Phase I Study of Olaparib and Temozolomide, in patients with recurrent and/or metastatic

Ewing sarcoma : An Interim Update

Edwin Choy, Gregory Cote, James Butrynski, David Harmon, Suzanne

George, Andrew Wagner, Jeffrey Morgan, David D’Adamo, George Demetri

Olaparib/EWS-FlI1 interaction is one of the strongest associations among

639 cell lines and 130 drugs screened

Olaparib prevents EWS-FLI1-positive xenograft growth and metastasis.

Single Agent Olaparib is Not Effective in Ewing Sarcoma

Choy et al. BMC Cancer. In Press

Single Agent Olaparib is Not Effective in Ewing Sarcoma

Choy et al. BMC Cancer. In Press

Olaparib synergizes with TMZ in EWS-FLI1-positive xenograft mice

Objectives of this Phase 1 trial

Study Design: Phase I 3+3 dose escalation study of olaparib and temozolomide in patients with recurrent and/or metastatic Ewing’s sarcoma.

Treatment regimen: Olaparib is administered orally with temozolomide on an outpatient basis, given for 7 days every 21 days.

Imaging:CT/MRI prior to starting study drug, after 6 and 12 weeks from starting study drug, and every 9 weeks thereafter. Additional scans may be performed as clinically indicated. Subjects will continue to be followed until disease progression or death.

Inclusion Criteria:

• Histologically-confirmed Ewing’s sarcoma. • Measurable disease on cross sectional imaging of

at least 1cm • ECOG performance status 0-2 • Life expectancy >3 months • Age ≥ 18 years.• Patients must have received at least one line of

chemotherapy, including adjuvant therapy, for the initial treatment of Ewing’s sarcoma. There will be no limits on number of prior regimens using chemotherapy or investigational agents.

• Allowed for prior treatment with temozolomide

Dose Levels

Attributable AEs

Best Response by RECIST 1.1

* Received prior TMD

* **

*

* * * *

Dose Level DLTs

1 0/3

2 0/3

3 0/3

4 0/3

5 2/2

# of DLTs per Dose Level

Conclusions

• We designed and conducted a phase I clinical trial to administer olaparib and temozolomide in patients with Ewing sarcoma progressing after prior chemotherapy

• 5 dose levels were tested

• minor responses were seen in 6 of 14 evaluable patients

• MTD was surpassed at dose level 5

• Dose expansion study will be performed using olaparib at 200 mg BID and temozolomide at 75 mg/m2 QD.

Acknowledgments

Mentorship• George Demetri, DFCI• Daniel Haber, MGH• Jose Baselga, MGH• Jane Robertson, Astra Zeneca

Clinical Trials Unit at DFCI and MGH• Coauthors• Kristina Goodman• Barbara Anderson• David Wells• Eleanor Saffian• Basyl Stuyvesant• Melissa Hohos• Mark Morley• Julie Field• Sarah Solomon

Funds• Ludwig Center at Dana-Farber / Harvard Cancer Center • Jennifer Hunter Yates Sarcoma Foundation• Brian MacIsaac Sarcoma Fund