Clinical Trials Protocol BT-27| Home Page Clinical Trials Protocol BT-27 |
Protocol for Candidate Drugs for Phase II Study
Sponsor
Burzynski Research Institute, Inc.
9432 Old Katy Road
Houston, Texas 77055
Principal Investigator
S. R. Burzynski, MD, Ph.D.
9432 Old Katy Road
Houston, Texas 77055
1996; Revised 08/30/00
TABLE OF CONTENTS
APPENDICES
APPENDIX A. . . . . . . . . Adverse Reactions to the Treatment with Antineoplaston A10, 300mg/mL Infusions
APPENDIX B. . . . . . . . . Children 4 Years Old and Younger Currently Treated with Antineoplaston A10 and AS2-1 Infusions
APPENDIX C. . . . . . . . . Karnofsky Performance Scale
APPENDIX D. . . . . . . . . NCI Common Toxicity Criteria
APPENDIX E. . . . . . . . . Provider 6000 Infusion Pump
APPENDIX F. . . . . . . . . Statement of Informed Consent for Investigational Clinical Study
APPENDIX G. . . . . . . . . Hypernatremia in Patients Treated with Antineoplastons
APPENDIX H. . . . . . . . . Hypersensitivity in Patients Treated with Antineoplastons
PHASE II STUDY OF ANTINEOPLASTONS A10 AND AS2-1 IN PATIENTS WITH GERM CELL TUMOR OF THE BRAIN
1996
1.1 To study the safety and possible effectiveness of antineoplastons infusions in patients with germ cell tumor of the brain.
Antineoplastons are naturally occurring peptides and amino acid derivatives, which control neoplastic growth. Research on peptides involved in cell-to-cell communication has grown at an impressive pace. Most of the effort has been concentrated in identification of the peptide growth factors, which by 1995 led to the discovery of approximately a hundred growth factors (1- 6). Much less activity has focused on the isolation of peptide growth inhibitors. Thirty years ago, when the research on antineoplastons was started, very few researchers were interested in biologically active peptides and only a few such peptides had been identified, including pituitary hormones, plasma kinins, and angiotensins (7-19).
Neoplastic process is a disease of cell differentiation. Given the large number of differentiating cells and assuming the possibility of error in the program of differentiation, groups of abnormally growing cells can arise very often under the influence of carcinogenic factors. Without a reliable mechanism, which can induce normal differentiation in cancer cells, chances for the survival of the organism will be very small. Such a corrective system can reprogram the growth of newly developed neoplastic cells and direct them into normal differentiation pathways. In the case of failure of this line of defense, the organism will not be able to defend itself against chemical and physical carcinogens, viruses and other neoplastic growth inducing agents, and will develop cancer.
We have proposed the name "antineoplastons" for the components of such a redifferentiation system, which exists in the human organism. According to our definition, antineoplastons are the substances produced by the living organism which protect it against the development of neoplastic growth by a non- immunological process that does not significantly inhibit the growth of normal tissues. Based on theoretical grounds, it is very likely that antineoplastons have a peptide or amino acid derivative structure. Assuming that an error in the program for normal cell differentiation is responsible for neoplastic growth, the components of such a biochemical defense system against cancer should be information-carrying molecules. Because of their high information content, peptides are ideal compounds to participate in such a line of defense.
The theory of antineoplastons was conceived through the application of the cybernetic theory of autonomous systems to studies of peptides in human blood (20,21). The ideal cancer treatment should provide a large amount of information and a small amount of energy. Such a treatment can control neoplastic growth by directing the cancer cells into normal channels of differentiation. The practically infinite variety of peptides that can be formed by the combination of the twenty common amino acids indicates the possibility of the existence of a peptide system carrying information from cell to cell that is able to correct errors in the program for differentiation.
The study of antineoplastic peptides existing in human blood and urine began in 1967 (22,23). During the analysis of peptides and amino acids in the blood of healthy people and of patients suffering from various diseases, including cancer, it was noticed that there are significant differences in the peptide content in serum of cancer patients as compared with the control group. In the next few years, it was found that similar peptide fractions exist in urine. It was postulated that these peptides are probably synthesized in the tissues and passed into the blood and urine. Urine was proposed as the most economic source for their isolation and, therefore, a research program was established for the isolation and identification of antineoplastic peptides from human urine.
Medicinal use of urine and urine extracts has been known for centuries. Serapion from Alexandria (III c.B.C.) was probably the most famous Greek physician to apply medicines derived from urine, but his experience was based on earlier Egyptian knowledge (24). Greek physicians practicing in ancient Rome were also very familiar with this type of treatment. Such therapy was described by Galen who is credited with the first medical description of cancer and also introducing the name "cancer." However, the most famous Greek in Rome in the second century A.D. to use urine therapy was Xenokrates (24). Medicinal use of urine was also known in ancient India, the importance of which is well described in a Sanskrit text entitled "Shivambu-kalp" (25). Specifically, it should be mentioned that the treatment of cancer with urine was also then known in India (25). The interest in urine from both the therapeutic and diagnostic points of view persisted during the Middle Ages in Europe. "Essentia urinae" was commonly used at that time, and the vessel for urine "matula" was as widely shown by painters as an emblem of the practice of medicine as a cane with a snake in antiquity and the stethoscope in modern time's (24). Medicine men in North and Central America were also quite familiar with urine treatment for various conditions, including cancer (26).
In modern times, the first approach to the study of growth inhibiting substances in urine was conducted in 1937. Rohdenburg and Nagy, after studying samples from 541 cases, described the method of isolation of growth inhibiting agents from human urine (27). Floyd C. Turner in 1939 went one step further and tested the effect of Rohdenburg and Nagy's preparation on tumors in mice. He was able to find that a growth inhibiting substance derived from human urine prevented the formation of tumors in mice following injections of carcinogens, but the urinary derivative had little specific inhibiting effect on transplanted or spontaneous tumors in mice (28). Magnelia, Kaplan, and Hyson in 1943 were among the first who tried to treat human cancer by urine injections. In several cases of inoperable cancer, treated by daily urine injections and observed up to 18 months, they noticed marked relief of symptoms with no side effects (29). Von Wollheim prepared in 1948 an ether extract from human urine, which showed an inhibitory effect on cancer in mice (30). Considerable research, both basic and clinical, was done in England and Germany on a polypeptide of unknown structure named H-11, which was isolated from urine (31-34). In the initial clinical studies, 16 cases of inoperable lung cancer were treated by injections of urine extract. Relief of symptoms, e.g., cough, improvement of the general condition and prolongation of life in comfort was observed in most cases without any significant side effects (35,36). In more extensive trials described in 1968 by von Klose and Below, 49 cases of inoperable lung cancer were treated by injections of H-11 extract in combination with chemotherapy. Combination therapy gave better results than treatment with urine extract or chemotherapy alone (37). H-11 extract contained polypeptides, which were chemically different from antineoplastons, as proved by our research and the analysis done by the manufacturer of H-11 (38).
Antineoplastons are also completely different from peptides and amino acid derivatives isolated from urine by the other authors. Investigations on peptides in urine began 97 years ago and were initiated by Polish researcher Bondzynski (39-42). Further studies were continued by Bondzynski's former assistants in the University of Lwow (43,44) and University of Warsaw (45). These compounds, initially named oxyproteic acids, were proven to be a well-characterized group of peptides by Skarzynski and Sarnecka-Keller (46).
Continuation of the research on antineoplastic peptides from urine by our team resulted in the separation of urinary peptides in 119 fractions (47). These fractions were further tested for the effect on the growth of neoplastic and normal cells. It was assumed that the simplest way of isolating antineoplastons would be extraction and separation of urinary peptides and screening for their effect on growth and DNA synthesis in neoplastic and normal tissue cultures. Fractions, which inhibit the growth of neoplastic cells and have less effect on normal cells, should contain antineoplastons. In our search for antineoplastons, we were able to find peptides existing in normal human urine, blood, and normal tissues active against every type of human neoplasm we tested, including myeloblastic leukemia, osteosarcoma, fibrosarcoma, chondrosarcoma, cancer of the uterine cervix, colon cancer, breast cancer, lung cancer, and lymphoma. The active peptides were initially isolated from 500 liters of normal human urine by extraction, gel filtration, free flow electrophoresis, and counter-current distribution. It was found that all antineoplastons inhibit up to 100 percent of the growth of neoplastic cells with less inhibitory effect on normal cells and no significant effect on isolated animal organs (48-56). Free flow electrophoretic technique allowed us to separate antineoplastons into two groups - one containing compounds which have activity against a single specific type of neoplasm and the other compounds, which have broad-spectrum activity. The initial preparation containing antineoplastons with broad-spectrum activity was called "Antineoplaston A.
After extensive tissue culture and animal toxicology studies, Antineoplaston A was used in the treatment of 21 cancer patients at Twelve Oaks Hospital, Houston, Texas (57). Chronic intravenous administration of Antineoplaston A to these patients showed pronounced antitumor effect without any significant toxicity.
Further purification of Antineoplaston A and application of preparative HPLC yielded products named Antineoplaston A1, A2, A3, A4, and A5 which possessed higher antitumor activity and lower toxicity. Antineoplastons A1, A2, A3, A4, and A5 were not homogenous substances, but mixtures of seven to thirteen different fractions as identified by HPLC on sulfonated polystyrene. Each of these formulations was submitted for tissue culture and acute and chronic animal toxicity studies. All formulations produced significant anticancer effect in the culture of human breast carcinoma. The acute toxicity in mice was very low and the respective LD50 for each formulation was as follows: Antineoplaston A1 - 1.35 g/kg, A2 - 3.55 g/kg, A3 - 3.55 g/kg, A4 - 5.33 g/kg, and A5 - 5.11 g/kg (58) Antineoplaston A2, A3, and A5 underwent further evaluation in chronic toxicity studies with daily intraperitoneal injections in mice for up to 365 days. The results of these studies have shown no significant chronic toxicity (59-62).
Antineoplastons A1 to A5 were submitted for Phase I clinical studies in advanced cancer patients. Initial clinical trials of Antineoplaston A2, A3, and A5 injections have been completed and revealed negligible side effects and promising clinical responses (63-68).
Antineoplaston A2, which contributed to the highest number of complete remissions in Phase I clinical studies, was elected for the final purification, isolation of the active components and structure determination. The first isolated component of Antineoplaston A2 was identified as 3-phenylacetylamino-2, 6-piperidinedione and was named "Antineoplaston A10" (69). Antineoplaston A10 has been reproduced by synthesis involving condensation of l-glutamine with phenylacetyl chloride and subsequent cyclization of phenylacetylglutamine (69,70). The synthetic product had an identical GC retention time, infrared spectrum, electron impact mass spectrum and chemical ionization mass spectrum as the urine product. The proton NMR and infrared spectrum of the synthetic product was consistent with 3-phenylacetylamino-2, 6-piperidinedione. The 13C NMR spectrum positively identified each carbon atom in the product. Acute and chronic toxicity studies of Antineoplaston A10 in mice did not reveal any significant toxic effects. LD50 in mice was determined at 10.33 g/kg. In chronic toxicity studies, Antineoplaston A10 was given to mice in the form of 1.0%, 1.5%, and 2.0% food mixture daily for 30 days and in the form of 1.0% food mixture daily for 365 days, which did not show any toxic effects (71).
2.3 ANTINEOPLASTON AS2- 1 AND ANTINEOPLASTON AS2-5
The determination of the structure of Antineoplaston A10 prompted further research on synthetic derivatives of this compound. Initially, the attention was concentrated on products of the hydrolysis of Antineoplaston A10. Initial hydrolysis of Antineoplaston A10 yields phenylacetylgutamine (PG) and phenylacetylisoglutamine (isoPG). When hydrolysis is carried further, the products of reaction include phenylacetic acid, glutamic acid, and ammonia. Sodium salt of phenylacetylglutamine was named "Antineoplaston AS2-5" and a mixture of sodium salts of phenylacetylglutamine and phenylacetic acid (PN) in the ratio of 1:4 was named "Antineoplaston AS2-1." Both formulations showed anticancer effect in the tissue culture and no significant toxicity (72-74).
Antineoplaston AS2-1 and AS2-5 injections and Antineoplaston AS2-1 capsules were submitted for Phase I clinical studies. Phase I clinical studies of Antineoplaston AS2-1 involved 20 patients diagnosed with 21 types of neoplastic diseases. The formulation was administered daily from 38 to 872 days. The highest dosage taken was 160 mg/kg/24 hours. Only minimal adverse effects were noticed. They included slight decrease of the white blood cell count, mild hypocalcemia, hypokalemia, and transient hypertension. Cancer responses included six complete remissions, two partial remissions, seven cases of stabilization, and six cases of increasing disease (75).
Phase I clinical studies of Antineoplaston AS2-5 injections involved thirteen patients diagnosed with fifteen types of neoplastic diseases. The formulation was administered from 41 to 436 days. The highest dosage was 168 mg/kg/24 hours. The treatment was free from significant side effects with the exception of febrile reaction in two patients and swelling of the small joints in one patient. Beneficial side effects included increase of platelet count and increase of concentration of plasma globulin. Responses to the treatment included two complete remissions, one mixed response, four cases of stabilization, and six cases of increasing disease. Complete remission was obtained in squamous cell carcinoma of the larynx, stage II, and large cell undifferentiated carcinoma of the lung with lymph node and liver metastases. In an additional case of carcinoma of the breast with metastases to the lymph nodes, liver, and skin, a complete remission was obtained in liver metastases, but increasing disease was observed in skin metastases (76,77).
Phase I clinical studies for Antineoplaston AS2-1 capsules involved 13 patients diagnosed with astrocytoma (3 cases), colorectal adenocarcinoma (2), squamous cell carcinoma of the head and neck (2), and single cases of adenocarcinoma of the lung and breast, transitional cell carcinoma of the bladder, medulloblastoma, lymphocytic lymphoma, and leiomyosarcoma (78). Antineoplaston AS2-1 was given orally daily in divided doses from 47 to 464 days. The highest dosage obtained was 238 mg/kg/24 hours. Eighty-five percent of patients did not have any adverse effects associated with the treatment. One patient complained of nausea and headache, which occurred only once during the entire course of the treatment, and another patient had decrease of white blood cell count to 3500 after six months of treatment. Fifty-four percent of patients had objective response to the treatment. The diagnoses of those patients included astrocytoma, stages III and IV, squamous cell carcinoma of the head and neck, stage IV, adenocarcinoma of the rectum, stage IV, leiomyosarcoma, stage IV, and lymphocytic lymphoma, stage IV. Fifteen percent of patients had increasing disease and 23% were classified as stable disease without objective involvement. One patient (8%) was in complete remission at the beginning of the study. The results of the study indicated that the treatment with Antineoplaston AS2-1, administered orally, is associated with minimal side effects and shows promising therapeutic results.
2.4 TOLERANCE OF ANTINEOPLASTON THERAPY
Burzynski et al. have reported negligible toxicity from the combined use of A10 0.8 to 21.4 g/kg/day and AS2-1 0.2 to 0.5 g/kg/day. The additional information in support of dosage of A10 ranging up to 20.0 g/kg/day and the information to support the safety of antineoplastons at the proposed dosage and schedule in children 4 years old and younger is attached in Appendices A and B.
The experience with PN is more extensive; total daily doses of up to 0.5 g/kg/day (20 g/m2) are well tolerated indefinitely. Since the intravenous Antineoplaston preparations will be administered as the sodium salt, patients should be followed closely for development of edema or other signs of sodium overload.
In addition to tissue culture, animal and human clinical studies, research has been done on the mode of action of antineoplastons. Antineoplaston A10 is a small molecule with the size and shape similar to DNA base pair. Previous reports have suggested that naturally occurring biologically active small molecules, which structurally mimic base pairs, may intercalate in a stereo-specific manner between base pairs in double helical DNA. It is possible that A10 may have an antagonistic effect against some common carcinogenic agents, for instance, benzo (a)pyrene analogs. Such antagonism may result from competitive intercalation. According to this preliminary work hypothesis, A10 may function as a naturally occurring anticarcinogenic agent (79-85).
Phenylacetylglutamine was originally described by Thierfelder and Sherwin (86). This compound was found to be a normal constituent of human urine and was present in large amounts in the plasma of patients with renal insufficiency (87,88). According to clinical observations, the incidence of cancer in patients with primary kidney failure is very low compared with patients with secondary kidney failure. This raises the question whether phenylacetylglutamine is one of the factors, which may contribute to that phenomenon. In the studies carried out by Lichtenstein, et al. (89), phenylacetylglutamine was shown to have slight effect on the growth of murine tumors.
The mechanism of the anticancer action of phenylacetylglutamine is unknown. The compound shows only a slight antineoplastic effect in tissue culture. It is possible that phenylacetylglutamine may interfere with the incorporation of glutamine into proteins in neoplastic cells. A relative excess of glutamine is essential for stimulation of the cells to undergo DNA replication and mitosis (90). According to published data, certain protozoa use stop codon TAG for incorporation of glutamine into the polypeptide chain (91,92). If a similar deviation from the genetic code occurs in some neoplastic cells, TAG may not represent termination codon in such cells. According to a previous study by Hendry, et al., TAG may in fact encode glutamine (93). Phenylacetylglutamine may compete with glutamine and selectively inhibit protein synthesis in some cancer cells. Studies are now being undertaken in an attempt to prove such hypothesis.
It is known since 1914 that phenylacetic acid given to humans is excreted in the urine as phenylacetylglutamine (86). According to most recent studies, over 90% of phenylacetic acid administered to man is bound with glutamine to form phenylacetylglutamine (94). The fate of phenylacetic acid given to animals is different and is correlated with their evolutionary status. The administration of a combination of phenylacetylglutamine and phenylacetic acid to the patient may result in formation of excessive amounts of phenylacetylglutamine and relative decrease of the concentration of glutamine versus other amino acids. Such conditions may inhibit mitosis and protein synthesis in cancer cells (90). In the previous studies, phenylacetylglutamine was found to have a slight effect on the growth of animal tumors, but was never used in the treatment of human cancer (89). The sodium salt of phenylacetic acid was used by Neisch in the treatment of Rd/3 sarcoma in rats, but did not inhibit neoplastic growth (95). It should be stressed, however, that pharmacokinetics of this substance are different in rats. Instead of making phenylacetylglutamine, the rats are conjugating phenylacetate with glycine. The product of such reaction is phenylacetylglycine (94).
3.0 EXPLANATION OF THE RATIONALE FOR THE USE OF THE DRUGS
3.1 Germ cell tumor of the brain remains incurable in most cases despite surgical resection, radiation therapy, and chemotherapy. Germ cell tumors of the brain are very rare tumors, accounting for 1-3% of all primary CNS tumors in children (about 10-35 cases per year in the US). The peak incidence is in adolescence, and tumor growth may be related to hormonal effects. Most of these tumors are found in the pineal area, although some are found in the sellar or hypothalamic area. Histologic types vary (e.g., germinomas, endodermal sinus tumors, embryonal cell carcinomas, choriocarcinomas, mixed germ cell tumors, teratocarcinomas), and these tumors may be classified as benign or malignant. Germinomas account for about 60% of brain germ cell tumors. Serum and CSF levels of alphafetoprotein and beta-HCG should be measured. There can be spinal involvement, and MRI of the spine in indicated. Surgery is indicated in all cases, at minimum to establish the diagnosis. Benign tumors such as teratomas and dermoid cysts can be cured with surgery alone. Germinomas are radiosensitive and chemotherapy-responsive. Non-germinomas are much less radiosensitive. Given the rarity of the tumor, published case series has been small, but 5-year survival rates of 85-100% have been reported for patients with germinomas. Chemotherapy with combinations that include a platinum agent with etoposide and bleomycin or high dose cyclophosphamide or methotrexate have produced complete responses in up to 70% of patients with non-germinomas, although 1 year survival is only about 50% in these patients. Refinements in neuroanesthesia, neurosurgical technique, radiation therapy (including interstitial brachytherapy and stereotactic radiosurgery), and conventional chemotherapy (either single or multiple agents) are unlikely to provide significant improvement in tumor control or increase the likelihood of long-term survival. In view of the unfavorable survival outlook with currently available treatment modalities, it is appropriate to evaluate unusual agents that appear to produce clinical antitumor effects in patients with germ cell tumor of the brain.
3.2 Antineoplastons are chemically defined compounds that were originally isolated from urine and are now produced using large-scale synthetic methods. The National Cancer Institute has recently reviewed the charts, MRI/CT scans and pathology slides of seven patients with primary brain tumor who were treated with a combination of A10 (3-phenylacetylamino-2, 6-piperidinedione, which forms PG and isoPG in a 4:1 ratio upon hydrolysis) and AS2-1 (PG and PN in a 1:4 ratio upon hydrolysis). These cases represented a selected group of patients (a so-called 'best case series") prepared by S.R.B. for the NCI review. In the NCI review of the selected case materials there appeared to be an association between antineoplaston administration and objective tumor regressions (described below) (96).
3.3 Results of the NCI Review (96)) In two adult patients with glioblastoma multiforme there was 1 CR, which lasted 6 months, and 1 MR of short duration. Of two adult patients with anaplastic astrocytomas, one patient with a brain stem primary achieved a CR, which is ongoing for 3+ years (1 year after completing therapy); the other patient had calcification of her primary tumor. The other adult patient had a histologically confirmed Grade III astrocytoma with intracerebral metastases (not biopsied) which resolved completely with the primary lesion decreased by over 50%. At the time of review this patient had received antineoplastons for over 3 years, after having previously failed XRT, procarbazine, CCNU, and vincristine, interferon-Beta and MGBG/DFMO. All of the adult cases had previously received radiotherapy. Two pediatric cases were reviewed; a child with Grade I astrocytoma achieved a PR for 5+ months; a child with an anaplastic astrocytoma achieved a CR for 9+ months. Burzynski et al. have reported 6 objective responses and 10 disease stabilization in 20 patients with advanced astrocytomas and four objective responses and four disease stabilization in 12 patients with high grade astrocytoma and glioblastoma multiforme (97,98).
Objective clinical responses were reported in primary and metastatic malignant brain tumors by Eriguchi et al., Yoshida et al., and Tsuda et al. (99-101).
3.4 One of the major ingredients of AS2-1 is PN; this compound has established biologic activity (72). PN and its prodrug phenylbutyric acid have been successfully used for over two decades in the treatment of children who are hyperammonemic because of genetic defects in urea metabolism (102-104). Furthermore, it was demonstrated that PN and its sodium salt is an active cytodifferentiating agent in cell culture systems at media concentrations (5mM) typical of the peak levels occurring in children who receive PN intravenously as therapy for hyperammonemia (105). The spectrum of cells demonstrating cytodifferentiation in the presence of PN has included HL-60 and K-562 leukemia, and preadipocytes; differentiation in HL-60 was associated with a rapid decline in myc oncogene expression. PN has also been growth inhibitory to human neoplastic cell lines of lung, prostate, melanoma, and glial tumor origin; the PN treated cells lost their capacity to proliferate in agar culture (105).
4.1 To demonstrate the antitumor activity of Antineoplaston A10 and AS2-1 in the treatment of patients with germ cell tumor of the brain by determining the proportion of patients who experience an objective tumor response.
4.2 To evaluate the adverse effects and tolerance of Antineoplaston A10 and AS2-1 in these patients.
5.1 This is a Phase II, open label evaluation of a therapy with Antineoplaston A10 and AS2-1 of patients with germ cell tumor of the brain with measurable tumor. Patients will be evaluated for response at the time they obtain complete or partial response, whichever comes first and will continue treatment until progression; any patient who develops progressive disease during the study will have the treatment with antineoplastons discontinued.
5.2 In order to assure that adequate patients are studied and to minimize exposure to experimental treatment, a two-stage design is proposed. After 20 patients have completed treatment, the proportion of patients showing complete and partial response will determine whether to stop the study due to absence of anticancer activity or to continue the study with an additional 20 patients due to inconclusive results.
6.1 IDENTIFICATION OF ANTINEOPLASTONS A10 AND AS2-1 INFUSIONS
6.1.1 Antineoplaston A10 infusion is a sterile solution of phenylacetylglutamine and phenylacetylisoglutamine in water which has pH adjusted to 7.0 with sodium hydroxide. Each mL of the infusion contains not less than 230mg and not more than 250mg of phenylacetylglutamine and not less than 55mg and not more than 65mg of phenylacetylisoglutamine. The combined concentration of active ingredients is 300mg/mL + 15mg/mL.
6.1.2 Antineoplaston AS2-1 infusion is a sterile solution of phenylacetic acid and phenylacetylglutamine in water which has pH adjusted to 7.0 with sodium hydroxide. Each mL of the infusion contains not less than 62mg and not more than 66mg of phenylacetic acid and not less than 15mg and not more than 17mg of phenylacetylglutamine. The combined concentration of active ingredients is 80mg/mL + 3mg/mL.
6.1.3 Storage and shipping- Antineoplastons A10 and AS2-1 are stored at room temperature (15-30oC) without refrigeration or freezing. The shipping of antineoplastons should be at controlled temperature within the storage range (15-30°C) for these drugs. Antineoplastons for parenteral injection should be visually inspected immediately before use. If the solution appears cloudy or discolored it should not be used, but should be returned to the Burzynski Research Institute, Inc. for analysis.
7.1.1 PATIENT SELECTION CRITERIA
7.1.1.1 Following an explanation by the Investigator about the treatment, its possible consequences and side effects, all candidates must read, understand, and sign in the presence of the Investigator the treatment written Consent Form prior to participation in the treatment.
7.1.1.2 All patients should be expected to complete the full course of the treatment.
7.1.2 PATIENT INCLUSION CRITERIA
7.1.2.1 Patients more than 6 months of age with a diagnosis of incurable germ cell tumor of the brain who are unlikely to respond to existing therapeutic regimens and for whom curative therapeutic regimens do not exist.
7.1.2.2 The patient should have histological confirmation of the brain tumor under study (either at the initial diagnosis or at the recurrence ); the only exceptions are some cases of dangerous locations of brain tumors such as brain stem tumors, where biopsy may entail unacceptable risk to the patient. There will be no exclusion based on tumor size, multifocality, or leptomeningeal or systemic metastases.
7.1.2.3 Any patients who have not been seen by radiation therapist, or by a neurosurgeon should obtain these consultations, to verify whether there are existing therapies of known benefit that should be persued before (or instead of) antineoplastons
7.1.2.4 Patients must have evidence of brain tumor by gadolinium- enhanced MRI, or if MRI is contraindicated, contrast-enhanced CT scan performed within two weeks prior to entry. The minimum size of the tumor must be not smaller than 5 mm.
7.1.2.5 Patients must have a performance status of 60% to 100% on the Karnofsky Performance Scale (Appendix C). Patients must have no evidence of hepatic insufficiency or renal insufficiency, and a total serum bilirubin and creatinine level not higher than 2.5 mg/ml; and SGOT and SGPT not higher than five times the upper limit of normal.
7.1.2.6 Patients must have a relatively normal hematopoietic function, WBC >= 2000/mm3, and platelets > 50,000/mm3.
7.1.2.7 Patients may be male or female. If female, the patient must not be pregnant or breast-feeding an infant, and either incapable of becoming pregnant or currently using contraceptive methods. Acceptable methods include the birth control pill, use of a diaphragm, intrauterine device, or condom by the patient's sexual partner. If male, the patient should use appropriate contraception, such as condoms, during the study and at least 4 weeks following completion of the study.
7.1.2.8 Patients should be outpatients, but must have a life expectancy of at least two months with the feasibility of doing a complete follow-up.
7.1.2.9 The use of corticosteroids is permitted to reduce symptoms and signs attributed to cerebral edema. It is recommended that the smallest dose be used which is compatible with the preservation of optimal neurologic function. Corticosteroids should be carefully monitored and recorded. Patients who are receiving corticosteroids must be on a fixed dose of corticosteroids for at least one week prior to baseline scan.
7.1.2.10 Patients must recover from the adverse effects of previous therapy. At least eight weeks must have elapsed since the last dose of radiation therapy and at least four weeks must have elapsed since the last dose of chemotherapy (six weeks for nitrosoureas) or immunotherapy.
7.1.3 PATIENT EXCLUSION CRITERIA
Patients should not have serious active infections, fever, or other serious concomitant disease that would interfere with the evaluation of treatment drug (e.g., severe heart or lung disease, or hepatic failure). Patients with hypertension are excluded unless the blood pressure is adequately controlled. Patients who have had prior antineoplaston treatment should be excluded from this protocol. The patients with history of congestive heart failure, or history of cardiovascular renal conditions that medically contraindicate administration of high dosages of sodium are not to be enrolled on treatment.
7.1.4.1 Medications that are considered necessary for the patient's welfare and that will not interfere with the evaluation of the treatment. Medication may be given at the discretion of the Investigator. The treatment with other antineoplastic or immunomodulatory agents is not permitted during the study.
7.1.4.2 Patients may receive full supportive care, including transfusions of blood and blood products, antibiotics, etc., when appropriate.
The Investigator may discontinue a patient from the treatment at any time when he feels this is in the best interest of the patient.
Patients should be discontinued from the treatment in the event of:
7.1.5.1 Progressive disease after one month of treatment with Antineoplastons A10 and AS2-1.
7.1.5.2 The development of hematopoietic suppression, unacceptable gastrointestinal side effects, or other adverse experiences exhibiting an unacceptable degree of toxicity (Appendix D: NCI Common Toxicity Criteria). For Grade 3 or 4 toxicity, the drugs will be held until that toxic effect has reduced to Grade 1 or less; therapy will then be restarted with a 25% dose reduction. If there is a recurrence of any Grade 3 or 4 toxicity at the reduced dose, the procedure will be repeated with a dose reduction to 50% of the original level. Patients should be removed from treatment for a third episode of Grade 3 or 4 toxicity or for any Grade 4 toxic effect that is truly life threatening or is not easily and rapidly reversible.
7.1.5.3 Intercurrent illness which would in the judgment of the Investigator affect the assessments of clinical status to a significant degree or which would require discontinuation of the drugs.
7.1.5.4 Patient's desire to withdraw from the treatment or serious or repeated participant non-compliance with the protocol specifications.
7.1.6 POST TREATMENT FOLLOW-UP
All patients who receive treatment under this Protocol will be followed for progressive disease and survival at reasonable intervals after the completion of the treatment.
The following definitions are referred to in the remainder of the Protocol:
7.2.1 A complete patients for the evaluation of antitumor activity is one who meets the entrance criteria, has completed at least two months of treatment with antineoplastons A10 and AS2-1, and has been compliant with the procedures required in the protocol.
7.2.2 The criteria of response to Antineoplaston AS2-1 are those suggested in Miller, et al., and Fleming, et al. (106,107).
7.2.3 Complete response - Complete disappearance of all contrast-enhancing tumors on neuroimaging studies, and ancillary radiographic studies if appropriate for a minimum duration of four weeks. Patient is off corticosteroids.
7.2.4 Partial response - More than 50% reduction in the sum of the products of the greatest perpendicular diameters of all measurable contrast enhancing lesions, compared to the corresponding baseline evaluation for four weeks or longer. No simultaneous increase in size of any lesion or the appearance of new lesions may occur. The corticosteroid dose is stable or decreasing.
7.2.5 Stable disease - Less than 50% change (either greater or smaller) in the sum of the products of the perpendicular diameters of the enhancing tumor compared to the baseline evaluation. This state must be maintained for a minimum of 12 weeks to qualify for stable disease. The corticosteroid dose is stable or decreasing.
7.2.6 Progressive disease - Greater than 50% increase in the sum of the products of the greatest perpendicular diameters of the enhancing tumor compared to the baseline evaluation. Appearance of significant new lesions will also constitute progressive disease.
7.2.7 If there is a discrepancy, excluding progression, in the response between the primary tumor site and any metastatic tumor site, the response for each site will be recorded separately. The primary analysis will be intent-to-treat analysis, using the overall response of each enrolled patient, determined as stated in the protocol.
7.3.1 Survival time for the patients will be measured from the time of initiation of Antineoplastons A10 and AS2-1.
7.3.2 Duration of response will be measured from the first time the criteria of maximum responses were obtained until progressive disease occurs.
Patients will take the medication, Antineoplastons A10 and AS2-1 daily until progression of disease. If, at the end of 12 months, the patient has not achieved either a partial or complete response to the treatment, the Investigator has the option of discontinuing the treatment. In case the patient's response is considered stable disease, the Investigator may continue the treatment, if the patient has experienced no significant toxicity.
7.4.2.1 Treatment for adult patients with Antineoplastons A10 and AS2-1 injections.
The patient shall reach the maximum tolerated dosage level in the safest and most efficient fashion. The treatment shall be administered through a double channel infusion pump (Appendix A) and intravenous catheter. A single lumen Broviac, Groshong, or equivalent catheter will be necessary for treatment. The two antineoplastons are to be administered through the same lumen. Patients will receive gradually escalating doses of the two antineoplastons by multiple intermittent intravenous injections using a portable programmable pump.
The first channel of the pump will deliver Antineoplaston A10 and the second Antineoplaston AS2-1. The treatment should begin with the injection of Antineoplaston A10. Antineoplaston AS2-1 injection should follow thereafter. The patient should receive 6 injections of each formulation per 24 hours. The individual injection shall be given over 1 hour or longer for a 70 kg patient depending on the patients tolerance. If a patient experiences a chemical taste in his/her 's mouth during injection decrease the flow rate of the pump to 200mL/h. If the patients still experienced the chemical taste decrease the flow rate to 150 ml/h, and so on in 50 ml/h increments to 100 ml/h , or until the taste is gone.
On the first day of treatment, the pump will be loaded with 240mL(72 g) of Antineoplaston A10 and 240mL(16g) of Antineoplaston AS2-1. on the first day of treatment, the patient should receive the initial infusion of 10 ml of Antineoplaston A10 at 100ml/h, followed 15 minutes later by 10 ml Antineoplaston AS2-1 at 100ml/h. For hours from the beginning of the first infusion 46 ml of A10 at 250mL/h followed by 38mL of AS2-1 at 250mL/h every 4 hours should be administrated. Beginning from the second day of treatment, the dose of each injection will be increased on a daily basis in increments of 16g of AS2-1 and 72g of A10 until the highest tolerated dosage or effective dosage is reached not exceeding 20.0 g/kg/day for Antineoplaston A10 and 0.2 to 0.4 g/kg/day for Antineoplaston AS2-1.
7.4.2.2 Treatment for children with Antineoplastons A10 and AS2-1 injections.
The patient shall reach the maximum tolerated dosage level in the safest and most efficient fashion. The treatment shall be administered through a double channel infusion pump (Appendix E) and intravenous catheter. A single lumen Broviac, Groshong, or equivalent catheter will be necessary for treatment. The two antineoplastons are to be administered through the same lumen. Patients will receive gradually escalating doses of the two antineoplastons by multiple intermittent intravenous injections using a portable programmable pump.
The first channel of the pump will deliver Antineoplaston A10 and the second Antineoplaston AS2-1. The treatment should begin with the injection of Antineoplaston A10. Antineoplaston AS2-1
On the first day of administration of antineoplastons the flow rate of the pump will be maintained at 25 mL/h. Beginning from the second day of administration of antineoplastons, the individual injection will be given at 50 to 250 mL/h depending on the patient's age and tolerance.
If the patient experiences a chemical taste in her/his mouth during injection the flow rate will be decreased by 25 mL/h until the patient no longer experiences the chemical taste.
On the first day of treatment, the pump will be loaded with 60mL of Antineoplaston A10 and 60mL of Antineoplaston AS2-1. The volume of each injection will be approximately 10mL every 4 hours six times a day. Beginning from the second day of treatment of children younger than 12 years of age, the dose of each injection will be increased on a daily basis in increments of 10mL until the highest tolerable dose or effective dose is reached not exceeding 25.0 g/kg/day of Antineoplaston A10 and 0.3 to 0.6g/kg/24h for Antineoplaston AS2-1. In other words, on the second day the dose will be increased to 20mL each of A10 and AS2-1 IV every 4 hours, on the third day to 30mL each of A10 and AS2-1 IV every 4 hours, etc. until the final dosage is reached. For children 12 years of age or older the dose of A10 will be escalated in increments of 20mL, and over 16 years of age in increments of 40 ml.
During the first week to two weeks of therapy, antineoplastons will be administered by nurses at the Burzynski Clinic who have been trained by Abbott Laboratories in the use of the Abbott Provider 6000 dual channel programmable pump.
For patients who live outside the Houston area and take treatment outside Houston area, arrangements will be made, prior to entering the patient in the study, for a physician in the patient's local area to provide continuing medical care and collect and report the data required in the protocol. The local physician will be requested to sign Form 1572, and be given a copy of the Investigator's Brochure, protocol and the case report form. Form 1572 does not need to be signed for patients who received a stable dose of antineoplastons (no greater than 5.5 g/kg/d A10) under the care of Principal Investigator for at least 21 days without any serious adverse effects noted; and who are returning to Principal Investigator at monthly intervals (or more frequently).
Following the first week to two weeks of therapy, subsequent administration will be on an outpatient basis, supported by the Clinic and a home infusion support company. The patients and the members of the family will receive training in the Burzynski Clinic regarding standard care of subclavian vein catheter, programming of the infusion pump, and replacement of IV bags with A10 and AS2-1 in the pump. The patient will not be allowed to leave home unless he and the members of his family are sufficiently trained in the above-mentioned procedure. Patients monitoring will consist of daily telephone calls to the patient by the physicians and nurses of Burzynski Clinic during the first two months of treatment and at least once a week thereafter. If the patient and members of the family are not capable to be sufficiently trained in the procedures required for outpatient treatment, the patient will be required to have daily visits in the Burzynski Clinic for the duration of the study. The patient at home should store Antineoplaston formulations at ambient temperature. They do not require refrigeration.
The average content of sodium in Antineoplaston AS2-1, 80mg/mL formulation, is 12.7mg/mL and in the Antineoplaston A10, 300mg/mL formulation is 24.5mg/mL.
The antitumor response of the treatment will be assessed by taking into consideration the demonstrable objective changes observed by physical examination and appropriate radiologic studies. The level of response (Section 7.2), duration of tumor regression, time to disease progression, and total survival will be observed.
The tolerance of Antineoplastons A10 and AS2-1 will be evaluated by means of subjective recording of symptomatology, physical examinations, radiological examinations and laboratory tests.
Insofar as possible, the evidence should be documented to allow second party verifications.
Results of all radiologic or diagnostic studies performed while participating in the treatment will be recorded in the patient's medical records.
Patients should be reexamined at least monthly while they are receiving antineoplastons infusions. Examination should include thorough neurological and ophtalmological examinations. Head circumference should also be followed in young children where appropriate.
Lesion measurements should be made by direct caliper determination when possible and by radiographs, scintigraphs, and sonographs. Unless the tumor has progressed on X-ray or scans while receiving most recent therapy, baseline x-ray and scans to assess tumor will be done at least four weeks after the last chemotherapy or immunotherapy, so that any shrinkage due to prior therapy will not be erroneously attributed to antineoplastons.
Prior to initiation of therapy:7.4.5 EVALUATION DURING THE TREATMENT
The patient will have laboratory tests, including hematology and chemistry studies, performed weekly during the first six weeks, and at least every three weeks thereafter during the course of treatment. Tumor measurements by MRI and CT scans shall be recorded at least every eight weeks during the first two years. After that, tumor measurements shall be recorded at least quarterly during the 3rd and 4th year, every 6 months during the 5th and 6th year, and yearly thereafter, depending on clinical status and response of the patient.
Patients receiving A10 at the dosage level of 2.0 to 5.5 g/kg/day will have serum electrolytes checked at least once weekly. Patients receiving A10 at dosages in excess of 5.5 g/kg/d should have serum electrolytes checked at least three times weekly (e.g., Monday - Wednesday - Friday), or more frequently as medically indicated. Serum sodium, potassium, chloride and bicarbonate should always be included; magnesium, calcium, and phosphorus should be included in at least half of those determinations. During antineoplaston dose escalation, all patients should have these electrolyte determinations at least every other day. Patients who have been on antineoplastons infusions for over 60 days, provided that they have been on a stable dosage for at least 2 weeks, have a normal serum sodium , and do not have any other serum electrolyte abnormalities may have electrolytes determination twice a week.
8.0 EVALUATION OF ANTITUMOR ACTIVITY
A positive response is defined to be a patient with complete or partial response of at least four weeks duration based on the definitions in Section 7.2.
The analysis of response will include:8.2 PRIMARY EVALUATION (Sample Size Determination)
Antitumor activity will be evaluated based upon a two-stage study design for determination of response rates based on a single treatment group.
Availability of a patient for antitumor activity cannot be determined until complete documentation has been received and accepted as satisfactory. Eligible patients must receive at least three months of treatment to be considered in response analysis above.
The primary evaluation of tumor response is based on the criteria in Section 7.2. Further assessment of the response will be based on improvement in clinical signs and symptoms, physical examination, quality of life assessment, and other evaluations of disease status. Follow-up time to progression and survival will be attempted in all patients who receive treatment. Estimation of the time to recurrence (duration of response) and survival curves will include all treated patients based on this data irrespective of subsequent treatment.
Toxicity will be evaluated based on the reported adverse experiences, physical examination, changes in laboratory results, and maximally tolerated dose.
Data for each patient who received medication will be summarized as a Treatment Summary.
The minimum follow-up will be two months after discontinuation of treatment in a patient.
Source documents, such as the original laboratory reports, radiographic results, and the patient's personal medical records, should be made available for review by the Sponsor at times convenient to the Investigator.
9.3 ADVERSE EXPERIENCE CONSIDERATIONS
Based on previous clinical studies, antineoplaston therapy can produce the following side effects: central nervous system toxicity, depression, lethargy, somnolence, agitation, dizziness, nausea and vomiting, anemia, increase of blood pressure, swelling, weakness, decrease of potassium, calcium, magnesium, and/or glucose and increase of sodium in the blood, decrease of white blood cell count and/or platelet count, fever, skin rash, muscle ache, and abdominal pain. There is a possibility for hepatic toxicity, hypovolemia, dehydration, polyuria, thirst or increased fluid retention.. AS2-1 also has a distinct chemical smell. Because the antineoplaston treatment will require prolonged administration by way of a central venous line, there is some likelihood of infection of that line and of phlebitis of the infused blood vessel.
The Investigator must report any adverse events to the Sponsor.
All first occurrences of any toxicity.
Adverse reactions that are unexpected and fatal or life threatening must be reported to FDA no later than 3 working days or 7 calendar days, whichever time period is shorter, by phone and within 10 working days or 15 calendar days, whichever time period is shorter, in writing from the time that the sponsor first receives the information concerning adverse reactions. Adverse reactions that are unexpected and serious must be reported to the FDA in writing within 10 working days or 15 calendar days, whichever time period is shorter.
9.3.3 FOLLOW-UP ADVERSE EXPERIENCES
Any adverse experience(s) must be followed up with the appropriate medical management until resolved, e.g., attributed to causes other than test article, return to pre-treatment condition, etc.
An attempt will be made to obtain autopsies on patients who die during the treatment so that histologic examinations of the organs affected by major toxicity and the effects of drug on the tumor may be studied.
10.0 INVESTIGATOR RESPONSIBILITIES
Participation in this treatment is voluntary. The participant may discontinue participation at any time without penalty and loss of benefits to which she is otherwise entitled. Any participant choosing to discontinue can do so by informing his doctor of this decision. Any new information that develops during the course of this treatment will be provided to him. The names of the participants will not be made public to anyone outside the Sponsoring Company, except for the FDA, should they choose to inspect the study records. The results of this study, however, may be made public without the inclusion of the names of any participants.
11.0 RATIONALE FOR THE DOSE AND SCHEDULE OF A10 AND AS2-1 ADMINISTRATION
Three FDA approved Phase II study protocols for the treatment of highly malignant brain tumors in children and adults including anaplastic astrocytoma and glioblastoma multiforme use regimen consisting of rapid bolus infusions. Such regimen provides additional benefit for patients with highly aggressive brain tumors because it may reduce intracranial pressure. Due to its high osmolality, the effect of Antineoplaston A10 may be comparable to the infusion of Mannitol. Such rapid infusion will also allow reaching higher concentrations of antineoplastons in blood and more effectively penetrate blood brain barrier.
Less aggressive brain tumors and cancers located outside the central nervous system do not require such rapid infusions because usually these patients do not have increased intracranial pressure. For such patients, slower infusion rate will be more comfortable because it won't force them urinate frequently. Based on our previous clinical experience, the tumors of lower grade may respond to lower dosages of Antineoplaston A10 and AS2-1. That's why the protocol for low-grade astrocytoma is using lower dosages than the other protocols.
The main active ingredient of Antineoplaston AS2-1 is phenylacetate. According to Phase I, and pharmacokinetic study of intravenous phenylacetate done by the researchers of The National Cancer Institute, both rapid IV boluses and continuous infusions are recommended (108).
APPENDIX A
ADVERSE REACTIONS TO THE TREATMENT WITH ANITNEOPLASTON A10, 300mg/mL INFUSIONS
APPENDIX B
CHILDREN 4 YEARS OLD AND YOUNGER CURRENTLY TREATED WITH ANTINEOPLASTONS A10 AND AS2-1 INUFSIONS
APPENDIX C
KARNOFSKY PERFORMANCE SCALE
APPENDIX D
APPENDIX E
PROVIDER 6000 INFUSION PUMP
APPENDIX F
STATEMENT OF INFORMED CONSENT FOR INVESTIGATIONAL CLINICAL STUDY
APPENDIX G
HYPERNATREMIA IN PATIENTS TREATED WITH ANTINEOPLASTONS
APPENDIX H
HYPERSENSITIVITY IN PATIENTS TREATED WITH ANTINEOPLASTONS