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CLINICAL TRIALS IN PROSTATE CANCER

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NEED FOR NOVEL THERAPIES FOR HORMONE RESISTENT PROSTATE CANCER. BACKGROUND ABOUT CLINICAL TRIALS ... PERCENT OF CHILDREN WITH CANCER ENROLL IN CLINICAL TRIALS ... – PowerPoint PPT presentation

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Title: CLINICAL TRIALS IN PROSTATE CANCER


1
CLINICAL TRIALS IN PROSTATE CANCER
  • PHASE II TRIAL OF HALICHONDRIN B ANALOG IN
    PATIENTS WITH METASTATIC HORMONE REFRACTORY
    PROSTATE CANCER

2
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3
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4
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

5
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)

6
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

7
PHASES OF TRIALS, CONT.
  • PHASE IV FOLLOWS PATIENTS FOR LONG TERM SAFETY ON
    NEW DRUGS
  • (HUNDREDS TO THOUSANDS OF PATIENTS INCLUDED)

8
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

9
CHALLENGES TO ENROLLEMENT
  • LACK OF AWARENESS
  • LACK OF ACCESS
  • FEAR, DISTRUST
  • PRACTICAL OR PERSONAL

10
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

11
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

12
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

13
ECOG E7389
  • A PHASE II TRIAL OF E7389 (HALICHONDRIN B ANALOG)
    IN PATIENTS WITH METASTATIC HORMONE REFRACTORY
    PROSTATE CANCER

14
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

15
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

16
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

17
MITOSIS
18
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19
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

20
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

21
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

22
THREE SUBGROUPS TO BE ANALYZED IN E7389
  • CHEMOTHERAPY NAÏVE
  • PRIOR TAXANE THERAPY ONLY
  • TWO PRIOR CYTOTOXIC CHEMOTHERAPY REGIMENS

23
ADMINISTRATION
  • HALICHONDRIN GIVEN IV PUSH OVER 5 MINUTES DAYS 1
    AND 8 OF EACH CYCLE
  • EACH CYCLE IS 21 DAYS

24
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

25
ELIGIBILITY, CONT
  • OFF CHEMOTHERAPY FOR 4 WEEKS
  • BIPHOSPHONATES CAN CONT IF PROGRESSION HAS
    OCCURRED ON SUCH A DRUG
  • NO RADIATION
  • NO RADIO ISOTOPES

26
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

27
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

28
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

29
COMMON SIDE EFFECTS
  • ANEMIA
  • FATIGUE
  • LOSS OF APPETITE
  • NAUSEA

30
LESS COMMON SIDE EFFECTS
  • BLEEDING, FEVER, HAIR LOSS
  • WEIGHT LOSS, RASH
  • CONSTIPATION, DEHYDRATION, DIARRHEA
  • VOMITING, MOUTH SORES
  • NEUROPATHY, LIVER TOXICITY
  • PAIN, SOB, SWELLING

31
BASELINE STUDIES
  • HISTORY, PHYSICAL EXAM, WEIGHT, HEIGHT, VITAL
    SIGNS
  • PERFORMANCE STATUS
  • SCANS
  • ECG
  • TESTOSTERONE LEVEL
  • CBC, CHEMISTRIES

32
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

33
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
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