Transcript A Phase II Trial of Perifosine in Patients with Chemo

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, extraskeletal 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 patient’s 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
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At least 13 years of age
Patients must have measurable disease
Life expectancy of more than 3 months.
Normal organ and marrow function
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 patient’s 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
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Sant Chawla, MD
– Century City Hospital
Gina D’Amatto, 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
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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