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Phase II Study of Sequential Gemcitabine and Docetaxel for Recurrent Bone Sarcomas

This Phase II study evaluates the efficacy of sequential Gemcitabine followed by Docetaxel in patients with recurrent Ewing’s Sarcoma, Osteosarcoma, or unresectable Chondrosarcoma. The primary objective is to determine the objective response rate according to RECIST criteria. Secondary objectives include assessing time to progression, toxicity, and pharmacokinetics of both drugs. Eligible participants include those aged 4 and older with measurable disease, and who have recovered from prior therapies. The study outlines detailed dosing schedules and monitoring for toxicity.

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Phase II Study of Sequential Gemcitabine and Docetaxel for Recurrent Bone Sarcomas

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  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

  12. 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]

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

  14. 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

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