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

To determine the maximum tolerated dose (MTD) and toxicity profile of combination temsirolimus and irinotecan both administered intravenously on a weekly basis.

To determine antitumor activity of this combination of drugs in refractory soft tissue sarcoma.

• Drug: irinotecan, temsirolimus
  This is a single arm, non-randomized phase I/II trial of temsirolimus and irinotecan. Successive groups of 3 patients will be entered at escalating dose levels. Irinotecan and temsirolimus will be repeated weekly x 3 doses followed by one week of rest.
  Other Name: INST 0909, irinotecan, temsirolimus,
• Drug: Temsirolimus and Irinotecan
  Other Names:

  • Temsirolimus
  • Irinotecan

• Experimental: Arm 1 Level 1
  Irinotecan at 80 mg/m2 weekly x3 Level 1: Temsirolimus 15 mg weekly x3
  Intervention: Drug: irinotecan, temsirolimus
• Experimental: Arm 1 Level 2
  Irinotecan at 80 mg/m2 weekly x3 Level 2: Temsirloimus 20 mg weekly x3
  Intervention: Drug: irinotecan, temsirolimus
• Experimental: Arm 1 Level 3
  Irinotecan at 80 mg/m2 weekly x3 Level 3 Temsirolimus 25 mg weekly x3
  Intervention: Drug: irinotecan, temsirolimus
• Experimental: Arm 2 Level 1
  Temsirolimus 25 mg weekly x3 Level 1 Irinotecan 50 mg/m2 weekly x3
  Intervention: Drug: Temsirolimus and Irinotecan
• Experimental: Amr 2 Level 2
  Temsirolimus 25 mg weekly x3 Level 2 Irinotecan 65 mg/m2 weekly x3
  Intervention: Drug: Temsirolimus and Irinotecan
• Experimental: Arm 2 Level 3
  Temsirolimus 25 mg weekly x3 Level 3 Irinotecan 80 mg/m2 weekly x3
  Intervention: Drug: Temsirolimus and Irinotecan

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 via 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 SGOT or 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.