CLINICAL TRIALS IN PROSTATE CANCER

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CLINICAL TRIALS IN PROSTATE CANCER

• PHASE II TRIAL OF HALICHONDRIN B ANALOG IN
  PATIENTS WITH METASTATIC HORMONE REFRACTORY
  PROSTATE CANCER

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THE PROBLEM

• 218,000 CASES PER YEAR
• 27,000 DEATHS
• ANDROGEN DEPRIVATION STANDARD FOR TREATMENT OF
  METASTATIC DISEASE
• NEED FOR NOVEL THERAPIES FOR HORMONE RESISTENT
  PROSTATE CANCER

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BACKGROUND ABOUT CLINICAL TRIALS

• TRIALS SUPERVISED BY FDA
• SPONSOR SUBMITS INVESTIGATIONAL DRUG APPLICATION
  (IND)
• IF DRUG APPROVED, TESTING STARTS IN HUMANS
• IF THE DRUG IS SAFE AND USEFUL, SPONSOR SUBMITS
  NEW DRUG APPLICATION (NDA)

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PHASES OF CLINICAL TRIALS

• PHASE I TESTS SAFETY, DOSES, PHARMACOLOGY (15-30
  SUBJECTS)
• PHASE II EVALUATES EFFECTIVENESS AND SIDE EFFECTS
  (100-150 PARTICIPANTS)
• PHASE III COMPARES NEW DRUG TO STANDARD THERAPY
  (HUNDREDS TO THOUSANDS

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PHASES OF TRIALS, CONT.

• PHASE IV FOLLOWS PATIENTS FOR LONG TERM SAFETY ON
  NEW DRUGS
• (HUNDREDS TO THOUSANDS OF PATIENTS INCLUDED)

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REPORTING TRIALS

• CLINICAL TRIALS ARE COMPLETED BEFORE RESULTS
  REPORTED
• HELPS AVOID BIAS
• EXCEPTIONS OCCUR IF MEDICAL ISSUES EMERGE
• USUAL TIME FROM BENCH TO CONSUMER ABOUT 15 YEARS

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CHALLENGES TO ENROLLEMENT

• LACK OF AWARENESS
• LACK OF ACCESS
• FEAR, DISTRUST
• PRACTICAL OR PERSONAL

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CHALLENGES, CONT

• INSURANCE COSTS
• UNWILLINGNESS TO GO AGAINST OR LOYALTY TO
  PERSONAL DOCTOR
• INTERESTING STAT 60 PERCENT OF CHILDREN WITH
  CANCER ENROLL IN CLINICAL TRIALS
• 3 PERCENT OF ADULTS

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WHY PARTICIPATE

• MAY BENEFIT FROM NOVEL THERAPY
• HELP FUTURE GENERATIONS
• STANDARD OF CARE IN CANCER UNTIL EVERYTHING IS
  CURABLE WITH EASY, NON TOXIC, AND COST EFFECTIVE
  TREATMENT

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NATIONAL CANCER INSTITUTE TRIALS

• SEVERAL SUB GROUPS EXIST WHICH ARE UNDER UMBRELLA
  OF NCI
• ECOG, NSABP, SWOG, CALGB
• DIFFERENT UNIVERSITIES AND COMMUNITY PRACTICES
  WORK IN DIFFERENT GROUPS

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ECOG E7389

• A PHASE II TRIAL OF E7389 (HALICHONDRIN B ANALOG)
  IN PATIENTS WITH METASTATIC HORMONE REFRACTORY
  PROSTATE CANCER

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RATIONALE

• ANTIMITOTIC AGENT
• DISRUPTS MITOTIC SPINDLE ASSEMBLY IN VITRO
• INHIBITED PROSTATE CANCER, COLON CANCER CELLS,
  LEUKEMIAS, LYMPHOMA, MELANOM, LUNG CANCER
• INHIBITED TAXANE RESISTENT OVARIAN CANCER

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RATIONALE CONT.

• HALICHONDRIN ACTIVITY SURPASSED PACLITAXEL BY 10
  TO 40 TIMES
• IMPORTANCE OF THIS POTENCY IS THAT DOCETAXEL
  (TAXOTERE) IS CURRENTLY ONLY DRUG WHICH IMPROVES
  SURVIVAL IN ANDROGEN RESISTENT PROSTATE CANCER

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CRASH REVIEW OF MITOSIS

• 4 PHASES OF CELL DIVISION
• PROPHASE ASSEMBLY OF CHROMOSOMES
• METAPHASE -- CHROMOSOMES ALIGN IN THE MIDDLE OF
  CELL
• ANAPHASECHROMOSOMES SEPARATE IN DIVIDING CELL
• TELOPHASEDAUGHTER CELLS ORGANIZE AFTER DIVISION

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MITOSIS
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OBJECTIVES OF STUDY

• TO DETERMINE THE NUMBER OF PATIENTS WITH A 50 OR
  BETTER DECREASE IN PSA OF AT LEAST 4 WEEKS
  DURATION IN PATIENTS WITH METASTATIC PROSTATE
  CANCER PROGRESSING ON ANDROGEN ABLATION

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SECONDARY OBJECTIVES

• TO ESTIMATE THE MEASURABLE DISEASE RESPONSE IN
  PATIENTS WITH 2-D LESIONS (LIVER METS)
• TO DETERMINE DURATION OF PSA AND MEASURABLE
  DISEASE RESPONSE
• TO CHARACTERIZE SAFETY AND TOLERABILITY OF E7389
  IN THIS PATIENT POPULATION

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INITIAL PHASE I STUDY OF HALICHONDRIN

• GIVEN INTRAVENOUSLY EVERY 3 WEEKS WITH ONE WEEK
  OFF
• THERE WERE 5 RESPONSES OUT OF 38 PATIENTS (13)
• LAB ANALYSIS PROVED THAT DRUG WAS REACHING THE
  TUMOR

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THREE SUBGROUPS TO BE ANALYZED IN E7389

• CHEMOTHERAPY NAÏVE
• PRIOR TAXANE THERAPY ONLY
• TWO PRIOR CYTOTOXIC CHEMOTHERAPY REGIMENS

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ADMINISTRATION

• HALICHONDRIN GIVEN IV PUSH OVER 5 MINUTES DAYS 1
  AND 8 OF EACH CYCLE
• EACH CYCLE IS 21 DAYS

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ELIGIBILITY

• BIOPSY PROVEN ADENOCA OF PROSTATE CANCER
• EVIDENCE OF PROGRESSIVE METS (BONE SCAN, CT,
  RISING PSA)
• MUST HAVE COMPLETE TESTOSTERONE ABLATION (LHRH
  AGONIST OR ORCHIECTOMY)
• MUST BE OFF FLUTAMIDE, NILUTAMIDE FOR 4 WEEKS

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ELIGIBILITY, CONT

• OFF CHEMOTHERAPY FOR 4 WEEKS
• BIPHOSPHONATES CAN CONT IF PROGRESSION HAS
  OCCURRED ON SUCH A DRUG
• NO RADIATION
• NO RADIO ISOTOPES

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ELIGIBILITY

• NO USE OF ESTROGEN OR ESTROGEN AGENTS (E.G. PC
  SPES), ADEQUATE BONE MARROW FUNCTION 1 WEEK PRIOR
  TO ENTERING
• ADEQUATE CHEMISTRIES
• NO ACTIVE ANGINA OR SEVERE HEART DISEASE, NO
  VENTRICULAR DYSRHYTHMIAS
• CANT BE ON COUMADIN BUT CAN USE HEPARIN

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ELIGIBILITY, CONT

• NO METS TO BRAIN OR CSF
• NO SEVERE PERIPHERAL NEUROPATHY
• PRIOR MALIGNANCIES MUST BE ABSENT FOR AT LEAST 5
  YEARS
• NO SERIOUS CONCURRENT MEDICAL ILLNESS OR
  INFECTION WHICH COULD COMPROMISE ABILITY TO GET
  CHEMOTHERAPY

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ELIGIBILITY, CONT

• SEXUALLY ACTIVE PATIENTS MUST AGREE TO GOOD
  CONTRACEPTION
• PERFORMANCE STATUS OF 0, 1, 2
• AT LEAST 18 YEARS OF AGE
• NO OTHER RESEARCH DRUGS
• ALL SITES OF DISEASE EVALUATED IWTHIN 4 WEEKS
  PRIOR TO REGISTRATION
• MUST NOT TAKE DRUGS THAT COMPETE WITH CYP3A4

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COMMON SIDE EFFECTS

• ANEMIA
• FATIGUE
• LOSS OF APPETITE
• NAUSEA

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LESS COMMON SIDE EFFECTS

• BLEEDING, FEVER, HAIR LOSS
• WEIGHT LOSS, RASH
• CONSTIPATION, DEHYDRATION, DIARRHEA
• VOMITING, MOUTH SORES
• NEUROPATHY, LIVER TOXICITY
• PAIN, SOB, SWELLING

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BASELINE STUDIES

• HISTORY, PHYSICAL EXAM, WEIGHT, HEIGHT, VITAL
  SIGNS
• PERFORMANCE STATUS
• SCANS
• ECG
• TESTOSTERONE LEVEL
• CBC, CHEMISTRIES

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FOLLOW UP

• WEEKLY EXAMS AND WEIGHTS, VITAL SIGNS
• PSA REPEATED 1 WEEK AFTER START
• LAB WORK WEEKLY
• SCANS REPEATED AFTER EVERY THIRD CYCLE UNTIL
  DISEASE PROGRESSES
• FOLLOW UP Q 3 MOS FOR FIRST 2 YEARS AND Q 6 MOS
  FOR THE NEXT 3 YEARS

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WHAT HAPPENS NEXT

• TRIALS OPEN AND CLOSE REGULARLY
• EACH ONE MOVES UNDERSTANDING OF BIOLOGY,
  PHARMACOLOGY, MOLECULAR UNDERPINNINGS
• FUTURE GENERATIONS OF SCIENTISTS, PHYSICIANS
  GRATEFUL TO THE COURAGE AND GENEROSITY OF PEOPLE
  WHO PARTICIPATE