1. 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

2. 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

3. 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

4. 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

5. 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 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

6. 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

7. Dose adjustments Recover to ANC > 1K, PLT > 100K each cycle
Sliding scale dose on d8
ANC > 1000: full dose day 8
ANC 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

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

9. Tumor histology Leiomyosarcoma 36 Liposarcoma 19 WD/DD 12 Myxoid / RC4
Pleomorphic 3
MFH (includes 1 myxofibro)
Unclassified 9
Synovial 8
MPNST 7
Angiosarcoma
Fibrosarcoma (2 SEF)
HPC/SFT
Rhabdomyosarcoma 2
Epithelioid
Others
TOTAL
120

10. 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 G2 allergic reaction = Rash, Urticaria, Drug Fever

11. 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)

12. 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

13. 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

14. 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

15. 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!

16. 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