Trial Outcomes & Findings for Safety and Efficacy Study of Torisel and Liposomal Doxorubicin for Patients With Recurrent Sarcoma (NCT NCT00949325)
NCT ID: NCT00949325
Last Updated: 2019-03-11
Results Overview
Dose limiting toxicities in each dose cohort.
Recruitment status
COMPLETED
Study phase
PHASE1/PHASE2
Target enrollment
24 participants
Primary outcome timeframe
End of second 28-day cycle
Results posted on
2019-03-11
Participant Flow
Participant milestones
| Measure |
Cohort 1, Dose Level 3
Temsirolimus 15 mg/m\^2
|
Cohort 2, Dose Level 4
Temsirolimus 20 mg/m\^2;
|
Cohort 3, Dose Level 5
Temsirolimus 27mg/m\^2
|
|---|---|---|---|
|
Overall Study
STARTED
|
3
|
18
|
3
|
|
Overall Study
COMPLETED
|
3
|
16
|
3
|
|
Overall Study
NOT COMPLETED
|
0
|
2
|
0
|
Reasons for withdrawal
| Measure |
Cohort 1, Dose Level 3
Temsirolimus 15 mg/m\^2
|
Cohort 2, Dose Level 4
Temsirolimus 20 mg/m\^2;
|
Cohort 3, Dose Level 5
Temsirolimus 27mg/m\^2
|
|---|---|---|---|
|
Overall Study
Adverse Event
|
0
|
2
|
0
|
Baseline Characteristics
Safety and Efficacy Study of Torisel and Liposomal Doxorubicin for Patients With Recurrent Sarcoma
Baseline characteristics by cohort
| Measure |
Temsirolimus Plus Liposomal Doxorubicin
n=24 Participants
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.
|
|---|---|
|
Age, Categorical
<=18 years
|
5 Participants
n=99 Participants
|
|
Age, Categorical
Between 18 and 65 years
|
17 Participants
n=99 Participants
|
|
Age, Categorical
>=65 years
|
2 Participants
n=99 Participants
|
|
Age, Continuous
|
39.5 years
n=99 Participants
|
|
Sex: Female, Male
Female
|
14 Participants
n=99 Participants
|
|
Sex: Female, Male
Male
|
10 Participants
n=99 Participants
|
|
Region of Enrollment
United States
|
24 participants
n=99 Participants
|
PRIMARY outcome
Timeframe: End of second 28-day cycleDose limiting toxicities in each dose cohort.
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=24 Participants
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.
|
Sirolimus- Active Metabolite
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Part 1: Incidence of Dose Limiting Toxicities
Temsirolimus 15 mg/m^2
|
1 participants
|
—
|
|
Part 1: Incidence of Dose Limiting Toxicities
Temsirolimus 20 mg/m^2
|
4 participants
|
—
|
|
Part 1: Incidence of Dose Limiting Toxicities
Temsirolimus 27 mg/m^2
|
3 participants
|
—
|
PRIMARY outcome
Timeframe: up to 5 yearsPopulation: The number of analyzed participants does not include the 2 participants treated at the MTD who stopped treatment for early disease-related adverse events.
Number of days from day 1 of treatment until date of death from any cause.
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=16 Participants
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.
|
Sirolimus- Active Metabolite
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Part 2: Median Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
|
254 days
Interval 50.0 to 1532.0
|
—
|
SECONDARY outcome
Timeframe: up to 3 yearsPopulation: The number of analyzed participants does not include the 2 participants treated at the MTD who stopped treatment for early disease-related adverse events.
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.
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=16 Participants
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.
|
Sirolimus- Active Metabolite
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Median Progression-free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
|
74 days
Interval 7.0 to 797.0
|
—
|
SECONDARY outcome
Timeframe: up to 5 yearsPopulation: Only participants who completed at least 2 treatment cycles (14/18 participants) were included to assess this outcome measure.
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
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=14 Participants
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.
|
Sirolimus- Active Metabolite
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Objective Response Rate
CR
|
0 Participants
|
—
|
|
Objective Response Rate
PR
|
1 Participants
|
—
|
|
Objective Response Rate
SD
|
8 Participants
|
—
|
|
Objective Response Rate
PD
|
5 Participants
|
—
|
SECONDARY outcome
Timeframe: 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.Population: 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.
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=7 Participants
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.
|
Sirolimus- Active Metabolite
n=7 Participants
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Maximum Observed Plasma Concentration (Cmax)
|
346.2 mg/mL
Standard Deviation 250
|
69.6 mg/mL
Standard Deviation 23.2
|
SECONDARY outcome
Timeframe: 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.Population: 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.
AUC was calculated using a single compartment model.
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=7 Participants
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.
|
Sirolimus- Active Metabolite
n=7 Participants
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Area Under the Curve (AUC)
|
1210 ng*hr/ml
Standard Deviation 340
|
7499 ng*hr/ml
Standard Deviation 4591.1
|
SECONDARY outcome
Timeframe: 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.Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS.
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=7 Participants
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.
|
Sirolimus- Active Metabolite
n=7 Participants
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Drug Clearance
|
17.8 L/hr/m2
Standard Deviation 7.1
|
NA L/hr/m2
Standard Deviation NA
Values are not available. Drug clearance was not assessed in the Sirolimus-Active Metabolite arm.
|
SECONDARY outcome
Timeframe: up to 3 yearsInterval 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
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=16 Participants
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.
|
Sirolimus- Active Metabolite
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Mean Progression Free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
|
195 Days
Interval 7.0 to 797.0
|
—
|
SECONDARY outcome
Timeframe: up to 5 yearsPopulation: 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.
Outcome measures
| Measure |
Number of Subjects Who Experienced Dose-Limiting Toxicities
n=16 Participants
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.
|
Sirolimus- Active Metabolite
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS. Cmax of Sirolimus was calculated using a non-compartmental model.
|
|---|---|---|
|
Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
|
632 Days
Interval 50.0 to 1532.0
|
—
|
SECONDARY outcome
Timeframe: up to 5 yearsPopulation: 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.
Number of days after 2 cycles of treatment, until maximal response is observed.
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: up to 5 yearsPopulation: 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.
Number of days until documentation of disease progression or date of death from other cause
Outcome measures
Outcome data not reported
SECONDARY outcome
Timeframe: up to 5 yearsPopulation: 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.
Number of days from documented improvement to disease progression.
Outcome measures
Outcome data not reported
Adverse Events
Temsirolimus Plus Liposomal Doxorubicin
Serious events: 7 serious events
Other events: 13 other events
Deaths: 0 deaths
Serious adverse events
| Measure |
Temsirolimus Plus Liposomal Doxorubicin
n=24 participants at risk
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.
|
|---|---|
|
Respiratory, thoracic and mediastinal disorders
Dyspnea
|
8.3%
2/24 • Number of events 2
|
|
Respiratory, thoracic and mediastinal disorders
pneumothorax
|
4.2%
1/24 • Number of events 1
|
|
Respiratory, thoracic and mediastinal disorders
Plural effusion
|
8.3%
2/24 • Number of events 2
|
|
General disorders
Respiratory failure
|
8.3%
2/24 • Number of events 2
|
|
Gastrointestinal disorders
Anorexia
|
4.2%
1/24 • Number of events 1
|
|
Infections and infestations
Fever and chills
|
4.2%
1/24 • Number of events 1
|
Other adverse events
| Measure |
Temsirolimus Plus Liposomal Doxorubicin
n=24 participants at risk
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.
|
|---|---|
|
Blood and lymphatic system disorders
Neutropenia
|
20.8%
5/24 • Number of events 5
|
|
Blood and lymphatic system disorders
anemia
|
4.2%
1/24 • Number of events 1
|
|
Blood and lymphatic system disorders
Thrombocytopenia
|
8.3%
2/24 • Number of events 2
|
|
Metabolism and nutrition disorders
Hypokalemia
|
8.3%
2/24 • Number of events 2
|
|
Metabolism and nutrition disorders
Hypocalcemia
|
4.2%
1/24 • Number of events 1
|
|
Hepatobiliary disorders
Elevated transaminases
|
8.3%
2/24 • Number of events 2
|
|
Metabolism and nutrition disorders
Hyperlipedemia
|
4.2%
1/24 • Number of events 1
|
|
Gastrointestinal disorders
Stomatitis
|
8.3%
2/24 • Number of events 2
|
|
Hepatobiliary disorders
Pancreatitis
|
4.2%
1/24 • Number of events 1
|
Additional Information
Results disclosure agreements
- Principal investigator is a sponsor employee
- Publication restrictions are in place