Phase I/II Study of Irinotecan and Temsirolimus in Patients With Refractory Sarcomas

Mammalian target of rapamycin (mTOR) inhibitors are anti-neoplastic agents with a wide
potential range of clinical applications. The topoisomerase I inhibitor irinotecan is a
potent DNA damaging drug. mTOR appears to enhance cancer cell survival following DNA damage,
so it's reasonable to expect that mTOR inhibition combined with irinotecan may result in
synergistic activity.

This is a single arm, non-randomized phase I trial of temsirolimus (an mTOR inhibitor) and
irinotecan (a topoisomerase I inhibitor) in refractory soft tissue sarcoma patients.
Successive groups of three patients will be entered at escalating dose levels. Irinotecan
and temsirolimus will be administered weekly for three weeks followed by one week of rest.
One course will therefore be four weeks. No intra-patient dose escalation will be allowed.
Each patient will be treated until disease progression or intolerable side effects develop.
Dose limiting toxicities will be assessed and the maximum tolerated dose will be reported.

Note that this trial was originally designed as a phase I/II study, but only the phase I
portion was completed and will be reported.

Inclusion Criteria:

- All patients, 10 years of age or older with biopsy proven advanced soft tissue
sarcoma, who have failed at least one prior treatment for metastatic disease are
eligible if there is measurable or evaluable disease per Response Evaluation Criteria
In Solid Tumors (RECIST).

- Patients must have a life expectancy of at least 12 weeks.

- Prior surgery or radiotherapy for primary tumor is acceptable but must be completed
at least 4 weeks from study entry, and patient should have completely recovered from
such procedures.

- Patients must have a Zubrod performance status of 0-2.

- Patients (or their legal guardian) must sign an informed consent.

- Patients should have adequate bone marrow function defined by an absolute peripheral
granulocyte count of ≥ 1500 cells/mm3, hemoglobin > 8 g/dl, platelet count ≥ 100
000/mm3 and absence of a regular red blood cell transfusion requirement.

- Patients should have a normal hepatic function with a total bilirubin < the upper
limit of normal and Serum glutamic oxaloacetic transaminase (SGOT) or Serum glutamic
pyruvic transaminase (SGPT) < 2 times the upper limit of normal, and adequate renal
function as defined by a serum creatinine ≤ 1.5 upper limit of normal.

- Fasting total cholesterol level < 350 mg/dL and triglyceride level < 400 mg/dL is
required.

- Women of childbearing potential must have a negative pregnancy test.

- Men and women of childbearing potential must be willing to consent to using effective
contraception while on treatment and at least for 3 months.

Patients with brain metastases are eligible if they have been appropriately treated,are
asymptomatic and no longer require corticosteroids.

Exclusion Criteria:

- Pregnant women or nursing mothers are not eligible.

- Patients must not receive any other concurrent chemotherapy or radiation during this
trial.

- Patients with severe medical illnesses such as uncontrolled diabetes, active
infections, or uncontrolled psychiatric illnesses are not eligible.

- Patients with known hypersensitivity to temsirolimus or sirolimus, receiving
concomitant antitumor therapy, or anticonvulsant therapy, or cardiac antiarrhythmic
drugs are not eligible.