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Physicians and Investigators: August 2016



 

Progress Report for Physicians and Investigator

Howard W Bruckner MD and Azriel Hirschfeld MD

MZB Foundation for Cancer Research, July 2016

 

Moderate dose multidrug chemotherapy -/+( Personalized) Targeted Therapy.

MZB regimens, alone and with added targeted therapy, have  increased SAFETY, RESPONSE, length of SURVIVAL, and disease  INDICATIONS. Three independent review groups, four IRBs and numerous collaborators, found our treatments to be very effective, against resistant  PANCREATIC, GASTRIC, BILE DUCT, RENAL, OVARIAN and UTERINE tumors. Large numbers of patients were high risk, aged and heavily treated..Response rates ranged from 60-90% and survival exceeded expectations by 2-4 fold... More than half of the patients in crises or with common dilemmas which have no standard treatments, had immediate benefit. (For refractory colon, lung and breast cancer MZB regimens produce better than 50% benefit rates pending review.) These same drugs in high doses had earlier failed or were only marginally effective -and less than safe for patients with the same resistant tumors, when used in high doses alone  and in other combinations.

MZB methodology creates novel and safe economical  options for patients now under treated or with no other options  because of safety concerns or because of predicted resistance to  drugs. Table X summarizes a thousand plus patient experience and independent support based on two thousand plus patients.


MZBF SEEKS HIGH VOLUME DISEASE SPECIFIC COLLABORATORS for development of additional drugs both in empirical and personalized regimens.  Use of the same translational setting as our earlier work is likely to benefit more than half of participating patients. Enquiries are welcome: Bruckneroncology@gmail.com 212-590-5838 


RATIONALE: METHODOLOGY. Both our laboratory tests and empirical experience based algorithms identify drugs with the best clinical and pre-clinical rates of synergism, they especially produce frequent reversal of drug resistance, Critical for design of exceptionally safe multidrug regimens drugs are synergistic at ¼ - 1/8th the conventional single drug’s effective concentrations . MZB designs have provided each standard drug and NOW TARGETED THERAPY with 3-4 highly vetted synergistic partner drugs (often six synergistic drug pairs , have non additive limiting side effects). Each pair can : potentiate best evidence based drugs; safety prolongs the period of treatment benefit and expands eligibility for treatment. Each drug in the regimen was shown in many labs  and clinics to reverse resistance to TT. Reciprocally, TT does the same for each of the cytotoxins.  Inactive drugs often become fully active with NEW partners. Anti Cancer Research 2005 2016 ASCO 2006 2012 AACR 2014  (In contrast work with the Chou model often found that standard high dose combinations produced antagonism at the IC 50.) Our regimens also improve immune function. (British Journal of Cancer)


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 otherwise ineffective standard and problematic test selected drugs.   Our translational experience can improve triage use of existing genomic and proteomic test information. One can improve chances of a drug’s efficacy against 60-80% of common resistant adenocarcinomas.


Resistant patients with the six diseases below have never before had the response rates or survival observed with MZB regimens THIS SIX DISEASE EXPERIENCE PROVIDES PROOF OF PRINCIPLE. The regimens are ready for phase III testing both for new and resistant disease.


PANCREATIC Cancer (PC) - For over 800 patients chemotherapy alone GFLIO > GFLIO DM, repeatedly produced a median survival of over a year and half—and advantages at every time point out to five years. Our current series is also on the same survival track. Work always included and was heavily weighted with poor risk, elderly and prior treated patients. Intent to treat analyses were performed in collaboration with IRB participants and oncologists at four institutions.  (The Oncologist 01 ASCO 01 05,08,12). Nine independent publications describe successes based on GFLIO.• Moderate dose multidrug use is extensively supported. NEW High Dose Vitamin C Reduces and Reverses Adverse Events when added to chemo —GFLIO, GFLIO D—as treatment for patients with either features predicting high risk of adverse events or preexisting complications. Our CRO monitored pilot study found • The vitamin C chemotherapy was safe and  virtually hospital free• RESOLUTION of preexisting symptoms due to chemotherapy and resolution of complications of disease occurred for half the patients..(ASCO 2015)

• A SUBSEQUENT ONGOING CONFIRMATORY TRIAL includes all patients with and without prior treatment because of overall experience. (ASCO 05,08). (ASCO 16) SAFETY• The rate of moderate side effects has been reduced by 2/3 compared to the strong standard folfoxiri folfurinox and by 1/2 compared to the mild standard Gemcitabine Abraxane regimens • the current trial is free of severe heretofore-common side effects • Disease related weight loss, pain, DVTs--were conspicuously “absent or uncommon” • SURVIVAL outcomes have been independently "confirmed" both for advanced disease and targeted therapy, (HirshautASCo 2012) and ADJUVANT  (Isacoff ICACT Paris ).• Our Adjuvant series median survival  ran three plus years ASCO 03,12).  PERSONALIZED TESTING. • Others recently  found that Vitamin C has anti tumor effects against KRAS mutated tumors, as we published in Cancer Letters—• MZB lab tests can select optimum partner drugs for vitamin C, and  personalize regimens for many GI & GYN tumors.

 

DRUG DEVELOPMENT—GFO, GFLIO, GFLIO D—are proven synergistic backbones for demonstration of NEW DRUG  INDICATIONS for added diseases  or phase II failed DRUGS. as demonstrated (irinotecan, gemcitabine, taxotere,and  targeted therapies (see below). FAST TRACK demonstration OPPORTUNITIES exist for a drug added to the combinations (see above).


TARGETED THERAPY, for fifty plus patients with refractory GASTRIC cancer, GFLIO D alone doubled survival. ASCO 2006 • In combination with TARGETED THERAPY, it produced exceptional third line response rates (after GFLIO no longer controlled the tumor), neoadjuvant responses—opportunities for ideal surgery—and long—sometimes five year—survivors. TT was effective with GFLIO vs pancreatic cancer (PC AntiCancer Research 05 ASCO 08 Benefit when both chemo and TT failed or are not normally effective also encouraged similar treatment for Cholangiocarcinoma and Gynecologic cancers.)

 

CHOLANGIOCARCINOMA CCA , BILE duct and GALLBLADDER  ca (ASCO Hirschfeld 2012) For one hundred plus patients  Stage IV  median SURVIVAL was  three years plus with GFLIO +/- D • Adjuvant CCA series median SURVIVAL was near 80% at three years. Retreatment after unmaintained remission produced  responses.

GFLIO enhanced TARGETED THERAPY  • Bevacizumab and Cetuximab individually produced 80% third line responses, which prolonged survival.IN PRESS—AntiCancer Research • —for GALL BLADDER cancers, GFLIO alone,reproduced  our 60% response rates.


OVARIAN: For 60 plus patients •  ACy Bevacizumab and Cyclophosphamide added to GFLIC Carboplatin produced 80% RESPONSE rates for intact end stage, five drug regimen failures—many long responses prolonged SURVIVAL  (AACR 2014) year plus • New analyses found A YEAR PLUS SURVIVAL IN ‪9/14 PATIENTS RECOMMENDED TO HOSPICE.• GFLIC  often reversed resistance to all already individually used standard drugs and bevacizumab.

• OUTCOMES are the best in class for each sub series :1- Hospice: survival and crises recovery rates 2-intact Five-regimen failed: response, safety and survival.3- De novo early platinum resistant, clinically failed first regimens: "all" had complete remissions CRs, (in our first test, of early intervention). UTERINE cancers, have the ovarian laboratory preclinical profile, ACy GFLIC produced a 9/10 response rate and some second line  complete responses CRs and 3rd line year plus, -18 mos. (3x) survival.  

SAFETY: both GYN series were free of the TARGETED THERAPY  severe vascular bleeding or GI perforations ( others have observed absent GFLIC )


RENAL RCC, metastatic and resistant to standard TT: Our laboratory dictated modification of an active University of Chicago regimen, Avastin, Navelbine, GFL(I)C. Half respond. SURVIVAL • ~ 80% overall at 2 years before use of checkpoint Now integrated with immunotherapy


IMMUNOTHERAPY:  Our immune sparing-stimulating regimens damage tumors. This creates vaccines which kick starts immunotherapy.

 

OVERALL SAFETY  Reasons include moderate dosage, and avoiding taxanes (in symptomatic patients), Quick responses "recondition "patients reverse risk factors. Restore bowel function, nutrition, and immune function o stepwise personalized drug and dose introduction algorithm: New strategies provide “bowel safety.”Integrated safety measures (Individualized dose modification) novel GI protection (diet and gI symptom specific low thresholds for dose modification (stop go targeted therapy)Experience and solutions •  identified and integrated five methods applicable to performance status, age, co-conditions, drug dosage, and safety concerns.  (HB JAMA Lavin ..HB CTR Hirshfeld ..HB ASCO 15,16)


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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