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), 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; 45:177Patel SR et al. J Clin Oncol 2001;19:3483Svankarova L et al. Eur J Cancer 2002; 38:556 Okuno S et al. Cancer 2003; 97:1969 Hensley ME et al. JCO 2002; 20:2824Leu 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

• 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

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

p (randomization to the superior arm) by patient enrollment

100 %

100%

50 %50 %

Superior therapy

Inferior therapy

Increasing number of patients

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 30MDACC 27Washington Hosp Center 17MSKCC 16Mayo 14Lutheran General, Chicago 10Emory 5MGH/Partners 2

Tumor histologyLeiomyosarcoma 36

Liposarcoma 19

WD/DD 12

Myxoid / RC 4

Pleomorphic 3

MFH (includes 1 myxofibro) 19

Unclassified 9

Synovial 8

MPNST 7

Angiosarcoma 3

Fibrosarcoma (2 SEF) 3

HPC/SFT 3

Rhabdomyosarcoma 2

Epithelioid 2

Others 9

TOTAL 120

Cumulative toxicity by patient, n=120

ToxicityGEM

(n=46)GEM+DOC

(n=74)

ANC G3 17% 5%

ANC G4 11% 11%

Hemoglobin G3 13% 7%

Platelets G3 28% 31%

Platelets G4 7% 9%

Blood transfusions 20% 16%

Platelet transfusion 11% 15%

Febrile neutropenia 7% 5%

Allergic reaction G2 (no G3, G4) 2% 1%

Pulmonary G3 2% 7%

Pulmonary G4 4% 0

Edema G3 0 4%

Neuropathy G2 (no G3, G4) 0 4%

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

Event 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

0 5

All other G3 1 17

Totals 11 51

Interim statistical model results

• p < 0.01 boundary stopping rule was not crossed for either leiomyosarcoma nor non-leiomyosarcoma groups

Enrollment, n=110

NO YES TOTAL

LMS

Gem/Doc 23 9 32Gem 12 6 18

NON-LMS

Gem/Doc 25 8 33Gem 20 7 27

TOTAL 80 30 110

Prior Irradiation

Randomization probability

(after n=100 patients)

NO YES

LMS

Gem/Doc 0.87 0.76

Gem 0.13 0.24

NON-LMS

Gem/Doc 0.66 0.60

Gem 0.34 0.40

Prior Irradiation

Combined p[ (A,Z) > (B,Z) | data]

NO YES TOTAL

LMS

Gem/Doc 0.98 0.91 0.987Gem 0.02 0.09 0.013

NON-LMS

Gem/Doc 0.79 0.69 0.81Gem 0.21 0.31 0.19

Prior Irradiation

Probability of Being Randomized to Gem / Doc

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

Patient

Ra

nd

om

iza

tio

n P

rob

ab

ility

No Prior Radiation, Leio Prior Radiation, Leio

No Prior Radiation, Other Prior Radiation, Other

0.86 (7:1 odds)0.82 (5.5:1 odds)

0.58 (~3:2 odds)0.65 (~2:1 odds)

RECIST “Best response” data (n=116 evaluable)

Gem

(n=47)

Gem / Doc

(n=69)

TOTAL

PR/CR 4 (9%) 13 (19%) 17 (15%)

SDSD: 24 week

24 (51%)9 (19%)

37 (54%)12 (17%)

61 (53%)21 (18%)

PD 19 (40%) 19 (27%) 38 (32%)

Histology n PR/CR SD 24 wkLMS 31 6 6MFH 18 6 5

Myxoid/round cell lipo 4 0 0WD DD lipo 9 1 1Pleo lipo 3 2 0

Other 11 1 2Unclassified sarcoma 8 0 2

Synovial 7 0 2MPNST 5 0 1

Fibrosarcoma 3 0 1Angiosarcoma 3 0 0

HPC/SFT 3 0 0Rhabdo 2 1 0

4 Gem PR: MFH (2), DDLS, Myxoid sarcoma13 Gem / Tax PR: LMS (6), MFH (4), Pleo lipo (2), Rhabdo (1)

Response by histology

19%; 39%33%; 61% PR PR + SD 24wk

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

• 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