National Oversight Perspectives on Cardiotoxicity of Anticancer

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					 National Oversight Perspectives on
 Cardiotoxicity of Anticancer Agents:

 Regulate the Agent or the Patient?

                 Joanna M. Brell, MD
National Cancer Institute/National Institutes of Health
              Bethesda, Maryland USA

          Cardiology Oncology Partnership
                    Milan , Italy
                  September 2009
Educational Objectives –
Discussed concomitantly

• Describe risk of treatment-induced arrhythmia,
  torsades de pointes (TdP) in cancer patients

• Discuss drug development issues for pro-arrhythmic

• Outline considerations for pro-arrhythmic anticancer
  drug regulation

  Anticancer therapy risk assessment distinct features
The problem……..

Oncology drugs prolong
action potential duration
                        risk factor TdP
QT interval biomarker prolongation
                     ECG measurement imprecise

 Goal: define arrhythmic potential of agent prior to
  utilization of resources for its development
  without denying access to potentially beneficial
Incidence Torsades Pointes (TdP) –
 Darpö 2003, Whellan et al 2009 difficult to diagnose   1.

TdP             symptoms       spontaneously   NSR

   V-fibrillation  sudden death

       Incidence non-cardiac medications:
           ~ 1 - 4 cases per 100,000?
              Incidence = Reporting
Discrepancies QTc interval measurements
Ahmad and Dorian 2007, Agin, 2003                          2.

Definition:     beginning QRS complex to end of T wave
Normal:            men < 450 msec       women < 460 msec
Variation:       normal volunteers 12 hours mean 36 msec
                               (range 8 -112 msec)

          Bradycardia **           Tachycardia **
          Position of ECG leads/one lead only
          Supine/upright position  Abnormal baseline ECG
          Time of day              Concomitant medications

     **No consensus on best method to correct heart rate
Treatment-induced risk of Torsades multi-factorial
NEJM Roden 2004                                 3.
Cancer patients: risks for prolonged QTc                    4.

 ECG             Percent          Reference

Prolonged QTc    10.6%            Barbey et al 2003

Borderline or    15%              Vaterasian, et al. 2003
prolonged QTc
any ECG          36%              Barbey et al 2003

    •molecularly targeted agents with  QTc
  •adjuvant regimens, long treatment periods
  • survival = emphasis toxicity reduction
Regulatory Guidelines  Drug Development
Issues re: QTc

  Repolarization toxicity highly important issue

• QTc most common reason for FDA
  withdrawal, non-approvals, delays all drugs Strevel
  et al 2007

• Essentially every drug pro-arrhythmic
• No method early prediction arrhythmic potential
• Can never control multiple patient variables

 QTc ≠ arrhythmia ≠ TdP ≠ sudden death
Regulatory issues for Potentially Pro-arrhythmic
Anticancer Therapies (PPAT) Darpo et al 2006

• European Committee for Proprietary Medicinal Products:
  “Points to Consider: Assignment of the Potential for QT
  Interval Prolongation by Non-Cardiovascular Medicinal
  Products”, 1997
• “Clinical Evaluation of QT/QTc Prolongation and Pro-
  arrhythmic Potential for Nonantiarrhythmic Drugs: the
  International Conference on Harmonization of Technical
  Requirements for Registration of Pharmaceuticals for
  Human Use E14 Guideline”, 2005
• ICH experts to provide guidance for drug development
  and regulation  standardize development process
• How to accurately test for cardiac repolarization?
Regulatory issues for PPAT: ICH-S7B
Shah, RR 2008; Darpo et al 2006

                    Non-clinical assays of currents:
1. Ikr (rapid component delayed rectifier repolarizing current)
2. cell line expressing hERG for K+ ion channels
3. animal models (not rodent)

• Not specific or replace clinical assessment
• FDA, Health Canada: negative trials are inconclusive
• FDA, Health Canada requires clinical testing

Early identification to guide clinical drug development
Regulation of PPAT: IHC-14
Shah RR 2008; Darpo et al 2006; Garnett et al 2008

                    Thorough QT Study (TQT Study)
• ECGs in healthy volunteers
• High doses drug compared to positive control
  agent and placebo
• When to perform TQT study (after Phase I or II ?)

  Positive study: change in ~ 5- 10 msec (95% CI)
        QTc >500 msec or 20-60 msec change
Regulation of PPAT: IHC-14:
Shah RR 2008; Darpo et al 2006; Garnett et al 2008

                   If TQT study positive
        No consensus on components of expanded study
    1. Assess  ECG and electrolyte status, h/o CHF,
         gender, dose, hepatic/renal dysfunction, age

             Expanded ECG study to include:

 phase II and III         heterogeneous population
 high-risk comorbidities      achieve highest doses
     (accounts for overdose, drug-drug interactions, altered
                 metabolism, kidney/renal failure)
TQT study: Specifics for advanced cancer patients
Rock et al 2009

•   Cannot push dose in normal controls
•   Multiple medications with substantial medical history
•   Lengthy washout periods inappropriate
•   No placebo or crossover design
•   Cannot give positive control drug (consider 5HT-3
• With best therapeutic dose, cannot push dose

Need revised TQT study and prevent:
1. delays in study completion 2. non-efficacious doses
3. # pts screened             4.non-approval rate
If QTc prolonged, decisions for continued
development Shah, RR 2008

•   Number of patients affected
•   Magnitude of prolongation
•   Indications for the drug
•   Ability to diminish the risk
•   If class effect compare to other agents
•   Other equally efficacious drug available without
•   Shared metabolic pathway with other agents
•   Drug-drug interactions
•   Overall risk:benefit of drug
Regulatory decision-making for cancer
therapeutics             population-based

Need therapies                            Sudden Death
Potential prolonged life           Less data for decision
Potential symptom relief          Prescriber fear of drug
                           Other adverse effects ignored
                                    Overall public safety
Patient decision-making for cancer
therapeutics         individual patient - based

Sudden death from therapy       Potential for prolonged life

Protracted death from cancer   Potential for symptom relief

Risk of recurrence             Sudden death from therapy
        QTc prolonging anti-cancer therapies
                    adapted from Strevel et al 2007, Schimmel et al 2004
Agent Class                       Mechanism                     Examples
Alkylating agents                 Free O2 radicals by           cyclophosphamide
                                  intracellular drug levels?
Anti-microtubules agents          Muscle damage? Histamine      paclitaxel
HDAC inhibitors                   myocardial inflamm; prolong   depsipeptide
Vascular disrupting agents        HERG K+ interaction           combretastatin A4P
Tyrosine kinase inhibitors        HERG K+ interaction           sunitinib
Protein kinase C inhibitors              ??                     enzastaurin
Scr kinase inhibitors             HERG K+ interaction;          dasatinib
                                  action potential delay
Farnysel transferase inhibitors          ??                     L-778123
Arsenic trioxide - FDA approved second-line
therapy for APML with boxed warning

• Initial studies with ~ 40% QTc prolongation Barbey 2003
• Blocks Ikr and other currents
• Package insert:
  “ QTc prolong should be expected during treatment”

  ECG and Electrolyte Monitoring Recommendations
12-lead ECG before drug
Correct electrolytes (K+ > 4 mEq/L , Mg+ >1.8 mg/dL)
Stop other meds
If QTc > 500 msec, assess risk-benefit ratio
If symptoms, stop drug and hospitalize for assessment
If resolution, re-start if QTc < 460 msec
Elements to decrease patient risk
Rock et al 2009

Risk minimization
• Make at-risk patients ineligible
• Exhaustive review of risk factors:
  CHF, sudden death family, medications, diuretics, age, gender, drug
• Extensive, personal informed consent
• Repeat informed consent with ECG changes
• Increase ECG, electrolyte monitoring with aggressive
• Set parameters for discontinuation
Elements to improve risk assessment
Fingert, Varterasian 2006

Change TQT test/clinical trials for advanced
  cancer patients:

1.   TQT study to allow 5HT-3 inhibitors as control
2.   Eligibility criteria
      CTCAE v4.0 grade I QTc interval (< 480 msec)
3.   Allow dose reductions if  QTc interval
4.   Account for  QTc concomitant medications
5.   Flexibility based on risk:benefit ratio
Elements to improve risk assessment-
Shah 2008

• Make available ECG data correlated with patient
  characteristics, heart rate, DNA samples, etc
• Stakeholders share as much data as possible
• Appropriate, detailed labeling when approved
• Continued post-market surveillance

• Educate prescribers about risks and benefits with
  oncology drugs
IHC conference excellent international effort

       to standardize development efficacious
    uncertain incidence of potentially fatal toxicity
         for patient benefit and safety………

•   Further genetic profiling of repolarization machinery
•   Factors effecting agent metabolism
•   Need cancer-specific recommendations
•   Continued discussion and collaboration
IHC conference excellent international effort

• FDA with QT Interdisciplinary Review Team
• FDA Critical Path Initiatives: national initiative improve
   methods for development, evaluation, production of
   products ( predicting cardiac toxicity
• International partnerships: COP
• Public-private partnerships: Cardiac Safety Research
  Consortium (
• Web sites with potentially pro-arrhythmic agents
•   Bass et al. J Pharmacol Toxicol Meth2005;52:12-21
•   Darpö, Europ Heart J Suppl 2003;3K:K70-K80
•   Vaterasian et al. J Clin Oncol 2003; 3378-3379
•   Ahmad, Dorian Europace 2007; iv16-iv22
•   Lasser et al JAMA 2002;287:2215-2230
•   Darpö et al J Clin Pharmacol 2006;46:498-507
•   Shah, RR. Pharmacol Thera 2008;119:215-221
•   Garnett et al J Clin Pharmacol 2008;48:13-18
•   Rock et al Am Heart J 2009;157:827-836.e.1.
•   Fingert, Varterasian AAPS J 2006:8:E89-E94

•   Strevel et al J Clin Oncol 2007;25:3362-3371
•   Barbey, et al J Clin Oncol 2003;21:3609-3615
•   Roden DM NEJM 2004;350: 1013-1020
•   Agin et al Proc Am Coll Clin Pathol 2003

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