Temozolomide, Cixutumumab, and Combination Chemotherapy in Treating Patients With Metastatic Rhabdomyosarcoma

Stage IV Adult Soft Tissue Sarcoma Clinical Trial

Official title:

A Pilot Study to Evaluate Novel Agents (Temozolomide and Cixutumumab [IMC-A12, Anti-IGF-IR Monoclonal Antibody NSC # 742460]) in Combination With Intensive Multi-agent Interval Compressed Therapy for Patients With High-Risk Rhabdomyosarcoma

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT01055314
• Other study ID #: NCI-2011-02005
• Secondary ID: NCI-2011-02005CD
• Status: Completed
• Phase: Phase 2
• First received: January 22, 2010
• Last updated: May 22, 2015
• Start date: January 2010
• Est. completion date: September 2014

Study information

• Verified date: September 2014
• Source: National Cancer Institute (NCI)
• Contact: n/a
• Is FDA regulated: No
• Health authority: United States: Food and Drug Administration
• Study type: Interventional

Clinical Trial Summary

This randomized pilot clinical trial is studying the side effects and how well giving temozolomide and cixutumumab together with combination chemotherapy works in treating patients with metastatic rhabdomyosarcoma. Drugs used in chemotherapy, such as temozolomide, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. 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. Giving temozolomide and cixutumumab together with combination chemotherapy may kill more tumor cells.

Description:

PRIMARY OBJECTIVES:

I. To determine the feasibility of administering IMC-A12 (cixutumumab) in combination with a multi-agent intensive chemotherapy regimen for the treatment of high-risk rhabdomyosarcoma (RMS).

II. To determine the feasibility of adding temozolomide to vincristine (vincristine sulfate)/irinotecan (irinotecan hydrochloride) cycles in patients with high-risk RMS.

III. To assess immediate and short-term side effects of delivery of concurrent temozolomide-vincristine-irinotecan with irradiation in patients with high-risk RMS.

SECONDARY OBJECTIVES:

I. To gain a preliminary estimate of the response rate to IMC-A12 or temozolomide plus vincristine/irinotecan in previously untreated high-risk RMS.

II. To obtain preliminary efficacy data for IMC-A12 or temozolomide in combination with a multi-agent interval compressed chemotherapy regimen in previously untreated high-risk RMS.

III. To determine the effectiveness of detecting metastatic disease with fludeoxyglucose F 18 positron emission tomography (FDG PET) and to compare assessment of response using standard imaging techniques with response assessed by FDG PET.

IV. To assess changes in serum levels of insulin-like growth factor (IGF)-I, IGF-II, IGF-BP3 as biomarkers of IGF-IR inhibition.

OUTLINE: This is a dose-escalation study of cixutumumab. Patients are assigned to 1 of 2 treatment groups according to the timing of their enrollment onto the study.

GROUP 1: Patients receive vincristine sulfate intravenously (IV) over 1 minute on day 1 of weeks 1-5, 7, 8, 11, 12, 15, 16, 20-24, 28, 29, 32, 33, 35, 38, 41-44, 47, 48, 50, and 51; irinotecan hydrochloride IV over 90 minutes on days 1-5 of weeks 1, 4, 20, 23, 47, and 50; ifosfamide IV over 1 hour and etoposide IV over 1-2 hours on days 1-5 of weeks 9, 13, 17, 26, and 30; doxorubicin hydrochloride IV over 1-15 minutes on days 1 and 2 of weeks 7, 11, 15, 28, and 32; cyclophosphamide IV over 30-60 minutes on day 1 of weeks 7, 11, 15, 28, 32, 35, 38, 41, and 44; dactinomycin IV over 1-5 minutes on day 1 of weeks 35, 38, 41, and 44; and cixutumumab IV over 1 hour on day 1 of weeks 1-51. Patients also undergo radiation therapy* on days 1-5 of weeks 20-24.

GROUP 2: Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, and dactinomycin and undergo radiation therapy* as in group 1. Patients also receive temozolomide orally (PO) on days 1-5 of weeks 1, 4, 20, 23, 47, and 50.

GROUP 3: Patients receive vincristine sulfate, irinotecan hydrochloride, ifosfamide, etoposide, doxorubicin hydrochloride, cyclophosphamide, dactinomycin, and cixutumumab and undergo radiation therapy* as in group 1. Patients also receive temozolomide as in group 2. (Discontinued as of January 2013)

NOTE: *Patients with parameningeal tumors and evidence of intracranial extension or those requiring emergency radiotherapy may receive radiation therapy starting in week 1; cixutumumab should be withheld during radiation therapy.

After completion of study therapy, patients are followed up at 3 weeks and then periodically for up to 5 years.

Recruitment information / eligibility

• Status: Completed
• Enrollment: 179
• Est. completion date: September 2014
• Est. primary completion date: September 2014
• Accepts healthy volunteers: No
• Gender: Both
• Age group: N/A to 49 Years

Eligibility

Inclusion Criteria:

• Patients must be eligible for, and enrolled on D9902 prior to enrollment on ARST08P1

• Patients with newly diagnosed, biopsy-proven metastatic rhabdomyosarcoma or ectomesenchymoma (stage IV, clinical group IV) are eligible for this study; patients with stage IV, clinical group IV RMS with parameningeal and paraspinal primary tumors, including those with intracranial extension (ICE) are eligible for ARST08P1; ICE is defined by contrast magnetic resonance imaging (MRI) showing that the primary tumor touches, displaces, invades, distorts, or otherwise causes signal abnormality of the dura in brain or spinal cord in contiguity to the primary site; ICE is also presumed to exist if the cerebrospinal fluid (CSF) cytopathology is positive for tumor at diagnosis

• Patients must have a performance status corresponding to Eastern Cooperative Oncology Group (ECOG) scores of 0, 1, or 2; use Karnofsky for patients > 16 years of age and Lansky for patients =< 16 years of age

• No prior chemotherapy or radiotherapy except for use of corticosteroids or emergent radiation therapy; patients requiring emergency radiation are eligible

• Creatinine clearance or radioisotope glomerular filtration rate (GFR) >= 70 mL/min/1.73m^2 OR maximum serum creatinine based on age/gender as follows:

• 0.4 mg/dL (for patients 1 to 5 months of age)

• 0.5 mg/dL (for patients 6 to 11 months of age)

• 0.6 mg/dL (for patients 1 year of age)

• 0.8 mg/dL (for patients 2 to 5 years of age)

• 1.0 mg/dL (for patients 6 to 9 years of age)

• 1.2 mg/dL (for patients 10 to 12 years of age)

• 1.5 mg/dL (males) or 1.4 mg/dL (females) (for patients 13 to 15 years of age)

• 1.7 mg/dL (males) or 1.4 mg/dL (females) (for patients >= 16 years of age)

• Patients with urinary tract obstruction by tumor must meet the renal function criteria listed above AND must have unimpeded urinary flow established via decompression of the obstructed portion of the urinary tract

• Total bilirubin =< 1.5 x upper limit of normal (ULN) for age, unless there is evidence of biliary obstruction by the tumor

• Shortening fraction >= 27% by echocardiogram (ECHO) OR ejection fraction >= 50% by radionuclide angiogram

• Absolute neutrophil count (ANC) >= 750/uL; abnormal blood counts are permissible if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma

• Platelet count >= 75,000/uL; abnormal blood counts are permissible if there is bone marrow biopsy or aspirate proven bone marrow involvement by rhabdomyosarcoma

• Sexually active patients of childbearing potential must agree to use effective contraception during therapy (Pilots 1 and 2) and for at least 3 months after the last dose of IMC-A12 (Pilots 1)

Exclusion Criteria:

• Female patients who are pregnant are not eligible

• Female patients who are breastfeeding are not eligible; female patients who are lactating must agree to stop breastfeeding to participate in this study

• Patients receiving growth hormone therapy are not eligible

• Patients with known type I or type II diabetes mellitus are not eligible for enrollment on Pilot 1

• Patients with evidence of uncontrolled infection are not eligible

• All patients and/or their parents or legal guardians must sign a written informed consent

• All institutional, Food and Drug Administration (FDA), and National Cancer Institute (NCI) requirements for human studies must be met

Study Design

Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Open Label, Primary Purpose: Treatment

Related Conditions & MeSH terms

• Adult Rhabdomyosarcoma
• Childhood Alveolar Rhabdomyosarcoma
• Childhood Embryonal Rhabdomyosarcoma
• Metastatic Childhood Soft Tissue Sarcoma
• Rhabdomyosarcoma
• Sarcoma
• Stage IV Adult Soft Tissue Sarcoma
• Untreated Childhood Rhabdomyosarcoma

Intervention

Biological:
• Cixutumumab
Given IV

Drug:
• Cyclophosphamide
Given IV

Biological:
• Dactinomycin
Given IV

Drug:
• Doxorubicin Hydrochloride
Given IV
• Etoposide
Given IV
• Ifosfamide
Given IV
• Irinotecan Hydrochloride
Given IV

Other:
• Laboratory Biomarker Analysis
Correlative studies

Drug:
• Temozolomide
Given PO
• Vincristine Sulfate Liposome
Given IV

Locations

Country	Name	City	State
Australia	Royal Brisbane and Women's Hospital	Herston	Queensland
Australia	Royal Children's Hospital-Brisbane	Herston	Queensland
Australia	Princess Margaret Hospital for Children	Perth	Western Australia
Australia	Sydney Children's Hospital	Randwick	New South Wales
Australia	The Children's Hospital at Westmead	Westmead	New South Wales
Canada	Alberta Children's Hospital	Calgary	Alberta
Canada	IWK Health Centre	Halifax	Nova Scotia
Canada	Chedoke-McMaster Hospitals	Hamilton	Ontario
Canada	McMaster Children's Hospital at Hamilton Health Sciences	Hamilton	Ontario
Canada	Centre Hospitalier Universitaire Sainte-Justine	Montreal	Quebec
Canada	The Montreal Children's Hospital of the MUHC	Montreal	Quebec
Canada	Children's Hospital of Eastern Ontario	Ottawa	Ontario
Canada	Centre Hospitalier Universitaire de Quebec	Quebec
Canada	Saskatoon Cancer Centre	Saskatoon	Saskatchewan
Canada	Hospital for Sick Children	Toronto	Ontario
Canada	British Columbia Children's Hospital	Vancouver	British Columbia
Canada	CancerCare Manitoba	Winnipeg	Manitoba
New Zealand	Starship Children's Hospital	Grafton	Auckland
United States	Children's Hospital Medical Center of Akron	Akron	Ohio
United States	Albany Medical Center	Albany	New York
United States	University of New Mexico	Albuquerque	New Mexico
United States	University of New Mexico Cancer Center	Albuquerque	New Mexico
United States	C S Mott Children's Hospital	Ann Arbor	Michigan
United States	Children's Healthcare of Atlanta - Egleston	Atlanta	Georgia
United States	Children's Hospital Colorado	Aurora	Colorado
United States	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland
United States	Sinai Hospital of Baltimore	Baltimore	Maryland
United States	Walter Reed National Military Medical Center	Bethesda	Maryland
United States	Lehigh Valley Hospital - Muhlenberg	Bethlehem	Pennsylvania
United States	Children's Hospital of Alabama	Birmingham	Alabama
United States	University of Alabama at Birmingham Cancer Center	Birmingham	Alabama
United States	Saint Luke's Mountain States Tumor Institute	Boise	Idaho
United States	Dana-Farber Cancer Institute	Boston	Massachusetts
United States	University of Vermont College of Medicine	Burlington	Vermont
United States	University of North Carolina at Chapel Hill	Chapel Hill	North Carolina
United States	Medical University of South Carolina	Charleston	South Carolina
United States	West Virginia University Charleston	Charleston	West Virginia
United States	Carolinas Medical Center	Charlotte	North Carolina
United States	Lurie Children's Hospital-Chicago	Chicago	Illinois
United States	University of Chicago Comprehensive Cancer Center	Chicago	Illinois
United States	Cincinnati Children's Hospital Medical Center	Cincinnati	Ohio
United States	Cleveland Clinic Foundation	Cleveland	Ohio
United States	Rainbow Babies and Childrens Hospital	Cleveland	Ohio
United States	Palmetto Health Richland	Columbia	South Carolina
United States	Nationwide Children's Hospital	Columbus	Ohio
United States	Driscoll Children's Hospital	Corpus Christi	Texas
United States	Medical City Dallas Hospital	Dallas	Texas
United States	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas
United States	Dayton Children's Hospital	Dayton	Ohio
United States	Rocky Mountain Hospital for Children-Presbyterian Saint Luke's Medical Center	Denver	Colorado
United States	Blank Children's Hospital	Des Moines	Iowa
United States	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan
United States	Southern California Permanente Medical Group	Downey	California
United States	Duke University Medical Center	Durham	North Carolina
United States	Broward Health Medical Center	Fort Lauderdale	Florida
United States	Golisano Children's Hospital of Southwest Florida	Fort Myers	Florida
United States	Cook Children's Medical Center	Fort Worth	Texas
United States	Helen DeVos Children's Hospital at Spectrum Health	Grand Rapids	Michigan
United States	Saint Vincent Hospital	Green Bay	Wisconsin
United States	BI-LO Charities Children's Cancer Center	Greenville	South Carolina
United States	Greenville Cancer Treatment Center	Greenville	South Carolina
United States	Hackensack University Medical Center	Hackensack	New Jersey
United States	Connecticut Children's Medical Center	Hartford	Connecticut
United States	Penn State Hershey Children's Hospital	Hershey	Pennsylvania
United States	Memorial Healthcare System - Joe DiMaggio Children's Hospital	Hollywood	Florida
United States	University of Hawaii Cancer Center	Honolulu	Hawaii
United States	Baylor College of Medicine	Houston	Texas
United States	Riley Hospital for Children	Indianapolis	Indiana
United States	University of Mississippi Medical Center	Jackson	Mississippi
United States	Nemours Children's Clinic-Jacksonville	Jacksonville	Florida
United States	Bronson Methodist Hospital	Kalamazoo	Michigan
United States	Kalamazoo Center for Medical Studies	Kalamazoo	Michigan
United States	The Childrens Mercy Hospital	Kansas City	Missouri
United States	East Tennessee Childrens Hospital	Knoxville	Tennessee
United States	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada
United States	University of Kentucky/Markey Cancer Center	Lexington	Kentucky
United States	Arkansas Children's Hospital	Little Rock	Arkansas
United States	Miller Children's and Women's Hospital Long Beach	Long Beach	California
United States	Children's Hospital Los Angeles	Los Angeles	California
United States	David Geffen School of Medicine at UCLA	Los Angeles	California
United States	Mattel Children's Hospital UCLA	Los Angeles	California
United States	Kosair Children's Hospital	Louisville	Kentucky
United States	Children's Hospital Central California	Madera	California
United States	Loyola University Medical Center	Maywood	Illinois
United States	St. Jude Children's Research Hospital	Memphis	Tennessee
United States	Midwest Children's Cancer Center	Milwaukee	Wisconsin
United States	Children's Hospitals and Clinics of Minnesota - Minneapolis	Minneapolis	Minnesota
United States	University of Minnesota Medical Center-Fairview	Minneapolis	Minnesota
United States	Morristown Memorial Hospital	Morristown	New Jersey
United States	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee
United States	UMDNJ - Robert Wood Johnson University Hospital	New Brunswick	New Jersey
United States	Yale University	New Haven	Connecticut
United States	The Steven and Alexandra Cohen Children's Medical Center of New York	New Hyde Park	New York
United States	Children's Hospital New Orleans	New Orleans	Louisiana
United States	Tulane University Health Sciences Center	New Orleans	Louisiana
United States	New York University Langone Medical Center	New York	New York
United States	Newark Beth Israel Medical Center	Newark	New Jersey
United States	Childrens Hospital-King's Daughters	Norfolk	Virginia
United States	Children's Hospital and Research Center at Oakland	Oakland	California
United States	Kaiser Permanente-Oakland	Oakland	California
United States	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma
United States	Childrens Hospital of Orange County	Orange	California
United States	Nemours Children's Hospital	Orlando	Florida
United States	Lucile Packard Children's Hospital Stanford University	Palo Alto	California
United States	Saint Joseph's Regional Medical Center	Paterson	New Jersey
United States	Nemours Children's Clinic - Pensacola	Pensacola	Florida
United States	Saint Jude Midwest Affiliate	Peoria	Illinois
United States	Children's Hospital of Philadelphia	Philadelphia	Pennsylvania
United States	Phoenix Childrens Hospital	Phoenix	Arizona
United States	Children's Hospital of Pittsburgh of UPMC	Pittsburgh	Pennsylvania
United States	Legacy Emanuel Children's Hospital	Portland	Oregon
United States	Legacy Emanuel Hospital and Health Center	Portland	Oregon
United States	Oregon Health and Science University	Portland	Oregon
United States	Rhode Island Hospital	Providence	Rhode Island
United States	Virginia Commonwealth University/Massey Cancer Center	Richmond	Virginia
United States	Mayo Clinic	Rochester	Minnesota
United States	University of Rochester	Rochester	New York
United States	Cardinal Glennon Children's Medical Center	Saint Louis	Missouri
United States	Saint John's Mercy Medical Center	Saint Louis	Missouri
United States	Washington University School of Medicine	Saint Louis	Missouri
United States	All Children's Hospital	Saint Petersburg	Florida
United States	Primary Children's Hospital	Salt Lake City	Utah
United States	Rady Children's Hospital - San Diego	San Diego	California
United States	UCSF Medical Center-Parnassus	San Francisco	California
United States	Seattle Children's Hospital	Seattle	Washington
United States	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota
United States	Providence Sacred Heart Medical Center and Children's Hospital	Spokane	Washington
United States	Southern Illinois University	Springfield	Illinois
United States	Overlook Hospital	Summit	New Jersey
United States	State University of New York Upstate Medical University	Syracuse	New York
United States	Mary Bridge Children's Hospital and Health Center	Tacoma	Washington
United States	Saint Joseph's Hospital/Children's Hospital-Tampa	Tampa	Florida
United States	Mercy Children's Hospital	Toledo	Ohio
United States	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma
United States	Children's National Medical Center	Washington	District of Columbia
United States	MedStar Georgetown University Hospital	Washington	District of Columbia
United States	Saint Mary's Hospital	West Palm Beach	Florida
United States	Alfred I duPont Hospital for Children	Wilmington	Delaware
United States	Wake Forest University Health Sciences	Winston-Salem	North Carolina

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

Countries where clinical trial is conducted

United States,  Australia,  Canada,  New Zealand, 

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Feasibility of the addition of cixutumumab to chemotherapy determined by patient enrollment		Up to 54 weeks	No
Primary	Feasibility of the addition of temozolomide to chemotherapy determined by patient enrollment		Up to 54 weeks	No
Primary	Incidence of adverse events assessed by Common Terminology Criteria for Adverse Events version 4.0		6 months	Yes
Secondary	Event-free survival		Up to 5 years	No
Secondary	Response rate assessed by Response Evaluation Criteria for Solid Tumors (RECIST)	An O'Brien-Fleming monitoring boundary (truncated at 3 standard deviations) and a spending function approach will be employed for interim monitoring of efficacy. A futility analysis will also be performed, testing a 'null hypothesis' that the relative risk of failure with this therapy is 0.60 (compared to the ID/IE therapy experience), with consideration of suspension of accrual should this hypothesis be rejected at any of the scheduled interim looks at a significance level of 0.005.	Up to 5 years	No