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

Study Overview
=================
Brief Summary
-----------------
Refractory soft tissue sarcoma remains a difficult malignancy to treat. The mammalian target of rapamycin (mTOR) is an enzyme that plays an important role in cancer cell survival. mTOR inhibitors, like temsirolimus, have shown activity in sarcoma. Irinotecan is a chemotherapy drug that has also been used to treat sarcoma. However, it is unknown whether combining these two drugs would result in improved efficacy with acceptable toxicity. Therefore, the goal of this phase I study is to determine the maximum tolerated dose (MTD) and toxicity profile of combination temsirolimus and irinotecan both administered intravenously on a weekly basis to refractory soft tissue sarcoma patients.

Detailed Description
-----------------
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.

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

Conditions
-----------------
Sarcoma

Intervention / Treatment
-----------------
* Drug: Irinotecan&Temsirolimus:Arm1, Level 1
* Drug: Irinotecan&Temsirolimus:Arm 1, Level 2
* Drug: Irinotecan&Temsirolimus:Arm 2, Level 1


Participation Criteria
=================
Eligibility Criteria
-----------------
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.

Ages Eligible for Study
-----------------
Minimum Age: 10 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Irinotecan&Temsirolimus:Arm 1, Level 1<br>Arm 1, Level 1: Irinotecan intravenously at 80 mg/m2 + Temsirolimus intravenously at 15 mg on a weekly basis for 3 consecutive doses followed by one week of rest. One cycle is four weeks. | Drug: Irinotecan&Temsirolimus:Arm1, Level 1<br>* Irinotecan is given first over 60 minutes followed by temsirolimus over 30 minutes. No intrapatient dose escalations are allowed. Treatment continues until disease progression or intolerable side effects develop.<br>* Other names: Temsirolimus = Toricel or CCI-779;|
| Experimental: Irinotecan&Temsirolimus:Arm 1, Level 2<br>Arm 1, Level 2: Irinotecan intravenously at 80 mg/m2 + Temsirolimus intravenously at 20 mg on a weekly basis for 3 consecutive doses followed by one week of rest. One cycle is four weeks. | Drug: Irinotecan&Temsirolimus:Arm 1, Level 2<br>* Irinotecan is given first over 60 minutes followed by temsirolimus over 30 minutes. No intrapatient dose escalations are allowed. Treatment continues until disease progression or intolerable side effects develop.<br>* Other names: Temsirolimus = Toricel or CCI-779;|
| Experimental: Irinotecan&Temsirolimus:Arm 2, Level 1<br>Arm 1, Level 2: Irinotecan intravenously at 50 mg/m2 + Temsirolimus intravenously at 25 mg on a weekly basis for 3 consecutive doses followed by one week of rest. One cycle is four weeks. | Drug: Irinotecan&Temsirolimus:Arm 2, Level 1<br>* Irinotecan is given first over 60 minutes followed by temsirolimus over 30 minutes. No intrapatient dose escalations are allowed. Treatment continues until disease progression or intolerable side effects develop.<br>* Other names: Temsirolimus = Toricel or CCI-779;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum Tolerated Dose (MTD) of Irinotecan | The MTD is the dose preceding that at which at least 2 out of 3 patients in the treatment group experience a dose limiting toxicity (DLT). DLT is defined as grade 3 neutropenia on retreatment day, a grade 4 febrile neutropenia, a drug-related grade 3 or 4 non-hematologic toxicity (except fatigue, nausea, vomiting or grade 3 hypersensitivity reaction) or a grade 2 or greater motor or sensory neuropathy | Up to 1 month | 
| Maximum Tolerated Dose (MTD) of Temsirolimus | The MTD is the dose preceding that at which at least 2 out of 3 patients in the treatment group experience a dose limiting toxicity (DLT). DLT is defined as grade 3 neutropenia on retreatment day, a grade 4 febrile neutropenia, a drug-related grade 3 or 4 non-hematologic toxicity (except fatigue, nausea, vomiting or grade 3 hypersensitivity reaction) or a grade 2 or greater motor or sensory neuropathy | Up to 1 month | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
INST 0909, Irinotecan, Temsirolimus, refractory sarcomas, 3066K1, 3066K1-1208, 20091334