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Physicians and Investigators: August 2016



Progress Report for Physicians and Investigators

 

Pancreatic (PC), gastric (GC), bile duct/cholangio (CCA), colorectal (CRC), small bowel (SBCa),  uterus (UC), ovary (OC), bladder (Blca) and kidney cancers (RC). Resistant to standard treatment (R)

 

This update describes:

 

A. An extra year of safety data, post AACR 17, which begins to confirm the novel safety reported in our pilot. ASCO 15 In addition to heme protection there is absence of severe DVT coagulopathy neuropathy enteritis. Weight loss was reversed, halved in incidence and severity, as was pain. 

 

B. Six other investigators confirmed our long in use novel combinations increase survival compared to the standard for Pancreatic (PC) reactivate the immune system second chance for check point treatment of gastric (GC) (our bile duct/cholangio (CCA/HCC finding) and and reverse drug resistance for colorectal cancer (CRC). 

 

C.  Analyses of our experience (confirmed) added new five and ten year survivors to six resistant patient series PC GC small bowel uterus ovary bladder and kidney series 

 

D. More examples novel chemotherapy reconditioned patients improved nutrition, immunity and performance making them eligible for premiere research personalized and immunotherapy

 

E. Additional immunotherapy apparent reactivation of checkpoint for gastric, bile duct, CCA, pancreatic localized (earlier positive experience lung, renal, liver)

 

F. Identification of new FDA approved drugs to reverse resistance including a series of anti apoptotic and non cancer drugs (80% of cell lines respond in others' laboratories) This expands clinical efforts to glioblastoma (GBM), prostate and has already been active in combinations with immunotherapy or chemotherapy for CRC, CCA and PC. 

 

G. New follow up on our Rexin-G gene therapy trial found ten year survivors PC,  soft tissue sarcoma in press on line and breast submitted 

   

 

Progress Report for Physicians and Investigators    

Howard W. Bruckner, MD and Azriel Hirschfeld, MD

MZB Foundation for Cancer Research, January 2019

 

Moderate dose multidrug chemotherapy (-/+ personalized) targeted therapy regimens GFLIO, GFLIO DM, and ACy GFLIC have increased safety, response, and length of survival, and expand the drugs' added disease indications. Three independent site visit groups, four IRBs and numerous collaborators, found our treatments to be uniquely effective, against resistant pancreatic, gastric, bile duct, renal, ovarian and uterine tumors as described below. Many patients were high risk, aged and heavily treated. Median survival often exceeded expectations by 2-4 fold. This broad, reproduced experience provides proof of principle and supports urgent development of both our translation methods and Phase III testing 

 

Also more than half of the patients in crises had immediate benefit. They had no remaining standard treatments for their refractory colon, lung, and breast cancers. These drugs in other combinations had been either marginally effective or unsafe. Our combinations provide better interaction and safety, moderate dosages make the difference (See B above): Independent trials found our drug classes and combinations had doubled rates of response, survival and cure for local and regional pancreatic cancer (PC) 1, 2 and doubled standard survival for advanced PC 3, 4. Regimens also produced exceptional response which improved/activated immunotherapy for refractory gastric cancer (GC) and improve resistant colorectal (CRC) patients’ response rates two fold and their immune competence 5, 6.

 

MZB methodology has discovered and developed safe economical, proven feasible, test worthy and unique Phase II options suitable for 150,000 patients now under treated or with no options. These are solutions for safety concerns and predicted testable resistance to standard drugs (ASCO 17, Table X on our website summarizes a thousand plus patient, our experience here, and independent support, a two thousand plus patient experience, elsewhere).

 

MZF seeks high volume collaborators for both empirical and personalized development of drugs. Our translational methods are likely to again benefit more than half of the patients. (Inquiries can be made to bruckneroncology@gmail.com or by phone 212-590-5838

 

New work identified and confirmed a large series of safe pro apoptotic drugs which seem ideal to reproduce and expand indications for regimens based on the GFLIP development model criteria of safety broad antitumor spectrum and drug interaction 

 

New FDA Bristol Myers Squibb duel checkpoint immunotherapy trials – regimens have been added to our integrated sequential treatment for gastric, ovarian, and triple negative breast cancers. A possible bonus is the potential activation of the immunotherapy (Chakrabati).Our combinations in sequence have produced some CRs for these patients and reconditioned patients –recovered  research eligibility.Anticancer Research18 B,C above 

 

Rationale: Methods 

Our lab work discovered three sequential non-cross resistant very safe (serial personalized test validated ) combination chemotherapy regimens. Each provides three added drug interactions and together double the chances to achieve high quality responses. Responses create ideal small residual tumors which improve the chances for successful radiotherapy, interventional radiology and immunotherapy for GC, CCA, CRC and other cancers 5, 6. Chemotherapy can improve the patients immune function.

 

Both our laboratory tests and empirical experience identify drugs with: high clinical and pre-clinical rates of synergism, frequent ability to reverse drug resistance; synergism at ¼-1/8 the single drug's effective concentrations. Peters, Amsterdam Cancer Center, has published a review of the powerful synergism of gemcitabine -  one of the many drugs which we have learned to exploit in the same fashion. Four highly vetted synergistic partner drugs, and now new drugs, F above, can potentiate each standard GFLIO DM drug and targeted therapy AntiCancer Research 16,18 (The synergistic drug pairs have non additive safe side effects). 

 

Each drug in the regimen has been found to reverse resistance to targeted therapy TT. Reciprocally, TT does the same for many of the cytotoxins. Inactive drugs often become fully active in combination with new partner drugs (AntiCancer Research 05, 16, ASCO 06, 12, AACR 2014). In contracts others found that standard high dose combinations produced antagonism at the IC 50. 



Work here and elsewhere has expanded the original geometric biochemical modulation, multiple salvage pathway inhibition - interaction hypothesis The combination are  pro immune, in many ways, and  also metronomic - anti angiogenic and possibly collateral sensitizers.

 

Our laboratory can now test individual tumors. Multidrug reversal of drug resistance can upgrade the practice of personalized medicine because it provides many potentiators for both achievable otherwise ineffective test drugs. Our translational experience can improve triage and application of existing genomic and proteomic test information As a supplemental test it can improve the rate of actionability; tests find translationally successful drugs  for 60-80% of common resistant epithelial tumors. Anticancer Research 16, Peters ...newly identified drugs are already active in clinical translation. In the laboratory these drugs have the same broad profile as prior successful partner drugs; they include: target drugs; cytotoxins; hormones; common non cancer drugs; PARP inhibitors and vitamins HDAA AACR17

 

Below please find our experience with individual tumors. It describes the development of GFlIP GFLIO GFLIO D M GFLIC GFLIC D and the regimens evolution as drug development  platforms with: Avastin PC >GC >CCA >O&U Avastin cyclophosphamide GFLIC( D) and with Erbitux for CCA, PC, GC and especially CRC. Each series found TT effective after it (TT)had failed standard use. Adverse events of TT were largely prevented because of new prophylactic strategies and possibly our moderate dosages and rapid reconditioning of patients. This overall experience  is considered to be proof of principal because the broad multidisease applications are  based on the same laboratory criteria, conditions - observed similar drug interactions.


Questions are welcome. Cited references are available. HIPAA appropriate

Invitations to review patients and charts

Sincerely,

H Bruckner and A Hirschfeld



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