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)

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

Burzynski Clinic, Houston, TX, USA.

DOI: 10.4236/jct.2015.64036                

Abstract

Inoperable brainstem gliomas (BSG) are among the most difficult to treat malignancies. In the intent-to-treat (ITT) population of the BT-11 study for BSG, forty patients (median age 11.2 years old) were enrolled. Antineoplastons A10 and AS2-1 (ANP) were administered intravenously daily. The median daily dose of A10 was 8.70 g/kg/day and AS2-1 was 0.32 g/kg/day. Efficacy analyses were conducted in two subgroups: recurrent pediatric diffuse intrinsic pontine glioma (RPDIPG, N = 17) and non-diffuse intrinsic pontine glioma (NDIPG, N = 11). This paper reports the results of the study of the efficacy and safety of ANP in patients with NDIPG. The results in the RPDIPG group were reported before; complete response (CR) was 6%, partial response (PR) 23.5%, and stable disease (SD) 17.6%. One year overall survival (OS) was 29.4%, 2 years 11.8%, and 5, 10, and 15 years 6%. In the NDIPG group, there were 36% CR and 27.5% SD. OS at 1, 5, 10, and 15 years was 82%, 73%, 62%, and 50% correspondingly. There was only one serious adverse event (9%) reported in NDIPG represented by hypokalemia, Grade 4. The results suggest that ANP shows efficacy and an acceptable tolerability profile in patients with RPDIPG and NDIPG.

Keywords

Antineoplastons A10 and AS2-1, Brainstem Glioma, Diffuse Intrinsic Pontine Glioma, Phase 2 Clinical Trial, Recurrent Glioma

Conflicts of Interest

The authors declare no conflicts of interest.

References

[1]	Ostrom, Q.T., Gittleman, H., Liao, P., Rouse, C., Chen, Y.W., Dowling, P., et al. (2014) CBTRUS Statistical Report: Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2007-2011. Neuro-Oncology, 16, iv1-iv63. http://dx.doi.org/10.1093/neuonc/nou223
[2]	Barkovich, A.J., Krischer, J., Kun, L.E., Packer, R., Zimmerman, R.A., et al. (1990) Brain Stem Gliomas: A Classification System Based on Magnetic Resonance Imaging. Pediatric Neurosurgery, 16, 73-83. http://dx.doi.org/10.1159/000120511
[3]	Albright, A.L., Packer, R.J., Zimmerman, R., Rorke, L.B., Boyett, J., Freeman, C.R., et al. (2013) Magnetic Resonance Scans Should Replace Biopsies for the Diagnosis of Diffuse Brain Stem Gliomas: A Report from the Children’s Cancer Group. Neuro-Oncology, 15, 1026-1030.
[4]	Donaldson, S.S., Laningham, F. and Fisher, P.G. (2006) Advances toward an Understanding of Brainstem Gliomas. Journal of Clinical Oncology, 24, 1266-1272. http://dx.doi.org/10.1200/JCO.2005.04.6599
[5]	Hargrave, D., Bartels, U. and Bouffet, E. (2006) Diffuse Brainstem Glioma in Children: Critical Review of Clinical Trials. Lancet, 7, 241-248. http://dx.doi.org/10.1016/S1470-2045(06)70615-5
[6]	Burzynski, S.R. (2007) Recent Clinical Trials in Diffuse Intrinsic Brainstem Glioma. Cancer Therapy, 5, 379-390.
[7]	Khuong-Quang, D.A., Buczkowicz, P., Rakopoulos, P., Liu, X.Y., Fontebasso, A.M., et al. (2012) K27M Mutation in Histone H3.3 Defines Clinically and Biologically Distinct Subgroups of Pediatric Diffuse Intrinsic Pontine Gliomas. Acta Neuropathologica, 124, 439-447. http://dx.doi.org/10.1007/s00401-012-0998-0
[8]	Burzynski, S.R. (2004) The Present State of Antineoplaston Research (1). Integrative Cancer Therapies, 3, 47-58. http://dx.doi.org/10.1177/1534735403261964
[9]	Burzynski, S.R. and Patil, S. (2014) The Effect of Antineoplastons A10 and AS2-1 and Metabolites of Sodium Phenylbutyrate on Gene Expression in Glioblastoma Multiforme. Journal of Cancer Therapy, 5, 929-945. http://dx.doi.org/10.4236/jct.2014.510099
[10]	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.
[11]	Burzynski, S.R. (2006) Treatments for Astrocytic Tumors in Children: Current and Emerging Strategies. Pediatric Drugs, 8, 167-168. http://dx.doi.org/10.2165/00148581-200608030-00003
[12]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Marszalek, A. (2013) Long-Term Survival (>13 Years) in a Child with Recurrent Diffuse Pontine Gliosarcoma: A Case Report. Journal of Pediatric Hematology/Oncology, 36, e433-e439. http://dx.doi.org/10.1097/MPH.0000000000000020
[13]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S., 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, 2051-2061. http://dx.doi.org/10.1007/s00381-014-2401-z
[14]	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
[15]	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
[16]	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
[17]	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
[18]	Burzynski, S.R., Janicki, T.J., Burzynski, G.S. and Brookman, S. (2014) Preliminary Findings on the Use of Targeted Therapy with Pazopanib and Other Agents in Combination with Sodium Phenylbutyrate in the Treatment of Glioblastoma Multiforme. Journal of Cancer Therapy, 5, 1423-1437. http://dx.doi.org/10.4236/jct.2014.514144
[19]	Burzynski, S.R., Burzynski, G.S. and Brookman, S. (2015) A Case of Sustained Objective Response of Recurrent/ Progressive Diffuse Intrinsic Pontine Glioma with Phenylbutyrate and Targeted Agents. Journal of Cancer Therapy, 6, 40-44. http://dx.doi.org/10.4236/jct.2015.61006
[20]	Packer, R.J., Boyett, J.M., Zimmerman, R.A., Rorke, L.B., Kaplan, A.M. (1993) Hyperfractionated Radiation Therapy (72 Gy) for Children with Brain Stem Gliomas. A Childrens Cancer Group Phase I/II Trial. Cancer, 72, 1414-1421.
[21]	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
[22]	Choux, M., Lena, G. and Do, L. (2000) Brainstem Tumors. In: Choux, M., Di Rocco, C. and Hockley, A., Eds., Pediatric Neurosurgery, Churchill Livingstone, New York, 471-491.
[23]	Leach, P.A., Estlin, E.J., Coope, D.J., Thorne, J.A. and Kamaly-Asl, I.D. (2008) Diffuse Brainstem Gliomas in Children: Should We or Shouldn't We Biopsy? British Journal of Neurosurgery, 22, 619-625. http://dx.doi.org/10.1080/02688690802366198
[24]	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.
[25]	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
[26]	Lashford, L.S., Thiesse, P., Jouvet, A., Jaspan, T., Couanet, D., et al. (2002) Temozolomide in Malignant Gliomas of Childhood: A United Kingdom Children’s Cancer Study Group and French Society for Pediatric Oncology Intergroup Study. Journal of Clinical Oncology, 20, 4684-4691.
[27]	Karajannis, M.A., Legault, G., Fisher, M.J., Milla, S.S., Cohen, K.J., et al. (2014) Phase II Study of Sorafenib in Children with Recurrent or Progressive Low-Grade Astrocytomas. Neuro-Oncology, 16, 1408-1416. http://dx.doi.org/10.1093/neuonc/nou059
[28]	Mauffrey, C. (2006) Paediatric Brainstem Gliomas: Prognostic Factors and Management. Journal of Clinical Neuroscience, 13, 431-437.
[29]	Guillamo, J.S., Monjour, A., Taillandier, L., Devaux, B., Varlet, P., Haie-Meder, C., et al. (2001) Brainstem Gliomas in Adults: Prognostic Factors and Classification. Brain, 124, 2528-2539. http://dx.doi.org/10.1093/brain/124.12.2528
[30]	Kesari, S., Kim, R.S., Markos, V., Drappatz, J., Wen, P.Y. and Pruitt, A.A. (2008) Prognostic Factors in Adult Brainstem Gliomas: A Multicenter, Retrospective Analysis of 101 Cases. Journal of Neuro-Oncology, 88, 175-183. http://dx.doi.org/10.1007/s11060-008-9545-1