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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
Tu
mo
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ize
Estimated ***
Actual
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