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

A Phase 1 Study of Doxorubicin and A12 in Advanced Soft Tissue Sarcoma

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Childhood Rhabdomyosarcoma; Recurrent Adult Soft Tissue Sarcoma; Stage III Adult Soft Tissue Sarcoma; Stage IV Adult Soft Tissue Sarcoma; Dermatofibrosarcoma Protuberans; Previously Treated Childhood Rhabdomyosarcoma; Recurrent Childhood Soft Tissue Sarcoma; Adult Rhabdomyosarcoma; 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 Synovial Sarcoma; Childhood Angiosarcoma; Childhood Epithelioid Sarcoma; Childhood Fibrosarcoma; Childhood Leiomyosarcoma; Childhood Liposarcoma; Childhood Malignant Mesenchymoma; Childhood Synovial Sarcoma; Metastatic Childhood Soft Tissue Sarcoma; Untreated Childhood Rhabdomyosarcoma; Childhood Malignant Peripheral Nerve Sheath Tumor; Adult Undifferentiated High Grade Pleomorphic Sarcoma of Bone; Childhood Desmoplastic Small Round Cell Tumor; Childhood Pleomorphic Rhabdomyosarcoma; Childhood Rhabdomyosarcoma With Mixed Embryonal and Alveolar Features; Malignant Adult Hemangiopericytoma; Malignant Childhood Hemangiopericytoma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Doxorubicin Hydrochloride; Biological: Cixutumumab

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 Type: Interventional
• Enrollment (Actual): 30
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Illinois
    • Chicago, Illinois, United States, 60637
      • University of Chicago Comprehensive Cancer Center
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital
    • Evanston, Illinois, United States, 60201
      • NorthShore University HealthSystem-Evanston Hospital
    • Harvey, Illinois, United States, 60426
      • Ingalls Memorial Hospital
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates Limited
    • Maywood, Illinois, United States, 60153
      • Loyola University Medical Center
    • Peoria, Illinois, United States, 61615
      • Illinois CancerCare-Peoria
    • Springfield, Illinois, United States, 62702
      • Central Illinois Hematology Oncology Center
  • Indiana
    • Fort Wayne, Indiana, United States, 46845
      • Fort Wayne Medical Oncology and Hematology Inc-Parkview
  • Maryland
    • Baltimore, Maryland, United States, 21201
      • University of Maryland/Greenebaum Cancer Center
  • Michigan
    • Ann Arbor, Michigan, United States, 48109
      • University of Michigan Comprehensive Cancer Center
  • Missouri
    • Saint Louis, Missouri, United States, 63141
      • Mercy Hospital Saint Louis
  • Wisconsin
    • Milwaukee, Wisconsin, United States, 53226
      • Froedtert and The Medical College of Wisconsin

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

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: Treatment (cixutumumab and 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.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Doxorubicin Hydrochloride; Given IV; Other Names: Adriamycin; 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 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; Biological: Cixutumumab; Given IV; Other Names: IMC-A12; Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 2 courses of treatment

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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	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.	Up to 6 months
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.	Until death due to any cause, or loss to follow-up, assessed up to 6 months
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.	Until documented disease progression or death or loss-to-follow-up, assessed up to 6 months

Collaborators and Investigators

• Sponsor: National Cancer Institute (NCI)
• Investigators: Principal Investigator: Rashmi Chugh, University of Chicago Comprehensive Cancer Center

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start: June 1, 2008
• Primary Completion (Actual): January 1, 2013

Study Registration Dates

• First Submitted: July 19, 2008
• First Submitted That Met QC Criteria: July 19, 2008
• First Posted (Estimate): July 22, 2008

Study Record Updates

• Last Update Posted (Estimate): May 17, 2016
• Last Update Submitted That Met QC Criteria: May 16, 2016
• Last Verified: May 1, 2016

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Pathologic Processes; Nervous System Diseases; Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms; Disease Attributes; Neuromuscular Diseases; Neoplasms, Nerve Tissue; Peripheral Nervous System Diseases; Nervous System Neoplasms; Neoplasms, Complex and Mixed; Neoplasms, Bone Tissue; Neoplasms, Connective Tissue; Neoplasms, Vascular Tissue; Neoplasms, Muscle Tissue; Peripheral Nervous System Neoplasms; Neoplasms, Adipose Tissue; Myosarcoma; Neoplasms, Fibrous Tissue; Neurofibroma; Histiocytoma; Sarcoma; Recurrence; Osteosarcoma; Leiomyosarcoma; Nerve Sheath Neoplasms; Liposarcoma; Rhabdomyosarcoma; Chondrosarcoma; Rhabdomyosarcoma, Embryonal; Hemangiosarcoma; Neurofibrosarcoma; Sarcoma, Synovial; Hemangiopericytoma; Solitary Fibrous Tumors; Dermatofibrosarcoma; Histiocytoma, Malignant Fibrous; Fibrosarcoma; Desmoplastic Small Round Cell Tumor; Mesenchymoma; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antineoplastic Agents; Immunologic Factors; Topoisomerase II Inhibitors; Topoisomerase Inhibitors; Antibiotics, Antineoplastic; Doxorubicin; Liposomal doxorubicin; Antibodies, Monoclonal
• Other Study ID Numbers: NCI-2009-00285 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); P30CA014599 (U.S. NIH Grant/Contract); N01CM00071 (U.S. NIH Grant/Contract); UCCRC-16227A; CDR0000600157; 16227A (Other Identifier: University of Chicago Comprehensive Cancer Center); 8131 (Other Identifier: CTEP)