Sarcoma
Conditions
Keywords
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
Brief summary
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
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.
Interventions
DRUGtemsirolimus plus 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.
Sponsors
National Comprehensive Cancer Network
Wyeth is now a wholly owned subsidiary of Pfizer
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
1 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Part 1: Incidence of Dose Limiting Toxicities | End of second 28-day cycle | Dose limiting toxicities in each dose cohort. |
| Part 2: Median Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | up to 5 years | Number of days from day 1 of treatment until date of death from any cause. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Maximum Observed Plasma Concentration (Cmax) | 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 |
| Area Under the Curve (AUC) | 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. | AUC was calculated using a single compartment model. |
| Drug Clearance | 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. |
| Mean Progression Free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | up to 3 years | 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 |
| Median Progression-free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | up to 3 years | 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. |
| Time to Response | up to 5 years | Number of days after 2 cycles of treatment, until maximal response is observed. |
| Duration of Response | up to 5 years | Number of days until documentation of disease progression or date of death from other cause |
| Clinical Benefit Rate | up to 5 years | Number of days from documented improvement to disease progression. |
| Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | up to 5 years | — |
| Objective Response Rate | up to 5 years | 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 |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Temsirolimus Plus Liposomal Doxorubicin 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. | 24 |
| Total | 24 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 |
|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 2 | 0 |
Baseline characteristics
| Characteristic | Temsirolimus Plus Liposomal Doxorubicin |
|---|---|
| Age, Categorical <=18 years | 5 Participants |
| Age, Categorical >=65 years | 2 Participants |
| Age, Categorical Between 18 and 65 years | 17 Participants |
| Age, Continuous | 39.5 years |
| Region of Enrollment United States | 24 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 10 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 13 / 24 |
| serious Total, serious adverse events | 7 / 24 |
Outcome results
Primary
Part 1: Incidence of Dose Limiting Toxicities
Dose limiting toxicities in each dose cohort.
Time frame: End of second 28-day cycle
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Part 1: Incidence of Dose Limiting Toxicities | Temsirolimus 15 mg/m^2 | 1 participants |
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Part 1: Incidence of Dose Limiting Toxicities | Temsirolimus 20 mg/m^2 | 4 participants |
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Part 1: Incidence of Dose Limiting Toxicities | Temsirolimus 27 mg/m^2 | 3 participants |
Primary
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.
Time frame: up to 5 years
Population: The number of analyzed participants does not include the 2 participants treated at the MTD who stopped treatment for early disease-related adverse events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Part 2: Median Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | 254 days |
Secondary
Area Under the Curve (AUC)
AUC was calculated using a single compartment model.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Area Under the Curve (AUC) | 1210 ng*hr/ml | Standard Deviation 340 |
| Sirolimus- Active Metabolite | Area Under the Curve (AUC) | 7499 ng*hr/ml | Standard Deviation 4591.1 |
Secondary
Clinical Benefit Rate
Number of days from documented improvement to disease progression.
Time frame: up to 5 years
Population: 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.
Secondary
Drug Clearance
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS.
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Drug Clearance | 17.8 L/hr/m2 | Standard Deviation 7.1 |
| Sirolimus- Active Metabolite | Drug Clearance | NA L/hr/m2 | — |
Secondary
Duration of Response
Number of days until documentation of disease progression or date of death from other cause
Time frame: up to 5 years
Population: 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.
Secondary
Maximum Observed Plasma Concentration (Cmax)
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS
Time frame: 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.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Maximum Observed Plasma Concentration (Cmax) | 346.2 mg/mL | Standard Deviation 250 |
| Sirolimus- Active Metabolite | Maximum Observed Plasma Concentration (Cmax) | 69.6 mg/mL | Standard Deviation 23.2 |
Secondary
Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
Time frame: up to 5 years
Population: 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.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | 632 Days |
Secondary
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
Time frame: up to 3 years
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Mean Progression Free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | 195 Days |
Secondary
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.
Time frame: up to 3 years
Population: The number of analyzed participants does not include the 2 participants treated at the MTD who stopped treatment for early disease-related adverse events.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Median Progression-free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2 | 74 days |
Secondary
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
Time frame: up to 5 years
Population: Only participants who completed at least 2 treatment cycles (14/18 participants) were included to assess this outcome measure.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Objective Response Rate | CR | 0 Participants |
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Objective Response Rate | PR | 1 Participants |
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Objective Response Rate | SD | 8 Participants |
| Number of Subjects Who Experienced Dose-Limiting Toxicities | Objective Response Rate | PD | 5 Participants |
Secondary
Time to Response
Number of days after 2 cycles of treatment, until maximal response is observed.
Time frame: up to 5 years
Population: 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.