A PHASE II TRIAL OF PERIFOSINE IN PATIENTS WITH CHEMO-INSENSITIVE SARCOMAS

A SARCOMA ALLIANCE FOR RESEARCH THROUGH COLLABORATION (SARC) STUDY

Study Update – November 2007

Joseph Ludwig, MDMD Anderson Cancer Center, Houston, TX

Background & Rationale for Perifosine

Preclinical:• Suspected interference with the plasma membrane (Leishmaniasis) • NCI (Evaluate first on PC-3 (mut PTEN) hyperactivated PI3K/Akt): reduced (p) Akt• Blocked effects in insulin, EGF, PDGF• Blocked localization of Akt to plasma membranePhase I Studies:• Single agent, 2 of 10 (20%) of sarcoma patients responded (1 CS, 1 LMS)• With Gemcitabine 1 patient with CS had 17% reduction in tumor size.

Phase II Studies (Single agent):• Mayo Clinic Phase II consortium - 1 PR (extra-skeletal myxoid) of 22 patients with

STS

The responses in a chondrosarcoma and a myxoid-chondrosarcoma are particularly notable because these tumors do not usually respond to cytotoxic chemotherapy

Perifosine (NSC 639996)

Phase I Trials Sarcoma Responder - Wisconsin

After 12 mo’s of 50 mg perifosine 52% decrease in size

Van Ummersen et. al., Clinical Cancer Research, Vol. 10, Nov 15, 2004

Patients with < 2 forms of prior chemotherapy stratified by

Evaluate q 3 months

Progression

Perifosine 100 mg qhs daily

Remove From Study

CR, PR, or SD

Continue On Study

ConventionalChondrosarcoma

Extra-Skeletal MyxoidChondrosarcoma

Alveolar Soft PartSarcoma

P.S. (0-1) & Measurable, Progressive disease (Choi)

Objectives

Primary– Evaluate the response rate defined by both Choi and

RECIST criteria of single agent perifosine

Secondary– Evaluate Time to Progression (TTP)– Evaluate the Clinical Benefit Rate (CR & PR + SD)– Continue to Monitor Drug Safety

Major Inclusion / Exclusion

Inclusion– Measurable Disease– Age > 13 years– ** Documented progression by Choi Criteria

• Exclusion– > 2 prior cytotoxic regimens for metastatic

disease (unless exempted)

Study Population – 59 Patients

• Gender: 35 Male / 24 Female

• Median age: 51 (range 20 – 85)

• Cycles on Treatment (1 – 9 cycles)

Protocol 214 – ToxicityN = 43 Perifosine 100 mg Daily

Number of EventsGrade

Side Effect 1 2 3Nausea 14 6 2Vomiting 8 6 1Diarrhea 17 4 0Anorexia 5 2 0Dyspepsia 3 1 0Stomach cramps 1 1 0Decreased hemoglobin 4 1 0Fatigue 8 1 1Dyspnea 2 0 1Photosensitivity 2 0 0Common Perifosine Events

Evaluate q 12 weeks

Progression

Perifosine 100 mg qhs daily

Remove From Study

CR, PR, or SD

Continue On Study

ConventionalChondrosarcoma

Extra-Skeletal MyxoidChondrosarcoma

Alveolar Soft PartSarcoma

Measurable progressive disease (Choi)

33 1115

59 enrolled

Enrollment Status since Nov. 28th, 2006; 12 sites open

Off Study10

31 17

Current Enrollment Status

Total Evaluable*PR (Choi)

N (%)

SD (> 12 wks)

N (%)Off Study

Progression

Off StudyOther

Chondro 33 25 1 (4%) 5 (20%) 10(40%) 7

Extra-skeletal Myxoid

15 13 2 (15%) 5 (38%) 6(46%) 0

Alveolar Soft Part

11 10 3 (30%) 3 (30%) 1(10%) 3

Total 59 48 6 (13%) 13 (27%) 17(35%) 10

* Evaluable: Pts receiving > 1 cycle of treatmentAll cohorts have met criteria for full enrollment – 37 pts per arm

Clinical Benefit Rate = 40%

Responses1) 35 y/o female with ASPS Perifosine toxicities to date:• Grade 2 Nausea / Vomiting / Diarrhea / FeverTarget Lesion: Right Manubrium• Baseline scan: 166.60 HU• 3 mo scan: 129.60 HU• 22% PR by Choi (SD by RECIST)

3) 69 y/o female with Conventional CS• Perifosine toxicities to date:

– Well tolerated with limited toxicitySum of Lesions:• Baseline scan: 185 HU• 3 mo scan: 120 HU• 6 mo scan: Pending• 35.2% PR by Choi (SD by RECIST)

2) 29 y/o female with ASPS Perifosine toxicities to date:Grade 2 Nausea / Vomiting / Abd. PainSum of Lesions:Baseline scan: 182.80 HU3 mo scan: 146 HU6 mo scan: 146 HU20.13% PR by Choi (SD by RECIST)

Response Criteria Difficulties

• Unable to obtain HU’s on a few patients

• Negative HU’s on one patient

Eligibility Exceptions

• Five patients had > 3 prior chemo regimens• One patient came off tx for 6 weeks for surgery

and now back on after an initial response

Interim Conclusions

• Generally well tolerated– Common AE’s = GI related and fatigue

• Criteria met to proceed to full study enrollment• Activity: Clinical Benefit (SD > 12 weeks)

– Overall: 40% (19/48) • Chondro: 24% (PR = 4% by Choi)

• ESMS: 54% (PR = 15% by Choi)

• ASPS: 60% (PR = 30% by Choi)• Chondrosarcoma arm almost complete

– 33 enrolled– 4 patients being screened

Questions

• Is the response rate of these sarcoma subtypes adequate to justify further study?

• What is the Mechanism of action.

• Does stable disease serve as a valid surrogate for improved survival.

Participants (12) / Enrollment (59)

MD Anderson – 13– Dejka Araujo, MD

Penn – 12– Arthur Staddon, MD

Sarcoma Oncology – 11– Sant Chawla, MD

MSKCC - 8– Robert Maki, MD

Michigan - 5– Scott Schuetze, MD

Mass General – 5– Edwin Choy, MD

Fox Chase – 2– Margaret von Mehren, MD

Washington Cancer – 2– Dennis Priebat, MD

OHSU – 1– Christopher Ryan, MD

Others Open:

DFCI, Moffitt, UFL

Extra-Skeletal MyxoidChondrosarcoma - 15

ConventionalChondrosarcoma - 33

Alveolar Soft PartSarcoma - 11

Increased reliance upon imaging

0 3 6 9 12 15

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ize

Estimated ***

Actual

Calculated delta