Adjuvant gemcitabine plus docetaxel for completely resected stage I-IV high grade uterine leiomyosarcoma: results of a phase II trial Martee L. Hensley, Nicole Ishill, Robert Soslow, Nadeem Abu- Rustum, Paul Sabbatini, Jason Konner, William Tew, David Spriggs, Carol A. Aghajanian Memorial Sloan-Kettering Cancer Center, New York, NY

RATIONALE 2-year progression-free survival (PFS) is estimated at 20-40% for women with completely resected HGuLMS Recurrence rates estimated at 50-80% No prospective trials have adequately assessed adjuvant systemic therapy for high-risk disease

RATIONALE Fixed dose-rate gemcitabine + docetaxel achieves high response rates in metastatic HGuLMS, even as 2 nd or 3 rd line therapy Need to determine whether 2-year PFS with adjuvant chemotherapy for HGuLMS is sufficiently promising to warrant study in a prospective, randomized phase III trial

Gemcitabine-Docetaxel in advanced uterine LMS Objective RRMedian duration of response Range, months MSKCC phase II 40%7 months GOG, second line 27%9+ months3.1 – GOG, first line 36%6+ months Hensley, JCO 2002; Hensley Gyn Onc 2008; Hensley Gyn Onc 2008

Background: historical PFS for uLMS Reference- Intervention Recurrence rate Patient details % recurrence at 2- 3 years Comments Kushner, Gyn Oncol 2000 Retrospective Ifos 4.5 gm 13 ut sarc pts 6 LMS pts 5/6 (83%) LMS pts recurred 4 pts stage I/II 2 pts stage III/IV 70% recurrence at 2y among stage I LMS pts Omura, GOG, J Clin Oncol 1985 Dox 60mg/m 2 x 8 v. observation Dox 44% (11/25 LMS) Obs 61% (14/23 LMS) All stage I/II (no data on grade, mitotic rate) 40% recurrence at 2y (for combined MMT and LMS pts) RT allowed, but no difference in recurrence rates No CT imaging required Gaducci, Gyn Onc 1996 Retrospective, some patients received adjuvant chemo, some RT, some no adjuvant No adjuvant Rx 25/64 (39%) Chemo 4/9 (44%) RT 5/15 (33%) 126 LMS pts 90 pts with stage I, II 60% recurrence at 2 y (35/90 pts recurred, at median of 16 mo) 2-year DFS by mitotic rate % % >20 25% Major, GOG, Cancer 1993 Retrospective study to determine prognostic factors 71% among the 59 LMS pts 59 pts (83% stage I, 17% II) 69% recurrence at 3y 3-y PFS by mitotic rate <10 100% % >20 21%

Reference- Intervention Recurrence rate Patient Details Recurrence rate at 2-3 y Comments Dinh, Gyn Onc 2004 Retrospective 9/11 stage I, II, IIIA-serosa only LMS pts recurred (82%) med PFS 17 mo, range mo 81% recurrence at 2 for all 27 pts Trend for poorer survival with higher mitotic rate Giuntoli, Gyn Onc 2003 Retrospective 17% received adjuvant RT 16% received adjuvant chemo 208 LMS patients 60% recurrence at 2y for subset of 62 patients (68% of whom were stage I or II) Case-control analysis for RT (n=31) v. no RT (n=31, matched for age, stage) showed no difference in PFS or OS Pautier, Cancer 2000 Retrospective 15% received chemo 26% received RT 10% received both 157 uterine sarcomas 78 LMS pts 75% recurrence at 3y among 78 LMS (73% of whom were stage I or II) Stage and mitotic rate were prognostic for LMS Wu, Gyn Oncol, 2006 Retrospective 12/41 (29%) stage I recurred 51 LMS 41 stage I 7 stage III 3 stage IV 33% recurrence at 3 y Approx 75% at 3 years among 41 stage 1 pts 9/41 stage I pts received adj chemo— 11% recurred 31/41 stage I had no adjuvant chemo— 36% recurred

Reference- Intervention Recurrence rate Patient Details Recurrence rate at 3-5 y Comments Odunsi, Int J Gyn Cancer, 2004 CYVADIC adjuvant chemo 8/24 (33%) recurred Stage I uterine sarcomas (n=24) 11 LMS 8 MMT 3 ESS 35% recurrence at 5 y Prospective phase II Pautier, Int J Gyn Cancer, 2004 dox-cis-ifos x 3, then RT 5/13 (38%) LMS recurred 18 uterine sarcoma pts 16/18 stage I-II 13/18 had LMS 24% recurrence at 3-Y for chemo-RT pts 57% recurrence at 3y for RT only Case-control study, with controls, matched on stage, age, histology, surgery Small studies of adjuvant chemotherapy

OBJECTIVES Primary: determine whether treatment with adjuvant fixed- dose-rate gemcitabine plus docetaxel following complete resection of stage I-IV high grade uterine LMS is associated with a >40% PFS at 2 years Secondary: assess tolerability of 4 cycles fixed-dose-rate gemcitabine plus docetaxel in an adjuvant treatment population

Study Schema Confirm histology: high-grade uterine LMS, stage I, II, III, or IV, completely resected Confirm No Evidence of Disease (NED) by CT C/A/P and physical examination CT scan and Physical Exam every 3 months Gemcitabine 900mg/m2 over 90 minutes days 1 and 8 + Docetaxel 75mg/m2 d8, with GCSF or Neulasta day 9, every 3 weeks for 4 cycles

ELIGIBILITY CRITERIA  Pathologically confirmed uterine LMS, stage I, II, III, or IV, completely resected  No prior chemotherapy for LMS; no prior gemcitabine or docetaxel  Age > 18 y; KPS > 80%  Adequate organ function and bone marrow reserve  No prior radiation therapy (RT) to abdomen or whole pelvis  No other cancer present within the past 3 years  No neuropathy greater than grade 1

PATIENT CHARACTERISTICS Total # patients enrolled25 Median age (range)49 (37-73) Number of patients evaluable for PFS endpoint 23 1-never treated 1-ineligible FIGO Stage I or II uterine LMS (all high grade)18 (78%) FIGO stage III or IV uterine LMS (all completely resected, high grade) 5 (22%) Median uterine tumor size, stage I and II patients 10 cm (6-28 cm) Median LMS tumor mitotic rate per 10 hpf (range) 20 (5-60)

GRADE 3/4 TOXICITIES Toxicity (N = 92 cycles) Grade 3Grade 4 Neutropenia2/23 (8.7%)0 Febrile neutropenia2/23 (8.7%)0 Anemia2/23 (8.7%)0 Thrombocytopenia1/23 (4.3%)0 Hyperglycemia2/23 (8.7%)0 Pulmonary toxicity2/23 (8.7%)0 Diarrhea1/23 (4.3%)0 All patients completed all 4 cycles of planned therapy

Progression-free survival % of patients progression-free at 2 years All patients (n=23) 45% Stage I or II uterine LMS (n=18) 59% Median follow-up for all patients = 49 months Median follow-up for Stage I, II patients = 40 months

Median PFS-all patients = 13 mo

Median PFS-Stage I and II = 39 mo

Median Overall survival- all patients = not yet reached (> 45 mo)

Median Overall survival- Stage I, II patients = not reached (>60 months)

Sites of 1 st Recurrence LungPelvisLung + Pelvis Stage I, II patients 3/18 (16%)2/18 (11%)3/18 (16%) All patients 3/23 (13%)5/23 (22%)

CONCLUSIONS Patients treated with adjuvant fixed-dose-rate gemcitabine + docetaxel for completely resected stage I-IV high-grade LMS had 2 year PFS of 45% Patients with stage I or II disease had 2 and 3-y PFS of 59% 2 year PFS appears superior to historical rates of 20-40% PFS at 2 years. Median OS for all patients is not yet reached— exceeds 45 months Assessment of adjuvant Gem-Doce therapy in high-risk stage I and II uterine LMS is warranted

REFERENCES Omura, J Clin Oncol 3: , 1985 Major, Cancer 71: , Gaducci, Gyn Oncol 62: 25-32, Kushner, Gyn Oncol 78: , Pautier, Cancer 88: Hensley, J Clin Oncol 20: , Hensley, Gyn Oncol 109: , 2008 Hensley, Gyn Oncol 109: , Giuntoli, Gyn Oncol 89: , Pautier, Int J Gyn Cancer 14: , Dinh, Gyn Oncol 92: , Wu, Gyn Oncol 100: , 2006.

Acknowledgments Carol Aghajanian, MD David Spriggs, MD GMO physicians and care team MSO physicians Robert Soslow, MD Kathy Appollo, RN GOG Uterine Corpus and DTC committees Laurence Baker, MD and SARC leadership CTOS leadership MSKCC patients and GOG patients and physicians