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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.

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a phase iii study of gemcitabine docetaxel for metastatic soft tissue sarcoma

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
Rationale for phase III study
  • Gemcitabine alone has at least activity in some sarcomas (LMS, osteosarcoma, angiosarcoma), most seen when gem given in a 10 mg/m2/min rate infusion
  • Two phase II studies show activity of gemcitabine + docetaxel in soft tissue sarcoma (STS)
    • Synergy in sarcoma cell lines 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
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
Entry Criteria
  • Recurrent STS, 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
Phase III regimens

● Dynamic randomization: Bayesian model

● 120 patient enrollment target

● Restage after cycles 2, 4, 6, 8, then ~Q 3 months

definition of response
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
p randomization to the superior arm by patient enrollment
p (randomization to the superior arm) by patient enrollment

100 %

Superior therapy

50 %

50 %

Increasing number of patients

Inferior therapy

100%

dose adjustments
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
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

other toxicity total events for all cycles
Other toxicity (total events for all cycles)

*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
Interim statistical model results
  • p < 0.01 boundary stopping rule was not crossed for either leiomyosarcoma nor non-leiomyosarcoma groups
enrollment n 110
Enrollment, n=110

Prior Irradiation

slide17

0.82 (5.5:1 odds)

0.86 (7:1 odds)

0.58 (~3:2 odds)

0.65 (~2:1 odds)

response by histology
Response by histology

19%; 39%

33%; 61%

 

PR PR

+

SD

24wk

4 Gem PR: MFH (2), DDLS, Myxoid sarcoma

13 Gem / Tax PR: LMS (6), MFH (4), Pleo lipo (2), Rhabdo (1)

conclusions
Conclusions
  • Gemcitabine in a dose controlled rate infusion has activity against metastatic soft tissue sarcomas
  • Gemcitabine / docetaxel is 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 and ethical study design to minimize the number of patients receiving the less active therapy
acknowledgements
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