Cixutumumab and Doxorubicin Hydrochloride in Treating Patients With Unresectable, Locally Advanced, or Metastatic Soft Tissue Sarcoma

Phase 1

Completed

• Conditions: Adult Synovial Sarcoma; Adult Undifferentiated High Grade Pleomorphic Sarcoma of Bone; Childhood Angiosarcoma; Childhood Desmoplastic Small Round Cell Tumor; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Malignant Peripheral Nerve Sheath Tumor
• Interventions: Biological: Cixutumumab; Drug: Doxorubicin Hydrochloride; Other: Laboratory Biomarker Analysis

• Registration Number: NCT00720174
• Lead Sponsor: National Cancer Institute (NCI)

Brief Summary

This phase I trial is studying the side effects and best dose of cixutumumab given together with doxorubicin hydrochloride and to see how well they work in treating patients with unresectable, locally advanced, or metastatic soft tissue sarcoma. Monoclonal antibodies, such as cixutumumab, can block tumor growth in different ways. Some block the ability of tumor cells to grow and spread. Others find tumor cells and help kill them or carry tumor-killing substances to them. Drugs used in chemotherapy, such as doxorubicin hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving monoclonal antibody cixutumumab together with doxorubicin hydrochloride may kill more tumor cells.

Detailed Description

PRIMARY OBJECTIVES:

I. To collect safety data about the combination of doxorubicin and Cixitumumab and determine if they can be combined with acceptable toxicity at full doses.

SECONDARY OBJECTIVES:

I. To assess the confirmed response rate (CR + PR as defined by RECIST) of patients with locally advanced or metastatic soft tissue sarcoma when treated with combination doxorubicin and Cixitumumab II. To assess the 3 and 6 month progression free survival rate of patients treated with doxorubicin and Cixitumumab.

III. To assess the progression free survival and overall survival of patients treated with doxorubicin and Cixitumumab.

IV. To evaluate changes in left ventricular ejection fraction assessed by MUGA scan after 2, 4 and 6 cycles of therapy compared to baseline.

OUTLINE: This is a multicenter, dose-escalation study of anti-IGF-1R recombinant monoclonal antibody cixutumumab.

Patients receive cixutumumab intravenously (IV) over 1 hour on days 1, 8, and 15 and doxorubicin hydrochloride IV continuously over 44-52 hours beginning on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease may continue to receive cixutumumab in the absence of disease progression or unacceptable toxicity.

Study Timeline

• Study Start: 2008-06
• Study First Submitted: 2008-07-19
• Study First Submitted QC: 2008-07-19
• Study First Posted: 2008-07-22
• Primary Completion: 2013-01
• Status Verified: 2016-05
• Last Update Submitted: 2016-05-16
• Last Update Posted: 2016-05-17

Recruitment & Eligibility

• Status: COMPLETED
• Sex: All
• Target Recruitment: 30

Inclusion Criteria

• Histologically or cytologically confirmed soft tissue sarcoma

  • Unresectable disease
  • Locally advanced or metastatic disease

• The following tumor types are not allowed:

  • Embryonal and alveolar rhabdomyosarcoma
  • Gastrointestinal stromal tumor
  • Alveolar soft part sarcoma
  • Clear cell sarcoma

• Measurable disease, defined as ≥ 1 unidimensionally measurable lesion ≥ 20 mm by conventional techniques or ≥ 10 mm by spiral CT scan

• No more than 1 prior therapy for sarcoma

• No known brain metastases

• ECOG performance status (PS) 0-2 OR Karnofsky PS 60-100%

• ANC ≥ 1,500/µL

• Platelet count ≥ 100,000/µL

• Leukocytes ≥ 3,000/µL

• Total bilirubin ≤ upper limit of normal(ULN)

• AST and ALT ≤ 2.5 times ULN

• Creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min

• Fasting serum glucose < 120 mg/dL OR below ULN

• LVEF ≥ 50% by MUGA scan

• Not pregnant or nursing

• Negative pregnancy test

• Fertile patients must use effective contraception during and for 3 months after the last dose of anti-IGF-1R recombinant monoclonal antibody IMC-A12

• No history of allergic reactions attributed to compounds of similar chemical or biological composition to anti-IGF-1R recombinant monoclonal antibody IMC-A12

• No poorly controlled diabetes mellitus

  • Patients with a history of diabetes mellitus are eligible provided their blood glucose is within normal range and they are on a stable dietary or therapeutic regimen for this condition

• No concurrent uncontrolled illness including, but not limited to, any of the following:

  • Ongoing or active infection
  • Symptomatic congestive heart failure
  • Unstable angina pectoris
  • Cardiac arrhythmia
  • Psychiatric illness or social situation that would preclude compliance with study requirements

• No other concurrent investigational or commercial agents or therapies

• Recovered from all prior therapy

• More than 4 weeks since prior chemotherapy (6 weeks for nitrosoureas or mitomycin C)

• More than 4 weeks since prior major surgery, hormonal therapy (other than replacement), or hormonal therapy

  • No prior radiotherapy to the heart, mediastinum, or chest wall

• No prior anthracycline therapy or anti-IGF-1R therapy

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Exclusion Criteria

Not provided

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Study & Design

• Study Type: INTERVENTIONAL
• Study Design: SINGLE_GROUP

Arm && Interventions

Group	Intervention	Description
Treatment (cixutumumab and doxorubicin hydrochloride)	Cixutumumab	Patients receive cixutumumab IV over 1 hour on days 1, 8, and 15 and doxorubicin hydrochloride IV continuously over 44-52 hours beginning on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease may continue to receive cixutumumab in the absence of disease progression or unacceptable toxicity.
Treatment (cixutumumab and doxorubicin hydrochloride)	Doxorubicin Hydrochloride	Patients receive cixutumumab IV over 1 hour on days 1, 8, and 15 and doxorubicin hydrochloride IV continuously over 44-52 hours beginning on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease may continue to receive cixutumumab in the absence of disease progression or unacceptable toxicity.
Treatment (cixutumumab and doxorubicin hydrochloride)	Laboratory Biomarker Analysis	Patients receive cixutumumab IV over 1 hour on days 1, 8, and 15 and doxorubicin hydrochloride IV continuously over 44-52 hours beginning on day 1. Treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity. Patients with stable or responding disease may continue to receive cixutumumab in the absence of disease progression or unacceptable toxicity.

Primary Outcome Measures

Name	Time	Method
Maximally tolerated dose (MTD) of cixitumumab when administered in a combination regimen with fixed dose doxorubicin hydrochloride, in patients with locally advanced or metastatic soft tissue sarcoma	Up to 2 courses of treatment	The MTD is defined as the dose of Cixitumumab that induces dose-limiting toxicity (DLT) in no more than 20% of patients.

Secondary Outcome Measures

Name	Time	Method
Changes in cardiac function as measured by MUGA scans of the left ventricular ejection fraction	Baseline to 6 courses of treatment
Confirmed response rate (CR + PR) for comparison with doxorubicin treatment in similar historical patient populations	Up to 6 months	The mean response probability with 90% credible interval will be reported for those patients treated at the dose of cixitumumab found to be the MTD.
Overall survival	Until death due to any cause, or loss to follow-up, assessed up to 6 months	Will be estimated using the product-limit method Kaplan and Meier. With point-wise estimates for the 3 and 6-month survival proportions reported with 95% confidence intervals using Greenwood's formula for calculation of the variance.
Progression-free survival	Until documented disease progression or death or loss-to-follow-up, assessed up to 6 months	Will be estimated using the product-limit method Kaplan and Meier. With point-wise estimates for the 3 and 6-month progression-free survival proportions reported with 95% confidence intervals using Greenwood's formula for calculation of the variance.

Trial Locations

Locations (13)

Decatur Memorial Hospital; 🇺🇸 Decatur, Illinois, United States

NorthShore University HealthSystem-Evanston Hospital; 🇺🇸 Evanston, Illinois, United States

Fort Wayne Medical Oncology and Hematology Inc-Parkview; 🇺🇸 Fort Wayne, Indiana, United States

Loyola University Medical Center; 🇺🇸 Maywood, Illinois, United States

University of Maryland/Greenebaum Cancer Center; 🇺🇸 Baltimore, Maryland, United States

University of Chicago Comprehensive Cancer Center; 🇺🇸 Chicago, Illinois, United States

Illinois CancerCare-Peoria; 🇺🇸 Peoria, Illinois, United States

Central Illinois Hematology Oncology Center; 🇺🇸 Springfield, Illinois, United States

Mercy Hospital Saint Louis; 🇺🇸 Saint Louis, Missouri, United States

Joliet Oncology-Hematology Associates Limited; 🇺🇸 Joliet, Illinois, United States

Ingalls Memorial Hospital; 🇺🇸 Harvey, Illinois, United States

University of Michigan Comprehensive Cancer Center; 🇺🇸 Ann Arbor, Michigan, United States

Froedtert and the Medical College of Wisconsin; 🇺🇸 Milwaukee, Wisconsin, United States