A Phase II Trial of Perifosine in Patients with Chemo-Insensitive Sarcomas Dejka M. Steinert, MD

Rationale for Study Phase I study: 2/10 (20%) evaluable sarcoma patients responded –One patient each Chondrosarcoma Leiomyosarcoma Phase I study of perifosine combined with gemcitabine: One patient with chondrosarcoma showed a 17% decrease in size of tumor after two cycles

Rationale for Study In one Phase II study in sarcoma, out of 19 evaluable patients: –One PR (extra-skeletal myxoid chondrosarcoma) –Two SD

Rationale of Study Two out of the three partial responses occurred in patients with sarcoma subtypes that have been previously unresponsive to conventional therapy: –Chondrosarcomas –Extraskeletal myxoid chondrosarcoma Will include alveolar soft part sarcoma as well since response rates to standard therapy are very poor

Protocol Design Phase II study of perifosine in patients with: –Chondrosarcoma –Alveolar soft part sarcoma –Extra-skeletal myxoid chondrosarcoma Patients will receive perifosine 100 mg orally daily with food until disease progression. Response to therapy will be based on Choi criteria

Objectives Primary: –To evaluate the response rate of perifosine 100 mg by mouth daily in patients with chondrosarcoma, extra-skeletal myxoid chondrosarcoma and alveolar soft part sarcoma

Objectives Secondary: 1)To determine the time to progression of perifosine 100 mg by mouth daily in patients with chondrosarcoma, extra- skeletal myxoid chondrosarcoma, and alveolar soft part sarcoma 2)To determine stable disease of six months or greater of perifosine 100 mg by mouth daily in the same patient population

Inclusion Criteria 1)Patients must have a diagnosis of chondrosarcoma, extra-skeletal myxoid chondrosarcoma, or alveolar soft part sarcoma 2)Patients may have had prior chemotherapy, but if the patient has had three or more forms of chemotherapy, the patients clinical coarse should be discussed with the study chairman 3)Patients must have progression of disease by Choi criteria 4)ECOG PS 0-1. Patients with a PS 2 may be admitted with approval from study chairman

Inclusion Criteria 5)At least 13 years of age 6)Patients must have measurable disease 7)Life expectancy of more than 3 months. 8)Normal organ and marrow function 9)Patients must have recovered from acute toxicity related to prior therapy including surgery or radiotherapy to a grade equal to or less than 1

Inclusion Criteria 10)Patients must be able to ingest oral medications or to obtain them through a gastrostomy tube 11)Female patients who are pregnant or lactating are ineligible. Negative pregnancy test within 72 hours of treatment. Patients must agree to employ adequate contraception while on therapy and for 4 weeks after completion of therapy 12)Patients must have the ability to understand and the willingness to sign a written informed consent document

Exclusion Criteria 1)Patients receiving therapies administered with the intent to treat the patients malignancies, except bisphosphonates 2)History of allergic reactions attributed to compounds of similar chemical or biologic composition to perifosine (miltefosine or edelfosine) 3)Uncontrolled intercurrent illness. Patients with a history of unstable or newly diagnosed angina pectoris, recent MI (within 6 months of enrollment) or New York Heart Association II – IV CHF

Treatment Plan Perifosine is available in 50 mg tablets Patients will take two perifosine 50 mg tablets orally once a day at bedtime with some food

Study Evaluations Patients will be seen and evaluated at baseline and then once every four weeks Evaluation for progression or response will be made at three months intervals Responses will be recorded using both RECIST and Choi criteria All protocol decisions will be made by the use of Choi criteria

Dose Modifications for Perifosine Related Toxicities Grade 1 Toxicities: –Treatment with perifosine will not be interrupted Grade 2 Toxicities: –Maintain dosing with symptomatic treatment –If persistent, reduce dose as follows: If > 50 mg/day, reduce dose by 50 mg If patient is receiving 50 mg/day and toxicity recurs, remove patient from study

Dose Modifications for Perifosine Related Toxicities Grade 3 & 4 toxicities: –Hold perifosine until less than or equal to grade 1 or has returned to baseline level –If > two weeks, consult study chairman –If less than or equal to two weeks, reduce dose by 50 mg. –If patient is receiving 50 mg/day and toxicity recurs, remove patient from study

Statistical Considerations Favorable outcome will be defined as a complete or partial response or stable disease for six months or longer by Choi criteria A favorable outcome rate of 10-20% will be taken as evidence that perifosine may have clinical benefit in these subtypes A multi-stage Bayesian design will be used to evaluate each sarcoma histology separately Maximum sample size of 37 per each subtype; total for trial of 111

SARC Participants Sant Chawla, MD –Century City Hospital Gina DAmatto, MD –H. Lee Moffitt Cancer Center George Demetri, MD –Dana-Farber Cancer Institute Michael Fanucchi, MD –Emory University Kenneth Hande, MD –Vanderbilt University David Harmon, MD –Massachusetts General Hospital Lee Helman, MD –NCI-Pediatric Branch Robert Maki, MD, PhD –Memorial Sloan Kettering Scott Okuno, MD –Mayo Clinic Dennis Priebat, MD –Washington Hospital Center Christopher Ryan, MD –Oregon Health & Science Univ. Scott Schuetze, MD, PhD –University of Michigan Amir Shahlee, MD –University of Florida Arthur Staddon, MD –Pennsylvania Hem/Onc Associates William Tap, MD –UCLA School of Medicine Meg Von Mehren, MD –Fox Chase Cancer Center Principle Investigator Dejka Steinert, MD MD Anderson Cancer Center

Status of Protocol CRF Design and Content –Completed EDC system beta testing –Oct 21 – Nov 7 Initiation Meeting at MD Anderson: –November 9, 2006 Activation: –Immediately following initiation meeting