A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Primary Brain Tumors—Final Report (Protocol BT-09)

Stanislaw R. Burzynski^*, Tomasz J. Janicki, Gregory S. Burzynski

Burzynski Clinic, Houston, Texas, USA.

DOI: 10.4236/jct.2015.612116                

Abstract

Antineoplastons A10 and AS2-1 (ANP) are synthetic derivatives of glutamine, isoglutamine, and phenylacetic acid. In 1993, a phase II clinical trial program began according to protocols based on the initial protocol, BT-06, which was transferred from the National Institutes of Health (NIH). Protocol BT-09 was designed for different types of primary brain tumors in adults that were not curable by standard treatment. The study was designed as a single arm, two-stage, phase II trial of ANP as a monotherapy in a high-risk, poor-prognosis population. The total number of registered subjects was 40. The majority of patients were diagnosed with high-grade tumors (N = 33). In this group, 12 patients carried diagnosis of anaplastic astrocytoma (AA) and 11 patients of glioblastoma. In the group of low-grade tumors (N = 7), there were 6 cases of low-grade glioma, and 1 neurocytoma grade 2. A group of 12 patients did not receive any prior treatment, 12 patients had surgical resection only, 5 patients received radiation therapy (RT) only, and 11 patients received both RT and chemotherapy. The median duration of ANP was 16.6 weeks. The median dosage of A10 was 7.16 g/kg/d and AS2-1 was 0.27 g/kg/d. Responses were accessed by gadolinium-enhanced magnetic resonance imaging (MRI). Objective responses (OR) in all patients were 22.5% and in the AA group were 41.7% of patients. The median progression-free survival (PFS) in the AA group was 5.4 months. The median overall survival (OS) was 12.7 months and OS at 1 and 2 years was 54.5% and 45.5% correspondingly. The treatment was well-tolerated with reversible grade 3 and 4 toxicities in 35% of all patients (N = 40). In conclusion, the study reached efficacy endpoint and ANP was well-tolerated and compared favorably to the current treatment of AA.

Keywords

Anaplastic Astrocytoma, Antineoplastons A10 and AS2-1, Low-Grade Astrocytoma, Phase II Clinical Trial, Tectal Glioma

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Burzynski, S.R. (2004) The Present State of Antineoplaston Research. Integrative Cancer Therapies, 3, 47-58. http://dx.doi.org/10.1177/1534735403261964
[2]	Burzynski, S.R., Kubove, E. and Burzynski, B. (1992) Phase II Clinical Trials of Antineoplastons A10 and AS2-1 Infusions in Astrocytoma. In: Adam, D., Ed., Recent Advances in Chemotherapy, Futuramed Publishers, Munich, 2506-2507.
[3]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Children with High-Grade Glioma. Final Report (Protocol BT-06), and Review of Recent Trials. Journal of Cancer Therapy, 5, 565-577. http://dx.doi.org/10.4236/jct.2014.56065
[4]	Burzynski, S.R., Lewy, R.I., Weaver, R., Janicki, T., Jurida, G., Khan, M., et al. (2004) Long-Term Survival and Complete Response of a Patient with Recurrent Diffuse Intrinsic Brain Stem Glioblastoma Multiforme. Integrative Cancer Therapies, 3, 257-261. http://dx.doi.org/10.1177/1534735404267748
[5]	Burzynski, S.R., Weaver, R.A., Janicki, T., Szymkowski, B., Jurida, G., et al. (2005) Long-Term Survival of High-Risk Pediatric Patients with Primitive Neuroectodermal Tumors Treated with Antineoplastons A10 AS2-1. Integrative Cancer Therapies, 4, 168-177. http://dx.doi.org/10.1177/1534735405276835
[6]	Burzynski, S.R., Janicki, T.J., Weaver, R.A. and Burzynski, B. (2006) Targeted Therapy with Antineoplastons A10 and AS2-1 of High-Grade, Recurrent, and Progressive Brainstem Glioma. Integrative Cancer Therapies, 5, 40-47. http://dx.doi.org/10.1177/1534735405285380
[7]	Burzynski, S.R. (2006) Treatments for Astrocytic Tumors in Children: Current and Emerging Strategies. Pediatric Drugs, 8, 167-178. http://dx.doi.org/10.2165/00148581-200608030-00003
[8]	Burzynski, S.R. (2007) Recent Clinical Trials in Diffuse Intrinsic Brainstem Glioma. Cancer Therapy, 5, 379-390.
[9]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) The Response and Survival of Children with Recurrent Diffuse Intrinsic Pontine Glioma Based on Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Brainstem Glioma. Child’s Nervous System, 30, 2051-2056. http://dx.doi.org/10.1007/s00381-014-2401-z
[10]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2014) Long-Term Survival (>13 Years) in a Child with Recurrent Diffuse Intrinsic Pontine Glioma: A Case Report. Journal of Pediatric Hematology/Oncology, 36, e433-e439. http://dx.doi.org/10.1097/MPH.0000000000000020
[11]	Burzynski, S.R., Janicki, T.J. and Burzynski, G.S. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Recurrent Glioblastoma Multiforme. Final Report (Protocol BT-21). Journal of Cancer Therapy, 5, 946-956. http://dx.doi.org/10.4236/jct.2014.510100
[12]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S., Marszalek, A. and Brookman, S. (2014) A Phase II Study of Antineoplastons A10 and AS2-1 in Children with Recurrent, Refractory or Progressive Primary Brain Tumors. Final Report (Protocol BT-22). Journal of Cancer Therapy, 5, 977-988. http://dx.doi.org/10.4236/jct.2014.510102
[13]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2015) A Phase II Study of Antineoplastons A10 and AS2-1 in Patients with Brainstem Gliomas. The Report on Non-Diffuse Intrinsic Pontine Glioma (Protocol BT-11). Journal of Cancer Therapy, 6, 334-344. http://dx.doi.org/10.4236/jct.2015.64036
[14]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2015) A Phase II Study of Antineoplastons A10 and AS2-1 in Adult Patients with Newly-Diagnosed Anaplastic Astrocytoma. Final Report (Protocol BT-08). Cancer and Clinical Oncology, 4, 28-38. http://dx.doi.org/10.5539/cco.v4n1p28
[15]	Burzynski, S.R., Janicki, T.J. and Burzynski, G.S. (2015) A Phase II Study of Antineoplastons A10 and AS2-1 Injections in Adult Patients with Recurrent Anaplastic Astrocytoma—Final Report (Protocol BT-15). Cancer and Clinical Oncology, 4, 13-23.
[16]	Burzynski, S.R., Burzynski, G.S., Janicki, T.J. and Marszalek, A. (2014-2015) Complete Response and Long-Term Survival (>20 Years) of a Child with Tectal Glioma: A Case Report. Pediatric Neurosurgery, 50, 99-103. http://dx.doi.org/10.1159/000369907
[17]	Burzynski, S.R., Burzynski, G.S., Marszalek, A., Janicki, T.J. and Martinez-Canca, J.F. (2015) Long-Term Survival (over 20 Years), Complete Response and Normal Childhood Development in Medulloblastoma Treated with Antineoplastons A10 and AS2-1. Journal of Neurology & Stroke, 2, Article ID: 00054.
[18]	Ogata, Y., Matono, K., Tsuda, H., Ushijima, M., Uchida, S., et al. (2015) Randomized Phase II Study of 5-Fluorouracil Hepatic Arterial Infusion with or without Antineoplastons as an Adjuvant Therapy after Hepatectomy for Liver Metastases from Colorectal Cancer. PLoS ONE, 10, e0120064. http://dx.doi.org/10.1371/journal.pone.0120064
[19]	Ostrom, Q.T., Gittleman, H., Farah, P., Ondracek, A., Chen, Y., et al. (2013) CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2006-2010. Neuro-Oncology, 15, ii1-ii56. http://dx.doi.org/10.1093/neuonc/not151
[20]	Louis, D.N., Ohgaki, H., Wiestler, O.D., Cavenee, W.K., Burger, P.C., et al. (2007) The 2007 WHO Classification of Tumours of the Central Nervous System. Acta Neuropathologica, 114, 97-109. http://dx.doi.org/10.1007/s00401-007-0243-4
[21]	Dinnes, J., Cave, C., Huang, S. and Milne, R. (2002) A Rapid and Systematic Review of the Effectiveness of Temozolomide for the Treatment of Recurrent Malignant Glioma. British Journal of Cancer, 86, 501-505. http://dx.doi.org/10.1038/sj.bjc.6600135
[22]	Yung, W.K., Prados, M.D., Yaya-Tur, R., Rosenfeld, S.S., Brada, M., et al. (1999) Multicenter Phase II Trial of Temozolomide in Patients with Anaplastic Astrocytoma or Anaplastic Oligoastrocytoma at First Relapse. Temodal Brain Tumor Group. Journal of Clinical Oncology, 17, 2762-2771.
[23]	Scoccianti, S., Magrini, S.M., Ricardi, U., Detti, B., Krengli, M., et al. (2012) Radiotherapy and Temozolomide in Anaplastic Astrocytoma: A Retrospective Multicenter Study by the Central Nervous System Study Group of AIRO (Italian Association of Radiation Oncology). Neuro-Oncology, 14, 798-807. http://dx.doi.org/10.1093/neuonc/nos081
[24]	Wick, W., Hartmann, C., Engel, C., Stoffels, M., Felsberg, J., et al. (2009) NOA-04 Randomized Phase III Trial of Sequential Radiochemotherapy of Anaplastic Glioma with Procarbazine, Lomustine, and Vincristine or Temozolomide. Journal of Clinical Oncology, 27, 5874-5880. http://dx.doi.org/10.1200/JCO.2009.23.6497
[25]	Sarganas, G., Orzechowski, H.D., Klimpel, A., Thomae, M., Kauffmann, W., et al. (2012) Severe Sustained Cholestatic Hepatitis Following Temozolomide in a Patient with Glioblastoma Multiforme: Case Study and Review of Data from the FDA Adverse Event Reporting System. Neuro-Oncology, 14, 541-546. http://dx.doi.org/10.1093/neuonc/nos056
[26]	Grossman, S.A., Ye, X., Lesser, G., Sloan, A., Carraway, H., et al. (2011) Immunosuppression in Patients with High-Grade Gliomas Treated with Radiation and Temozolomide. Clinical Cancer Research, 17, 5473-5480. http://dx.doi.org/10.1158/1078-0432.CCR-11-0774
[27]	Chang, S.M., Kuhn, J.G., Robins, H.I., Schold, S.C., Spence, A.M., et al. (1999) Phase II Study of Phenylacetate in Patients with Recurrent Malignant Glioma: A North American Brain Tumor Consortium Report. Journal of Clinical Oncology, 17, 984-990.
[28]	Wen, P.Y., Macdonald, D.R., Reardon, D.A., Cloughesy, T.F., Sorensen, A.G., et al. (2010) Updated Response Assessment Criteria for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. Journal of Clinical Oncology, 28, 1963-1972. http://dx.doi.org/10.1200/JCO.2009.26.3541
[29]	Weller, M., Cloughesy, T., Perry, J.R. and Wick, W. (2013) Standards of Care for Treatment of Recurrent Glioblastoma—Are We There Yet? Neuro-Oncology, 15, 4-27. http://dx.doi.org/10.1093/neuonc/nos273
[30]	MedCalc Software bvba, Ostend, Belgium. http://www.medcalc.org
[31]	Chamberlain, M.C., Tsao-Wei, D.D. and Groshen, S. (2006) Salvage Chemotherapy with Cyclophosphamide for Recurrent Temozolomide-Refractory Anaplastic Astrocytoma. Cancer, 106, 172-179. http://dx.doi.org/10.1002/cncr.21582
[32]	Chamberlain, M.C., Wei-Tsao, D.D., Blumenthal, D.T. and Glantz, M.J. (2008) Salvage Chemotherapy with CPT-11 for Recurrent Temozolomide-Refractory Anaplastic Astrocytoma. Cancer, 112, 2038-2045. http://dx.doi.org/10.1002/cncr.23404
[33]	Fine, H.A., Dear, K.B., Loeffler, J.S., Black, P.M. and Canellos, G.P. (1993) Meta-Analysis of Radiation Therapy with and without Adjuvant Chemotherapy for Malignant Gliomas in Adults. Cancer, 71, 2585-2597. http://dx.doi.org/10.1002/1097-0142(19930415)71:8<2585::AID-CNCR2820710825>3.0.CO;2-S
[34]	Stewart, L.A. (2002) Chemotherapy in Adult High-Grade Glioma: A Systematic Review and Meta-Analysis of Individual Patient Data from 12 Randomised Trials. The Lancet, 359, 1011-1018. http://dx.doi.org/10.1016/S0140-6736(02)08091-1
[35]	Stupp, R., Reni, M., Gatta, G., Mazza, E. and Vecht, C. (2007) Anaplastic Astrocytoma in Adults. Critical Reviews in Oncology/Hematology, 63, 72-80. http://dx.doi.org/10.1016/j.critrevonc.2007.03.003
[36]	Glantz, M., Chamberlain, M., Liu, Q., Litofsky, N.S. and Recht, L.D. (2003) Temozolomide as an Alternative to Irradiation for Elderly Patients with Newly Diagnosed Malignant Gliomas. Cancer, 97, 2262-2266. http://dx.doi.org/10.1002/cncr.11323
[37]	Burzynski, S.R., Burzynski, G.S. and Janicki, T.J. (2014) Recurrent Glioblastoma Multiforme. A Strategy for Long-Term Survival. Journal of Cancer Therapy, 5, 957-976. http://dx.doi.org/10.4236/jct.2014.510101