGROUND

• Huber SM, Butz L, Stegen B, Klumpp D, Braun N, Ruth P, Eckert F. Ionizing radiation, ion transports, and radioresistance of cancer cells. Front Physiol. 2013 Aug 14;4:212. doi: 10.3389/fphys.2013.00212. eCollection 2013.

  PMID: 23966948 BACKGROUND

• Tian J, Luo Y, Xiang J, Tang J. Combined treatment for non-small cell lung cancer and breast cancer patients with brain metastases with whole brain radiotherapy and temozolomide: a systematic review and meta-analysis. J Neurooncol. 2017 Nov;135(2):217-227. doi: 10.1007/s11060-017-2572-z. Epub 2017 Jul 19.

  PMID: 28726172 BACKGROUND

• Rojas-Puentes LL, Gonzalez-Pinedo M, Crismatt A, Ortega-Gomez A, Gamboa-Vignolle C, Nunez-Gomez R, Dorantes-Gallareta Y, Arce-Salinas C, Arrieta O. Phase II randomized, double-blind, placebo-controlled study of whole-brain irradiation with concomitant chloroquine for brain metastases. Radiat Oncol. 2013 Sep 8;8:209. doi: 10.1186/1748-717X-8-209.

  PMID: 24010771 BACKGROUND

• Berghoff AS, Preusser M. The inflammatory microenvironment in brain metastases: potential treatment target? Chin Clin Oncol. 2015 Jun;4(2):21. doi: 10.3978/j.issn.2304-3865.2015.06.03.

  PMID: 26112807 BACKGROUND

• Barker HE, Paget JT, Khan AA, Harrington KJ. The tumour microenvironment after radiotherapy: mechanisms of resistance and recurrence. Nat Rev Cancer. 2015 Jul;15(7):409-25. doi: 10.1038/nrc3958.

  PMID: 26105538 BACKGROUND

• Liu Y, Christou H, Morita T, Laughner E, Semenza GL, Kourembanas S. Carbon monoxide and nitric oxide suppress the hypoxic induction of vascular endothelial growth factor gene via the 5' enhancer. J Biol Chem. 1998 Jun 12;273(24):15257-62. doi: 10.1074/jbc.273.24.15257.

  PMID: 9614141 BACKGROUND

• Moeller BJ, Dreher MR, Rabbani ZN, Schroeder T, Cao Y, Li CY, Dewhirst MW. Pleiotropic effects of HIF-1 blockade on tumor radiosensitivity. Cancer Cell. 2005 Aug;8(2):99-110. doi: 10.1016/j.ccr.2005.06.016.

  PMID: 16098463 BACKGROUND

• Moeller BJ, Cao Y, Li CY, Dewhirst MW. Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules. Cancer Cell. 2004 May;5(5):429-41. doi: 10.1016/s1535-6108(04)00115-1.

  PMID: 15144951 BACKGROUND

• Moeller BJ, Cao Y, Vujaskovic Z, Li CY, Haroon ZA, Dewhirst MW. The relationship between hypoxia and angiogenesis. Semin Radiat Oncol. 2004 Jul;14(3):215-21. doi: 10.1016/j.semradonc.2004.04.005.

  PMID: 15254864 BACKGROUND

• Choudhari SK, Chaudhary M, Bagde S, Gadbail AR, Joshi V. Nitric oxide and cancer: a review. World J Surg Oncol. 2013 May 30;11:118. doi: 10.1186/1477-7819-11-118.

  PMID: 23718886 BACKGROUND

• Arrieta O, Blake M, de la Mata-Moya MD, Corona F, Turcott J, Orta D, Alexander-Alatorre J, Gallardo-Rincon D. Phase II study. Concurrent chemotherapy and radiotherapy with nitroglycerin in locally advanced non-small cell lung cancer. Radiother Oncol. 2014 May;111(2):311-5. doi: 10.1016/j.radonc.2014.01.021. Epub 2014 May 14.

  PMID: 24836861 BACKGROUND

• Reinmuth N, Meyer A, Hartwigsen D, Schaeper C, Huebner G, Skock-Lober R, Bier A, Gerecke U, Held CP, Reck M. Randomized, double-blind phase II study to compare nitroglycerin plus oral vinorelbine plus cisplatin with oral vinorelbine plus cisplatin alone in patients with stage IIIB/IV non-small cell lung cancer (NSCLC). Lung Cancer. 2014 Mar;83(3):363-8. doi: 10.1016/j.lungcan.2014.01.001. Epub 2014 Jan 8.

  PMID: 24462464 BACKGROUND

• Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018 Nov;68(6):394-424. doi: 10.3322/caac.21492. Epub 2018 Sep 12.

  PMID: 30207593 RESULT

• Arrieta O, Hernandez-Pedro N, Maldonado F, Ramos-Ramirez M, Yamamoto-Ramos M, Lopez-Macias D, Lozano F, Zatarain-Barron ZL, Turcott JG, Barrios-Bernal P, Orozco-Morales M, Flores-Estrada D, Cardona AF, Rolfo C, Cacho-Diaz B. Nitroglycerin Plus Whole Intracranial Radiation Therapy for Brain Metastases in Patients With Non-Small Cell Lung Cancer: A Randomized, Open-Label, Phase 2 Clinical Trial. Int J Radiat Oncol Biol Phys. 2023 Mar 1;115(3):592-607. doi: 10.1016/j.ijrobp.2022.02.010. Epub 2022 Feb 12.

  PMID: 35157994 DERIVED

MeSH Terms

Conditions

Brain Neoplasms; Lung Neoplasms; Hypoxia

Condition Hierarchy (Ancestors)

Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Neoplasms; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Diseases; Respiratory Tract Diseases; Signs and Symptoms, Respiratory; Signs and Symptoms; Pathological Conditions, Signs and Symptoms

Study Design

• Study Type: interventional
• Phase: phase 2
• Allocation: RANDOMIZED
• Masking: NONE
• Masking Details: Patients were randomized 1:1 to received TN plus WBR or only WBR. ICPFS was evaluated by two blinded and independent radio-oncologist with MRI.
• Purpose: TREATMENT
• Intervention Model: CROSSOVER
• Sponsor Type: OTHER
• Responsible Party: PRINCIPAL INVESTIGATOR
• PI Title: MD MSc

Model Details: We perform an open phase II clinical trial among ninety-six histologically confirmed NSCLC patients with BM.

Study Record Dates

• First Submitted: March 5, 2020
• First Posted: April 8, 2020
• Study Start: March 1, 2020
• Primary Completion: March 1, 2020
• Study Completion: March 1, 2020
• Last Updated: April 22, 2020

Record last verified: 2020-04

Data Sharing

• IPD Sharing: Will not share

Locations

ME (1)