PI: Lee Helman, MD Co-PI: Shreyaskumar Patel, MD

1. Phase II Study of Sequential Gemcitabine Followed by Docetaxel for Recurrent Ewing’s Sarcoma, Osteosarcoma, or Unresectable or Locally Recurrent Chondrosarcoma PI: Lee Helman, MD Co-PI: Shreyaskumar Patel, MD

2. Objectives • Primary Objective: • Determine Objective Response Rate (RECIST) of Gemcitabine followed by Docetaxel in OS, EWS, and Chondrosarcoma • Secondary Objectives: • Determine Time to Progression • Assess toxicity • Pharmacokinetics of gemcitabine alone and gemcitabine followed by docetaxel • Gene expression profiling, when possible

3. Eligibility • Recurrent high grade OS, recurrent EWS, unresectable or locally recurrent unresectable chondrosarcoma • Age ≥ 4 years • Measurable Disease by RECIST Criteria • Prior Therapy: Recovered from toxicity (< grade 2) prior therapy ≤ 2 prior retrieval chemotherapy regimens (OS, EWS) • ≥ 2 weeks from myelosuppressive therapy • ≥ 6 months from myeloablative chemotherapy or TBI • ≥ 6 weeks local XRT, ≥ 4 months extensive XRT • ≥ 72 hr from last dose of filgrastim • Adequate Organ Function and Performance Status • Neuropathy ≤ grade 1(chemo); ≤ grade 2 (tumor/surgery) • No prior gemcitabine or taxane therapy (or allergy) • No prior allogeneic stem cell transplant

4. Dose and Schedule • Gemcitabine 675 mg/m2 IV over 90 min Day 1, 8 • Docetaxel 75 mg/m2 IV over 60 min on Day 8 • Pre-medication with dexamethasone • Filgrastim : Day 9 until ANC≥ 1200/µL or Peg-filgrastim on Day 9 • Cycle Duration 21 days • Maximum 14 cycles • Restaging Prior to C 1, 3, 5, 9, 13, then off study

5. Pharmacokinetic Sampling • Cycle 1 Only • Gemcitabine day 1 and 8: prior, 75, 85, 95, 105, 120 min. • Docetaxel day 8: prior, 55min, 90 min, 5 hr, 24hr. • All samples collected in THU containing heparinized tubes (Obtained from NCI) • PK collected on 5 patients (42%)

6. Accrual

7. Patient Characteristics

8. Toxicity Cycle 1 (n= 11)

9. Toxicity Subsequent Cycles (n=17 cycles)

10. Interim Conclusions • Toxicity profile requires close monitoring • Hematological -Pulmonary • Hepatic -Hypersensitivity • Serious infections with/without neutropenia • Hematological toxicity in Cycle 1 resulted in dose reduction for 27% of patients (3/11) • 27 cycles of therapy have been delivered • 5 patients required dose modifications in Cycle 2+ • 3 patients removed for toxicity • Response data- too early • Acquisition of PK samples is marginal (42%) • Accrual could be better

11. Proposed Actions • Toxicity • Verify the use of filgrastim/peg-filgrastim in all patients • Increase gemcitabine dose rate to 10 mg/m2/min • Pharmacokinetics • PK was not obtained in patients who experienced hematological toxicity • Accrual • Agreements/IRB approval at additional SARC Institutions • Extend to Children’s Oncology Group Institutions • Possible International Cooperation

13. Gemcitabine Pharmacology Cytidine deaminase Difluorodeoxyuridine [dFdU] Gemcitabine [dFdC] / THU • Intracellular dFdCTP inhibits DNA synthesis. • dFdC dose rates of > 10 mg/m2/min result in plasma dFdC conc > 10-15 µM which saturate the rate of intracellular dFdCTP accumulation. • The plasma pharmacokinetics of dFdC 675 mg/m2 IV over 90 minutes (dose rate 7.5 mg/m2/min) have not been described. • Impact of dose-rate infusions on toxicity should be explored. [Parker et.al. ASCO 2005 Abstr 2025] Gemcitabine Triphosphate [dFdCTP]

14. Intracellular dFdCTP Accumulation dFdCTP Concentration (µM) Patel et.al. JCO 2001, 19: 3483

15. Docetaxel Pharmacokinetics • Docetaxel is metabolized by CYP3A4 • Pharmacokinetic interactions between gemcitabine and docetaxel are unlikely • Bruno et.al. JCO 1993 17: 305 • Limited sampling strategy • Docetaxel exposure (AUC) was predictive of TTP in NSCLC • Docetaxel clearance was a strong independent predictor of grade 4 neutropenia and febrile neutropenia