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Single arm study: Dose escalation of temsirolimus plus constant dose of liposomal doxorubicin.

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.

temsirolimus plus liposomal doxorubicin

David M Loeb, MD, PhD

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.

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.

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

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

Dose limiting toxicities in each dose cohort.

Number of days from day 1 of treatment until date of death from any cause.

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.

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

Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS

AUC was calculated using a single compartment model.

Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS.

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

Number of days after 2 cycles of treatment, until maximal response is observed.

Number of days until documentation of disease progression or date of death from other cause

Number of days from documented improvement to disease progression.

National Comprehensive Cancer Network

Wyeth is now a wholly owned subsidiary of Pfizer

Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Single arm consists of temsirolimus (Torisel) plus liposomal doxorubicin (Doxil). Temsirolimus is administered IV in sequentially escalating cohorts at doses between 15 and 50 mg/M2 (body surface area), once weekly. Liposomal doxorubicin is administered IV at 30 mg per M2 (body surface area) once every 28 days. Treatment may continue with both drugs for 2 years. Temsirolimus may continue beyond 2 years.

temsirolimus plus liposomal doxorubicin: Patients will be treated with temsirolimus (Torisel) temsirolimus 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 maximally tolerated dose (MTD) is reached. Once MTD (standard dose) is achieved, dosing will be with standard doses for each drug, but dosing will be modified based on toxicity.

Temsirolimus Plus Liposomal Doxorubicin

Age, Categorical

Age, Continuous

Sex: Female, Male

United States

Region of Enrollment

David M. Loeb, M.D., Ph.D.

Temsirolimus 15 mg/m^2

Temsirolimus 20 mg/m^2

Temsirolimus 27 mg/m^2

Number of Subjects Who Experienced Dose-Limiting Toxicities

Part 1: Incidence of Dose Limiting Toxicities

Subjects who received Temsirolimus MTD, 20 mg/m\^2 in Phase I of the study and all subjects in the Phase II study were included. from both Phase I and Phase II of the study are included.

Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2

The number of analyzed participants does not include the 2 participants treated at the MTD who stopped treatment for early disease-related adverse events.

Part 2: Median Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2

Subjects who received Temsirolimus MTD, 20 mg/m\^2 in Phase I of the study and all subjects in the Phase II study were included from both Phase I and Phase II of the study who were not taken off study for early toxicity were included. Two of the eighteen subjects who were treated at the MTD were excluded.

Median Progression-free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2

Subjects who completed at least 2 cycles of treatment with temsirolimus dose of 20 mg/m\^2 or 27 mg/m\^2 were assessed for radiologic response.

Temsirolimus 20 mg/m^2 and 27 mg/m^2

Only participants who completed at least 2 treatment cycles (14/18 participants) were included to assess this outcome measure.

Objective Response Rate

Temsirolimus- Parent Drug

Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.

Sirolimus- Active Metabolite

Seven subjects had complete series of blood samples available for evaluation for both Temsirolimus, the parent drug and Sirolimus, the active metabolite. The number (N) evaluable participants is less than the number of participants from whom samples were collected due to inadvertent processing mishaps.

Maximum Observed Plasma Concentration (Cmax)

Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. AUC was calculated using a single compartment model.

Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. AUC was calculated using a single non- compartment model.

Seven subjects had complete series of blood samples available for evaluation for both Temsirolimus, the parent drug and Sirolimus, the active metabolite. The analysis was per protocol. The number (N) evaluable samples is less than the number of collected samples due to inadvertent processing mishaps.

Area Under the Curve (AUC)

Clearance was calculated using a single compartment model.

Drug Clearance

All subjects who received at least one dose of temsirolimus at the MTD, 20 mg/M\^2 plus liposomal doxorubicin were included.

Subjects Who Received Temsirolimus MTD, 20 mg/m^2

Mean Progression Free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2

Subjects who received Temsirolimus MTD, 20 mg/m\^2 in Phase I of the study and all subjects in the Phase II study were included from both Phase I and Phase II of the study are included.

Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2

Although the original protocol specified that "time to maximal response" would be an outcome measure that would be obtained, appropriate data were not collected, so this outcome measure cannot be evaluated or reported.

Time to Response

Although the original protocol specified that "duration of response" would be an outcome measure that would be obtained, appropriate data were not collected, so this outcome measure cannot be evaluated or reported.

Duration of Response

Although the original protocol specified that "clinical benefit rate" would be an outcome measure that would be obtained, appropriate data were not collected, so this outcome measure cannot be evaluated or reported.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
Safety and Efficacy Study of Torisel and Liposomal Doxorubicin for Patients With Recurrent Sarcoma	NCT00949325	Sarcoma	temsirolimus pl...	1 Year -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Safety and Efficacy Study of Torisel and Liposomal Doxorubicin for Patients With Recurrent Sarcoma	NCT00949325	Sarcoma	temsirolimus pl...	1 Year -	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

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