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PHASE I CLINICAL TRIAL OF THE IGF-1R INHIBITOR, AXL1717, FOR TREATMENT OF RECURRENT MALIGNANT ASTROCYTOMAS by Robert Aiken, MD

PHASE I CLINICAL TRIAL OF THE IGF-1R INHIBITOR, AXL1717, FOR TREATMENT OF RECURRENT MALIGNANT ASTROCYTOMAS

Led by Robert Aiken, MD at Rush University Medical Center

MORE EFFECTIVE THERAPIES FOR THE TREATMENT OF PRIMARY MALIGNANT BRAIN CANCERS ARE NEEDED. THE MOST COMMON AND MOST LETHAL OF THESE TUMORS IN ADULTS ARE ANAPLASTIC ASTROCYTOMAS AND GLIOBLASTOMAS. THEY CONSTITUTE 60% OF NEWLY DIAGNOSED BRAIN TUMORS OR ABOUT 12,000 NEW CASES YEARLY. CURRENTLY AVAILABLE CONSISTS OF CHEMOTHERAPY WITH TEMOZOLOMIDE DURING AND FOLLOWING CONFORMAL RADIATION THERAPY AND THEN CONTINUED FOR 6-12 MONTHS OR UNTIL RELAPSE OR PROGRESSION. MEDIAN SURVIVAL IS PRESENTLY 15 MONTHS. AFTER RELAPSE OR PROGRESSION, BEVACIZUMAB, AN ANTI-VEGF MONOCLONAL ANTIBODY, PROLONGS LIFE BY A MERE 4-MONTHS AND IS ACTIVE IN ONLY 40% OF PATIENTS. CLEARLY, THERE IS NEED FOR BETTER TREATMENT. DRUGS TARGETING CELL SURFACE RECEPTORS ON TUMOR CELLS HAVE BEEN EVALUATED BUT NONE HAVE YET DEMONSTRATED UNEQUIVOCAL EVIDENCE OF BENEFIT IN THIS GROUP OF DISEASES. THE IGF—-1R (INSULIN-LIKE GROWTH FACTOR-TYPE 1RECEPTOR) IS AN IMPORTANT CELL SURFACE RECEPTOR AND IS STRUCTURALLY RELATED TO THE INSULIN RECEPTOR WHICH PLAYS A CRUCIAL ROLE IN THE CELLULAR METABOLISM OF SUGAR. IT IS KNOWN THAT THE IGF-1R REGULATES A BROAD RANGE OF CELLULAR FUNCTIONS INCLUDING CELL GROWTH AND SURVIVAL AND ALSO PLAYS AN IMPORTANT ROLE IN THE
TRANSFORMATION OF CELLS INTO CANCER CELLS. INHIBITING THE IGF-1R IS EMERGING AS AN IMPORTANT STRATEGY IN THE TREATMENT OF A NUMBER OF CANCERS INCLUDING MULTIPLE MYELOMA AND MELANOMA, AS WELL AS CANCERS OF THE BREAST, LUNG, COLON AND RECTUM, PANCREAS, AND PROSTATE IN ADULTS, AND EWING’S SARCOMA AND RHABDOMYOSARCOMAS IN CHILDREN. HOWEVER, TARGETING THESE TUMORS WITH MONOCLONAL ANTIBODIES DIRECTED AGAINST THE IGF-1R HAVE BEEN DISAPPOINTING.
AXL1717 IS A SMALL MOLECULE AND A PURE INHIBITOR OF IGF-1R AND IR-A (INSULIN RECEPTOR, TYPE A), HAVING NO OTHER KNOWN EFFECTS WHEN ADMINISTERED TO LABORATORY ANIMALS. IT HAS A DEMONSTRATED ANTI-TUMOR EFFECT IN A RECENTLY REPORTED PHASE 1 FIRST-IN-MAN CLINICAL TRIAL OF PATIENTS WITH ADVANCED NON-SMALL CELL LUNG CANCER AS A SINGLE THERAPY AND IS RELATIVELY NON-TOXIC. I AM PROPOSING A CLINICAL TRIAL TO EVALUATE THE EFFECTIVENESS OF THIS STRATEGY IN PATIENTS WITH RECURRENT MALIGNANT ASTROCYTOMAS. SUBSTANTIAL EVIDENCE INDICATES THAT THIS STRATEGY IS PROMISING. RUSH UNIVERSITY MEDICAL CENTER (RUMC) AND AXELAR AB HAVE CONCLUDED AN AGREEMENT TO SHARE THEIR IP AND OUR CLINICAL EXPERTISE IN ORDER TO EXPLORE THIS STRATEGY IN PATIENTS WITH RECURRENT MALIGNANT ASTROCYTOMAS. I PLAN TO BEGIN A PHASE 1 INVESTIGATOR-INITIATED,FDA APPROVED, SINGLE-CENTER, OPENLABEL STUDY OF THIS SMALL MOLECULE AT RUMC IN CHICAGO, IL, IN 2012. THIS IS AN APPLICATION FOR START-UP FUNDING. THE PHASE 1 STUDY WILL ENROLL UP TO 20 PATIENTS WITH A KPS ≥60 WHO HAVE FAILED AT LEAST ONE
STANDARD THERAPY.

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