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

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.

Study Overview

• Status: Completed
• Conditions: Sarcoma
• Intervention / Treatment: Drug: temsirolimus plus liposomal doxorubicin

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.

• Study Type: Interventional
• Enrollment (Actual): 24
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • Maryland
    • Baltimore, Maryland, United States, 21231
      • Johns Hopkins University

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 1 year and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

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

Drug: temsirolimus 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.; Other Names: Doxil; Torisel

What is the study measuring?

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

Collaborators and Investigators

• Sponsor: Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
• Collaborators: Wyeth is now a wholly owned subsidiary of Pfizer; National Comprehensive Cancer Network
• Investigators: Principal Investigator: David M Loeb, MD, PhD, Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins

Publications and helpful links

General Publications

• 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.
• 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.

Study record dates

Study Major Dates

• Study Start: September 1, 2009
• Primary Completion (Actual): September 1, 2012
• Study Completion (Actual): September 1, 2012

Study Registration Dates

• First Submitted: July 28, 2009
• First Submitted That Met QC Criteria: July 29, 2009
• First Posted (Estimate): July 30, 2009

Study Record Updates

• Last Update Posted (Actual): March 11, 2019
• Last Update Submitted That Met QC Criteria: March 8, 2019
• Last Verified: March 1, 2019

More Information

Terms related to this study

• Keywords: osteosarcoma; chondrosarcoma; rhabdomyosarcoma; leiomyosarcoma; soft tissue sarcoma; Ewing's sarcoma; liposarcoma; synovial sarcoma; malignant fibrous histiocytoma; malignant peripheral nerve sheath tumor; pleiomorphic sarcoma; spindle cell sarcoma; cancer stem cell
• Additional Relevant MeSH Terms: Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Sarcoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Enzyme Inhibitors; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Anti-Bacterial Agents; Antibiotics, Antineoplastic; Antifungal Agents; Doxorubicin; Liposomal doxorubicin; Sirolimus
• Other Study ID Numbers: J0963; NA_00028490 (Other Identifier: JHMI-IRB)