[9] – 1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[9] – 1993 (11/2/1993) – Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment, National Cancer Institute (NCI), Department of Health & Human Services (HHS), Public Health Services, National Institutes of Health (NIH) to Burzynski [3 pgs.]

Department of Health and Human Services, Public Health Services, National Institutes of Health

Dear Dr. Burzynski:

With regard to your letter of 10/26/1993, you specifically state

“The medicine will be sent to you immediately once you make the corrections to the protocol that we have requested”

We have substantial factual disagreements and scientific reservations with many of the comments made in your 10/26/1993 letter, including your preposterous claim that the NCI wasted 8 months

Nonetheless, we will accede to all the modifications that you have stipulated

We do so because we are committed to beginning the clinical studies as quickly as possible

We presume that these are your final comments, since all the changes will have been made and we will have addressed all of your concerns regarding these studies

The revised protocol will be sent to you as soon as it is received from the investigators

Based on the promise in your letter, we expect that the drug will be shipped to the NCI repository the next day

The changes to made to the protocol are as follows:

1. The dose and schedule will be modified as exactly as your require

We believe this to be the dose and schedule found in your protocol BT6, with dose escalation and maximum dose guidelines for adults clarified in your letter of 10/13/1993

2. The Memorial study, as written, has 2 separate components, one for patients with glioblastoma multiforme and one for patients with anaplastic astrocytoma

Accrual to each stratum proceeds independently, and analyses of each stratum is separate

However, we will ask the investigators from Mayo Clinic to join the Memorial study, rather than conducting an independent trial

This will effectively evaluate on the one hand patients with glioblastoma multiforme, and on the other hands those with anaplastic astrocytoma

Pg. 2

Patients with either disease will be enrolled at both Memorial and Mayo sites

This modification has 2 advantages — it limits total accrual to 35 patients per histology, as you request; and it accelerates accrual, since each institution can enter both types of patients on the studies

3. As you stipulated, Fleming’s original statistical design will be used utilized
15 patients will be entered independently to each stratum; for each stratum, if there is 1 response, accrual will proceed to a total of 35 patients

Thus total accrual will be 70 patients if both strata proceed past the 1st stage

(the initial 15 patients per histology)

4. According to your wishes, all scans for tumor measurements and laboratory test will be performed within 7 days of initiating protocol therapy, rather than the standard 14 days now specified in the protocol

5. The eligibility criteria will be modified to accept only patients with a Karnofsky performance status of 70-100%

6. As you require, the protocol response criteria will be based on objective tumor measurements and will not include assessment of neurologic status

Neurologic status will be evaluated separately

7. In accordance with your letter, we will arrange a review of data after accrual of the 1st 5-6 patients, which should occur 6 months after the study has been initiated

This should be sufficient to assure that the conduct of the study is satisfactory

The Theradex database is also available to precisely determine if the conduct of the study has followed protocol guidelines; the study centers will also be audited on-site by Theradex (independent contractors) every 3 months

In your letter you express concern regarding what you perceive to be bias against alternative treatments by Mayo Clinic and Memorial investigators

Please note that the investigators participating in the antineoplaston studies volunteered to do so because of the findings of the NCI review of your best case series

To my knowledge none of the participating investigators have expressed (publicly or privately) a position for or against Antineoplastons

Both institutions have a distinguished record in clinical investigations, and have been leaders in subjecting all treatments (including alternative interventions) to fair and objective clinical research

We are confident that credible clinical studies will be conducted

Pg. 3

Finally, if even after modifying these studies in accordance with your stated wishes, you are unwilling to supply the antineoplaston materials, please inform me as quickly as possible

We will then seek alternative sources of this family of molecules for proper clinical evaluation

Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program, Division of Cancer Treatment, NCI

cc:

Dr. Samuel Broder
Dr. Jan Bruckner
Dr. Bruce Chabner
Dr. Jay Greenblatt
Dr. Joseph Jacobs
Dr. Mark Malkin
Ms. Mary McCabe
Dr. David Parkinson
Dr. Mario Sznol
Ms. Dorothy Tisevich
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1993 (11/2/1993) – Dr. Michael A. Friedman to SRB [9]
1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski [14]
1993 (11/2/1993) – Dr. Michael A. Friedman to SRB [19] (3 pgs.)
1993 (11/2/1993) – Dr. Michael A. Friedman to Burzynski [24]
1993 (10/13/1993) – Burzynski to Dr. Michael A. Friedman
1993 (10/26/1993) – Burzynski to Dr. Michael A. Friedman
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[7] – 1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski (4 pgs.)

This page is linked to:
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Critiquing: Dr. Michael A. Friedman, Dr. Mark G. Malkin, Dr. Mario Sznol, Robert B. Lanman, Memorial Sloan-Kettering Cancer Center, Mayo Clinic, Department of Health & Human Services (HHS), Public Health Service, Quality Assurance and Compliance Section, Regulatory Affairs Branch (RAB), Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment (DCT), National Cancer Center (NCI) at the National Institutes of Health (NIH), Stanislaw Burzynski: On the arrogance of ignorance about cancer and targeted therapies
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https://stanislawrajmundburzynski.wordpress.com/2013/09/08/critiquing-stanislaw-burzynski-on-the-arrogance-of-ignorance-about-cancer-and-targeted-therapies/
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[7] – 1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski (4 pgs.)

Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program (CTEP), Division of Cancer Treatment, National Cancer Institute (NCI), Department of Health & Human Services (HHS), National Institutes of Health (NIH) letter to Burzynski [4 Pgs.]

Dear Dr. Burzynski:

This letter is in response to your correspondence of 10/11/1993

(addressed to Dr. Sznol)

and of 10/13/1993

(to Dr. Greenblatt)

Your most recent comments regarding the approved study of antineoplastons in adults brain tumor patients, faxed to Dr. Greenblatt on 10/13/1993, come as quite a surprise

Particularly confusing are your comments regarding dose and schedule of antineoplastons proposed in that study (your comment #1)

Originally the dosage and schedule for this study was based on your protocol BT4

This version of BT4 was entitled,
“Therapy of high-grade glioma with continuous infusions of antineoplastons A10 and AS2-1”,
and was accompanied by 12 case histories

(patients with either anaplastic astrocytoma or glioblastoma multiforme treated apparently according to BT4)

In your letter of 4/26/1993, however you stated that protocol BT4 was only for low-grade gliomas

Furthermore, you noted that protocols BT5 or BT6 should be used for patients with anaplastic astrocytoma and gliobastoma multiforme

In that same letter (4/20/1993), you noted that AS 2-1 was tolerated well at doses of .5 gm/kg/24h by adult patients when administered in intermittent injections (this is method of administration in BT6 and in the IND study)

You stated that if given by continuous infusion, adults would experience increased sleepiness and tiredness, and specifically stated that the dosage of AS2-1 by continuous infusion for low-grade gliomas should be reduced to 0.4 g/kg/24h

You did not provide data to support these assertions, nevertheless, based on these comments and our review of the protocols BT4, BT5, BT6, we instructed the investigators to revise their protocol in accordance with your instructions

In the Consensus Review sent 5/5/1993, we instructed the Memorial Sloan Kettering investigators to pattern their protocol according to BT5, which was written for both children and adults
We specifically pointed out that BT6 was written for children

In your letter of 6/9/1993, regarding our Consensus Review, you specifically asked that the investigators use the treatment program according to BT6, knowing that the Memorial protocol was for adults with AA and/or GM

You did not at any time mention that dose escalation should be modified for adults, or mention any dose limitation for adults given the intermittent as specified in the BT6 protocol

Page 2

Your concerns regarding dose limitation in the previous letter appeared to be related to continuous infusion administration

The letter of 6/9/1993, contained only 4 comments and at that time you had both the protocol and Consensus Review in your possession

We transmitted your letter of 6/9 directly to the investigators, and all your requested changes were made

Our sincere efforts to attempt to duplicate your findings and follow your recommendations are frustrated by receiving contradictory, incomplete, and inconsistent information from you

We have, at multiple points in the protocol development, solicited your input and followed your guidance in getting recommended dose escalation and modification guidelines for adults

Please note that, one last time, we will ask the investigator to revise the protocol with regard to dose and schedule in compliance with your latest letter

However, we plan that the study will begin immediately and this will be the last such modification

Although you have not provided data to support each of your specific recommendation, we have incorporated them

With regard to comment #2 of your Fax of 10/13/1993, you have misinterpreted the protocol

The total number of potential patients is 35/stratum, (ie a total of 70 patients) allowing for an adequate Phase II evaluation of each group of patients

With regard to the statistical section, your #3 comment, there is little reason to assume that the modified Fleming design currently used in the protocol for the first stage of accrual is less appropriate than a design using 15 patients in the first stage

If the true response rate of the antineoplastons is 20% (standard criteria for activity in all our phase II trials considered worthy of further study), the chance of proceeding to the second stage of accrual with the current design is 93.1%

The chance of proceeding to the second stage using 15 patients in the first stage of accrual is 96.5%

These differences are not considered meaningful

With regard to your comment #4, we wish to maintain the standard clinical trials methodology used to evaluate new agents

We know of no evidence that obtaining a brain scan within 7 days of treatment versus within 14 days of treatment will in any way affect the evaluation of activity of a drug in this disease

The protocol clearly states that scans must be obtained within 2 weeks of study entry

Please also note that the practical difficulties in scheduling scans and completing the pretreatment work-up in just one week; the costs of repeating tests simply to meet this artificial deadline could not be justified and probably would not be covered by insurance companies

With regard to your point #5, (performance status) your own protocols allow patients with Karnofsky performance status of 60

We see no reason to demand a more stringent entry criteria for performance status than you have employed for your own patients

Page 3

With regard to your point #6, the use of neurologic status as well as CT scans/MRI findings to determine response, this was suggested to the investigators in our Consensus Review of 5/5/1993

You made no comment regarding this in your letter of 6/9/1993

This use of neurologic function as an additional criteria to determine response is an objective measurement and is standard among protocols we sponsor for glioma patients . .

It is scientifically acceptable to include the criteria for response as currently written in the protocol

At analysis, both scan data and objective neurologic assessment can be described

With regard to your letter of 10/11/1993, concerning data reviews, we are satisfied that reviewing the data after accrual of the first 14 patients/stratum is sufficient

We share your concerns about patient safety but believe that these investigators have extensive experience treating glioma patients, are superb and careful physicians, and have extensive experience administrating a range of investigational agents to these patients

Furthermore, the patients will be followed carefully, and dose reductions for expected toxicities will be carried out as specified in the protocol

Nevertheless, your experience with the agents is valuable and the availability of your guidance is much appreciated

If necessary, we will arrange a conference call at the end of treatment of the first 5 patients, or sooner if problems occur

Your participation in such a conference call, if necessary, would be welcome

We will provide the Theradex (CTMS) printout to you on a monthly basis as we receive it

We do not believe it is practical or necessary to supply data on an every 2 week basis

The most important unresolved issue at this time is that we are still waiting to receive the promised supply of antineoplastons to conduct these studies

Your letter of 11/5/1992, guaranteed a supply of the antineoplastons by 3/31/1993

(see attached)

As of today we still have not received it

Believing that you would be shipping drug to the NCI, and since the protocol is approved at Memorial Sloan Kettering, recruitment of patients has begun

As you point out, these patients have aggressive disease, and cannot afford to wait to begin treatment

We are prepared to try to assist you in meeting this commitment, but we know of no obstacle here at NCI

We urgently request, again, that you ship the drug immediately

Please be aware that our mission is to find and develop better therapies for cancer patients, and our only obligation is to those patients

Our agreement to pursue these studies with antineoplastons was based on suggestive evidence

Page 4

of activity noted in your best case studies

If you are unable or unwilling to provide the antineoplastons in the near future, we will pursue alternative sources to procure the drug or its active components, and will proceed with a clinical development plan to determine whether these chemicals have activity and are beneficial for patients

Michael A. Friedman, M.D., Associate Director, Cancer Therapy Evaluation Program, Division of Cancer Treatment, NCI, Department of Health and Human Services, National Institutes of Health

cc:

Dr. Samuel Broder
Dr. Jan Buckner
Dr. Bruce Chabner
Dr. Jay Grabnett
Dr. Joseph Jacobs
Dr. Mark Malkin
Ms. Mary McCabe
Dr. David Parkinson
Dr. Mario Sznol
Ms. Dorothy Tisevich
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1993 (10/20/1993) – Dr. Michael A. Friedman to Burzynski [8]
1992 (11/5/1992) – Burzynski ANP 3/31/1993
1993 (4/20/1993) – Burzynski (4/26/1993)? in that same letter
1993 (4/26/1993) – Burzynski
1993 (5/5/1993) – Consensus Review
1993 (6/9/1993) – Burzynski re Consensus Review
1993 (10/11/1993) – Burzynski to Dr. Mario Sznol
1993 (10/13/1993) – Burzynski fax to Dr. Jay Greenblatt
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