Burzynski: Why has the FDA NOT granted Accelerated Approval for Antineoplastons A10 (Atengenal) and AS2-1 (Astugenal) ?

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1996 – Accelerated approval started by United States Food and Drug Administration Commissioner, Dr. David A. Kessler
(.4:18 – .6:10):

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Tamoxifen:
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7/1997 – A phase I study of high-dose tamoxifen for the treatment of refractory malignant GLIOMAS OF CHILDHOOD
http://www.ncbi.nlm.nih.gov/pubmed/9815790/
Clin Cancer Res. 1997 Jul;3(7):1109-15
http://www.ncbi.nlm.nih.gov/m/pubmed/9815790/
Clin Cancer Res July 1997 3; 1109
http://m.clincancerres.aacrjournals.org/content/3/7/1109.full.pd
Departments of Neurosurgery, Children’s Hospital of Pittsburgh, Pittsburgh, Pennsylvania, USA

http://clincancerres.aacrjournals.org/content/3/7/1109
Children with malignant GLIOMAS THAT PROGRESSED AFTER CONVENTIONAL THERAPY
——————————————————————
0 / 0% – EXHIBITED CLEAR-CUT TUMOR regression
——————————————————————
17 months (1 year 5 months) – longest survivor lived for after beginning tamoxifen
======================================
2000 – Radiation therapy and high-dose tamoxifen in the treatment of patients with diffuse BRAINSTEM GLIOMAS:

results of a Brazilian cooperative study
http://www.ncbi.nlm.nih.gov/pubmed/10715294/
Brainstem Glioma Cooperative Group
http://www.ncbi.nlm.nih.gov/m/pubmed/10715294/
J Clin Oncol 18, 1246-1253
http://m.jco.ascopubs.org/content/18/6/1246.long
——————————————————————
22 – assessable patients
——————————————————————
10.3 months – Median Survival
——————————————————————
4 / 18% – remain alive without tumoral progression
——————————————————————
8 / 37.0% {+/- 2 / 9.5%} (mean +/- SD) – 1-year Survival rate
——————————————————————
treatment combination PRODUCED NO SIGNIFICANT CHANGE in overall POOR prognosis of patients

Most tumors responded initially to treatment but recurred as study progressed

Based on POOR RESULTS, recommend ALTERNATIVE TREATMENTS be tested in patients with this type of tumor
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Temodar (Temozolomide):
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Temozolomide received accelerated approval by the U.S. Food and Drug Administration 1/1999 for treatment of ANAPLASTIC ASTROCYTOMA (brain cancer) patients
——————————————————————
54 patients
——————————————————————
12 / 22% – response rate
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5 / 9% – Complete Response rate
——————————————————————
50 weeks (16-114 weeks) – Median duration of all responses
——————————————————————
64 weeks (52-114 weeks) – Median duration of Complete Response
——————————————————————
4.4 months – Median Progression-Free Survival
——————————————————————
15.9 months (1 year 3.9 months) – Median Overall Survival
——————————————————————
At time of approval, NO RESULTS were available from randomized controlled trials in refractory ANAPLASTIC ASTROCYTOMA that show clinical benefit such as improvement in disease-related symptoms or prolonged survival
——————————————————————
http://clincancerres.aacrjournals.org/content/11/19/6767.full
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Was the United States Food and Drug Administration’s 1/1999 accelerated approval based on the PUBLISHED FINAL RESULTS OF A PHASE II (2) CLINICAL TRIAL?
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12/2000 – Temozolomide and ANAPLASTIC ASTROCYTOMA:

new indication

NO CLEAR PROOF OF EFFICACY
http://www.ncbi.nlm.nih.gov/pubmed/11475493/
Prescrire Int. 2000 Dec;9(50):170-1.
http://www.ncbi.nlm.nih.gov/m/pubmed/11475493/
(1) Temozolomide recently licensed in France for treating patients with ANAPLASTIC ASTROCYTOMA who are in relapse or progression after standard therapy
——————————————————————
(2) clinical dossier contains only one non comparative trial
——————————————————————
(3) 111 patients with ANAPLASTIC ASTROCYTOMA or oligoanaplastic astrocytoma had not all had the standard treatment with surgery, radiotherapy and chemotherapy
——————————————————————
54 patients – subgroup who met criteria
——————————————————————
16 months (1 year 4 months) – Median Global Survival
——————————————————————
31 months (2 years 7 months) – Median Global Survival from start of initial treatment
——————————————————————
NO BETTER THAN SURVIVAL BEFORE THE INTRODUCTION OF temozolomide
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The answer is: NO

1/1999 – FDA Accelerated Approval
9/1999 – Phase 2 publication
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9/1999 – Multicenter phase II trial of temozolomide in patients with ANAPLASTIC ASTROCYTOMA or anaplastic oligoastrocytoma at first relapse

Temodal Brain Tumor Group
http://www.ncbi.nlm.nih.gov/pubmed/10561351/
J Clin Oncol. 1999 Sep;17(9):2762-71.
http://www.ncbi.nlm.nih.gov/m/pubmed/10561351/
University of Texas M.D. Anderson Cancer Center, Houston, TX, USA
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http://www.drugs.com/pro/temodar.html
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http://www.pharmainfo.net/fda-articles/fda-safety-page-fatal-medication-errors-associated-temodar
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TEMODAR ADVERSE EVENTS REPORTED TO THE FDA OVER TIME:
http://www.drugcite.com/?q=TEMODAR
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ADVERSE EVENTS:
Primary Suspect Reports: 4,436
Total Reports: 6,350
http://www.adverseevents.com/drugdetail.php?AEDrugID=1794&BrandName=TEMODAR
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http://www.temodar.com/temodar/index.do
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2004 – Supratentorial high-grade ASTROCYTOMA and DIFFUSE BRAINSTEM GLIOMA:

two challenges for the pediatric oncologist
http://www.ncbi.nlm.nih.gov/pubmed/15047924/
Oncologist. 2004;9(2):197-206.
http://www.ncbi.nlm.nih.gov/m/pubmed/15047924/
Oncologist 9, 197-206
http://m.theoncologist.alphamedpress.org/content/9/2/197.long
Division of Neuro-Oncology, Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA

neoplasms predominantly involve supratentorial hemispheres or pons, in which case tumors are usually called DIFFUSE BRAINSTEM GLIOMAS

supratentorial neoplasms
——————————————————————
diagnosis of DIFFUSE BRAINSTEM GLIOMA based upon typical imaging, dispensing with need for surgery in majority of cases

Radiation therapy is mainstay of treatment for children with DIFFUSE BRAINSTEM GLIOMAS
——————————————————————
2 years – Less than 10% of children with diffuse brainstem gliomas survive
——————————————————————
outcome for patients with either type of tumor is POOR when standard multimodality therapy is used

children are ideal candidates for INNOVATIVE TREATMENT approaches
——————————————————————
3-21 years Patients were eligible for current multiinstitutional study
——————————————————————
33 patients (6.4 years – Median age at diagnosis) enrolled
——————————————————————
33 / 100% – DIED OF DISEASE PROGRESSION
——————————————————————
12 months (1 year) – Median Survival
——————————————————————
16 / 48% – estimated 1-year Survival rate (standard error, 1 / 8%)
——————————————————————
administration of temozolomide after RT DIDN’T ALTER POOR PROGNOSIS associated with newly diagnosed diffuse BRAINSTEM GLIOMA in children
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1/1/2005 (11/24/2004) – Role of temozolomide after radiotherapy for newly diagnosed diffuse BRAINSTEM GLIOMA in children:

results of a multiinstitutional study (SJHG-98)
http://www.ncbi.nlm.nih.gov/pubmed/15565574
Cancer. 2005 Jan 1;103(1):133-9.
http://www.ncbi.nlm.nih.gov/m/pubmed/15565574
Cancer 103, 133-139
http://onlinelibrary.wiley.com/doi/10.1002/cncr.20741/abstract;jsessionid=6717837591CCC8FCBD8E46163808E221.d03t01
Cancer
Volume 103, Issue 1, pages 133–139, 1 January 2005
http://onlinelibrary.wiley.com/doi/10.1002/cncr.20741/full
Article first published online: 24 NOV 2004
References:
http://onlinelibrary.wiley.com/doi/10.1002/cncr.20741/references
Cited By:
http://onlinelibrary.wiley.com/doi/10.1002/cncr.20741/citedby
DOI: 10.1002/cncr.20741

Department of Hematology-Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee, USA
——————————————————————
33 patients: (33 / 100% – 6.4 years: Median age)
——————————————————————
33 / 100% – ALL DIED OF DISEASE PROGRESSION
——————————————————————
12 months (1 year) – Median Survival
——————————————————————
16 / 48% – 1 year estimated Survival rate
——————————————————————
Table 1. Results of radiation therapy in combination with chemotherapy for newly diagnosed, diffuse, intrinsic BRAIN STEM GLIOMA

Author
Study Type
Patients Total No.
Treatment Radiation Therapy
Additional Chemotherapy
Efficacy
OS MST CR PR SD PD

Multiinstitutional 33 56 Temozolomide, irinotecan 0 0 12 NA NA NA

response rates based on evaluable patients
32 54 Topotecan

CR – complete response
GCSF – granulocyte colony stimulating factor
HD – high dose tamoxifen
HDB – high dose chemotherapy and autologous bone marrow transplantation HF – hyperfractionated
M – months
MST – median survival time
NA – not available
OS – overall survival
PD – progressive disease
PR – partial response
SD – stable disease
UNK – unknown
* 1 patient had radiological improvement

Cancer 103, 133-139
——————————————————————
3-21 years – eligible for current multiinstitutional study
——————————————————————
33 – (Median age at diagnosis
6.4 years) enrolled
——————————————————————
ALL PATIENTS DIED OF DISEASE PROGRESSION
——————————————————————
12 months (1 year) – Median Survival
——————————————————————
48% – estimated 1-year Survival rate (standard error 8%)
——————————————————————
administration of temozolomide after RT DIDN’T ALTER POOR PROGNOSIS associated with newly diagnosed diffuse BRAINSTEM GLIOMA in children
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2/2008 (2/2/2007)
Treatment of children with diffuse intrinsic BRAIN STEM GLIOMA
with radiotherapy, vincristine and oral VP-16:

a Children’s Oncology Group phase II study
http://www.ncbi.nlm.nih.gov/pubmed/17278121
Pediatr Blood Cancer. 2008 Feb;50(2):227-30
http://www.ncbi.nlm.nih.gov/m/pubmed/17278121
University of Rochester Medical Center, Rochester, New York, USA.

http://onlinelibrary.wiley.com/doi/10.1002/pbc.21154/abstract;jsessionid=DE7A67EFBAC1A184F6805F11CFC4F30B.d02t02
Article first published online: 2 FEB 2007
DOI: 10.1002/pbc.21154

prognosis for children with BRAIN STEM GLIOMA remains grim

The Pediatric Oncology Group (POG, now part of Children’s Oncology Group) conducted study using agents in combination with standard external beam radiation for children with newly diagnosed BRAIN STEM GLIOMA
——————————————————————
Children eligible
3-21 years of age, had MRI-evidence of diffuse intrinsic pontine glioma, and had neurologic deficits of <6 months duration
——————————————————————
30 eligible and evaluable for Survival / toxicity
——————————————————————
8 years (3-14 years) – Median age
——————————————————————
7 / 23% – Partial Response following radiation
18 / 60% – Stable Disease
2 / 7% – Progressive Disease
3 / 10% – Response Not measured
——————————————————————
30 / 100% CHILDREN DIED
——————————————————————
Overall Survival 1 year
27 +/- 7%
2 years, 3 +/- 2%
——————————————————————
9 months (3-36 months) – Median Survival
——————————————————————
addition of vincristine and oral VP-16 to standard external beam radiation causes moderate toxicity and DOESN’T IMPROVE SURVIVAL OF CHILDREN WITH DIFFUSE INTRINSIC BRAIN STEM GLIOMA
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Avastin (Bevacizumab):
======================================
5/6/2009 – U.S. Food and Drug Administration (FDA) granted accelerated approval of Avastin (bevacizumab) for people with GLIOBLASTOMA (brain cancer) with progressive disease following prior therapy

effectiveness of Avastin in AGGRESSIVE form of BRAIN CANCER based on improvement in objective response rate

Currently, NO DATA available from randomized controlled trials demonstrating improvement in disease-related symptoms or increased survival with Avastin in GLIOBLASTOMA
——————————————————————
11.3 months – Progression-Free Survival
——————————————————————
http://www.drugs.com/newdrugs/fda-grants-accelerated-approval-avastin-combination-paclitaxel-chemotherapy-first-line-advanced-852.html
According to FDA analysis of study

Study AVF3708g
——————————————————————
22 / 26% – tumor responses observed of 85 patients treated with Avastin alone
——————————————————————
4.2 months – Median duration of response in patients
——————————————————————
Study NCI 06-C-0064E

Efficacy of Avastin in GLIOBLASTOMA that progressed following prior therapy supported by another study that used same response assessment criteria as AVF3708g

56 patients treated with Avastin alone
——————————————————————
11 / 20% of patients – Responses were observed
——————————————————————
3.9 months – Median duration of response
——————————————————————
http://www.cancer.gov/cancertopics/druginfo/fda-bevacizumab
FDA – “People with this type of brain cancer have had no new treatments in more than a decade”
http://www.drugs.com/newdrugs/fda-grants-accelerated-approval-avastin-brain-cancer-glioblastoma-has-progressed-following-prior-1342.html
——————————————————————
Avastin is gene-targeted therapy, which can only target certain specific genes
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Afinitor (Everolimus):
======================================
Afinitor (ubependymal giant cell ASTROCYTOMA (SEGA) brain tumor)
——————————————————————
10/29/2010 – FDA granted accelerated approval for Afinitor after single Phase 2 study of only 28 patients
——————————————————————
32% experienced 50% reduction of tumor
——————————————————————
none of their tumors went away completely
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Was the United States Food and Drug Administration’s 10/29/2010 accelerated approval based on the PUBLISHED FINAL RESULTS OF A PHASE II (2) CLINICAL TRIAL?
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10/12/2011 (8/1/2011) – Everolimus tablets for patients with subependymal giant cell ASTROCYTOMA
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3389821/
Expert Opin Pharmacother. Author manuscript; available in PMC 2012 July 5.
Published in final edited form as:
Expert Opin Pharmacother. 2011 October; 12(14): 2265–2269.
Published online 2011 August 1. doi: 10.1517/14656566.2011.601742
PMCID: PMC3389821
NIHMSID: NIHMS385824
——————————————————————
http://www.fda.gov/AboutFDA/CentersOffices/OfficeofMedicalProductsandTobacco/CDER/ucm231967.htm
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The answer is: NO

10/29/2010 – FDA Accelerated Approval
10/12/2011 – publication
� � � � � � � � � � � � � � � � �
COMPARE COMBINED:
� � � � � � � � � � � � � � � � �
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ANAPLASTIC ASTROCYTOMA
==========================
22% – Objective Response: Objective response = complete response and partial response – Antineoplastons

22% – response rate: Temodar
——————————————————————
11% – Complete Response: Antineoplastons

9% – Complete Response rate: Temodar
——————————————————————
17+ years – Maximum Survival : patient with ANAPLASTIC ASTROCYTOMA – Antineoplastons

50 weeks (16-114 weeks) – Median duration of all responses: Temodar
——————————————————————
17+ years – Maximum Survival : patient with ANAPLASTIC ASTROCYTOMA – Antineoplastons

64 weeks (52-114 weeks) – Median duration of Complete Response: Temodar
——————————————————————
6 months – 7 / 39% Progression-Free Survival: Antineoplastons

4.4 months – Median Progression-Free Survival: Temodar
——————————————————————
5 years – 4 / 22% Overall Survival: Antineoplastons

2 years – 7 / 39% Overall Survival: Antineoplastons

2 years – Most patients with brainstem glioma fail standard radiation therapy and chemotherapy and do not survive longer

15.9 months (1 year 3.9 months) – Median Overall Survival: Temodar
� � � � � � � � � � � � � � � � �
COMPARE COMBINED:
� � � � � � � � � � � � � � � � �
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GLIOBLASTOMA
======================================
39% – Progression-Free Survival (PFS) at 6 months: Antineoplastons

5.28 months – Median Progression-Free Survival (PFS): Antineoplastons

11.3 months – Progression-Free Survival: Avastin
——————————————————————
32% – % of Patients Showing Objective Response = complete response and partial response: Antineoplastons

26% – tumor responses observed Avastin
——————————————————————
42% – special exception (SE): Overall survival (OS) – 2 years: Antineoplastons

36% – BT-11: Overall survival (OS) – 2 years: Antineoplastons

19% – special exception (SE): Overall survival (OS) – 5 years: Antineoplastons

25% – BT-11: Overall survival (OS) – 5 years: Antineoplastons

4.2 months – Median duration of response in patients: Avastin
——————————————————————
9 / 32% – # and % of Patients Showing Objective response = complete response and partial response – Antineoplastons

11 / 20% of patients – Responses were observed: Avastin
——————————————————————
5+ years – Maximum Survival : patient with GLIOBLASTOMA – Antineoplastons

3.9 months – Median duration of response: Avastin
� � � � � � � � � � � � � � � � �
COMPARE COMBINED:
� � � � � � � � � � � � � � � � �
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ASTROCYTOMA
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47% / 7 – % and # of Patients Showing Objective response = complete response (6) and partial response (1) – Antineoplastons

32% experienced 50% reduction of tumor – Afinitor
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Burzynski: Complete Response, Partial Response, Stable Disease, Progressive Disease, Objective Response, and Response:
https://stanislawrajmundburzynski.wordpress.com/2013/07/04/burzynski-complete-response-partial-response-stable-disease-progressive-disease-objective-response-and-response/
� � � � � � � � � � � � � � � � �
Burzynski: Progression-Free Survival:
https://stanislawrajmundburzynski.wordpress.com/2013/07/04/burzynski-progression-free-survival/
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WHAT IS MISDIRECTION ? Critiquing “Antineoplastons: Has the FDA kept its promise to the American people ?”:
https://stanislawrajmundburzynski.wordpress.com/2013/06/08/what-is-misdirection-critiquing-antineoplastons-has-the-fda-kept-its-promise-to-the-american-people/
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