Safety and Efficacy Study of Torisel and Liposomal Doxorubicin for Patients With Recurrent Sarcoma

Study Overview
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Brief Summary
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The purpose of this study is to identify a safe dosing regimen for the combination of Torisel and liposomal doxorubicin in patients with recurrent sarcoma. A secondary purpose of the study is to determine how effective this combination is for the treatment of recurrent sarcoma.

Detailed Description
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The effectiveness of treatments for recurrent sarcomas is quite limited. One hypothesis to explain the refractory nature of recurrent sarcomas is the existence of chemotherapy-resistant sarcoma stem cells.

Official Title
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Phase I/II Trial of Torisel and Liposomal Doxorubicin in Patients With Advanced Soft Tissue and Bone Sarcomas

Conditions
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Sarcoma

Intervention / Treatment
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* Drug: temsirolimus plus liposomal doxorubicin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically confirmed sarcoma that is recurrent or refractory to conventional treatment Measurable disease by RECIST criteria ECOG (Eastern Cooperative Oncology Group) performance status < 2 (or Lansky/Karnofsky > 60% for children) Life expectancy greater than 3 months Adequate organ function absolute neutrophil count at least 1,500 platelets at least 100,000 bilirubin less than 1.5 x upper limit of normal AST (aspartate aminotransferase) and ALT(alanine aminotransferase) less than 2.5 x upper limit of normal creatinine less than 1.5 x upper limit of normal OR creatinine clearance at least 60 ml/min/1.73 m2 fasting serum cholesterol less than 350 fasting serum triglycerides less than 400 PT (prothrombin) or INR (international normalized ratio) less than 1.3 x upper limit of normal normal urinalysis Ability to understand and sign the informed consent document Exclusion Criteria: Prior chemotherapy or radiotherapy within 3 weeks of entering the study (6 weeks for nitrosoureas or mitomycin C) Prior treatment with a tyrosine kinase inhibitor within 10 days of entering the study History of pulmonary hypertension or pneumonitis Patients may not be receiving other investigational agents Prior therapy with rapamycin, rapamycin analogues, or tacrolimus Uncontrolled brain metastases History of grade 3 or 4 hypersensitivity to macrolide antibiotics Concurrent treatment with immunosuppressive agents other than a stable (for more than 2 weeks) dose of corticosteroids Uncontrolled intercurrent illness Pregnancy or breast feeding HIV-positive patients on combination antiretroviral therapy Grade 3 or 4 proteinuria

Ages Eligible for Study
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Minimum Age: 1 Year

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: temsirolimus plus liposomal doxorubicin<br>Single arm study: Dose escalation of temsirolimus plus constant dose of liposomal doxorubicin. | Drug: temsirolimus plus liposomal doxorubicin<br>* Patients were treated with temsirolimus (Torisel) weekly by IV and with liposomal doxorubicin (Doxil) (standard dose) by IV once every 28 days. Cohorts of patients receive sequentially increasing dose of temsirolimus until dose limiting toxicity (DLT) occurred and the maximally tolerated dose (MTD) was identified. The MTD dose was the standard dose of temsirolimus used for the remainder of the study. Dose modifications were based on protocol parameters for toxicities.<br>* Other names: Doxil;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Part 1: Incidence of Dose Limiting Toxicities | Dose limiting toxicities in each dose cohort. | End of second 28-day cycle | 
| Part 2: Median Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | Number of days from day 1 of treatment until date of death from any cause. | up to 5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Median Progression-free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | Interval from Date of start of treatment to date of disease progression or death from any cause. Disease progression is defined as at least 20% increase in sum of longest diameter of target lesions or appearance of any new lesions. Subjective determination of significant worsening of disease-related symptoms was considered clinical disease progression. | up to 3 years | 
| Objective Response Rate | Number of participants who completed at least 2 treatment cycles with evidence of response. Response is defined by Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.0) for target lesions and assessed by MRI: Complete Response (CR), Disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; Progression, as a 20% increase in the sum of the longest diameter of target lesions, or a measurable increase in a non-target lesion, or the appearance of new lesions; Stable Disease (SD), neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for disease progression | up to 5 years | 
| Maximum Observed Plasma Concentration (Cmax) | Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS | Prior to the initial dose on day 1, then 2, 6, and 24 hours post dose; prior to first dose of Cycle 2, then at 1, 2, 6, 24, 96, and 120 hours post dose in patients treated at the recommended phase 2 dose, Dose Level 4. | 
| Area Under the Curve (AUC) | AUC was calculated using a single compartment model. | Prior to the initial dose on day 1, then 2, 6, and 24 hours post dose; prior to first dose of Cycle 2, then at 1, 2, 6, 24, 96, and 120 hours post dose in patients treated at the recommended phase 2 dose, Dose Level 4. | 
| Drug Clearance | Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. | Prior to the initial dose on day 1, then 2, 6, and 24 hours post dose; prior to first dose of Cycle 2, then at 1, 2, 6, 24, 96, and 120 hours post dose in patients treated at the recommended phase 2 dose, Dose Level 4. | 
| Mean Progression Free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | Interval from start of treatment to disease progression or death from any cause. Disease progression is defined as at least 20% increase in sum of longest diameter of target lesions or appearance of any new lesions. Subjective determination of significant worsening of disease-related symptoms was considered clinical disease progression | up to 3 years | 
| Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 |  | up to 5 years | 
| Time to Response | Number of days after 2 cycles of treatment, until maximal response is observed. | up to 5 years | 
| Duration of Response | Number of days until documentation of disease progression or date of death from other cause | up to 5 years | 
| Clinical Benefit Rate | Number of days from documented improvement to disease progression. | up to 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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osteosarcoma, soft tissue sarcoma, rhabdomyosarcoma, leiomyosarcoma, Ewing's sarcoma, chondrosarcoma, liposarcoma, malignant fibrous histiocytoma, malignant peripheral nerve sheath tumor, pleiomorphic sarcoma, spindle cell sarcoma, synovial sarcoma, cancer stem cell