Joseph Ludwig, MD MD Anderson Cancer Center, Houston, TX
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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
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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)
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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
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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)
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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
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Major Inclusion / Exclusion
Inclusion– Measurable Disease– Age > 13 years– ** Documented progression by Choi Criteria
• Exclusion– > 2 prior cytotoxic regimens for metastatic
disease (unless exempted)
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Study Population – 59 Patients
• Gender: 35 Male / 24 Female
• Median age: 51 (range 20 – 85)
• Cycles on Treatment (1 – 9 cycles)
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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
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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
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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%
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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)
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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
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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
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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.
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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
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Increased reliance upon imaging
0 3 6 9 12 15
Tu
mo
r S
ize
Estimated ***
Actual
Calculated delta