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

Primary Purpose

Adult Angiosarcoma, Adult Desmoplastic Small Round Cell Tumor, Adult Epithelioid Sarcoma

Status
Completed
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Cixutumumab
Doxorubicin Hydrochloride
Laboratory Biomarker Analysis
Sponsored by
National Cancer Institute (NCI)
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Adult Angiosarcoma

Eligibility Criteria

16 Years - undefined (Child, Adult, Older Adult)All SexesDoes not accept healthy volunteers

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

Sites / Locations

  • University of Chicago Comprehensive Cancer Center
  • Decatur Memorial Hospital
  • NorthShore University HealthSystem-Evanston Hospital
  • Ingalls Memorial Hospital
  • Joliet Oncology-Hematology Associates Limited
  • Loyola University Medical Center
  • Illinois CancerCare-Peoria
  • Central Illinois Hematology Oncology Center
  • Fort Wayne Medical Oncology and Hematology Inc-Parkview
  • University of Maryland/Greenebaum Cancer Center
  • University of Michigan Comprehensive Cancer Center
  • Mercy Hospital Saint Louis
  • Froedtert and the Medical College of Wisconsin

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

Treatment (cixutumumab and doxorubicin hydrochloride)

Arm Description

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.

Outcomes

Primary Outcome Measures

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
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

Changes in cardiac function as measured by MUGA scans of the left ventricular ejection fraction
Confirmed response rate (CR + PR) for comparison with doxorubicin treatment in similar historical patient populations
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
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
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.

Full Information

First Posted
July 19, 2008
Last Updated
May 16, 2016
Sponsor
National Cancer Institute (NCI)
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1. Study Identification

Unique Protocol Identification Number
NCT00720174
Brief Title
Cixutumumab and Doxorubicin Hydrochloride in Treating Patients With Unresectable, Locally Advanced, or Metastatic Soft Tissue Sarcoma
Official Title
A Phase 1 Study of Doxorubicin and A12 in Advanced Soft Tissue Sarcoma
Study Type
Interventional

2. Study Status

Record Verification Date
May 2016
Overall Recruitment Status
Completed
Study Start Date
June 2008 (undefined)
Primary Completion Date
January 2013 (Actual)
Study Completion Date
undefined (undefined)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
National Cancer Institute (NCI)

4. Oversight

5. Study Description

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Adult Angiosarcoma, Adult Desmoplastic Small Round Cell Tumor, Adult Epithelioid Sarcoma, Adult Extraskeletal Myxoid Chondrosarcoma, Adult Extraskeletal Osteosarcoma, Adult Fibrosarcoma, Adult Leiomyosarcoma, Adult Liposarcoma, Adult Malignant Mesenchymoma, Adult Malignant Peripheral Nerve Sheath Tumor, Adult Rhabdomyosarcoma, 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, Childhood Pleomorphic Rhabdomyosarcoma, Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features, Childhood Synovial Sarcoma, Dermatofibrosarcoma Protuberans, Malignant Adult Hemangiopericytoma, Malignant Childhood Hemangiopericytoma, Metastatic Childhood Soft Tissue Sarcoma, Previously Treated Childhood Rhabdomyosarcoma, Recurrent Adult Soft Tissue Sarcoma, Recurrent Childhood Rhabdomyosarcoma, Recurrent Childhood Soft Tissue Sarcoma, Stage III Adult Soft Tissue Sarcoma, Stage IV Adult Soft Tissue Sarcoma, Untreated Childhood Rhabdomyosarcoma

7. Study Design

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

8. Arms, Groups, and Interventions

Arm Title
Treatment (cixutumumab and doxorubicin hydrochloride)
Arm Type
Experimental
Arm Description
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.
Intervention Type
Biological
Intervention Name(s)
Cixutumumab
Other Intervention Name(s)
Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12, IMC-A12
Intervention Description
Given IV
Intervention Type
Drug
Intervention Name(s)
Doxorubicin Hydrochloride
Other Intervention Name(s)
5,12-Naphthacenedione, 10-[(3-amino-2,3,6-trideoxy-alpha-L-lyxo-hexopyranosyl)oxy]-7,8, 9,10-tetrahydro-6,8,11-trihydroxy-8-(hydroxyacetyl)-1-methoxy-, hydrochloride, (8S-cis)- (9CI), ADM, Adriacin, Adriamycin, Adriamycin Hydrochloride, Adriamycin PFS, Adriamycin RDF, ADRIAMYCIN, HYDROCHLORIDE, Adriamycine, Adriblastina, Adriblastine, Adrimedac, Chloridrato de Doxorrubicina, DOX, DOXO-CELL, Doxolem, Doxorubicin.HCl, Doxorubin, Farmiblastina, FI 106, FI-106, hydroxydaunorubicin, Rubex
Intervention Description
Given IV
Intervention Type
Other
Intervention Name(s)
Laboratory Biomarker Analysis
Intervention Description
Correlative studies
Primary Outcome Measure Information:
Title
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
Description
The MTD is defined as the dose of Cixitumumab that induces dose-limiting toxicity (DLT) in no more than 20% of patients.
Time Frame
Up to 2 courses of treatment
Secondary Outcome Measure Information:
Title
Changes in cardiac function as measured by MUGA scans of the left ventricular ejection fraction
Time Frame
Baseline to 6 courses of treatment
Title
Confirmed response rate (CR + PR) for comparison with doxorubicin treatment in similar historical patient populations
Description
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.
Time Frame
Up to 6 months
Title
Overall survival
Description
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.
Time Frame
Until death due to any cause, or loss to follow-up, assessed up to 6 months
Title
Progression-free survival
Description
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.
Time Frame
Until documented disease progression or death or loss-to-follow-up, assessed up to 6 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
16 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Rashmi Chugh
Organizational Affiliation
University of Chicago Comprehensive Cancer Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
University of Chicago Comprehensive Cancer Center
City
Chicago
State/Province
Illinois
ZIP/Postal Code
60637
Country
United States
Facility Name
Decatur Memorial Hospital
City
Decatur
State/Province
Illinois
ZIP/Postal Code
62526
Country
United States
Facility Name
NorthShore University HealthSystem-Evanston Hospital
City
Evanston
State/Province
Illinois
ZIP/Postal Code
60201
Country
United States
Facility Name
Ingalls Memorial Hospital
City
Harvey
State/Province
Illinois
ZIP/Postal Code
60426
Country
United States
Facility Name
Joliet Oncology-Hematology Associates Limited
City
Joliet
State/Province
Illinois
ZIP/Postal Code
60435
Country
United States
Facility Name
Loyola University Medical Center
City
Maywood
State/Province
Illinois
ZIP/Postal Code
60153
Country
United States
Facility Name
Illinois CancerCare-Peoria
City
Peoria
State/Province
Illinois
ZIP/Postal Code
61615
Country
United States
Facility Name
Central Illinois Hematology Oncology Center
City
Springfield
State/Province
Illinois
ZIP/Postal Code
62702
Country
United States
Facility Name
Fort Wayne Medical Oncology and Hematology Inc-Parkview
City
Fort Wayne
State/Province
Indiana
ZIP/Postal Code
46845
Country
United States
Facility Name
University of Maryland/Greenebaum Cancer Center
City
Baltimore
State/Province
Maryland
ZIP/Postal Code
21201
Country
United States
Facility Name
University of Michigan Comprehensive Cancer Center
City
Ann Arbor
State/Province
Michigan
ZIP/Postal Code
48109
Country
United States
Facility Name
Mercy Hospital Saint Louis
City
Saint Louis
State/Province
Missouri
ZIP/Postal Code
63141
Country
United States
Facility Name
Froedtert and the Medical College of Wisconsin
City
Milwaukee
State/Province
Wisconsin
ZIP/Postal Code
53226
Country
United States

12. IPD Sharing Statement

Citations:
PubMed Identifier
25858498
Citation
Chugh R, Griffith KA, Davis EJ, Thomas DG, Zavala JD, Metko G, Brockstein B, Undevia SD, Stadler WM, Schuetze SM. Doxorubicin plus the IGF-1R antibody cixutumumab in soft tissue sarcoma: a phase I study using the TITE-CRM model. Ann Oncol. 2015 Jul;26(7):1459-64. doi: 10.1093/annonc/mdv171. Epub 2015 Apr 9. Erratum In: Ann Oncol. 2019 Aug 1;30(8):1405.
Results Reference
derived

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

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