Amie Davé November 16, 2007

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Amie Davé November 16, 2007

  1. 1. Amie Davé November 16, 2007 Columbia College of Physicians and Surgeons Morgan Stanley Children’s Hospital of New York- Presbyterian New York University School of Medicine
  2. 2. Vincristine in Cancer Therapy Vinca-alkaloid derived from the periwinkle plant Integral part of many pediatric protocols ALL, Hodgkin’s disease, non-Hodgkins lymphoma, rhabdomyosarcoma, neuroblastoma, Ewing’s sarcoma, Wilms tumor Mechanism of vincristine (VCR) Binds to tubulin  disrupts microtubule function  mitotic arrest & cell death Interfere with many biochemical processes: amino acid uptake, inhibition of protein, DNA, & RNA synthesis, disrupts lipid & glucose metabolism
  3. 3. Vincristine-Induced Neuropathy Neurotoxicity is the dose-limiting toxicity of VCR therapy Manifests as a sensory and/or motor neuropathy Presentation of neuropathy in children Paresthesias, numbness, loss of proprioception, gait disturbances More difficult to detect May be subtle Believed to be related to cumulative dose in adults
  4. 4. Glutamine Neutral non-essential amino acid, frequent use as a nutritional supplement Glutamine depletion over time in cancer patients May have a promising role in prophylaxis against VCR- induced neuropathy Proposed mechanisms of neuroprotectant effect Related to circulating nerve growth factor (NGF) levels; glutamine’s ability to upregulate NGF mRNA Glutamine enhances microtubule formation and/or stability Low toxicity
  5. 5. Study Objectives Eligibility Criteria Evaluate effect of glutamine on VCR-mediated antitumor efficacy in vitro Describe the incidence of VCR- induced peripheral neuropathy in pediatric oncology patients Investigate the efficacy of glutamine in ameliorating VCR- induced peripheral neuropathy To investigate the effect of glutamine on serum nerve growth factor and glutamine levels Inclusion Ages 5 to 21 years Ability to complete baseline assessment Diagnosis of leukemia or solid tumors and expected to receive ≥ 15 mg/m2 of VCR over 30 weeks Exclusion Primary CNS tumors or CNS metastases Recurrent disease Grade II, III or IV neurological status by the NCI CTC 3.0 on clinical exam Already received > 8mg/m2 of VCR during therapy at the time of consent
  6. 6. Study Instruments Purdue Pegboard Test Symbol Digits Test Hand Dynamometer Grip Strength
  7. 7. Study Design Double-blind, randomized, placebo-controlled trial Baseline Neurological Status evaluated every 3 weeks Meet criteria  Randomization Glutamine Placebo Day 0 Day 42 Day 21 Day 0 Day 42 Day 21 Neurological Assessments • Clinical exam • Purdue Pegboard Test • Symbol Digits Test • Grip Strength Test Blood Collection • Serum NGF • Serum glutamine • Baseline, Day 0, 21, & 42 Day 21 - discontinue supplement Randomization Criteria • Clinically progressive neurological findings • Increase in one toxicity grade by the NCI CTC 3.0 on clinical exam or • Clinically progressive neuropsychological findings • ≥ 1 /2 SD from patient’s own baseline score on any of the instruments that measure fine and gross motor function Glutamine dose 6 g/m2 (max of 10 g/dose) BID
  8. 8. In vitro testing David J. Kroll, Ph.D. Senior Research Pharmacologist Research Triangle Park, NC Physiologic levels of glutamine: 500 – 600 µM CCRF-CEM human T-cell leukemia cells The effects of 0.5, 2, 5, and 10 mM of glutamine on cell cycle distribution cellular growth rate sensitivity to vincristine cytotoxicity sensitivity to L-asparaginase cytotoxicity
  9. 9. Results – In vitro testing Effect of glutamine culture conditions on growth of CCRF-CEM human T-cell leukemia cells Days 0 1 2 3 4 5 cellnumber/mLX10,000 0 50 100 150 200 250 0.5 mM Gln 2 mM Gln 5 mM Gln 10 mM Gln
  10. 10. Results – In vitro testing No effect of glutamine on cell cycle distribution Sub G0 G0/G1 S G2/M 0.5 mM Gln 2.70 ± 0.85 46.06 ± 1.31 21.05 ± 0.45 30.13 ± 1.59 2 mM Gln 3.81 ± 0.70 46.55 ± 2.06 20.69 ± 0.40 28.81 ± 1.85 5 mM Gln 3.78 ± 1.76 47.01 ± 2.53 20.81 ± 0.28 28.17 ± 2.17 10 mM Gln 2.25 ± 0.19 45.45 ± 0.67 21.36 ± 0.16 30.90 ± 0.59
  11. 11. Results – In vitro testing No effect of glutamine on vincristine sensitivity in CCRF-CEM cells Vincristine IC50 (nM) 0.5 mM Gln 0.695 2 mM Gln 0.740 5 mM Gln 0.772 10 mM Gln 0.791
  12. 12. Results – In vitro testing Effect of glutamine on CCRF-CEM response to vincristine -10 -9 -8 -7 -6 0 25 50 75 100 0.5 mM glutamine 2 mM glutamine 5 mM glutamine 10 mM glutamine log [vincristine] (M) %cellularsurvival
  13. 13. Clinical Trial Demographics 23 patients, 3 removed, 2 on observation Ages 5 – 19 years Mean 9.9, Median 8.5 10 males, 8 females Diagnosis ALL – 16 Rhabdomyosarcoma – 2 Ewings sarcoma – 2 Wilms tumor – 2 Hodgkin’s Disease – 2
  14. 14. Results – Randomization Criteria for randomization met in first 18 of 18 patients Criteria met by Clinical exam – 5 patients Neuropsych. Testing – 6 patients Both – 7 patients VCR-related neuropathy is prevalent in children with overt progression by clinical exam in 67% May be greater if in fact neuropsych. testing is picking up signs at an earlier stage
  15. 15. Results – Neuropsych. Testing Potential practice effect with Symbol Digits test       Neuropsychologic Test Mean change in z- score* Range Purdue Pegboard - Dominant -0.1 -2.5 to 1.72 Purdue Pegboard - Non-dominant -0.54 -2.68 to 1.83 Purdue Pegboard - Both -0.7 -2.34 to 1.11 Hand Dynamometer - Right -0.02 -1.76 to 1.71 Hand Dynamometer - Left -0.46 -2.38 to 0.77 Symbol Digits† 0.89 .-0.54 to 2.84 *Negative score indicates decline (z-score at randomization minus baseline z-score) from baseline to randomization test †Ten patients administers symbols digits test, no norms for patients age five
  16. 16. Results – Cumulative VCR Cumulative dose of approximately 6 mg/m2 required for detection of signs by clinical exam or neuropsych. testing in all but one patient No difference in number of days to randomization between patients with ALL compared to other diseases It is the cumulative dose as opposed to dose-intensity (mg/m2 /28-day interval) that determines randomization Among six patients that received 6 mg/m2 ± 0.5, dose intensity varied from 2.5 to 5.8 mg/m2 /28-day interval
  17. 17. Results – Serum glutamine levels No significant difference found between glutamine levels at baseline and at time of randomization (Z=-0.31, p=0.76) Significant correlation between baseline and the change in glutamine (rho=-0.531, p=0.034)
  18. 18. Results – Serum glutamine levels No significant differences between ALL and other diseases
  19. 19. Results – Glutamine & time to randomization Significant difference in the number of days to randomization between patients who had a decrease and increase in glutamine (Z= -2.119, p=0.034) Decrease – mean 80.9 days, SD=36.96 Increase – mean 49.0 days, SD= 19.71
  20. 20. Findings No current evidence to suggest any adverse effect of glutamine on CCRF- CEM leukemia  cell growth,  cell cycle distribution, or  sensitivity to vincristine even at 20 times normal circulating concentrations First 18 of 18 patients met criteria for randomization  12 patients randomized due to progression of score on clinical exam Cumulative dose of approximately 6 mg/m2 required for detection of signs by clinical exam or neuropsych. testing No differences in in glutamine levels between baseline and randomization  No difference between patients with ALL and other diseases Trends in glutamine levels may help predict who develops neuropathy
  21. 21. Acknowledgments Study group – E. Ladas RD MS, D. Hughes BA, S. Sands PsyD, D. Kroll PhD, L. Vahdat MD, O. Bessmertny PharmD, M. Weiner MD, K. Kelly MD, J. Glade Bender MD GCRC, Irving Center for Clinical Research at Columbia University Society for Integrative Oncology

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