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

Primary Purpose

Sarcoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
temsirolimus plus liposomal doxorubicin
Sponsored by
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Sarcoma focused on measuring 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

Eligibility Criteria

1 Year - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • Johns Hopkins University

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

temsirolimus plus liposomal doxorubicin

Arm Description

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

Outcomes

Primary Outcome Measures

Part 1: Incidence of Dose Limiting Toxicities
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
Number of days from day 1 of treatment until date of death from any cause.

Secondary Outcome Measures

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.
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
Maximum Observed Plasma Concentration (Cmax)
Whole blood temsirolimus and sirolimus levels were measured by LC/MS/MS
Area Under the Curve (AUC)
AUC was calculated using a single compartment model.
Drug Clearance
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
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
Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
Time to Response
Number of days after 2 cycles of treatment, until maximal response is observed.
Duration of Response
Number of days until documentation of disease progression or date of death from other cause
Clinical Benefit Rate
Number of days from documented improvement to disease progression.

Full Information

First Posted
July 28, 2009
Last Updated
March 8, 2019
Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Comprehensive Cancer Network, Wyeth is now a wholly owned subsidiary of Pfizer
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1. Study Identification

Unique Protocol Identification Number
NCT00949325
Brief Title
Safety and Efficacy Study of Torisel and Liposomal Doxorubicin for Patients With Recurrent Sarcoma
Official Title
Phase I/II Trial of Torisel and Liposomal Doxorubicin in Patients With Advanced Soft Tissue and Bone Sarcomas
Study Type
Interventional

2. Study Status

Record Verification Date
March 2019
Overall Recruitment Status
Completed
Study Start Date
September 2009 (undefined)
Primary Completion Date
September 2012 (Actual)
Study Completion Date
September 2012 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Collaborators
National Comprehensive Cancer Network, Wyeth is now a wholly owned subsidiary of Pfizer

4. Oversight

Data Monitoring Committee
No

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Sarcoma
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

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
24 (Actual)

8. Arms, Groups, and Interventions

Arm Title
temsirolimus plus liposomal doxorubicin
Arm Type
Experimental
Arm Description
Single arm study: Dose escalation of temsirolimus plus constant dose of liposomal doxorubicin.
Intervention Type
Drug
Intervention Name(s)
temsirolimus plus liposomal doxorubicin
Other Intervention Name(s)
Torisel, Doxil
Intervention Description
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.
Primary Outcome Measure Information:
Title
Part 1: Incidence of Dose Limiting Toxicities
Description
Dose limiting toxicities in each dose cohort.
Time Frame
End of second 28-day cycle
Title
Part 2: Median Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
Description
Number of days from day 1 of treatment until date of death from any cause.
Time Frame
up to 5 years
Secondary Outcome Measure Information:
Title
Median Progression-free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
Description
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
Title
Objective Response Rate
Description
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
Title
Maximum Observed Plasma Concentration (Cmax)
Description
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.
Title
Area Under the Curve (AUC)
Description
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.
Title
Drug Clearance
Description
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.
Title
Mean Progression Free Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
Description
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
Title
Mean Overall Survival of Subjects Who Were Treated at the Temsirolimus MTD, 20 mg/m^2
Time Frame
up to 5 years
Title
Time to Response
Description
Number of days after 2 cycles of treatment, until maximal response is observed.
Time Frame
up to 5 years
Title
Duration of Response
Description
Number of days until documentation of disease progression or date of death from other cause
Time Frame
up to 5 years
Title
Clinical Benefit Rate
Description
Number of days from documented improvement to disease progression.
Time Frame
up to 5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
1 Year
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
David M Loeb, MD, PhD
Organizational Affiliation
Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
Official's Role
Principal Investigator
Facility Information:
Facility Name
Johns Hopkins University
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21231
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
23382028
Citation
Thornton KA, Chen AR, Trucco MM, Shah P, Wilky BA, Gul N, Carrera-Haro MA, Ferreira MF, Shafique U, Powell JD, Meyer CF, Loeb DM. A dose-finding study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcoma. Int J Cancer. 2013 Aug 15;133(4):997-1005. doi: 10.1002/ijc.28083. Epub 2013 Mar 4.
Results Reference
result
PubMed Identifier
30410720
Citation
Trucco MM, Meyer CF, Thornton KA, Shah P, Chen AR, Wilky BA, Carrera-Haro MA, Boyer LC, Ferreira MF, Shafique U, Powell JD, Loeb DM. A phase II study of temsirolimus and liposomal doxorubicin for patients with recurrent and refractory bone and soft tissue sarcomas. Clin Sarcoma Res. 2018 Nov 5;8:21. doi: 10.1186/s13569-018-0107-9. eCollection 2018.
Results Reference
derived

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

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