A phase III study of gemcitabine ± docetaxel for metastatic soft tissue sarcoma Maki RG, Wathen JK, Patel SR, Priebat DA, Okuno S, Samuels B, Harmon DC, Fanucchi M, Hensley ML, Reinke D, Thall PF, Benjamin RS, Baker LH CTOS 2005, Boca Raton, FL

Rationale for phase III study Gemcitabine alone has at least activity in some sarcomas (LMS, osteosarcoma, angiosarcoma) Two phase II studies show activity of gemcitabine + docetaxel in soft tissue sarcoma (STS) There appears to be synergy in sarcoma cell lines between the two drugs when given in the sequence gem→doc Merimsky O et al. Cancer Chemother Pharmacol 2000; 45:177 Patel SR et al. J Clin Oncol 2001;19:3483. Svankarova L et al. Eur J Cancer 2002; 38:556 Okuno S et al. Cancer 2003; 97:1969 Hensley ME et al. JCO 2002; 20:2824 Leu KM et al. JCO 2004; 22: 1706

Purpose Execute a phase III study of gemcitabine +/- docetaxel in patients with up to 3 prior lines of therapy for metastatic disease Is it the controlled rate infusion of gemcitabine that yields the activity in this combination? In which subtypes is combination active? Is the combination better, or more toxic, or both? Utilize a novel Bayesian design, dynamic randomization, to minimize the number of patients necessary to determine a statistically significant difference between arms

Entry Criteria Soft tissue sarcoma, no GIST, KS, meso Age ≥ 10 Measurable disease No more than 3 prior regimens for metastatic disease Good organ function; T Bili ≤ ULN, Cr ≤ 2 Not pregnant No neuropathy > G1 No uncontrolled CNS metastases

Phase III regimens No prior pelvic XRT Prior Pelvic XRT Arm A G 1200 mg/m2 over 120 min, d 1, d8, q21d + GCSF G 900 mg/m2 over 90 min, d 1, d8, q21d + GCSF Arm B G 900 mg/m2 over 90 min, d1, d8, Doc 100 mg/m2 d8, q21d + GCSF G 675 mg/m2 over 60-75 min, d1, d8, Doc 75 mg/m2 d8, q21d + GCSF ● Dynamic randomization: Bayesian model ● 120 patient enrollment target ● Restage after cycles 2, 4, 6, 8, then ~Q 3 months

Definition of response RECIST used for classic response criteria For purposes of the dynamic randomization model, a different definition of success was defined: Any PR or better after 2, 4, 6, 8 cycles = success Any RECIST progression = failure Stability recorded as SD for any of the 1st four time points We arbitrarily decided that lowering the failure rate is 1.3 times as important as increasing the response rate This weighs stable disease as more important in the model than frank response

Dose adjustments Recover to ANC > 1K, PLT > 100K each cycle Sliding scale dose on d8 ANC > 1000: full dose day 8 ANC 500-999 or PLT 50-99: 75% dose G, (Doc) ANC < 500 or PLT < 50: Hold Rx Febrile neutropenia, G 3-4 non heme toxicity → 25% dose reduction May reduce dose up to twice before stopping

Status as of 3 October 2005 120 patients are enrolled; 118 are assessable for use in the dynamic randomization model U Michigan 30 MDACC 27 Washington Hosp Center 17 MSKCC 16 Mayo 14 Lutheran General, Chicago 10 Emory 5 MGH/Partners 2

Tumor histology Leiomyosarcoma 36 Liposarcoma 19 WD/DD 12 Myxoid / RC 4 Pleomorphic 3 MFH (includes 1 myxofibro) Unclassified 9 Synovial 8 MPNST 7 Angiosarcoma Fibrosarcoma (2 SEF) HPC/SFT Rhabdomyosarcoma 2 Epithelioid Others TOTAL 120

All events: toxicity data for 120 patients Type of toxicity Total GEM (n= 46) GEM+DOC (n=74) ANC G3 19 14 5 ANC G4 13 8 Hemoglobin G3 12 7 Platelets G3 83 26 57 Platelets G4 3 10 Blood transfusions 36 15 21 Platelet txfusion (some require > 1) 32 24 Febrile neutropenia 4 Allergic reaction G2 2 1 Pulmonary G3 9 Pulmonary G4 Edema G3 Neuropathy G2 As of 02 Nov 2005, NCI-CTC 2.0. G2 allergic reaction = Rash, Urticaria, Drug Fever

Cumulative toxicity by patient, n=120 Type of toxicity Total GEM (n=46) GEM+DOC (n=74) ANC G3 12 8 4 ANC G4 13 5 Hemoglobin G3 11 6 Platelets G3 36 23 Platelets G4 10 3 7 Blood transfusions 21 9 Platelet transfusion 16 Febrile neutropenia Allergic reaction G2 (no G3, G4) 2 1 Pulmonary G3 Pulmonary G4 Edema G3 Neuropathy G2 (no G3, G4)

Other toxicity (all events) Gem (n=46) Gem/Doc (n=74) Fatigue G3-4 7 17 Myalgia / Muscle weakness G3 1 9 DVT / PE G3 2 3 Nausea / Vomiting / anorexia G3 5 All other G3 1 (glucose G3) 17* Totals 11 51 *Other G3 includes: lymphopenia (4), GI bleed (2), abdominal pain, diarrhea, mucositis, cough, pleural effusion, hiccups, bone pain, back spasm/pain, rash, nail changes, hypokalemia; data as of 02 Nov 2005

Interim statistical model results Dynamic randomization model includes 100 of 110 patients accrued as of June, 2005 p < 0.01 boundary stopping rule was not crossed for either leiomyosarcoma nor non-leiomyosarcoma groups

Randomization probability (after n=100 patients) Prior Irradiation NO YES LMS Gem/Doc 0.87 0.76 Gem 0.13 0.24 NON-LMS 0.66 0.60 0.34 0.40

Conclusions In analysis of the randomization of patients, gemcitabine + docetaxel appears superior to higher dose single agent gemcitabine for patients with leiomyosarcoma. There is a trend toward improved response rate with the combination of therapy for patients with other types of soft tissue sarcomas Low platelet count most common toxicity Nearly no febrile neutropenia using (peg)-filgrastim Fatigue, edema, myalgias occasionally dose limiting Dynamic randomization is an effective study design to minimize the number of patients receiving the less active therapy More data will be presented tomorrow!

Acknowledgements Patients and families who participated in this study Lilly and Sanofi-Aventis for their participation and support Staff at SARC and the multiple centers responsible for the execution of this study