Clinical trial NCT00617708: S0727 Gemcitabine Hydrochloride and Erlotinib Hydrochloride With or Without Monoclonal Antibody Therapy in Treating Patients With Metastatic Pancreatic Cancer That Cannot Be Removed By Surgery
Official title: A Phase I and Randomized Phase II Trial of Gemcitabine + Erlotinib (NSC-718781) + IMC-A12 (NSC-742460) vs. Gemcitabine + Erlotinib as First-Line Treatment in Patients With Metastatic Pancreatic Cancer
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Stage IV Pancreatic Cancer
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2008-02-18
Enrollment: 134
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This randomized phase I/II trial is studying the side effects and best dose of monoclonal antibody therapy when given together with gemcitabine hydrochloride and erlotinib hydrochloride and to see how well they work compared with giving gemcitabine hydrochloride and erlotinib hydrochloride alone as first-line therapy in treating patients with metastatic pancreatic cancer that cannot be removed by surgery. Drugs used in chemotherapy, such as gemcitabine hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Erlotinib hydrochloride may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Monoclonal antibodies 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 erlotinib hydrochloride and gemcitabine hydrochloride together with monoclonal antibody therapy may kill more tumor cells.

Detailed description: PRIMARY OBJECTIVES:

I. To assess the appropriate dose of IMC-A12 (cixutumumab) to use in combination with gemcitabine (gemcitabine hydrochloride) and erlotinib (erlotinib hydrochloride). (Phase I) II. To assess progression-free survival in patients with metastatic pancreatic cancer treated with IMC-A12 plus gemcitabine and erlotinib compared to those treated with gemcitabine plus erlotinib alone. (Phase II) III. To assess overall survival in each of the two treatment arms in this group of patients. (Phase II) IV. To assess the total response probability (confirmed and unconfirmed, complete and partial responses) in each of the two treatment arms in the subset of this group of patients with measurable disease. (Phase II) V. To assess the qualitative and quantitative toxicities in each of the two treatment arms in this group of patients. (Phase II)

OUTLINE: This is a multicenter, phase I, dose-escalation study of cixutumumab followed by a randomized, phase II study.

Patients are initially enrolled into the phase I portion of the study to determine the recommended phase II dose (RPTD) of cixutumumab. Once the RPTD is determined, patients are enrolled into the phase II portion of the study.

PHASE I (LIMITED INSTITUTIONS): Patients receive erlotinib hydrochloride orally (PO) once daily on days 1-28, gemcitabine hydrochloride intravenously (IV) over 30 minutes on days 1, 8, and 15, and cixutumumab IV over 60 minutes on days 1, 8, 15, and 22. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

PHASE II (ALL SWOG MEMBERS): Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive erlotinib hydrochloride, gemcitabine hydrochloride, and cixutumumab at the RPTD as in phase I.

ARM II: Patients receive erlotinib hydrochloride and gemcitabine hydrochloride as in arm I.

In both arms, treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

Previously collected tumor tissue is obtained for gene expression analyses by RT-PCR, RNA isolation, and cDNA synthesis. Blood samples are collected periodically for correlative studies. Samples are assessed for the potential relationship between gene expression levels, germline polymorphisms, Ras and P13K mutations and progression-free survival and overall survival.

After completion of study treatment, patients are followed every 6 months for up to 3 years.

Eligibility criteria: Inclusion Criteria:

* Histologically or cytologically confirmed pancreatic adenocarcinoma

  * Stage IV disease (any T, any N, M1 \[distant metastases\])
  * Unresectable disease
  * Histologic diagnosis based on a metastatic site must be compatible with pancreatic cancer
* Measurable and/or nonmeasurable disease
* No endocrine or neuroendocrine tumors, lymphoma of the pancreas, or ampullary cancer
* No macroscopic residual disease post-resection as the only site of disease
* No clinically significant ascites
* No known brain metastases

  * Patients with neurologic signs or symptoms must undergo brain imaging studies AND studies must be negative for disease
* Zubrod performance status 0-1
* ANC ≥ 1,500/mcL
* Platelet count ≥ 100,000/mcL
* Hemoglobin ≥ 9 g/dL
* Leukocytes ≥ 3,000/mcL
* Total bilirubin normal
* SGOT or SGPT ≤ 2.5 times upper limit of normal (ULN)
* Serum creatinine ≤ 1.5 times ULN OR creatinine clearance ≥ 60 mL/min
* Fasting serum glucose \< 120 mg/dL or below the ULN

  * Patients with diabetes mellitus who meet this criterion must be on a stable dietary or therapeutic regimen for this condition
* INR ≤ 1.5 and PTT ≤ 5 seconds above ULN
* Not pregnant or nursing
* Fertile patients must use effective contraception
* Willing to submit previously collected tumor tissue specimens
* No history of allergic reaction attributed to compounds of similar chemical or biological composition to anti-IGF-1R recombinant monoclonal antibody IMC-A12
* No active acute or chronic infections requiring antibiotics
* No significant ongoing cardiac problems, including any of the following:

  * Myocardial infarction within the past 6 months
  * Uncontrolled hypertension
  * Unstable angina
  * Uncontrolled arrhythmia
  * Congestive heart failure
* No known HIV infection
* No other prior malignancy, except for the following:

  * Adequately treated basal cell or squamous cell skin cancer
  * Carcinoma in situ of the cervix
  * Adequately treated stage I or II cancer from which the patient is currently in complete remission
  * Any other cancer from which the patient has been disease-free for 5 years
* At least 14 days since prior surgery
* At least 28 days since prior radiotherapy for palliation to metastatic sites

  * Patient must have other untreated metastatic sites that would qualify them for this protocol
* At least 6 months since prior adjuvant chemotherapy
* No prior chemotherapy, hormonal therapy, immunotherapy, or chemoradiotherapy for advanced or locally advanced pancreatic cancer, including drugs that target either EGFR or IGFR
* No plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy, or any other type of therapy for treatment of cancer
* No prior gemcitabine hydrochloride
* No prior chimerized or murine monoclonal antibody therapy
* No concurrent CYP3A4 inducers including, but not limited to, any of the following:

  * Rifampicin
  * Rifabutin
  * Rifapentine
  * Phenytoin
  * Carbamazepine
  * Phenobarbital
  * Hypericum perforatum (St. John's wort)
* No concurrent CYP3A4 inhibitors including, but not limited to, any of the following:

  * Atazanavir
  * Clarithromycin
  * Indinavir
  * Itraconazole
  * Ketoconazole
  * Nefazodone
  * Nelfinavir
  * Ritonavir
  * Saquinavir
  * Telithromycin
  * Troleandomycin
  * Voriconazole
* Concurrent prophylactic low-dose coumadin or low molecular weight heparin allowed provided coagulation criteria are met
* Full-dose anticoagulation allowed provided coagulation criteria are met and are under strict control and monitoring

Primary outcomes:
measure: Maximum Tolerated Dose Determination
timeFrame: 28 days
measure: Progression-Free Survival
timeFrame: Up to 3 years
Secondary outcomes:
measure: Overall Survival
timeFrame: Up to 3 years
measure: Response
timeFrame: Up to 3 years
measure: Toxicity
timeFrame: Up to 3 years
Other outcomes:
Locations:
city: Jonesboro
country: United States
facility: NEA Baptist Memorial Hospital
state: Arkansas
city: Berkeley
country: United States
facility: Alta Bates Summit Medical Center-Herrick Campus
state: California
city: Burlingame
country: United States
facility: Mills - Peninsula Hospitals
state: California
city: Castro Valley
country: United States
facility: East Bay Radiation Oncology Center
state: California
city: Castro Valley
country: United States
facility: Eden Hospital Medical Center
state: California
city: Castro Valley
country: United States
facility: Valley Medical Oncology Consultants-Castro Valley
state: California
city: Duarte
country: United States
facility: City of Hope Medical Center
state: California
city: Fremont
country: United States
facility: Valley Medical Oncology Consultants-Fremont
state: California
city: Glendale
country: United States
facility: Glendale Memorial Hospital and Health Center
state: California
city: Greenbrae
country: United States
facility: Marin General Hospital
state: California
city: Greenbrae
country: United States
facility: Sutter Health Western Division Cancer Research Group
state: California
city: Los Angeles
country: United States
facility: University of Southern California
state: California
city: Martinez
country: United States
facility: Contra Costa Regional Medical Center
state: California
city: Mountain View
country: United States
facility: El Camino Hospital
state: California
city: Oakland
country: United States
facility: Highland General Hospital
state: California
city: Oakland
country: United States
facility: Alta Bates Summit Medical Center - Summit Campus
state: California
city: Oakland
country: United States
facility: Bay Area Breast Surgeons Inc
state: California
city: Oakland
country: United States
facility: Bay Area Tumor Institute
state: California
city: Oakland
country: United States
facility: Larry G Strieff MD Medical Corporation
state: California
city: Oakland
country: United States
facility: Tom K Lee Inc
state: California
city: Orange
country: United States
facility: University of California Medical Center At Irvine-Orange Campus
state: California
city: Pleasanton
country: United States
facility: Valley Care Health System - Pleasanton
state: California
city: Pleasanton
country: United States
facility: Valley Medical Oncology Consultants
state: California
city: San Francisco
country: United States
facility: California Pacific Medical Center
state: California
city: San Pablo
country: United States
facility: Doctors Medical Center- JC Robinson Regional Cancer Center
state: California
city: Vallejo
country: United States
facility: Sutter Solano Medical Center
state: California
city: Fort Collins
country: United States
facility: Poudre Valley Hospital
state: Colorado
city: Atlanta
country: United States
facility: Piedmont Hospital
state: Georgia
city: Atlanta
country: United States
facility: Atlanta Regional CCOP
state: Georgia
city: Atlanta
country: United States
facility: Northside Hospital
state: Georgia
city: Atlanta
country: United States
facility: Saint Joseph's Hospital of Atlanta
state: Georgia
city: Austell
country: United States
facility: Well Star Cobb Hospital
state: Georgia
city: Columbus
country: United States
facility: John B Amos Cancer Center
state: Georgia
city: Decatur
country: United States
facility: Dekalb Medical Center
state: Georgia
city: Lawrenceville
country: United States
facility: Gwinnett Medical Center
state: Georgia
city: Marietta
country: United States
facility: Wellstar Kennestone Hospital
state: Georgia
city: Riverdale
country: United States
facility: Southern Regional Medical Center
state: Georgia
city: Rome
country: United States
facility: Harbin Clinic Medical Oncology and Clinical Research
state: Georgia
city: Savannah
country: United States
facility: Memorial Health University Medical Center
state: Georgia
city: Savannah
country: United States
facility: Saint Joseph's-Candler Health System
state: Georgia
city: Valdosta
country: United States
facility: South Georgia Medical Center
state: Georgia
city: Decatur
country: United States
facility: Cancer Care Center of Decatur
state: Illinois
city: Decatur
country: United States
facility: Decatur Memorial Hospital
state: Illinois
city: Effingham
country: United States
facility: Crossroads Cancer Center
state: Illinois
city: Overland Park
country: United States
facility: Menorah Medical Center
state: Kansas
city: Overland Park
country: United States
facility: Saint Luke's South Hospital
state: Kansas
city: Shawnee Mission
country: United States
facility: Shawnee Mission Medical Center
state: Kansas
city: Alexandria
country: United States
facility: Christus Saint Frances Cabrini Hospital
state: Louisiana
city: Baltimore
country: United States
facility: Sinai Hospital of Baltimore
state: Maryland
city: Boston
country: United States
facility: Boston Medical Center
state: Massachusetts
city: Battle Creek
country: United States
facility: Bronson Battle Creek
state: Michigan
city: Big Rapids
country: United States
facility: Mecosta County Medical Center
state: Michigan
city: Detroit
country: United States
facility: Wayne State University
state: Michigan
city: Grand Rapids
country: United States
facility: Grand Rapids Clinical Oncology Program
state: Michigan
city: Grand Rapids
country: United States
facility: Saint Mary's Health Care
state: Michigan
city: Grand Rapids
country: United States
facility: Spectrum Health at Butterworth Campus
state: Michigan
city: Muskegon
country: United States
facility: Mercy Health Partners-Mercy Campus
state: Michigan
city: Royal Oak
country: United States
facility: William Beaumont Hospital
state: Michigan
city: Traverse City
country: United States
facility: Munson Medical Center
state: Michigan
city: Wyoming
country: United States
facility: Metro Health Hospital
state: Michigan
city: Jackson
country: United States
facility: University of Mississippi Medical Center
state: Mississippi
city: Kansas City
country: United States
facility: Truman Medical Center
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Cancer Institute
state: Missouri
city: Kansas City
country: United States
facility: Saint Luke's Hospital of Kansas City
state: Missouri
city: Kansas City
country: United States
facility: Saint Joseph Health Center
state: Missouri
city: Kansas City
country: United States
facility: North Kansas City Hospital
state: Missouri
city: Kansas City
country: United States
facility: Heartland Hematology and Oncology Associates Incorporated
state: Missouri
city: Kansas City
country: United States
facility: Research Medical Center
state: Missouri
city: Lee's Summit
country: United States
facility: Saint Luke's East - Lee's Summit
state: Missouri
city: Liberty
country: United States
facility: Liberty Hospital
state: Missouri
city: Liberty
country: United States
facility: Liberty Radiation Oncology Clinic
state: Missouri
city: Saint Joseph
country: United States
facility: Heartland Regional Medical Center
state: Missouri
city: Saint Joseph
country: United States
facility: Saint Joseph Oncology Inc
state: Missouri
city: Saint Louis
country: United States
facility: Saint Louis University Hospital
state: Missouri
city: Billings
country: United States
facility: Montana Cancer Consortium CCOP
state: Montana
city: Billings
country: United States
facility: Northern Rockies Radiation Oncology Center
state: Montana
city: Billings
country: United States
facility: Saint Vincent Healthcare
state: Montana
city: Billings
country: United States
facility: Hematology-Oncology Centers of the Northern Rockies PC
state: Montana
city: Billings
country: United States
facility: Billings Clinic
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Cancer Center
state: Montana
city: Bozeman
country: United States
facility: Bozeman Deaconess Hospital
state: Montana
city: Butte
country: United States
facility: Saint James Community Hospital and Cancer Treatment Center
state: Montana
city: Great Falls
country: United States
facility: Benefis Healthcare- Sletten Cancer Institute
state: Montana
city: Great Falls
country: United States
facility: Berdeaux, Donald MD (UIA Investigator)
state: Montana
city: Great Falls
country: United States
facility: Great Falls Clinic
state: Montana
city: Havre
country: United States
facility: Northern Montana Hospital
state: Montana
city: Helena
country: United States
facility: Saint Peter's Community Hospital
state: Montana
city: Kalispell
country: United States
facility: Glacier Oncology PLLC
state: Montana
city: Kalispell
country: United States
facility: Kalispell Medical Oncology
state: Montana
city: Kalispell
country: United States
facility: Kalispell Regional Medical Center
state: Montana
city: Missoula
country: United States
facility: Community Medical Hospital
state: Montana
city: Missoula
country: United States
facility: Montana Cancer Specialists
state: Montana
city: Missoula
country: United States
facility: Saint Patrick Hospital - Community Hospital
state: Montana
city: Missoula
country: United States
facility: Guardian Oncology and Center for Wellness
state: Montana
city: Albuquerque
country: United States
facility: University of New Mexico Cancer Center
state: New Mexico
city: Elmira
country: United States
facility: Arnot Ogden Medical Center
state: New York
city: Rochester
country: United States
facility: Highland Hospital
state: New York
city: Rochester
country: United States
facility: Interlakes Foundation Inc-Rochester
state: New York
city: Rochester
country: United States
facility: University of Rochester
state: New York
city: Asheboro
country: United States
facility: Randolph Hospital
state: North Carolina
city: Charlotte
country: United States
facility: Carolinas Medical Center
state: North Carolina
city: Charlotte
country: United States
facility: Presbyterian Hospital
state: North Carolina
city: Goldsboro
country: United States
facility: Wayne Memorial Hospital
state: North Carolina
city: Greensboro
country: United States
facility: Cone Health Cancer Center
state: North Carolina
city: Hendersonville
country: United States
facility: Margaret R Pardee Memorial Hospital
state: North Carolina
city: Reidsville
country: United States
facility: Annie Penn Memorial Hospital
state: North Carolina
city: Akron
country: United States
facility: Akron General Medical Center
state: Ohio
city: Cincinnati
country: United States
facility: Veterans Administration Medical Center - Cincinnati
state: Ohio
city: Cincinnati
country: United States
facility: University of Cincinnati
state: Ohio
city: Charleston
country: United States
facility: Medical University of South Carolina
state: South Carolina
city: Amarillo
country: United States
facility: The Don and Sybil Harrington Cancer Center
state: Texas
city: Galveston
country: United States
facility: University of Texas Medical Branch at Galveston
state: Texas
city: Houston
country: United States
facility: Baylor College of Medicine
state: Texas
city: Houston
country: United States
facility: Ben Taub General Hospital
state: Texas
city: Houston
country: United States
facility: Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Saint Luke's Episcopal Hospital
state: Texas
city: Houston
country: United States
facility: Veterans Administration Medical Center
state: Texas
city: Temple
country: United States
facility: Scott and White Memorial Hospital
state: Texas
city: American Fork
country: United States
facility: American Fork Hospital
state: Utah
city: Cedar City
country: United States
facility: Sandra L Maxwell Cancer Center
state: Utah
city: Logan
country: United States
facility: Logan Regional Hospital
state: Utah
city: Murray
country: United States
facility: Intermountain Medical Center
state: Utah
city: Ogden
country: United States
facility: McKay-Dee Hospital Center
state: Utah
city: Provo
country: United States
facility: Utah Valley Regional Medical Center
state: Utah
city: Saint George
country: United States
facility: Dixie Medical Center Regional Cancer Center
state: Utah
city: Salt Lake City
country: United States
facility: Intermountain Health Care
state: Utah
city: Salt Lake City
country: United States
facility: Utah Cancer Specialists-Salt Lake City
state: Utah
city: Salt Lake City
country: United States
facility: LDS Hospital
state: Utah
city: Martinsville
country: United States
facility: Memorial Hospital Of Martinsville
state: Virginia
city: Bellingham
country: United States
facility: PeaceHealth Saint Joseph Medical Center
state: Washington
city: Bremerton
country: United States
facility: Harrison Bremerton Hematology and Oncology
state: Washington
city: Kennewick
country: United States
facility: Columbia Basin Hematology and Oncology PLLC
state: Washington
city: Mount Vernon
country: United States
facility: Skagit Valley Hospital
state: Washington
city: Poulsbo
country: United States
facility: Harrison Poulsbo Hematology and Oncology
state: Washington
city: Seattle
country: United States
facility: Harborview Medical Center
state: Washington
city: Seattle
country: United States
facility: Minor and James Medical PLLC
state: Washington
city: Seattle
country: United States
facility: Fred Hutchinson Cancer Research Center/University of Washington Cancer Consortium
state: Washington
city: Seattle
country: United States
facility: Group Health Cooperative
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Seattle
country: United States
facility: The Polyclinic
state: Washington
city: Seattle
country: United States
facility: University of Washington Medical Center
state: Washington
city: Spokane
country: United States
facility: Cancer Care Northwest - Spokane South
state: Washington
city: Spokane
country: United States
facility: Evergreen Hematology and Oncology PS
state: Washington
city: Wenatchee
country: United States
facility: Wenatchee Valley Medical Center
state: Washington
city: Casper
country: United States
facility: Rocky Mountain Oncology
state: Wyoming
city: Sheridan
country: United States
facility: Welch Cancer Center
state: Wyoming
Study officials:
affiliation: SWOG Cancer Research Network
name: Philip Philip
role: PRINCIPAL_INVESTIGATOR
References: