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

Study Overview

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

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.

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.

Stage IV Pancreatic Cancer

BIOLOGICAL: cixutumumab
DRUG: erlotinib hydrochloride
DRUG: gemcitabine hydrochloride

NCI-2009-00797
NCI-2009-00797 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))
CDR0000586427
SWOG-S0727
S0727 (OTHER Identifier) (OTHER: Southwest Oncology Group)
S0727 (OTHER Identifier) (OTHER: CTEP)
U10CA032102 (U.S. NIH Grant/Contract)

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2008-02-15	Results First Submitted 2013-10-07	Last Update Submitted that met QC Criteria 2022-01-13
First Submitted that Met QC Criteria 2008-02-15	Results First Submitted that Met QC Criteria 2013-10-07	Last Update Posted (ACTUAL) 2022-02-08
First Posted (ACTUAL) 2008-02-18	Results First Posted 2013-12-05	Last Verified 2022-01

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Treatment

Allocation:
Randomized

Interventional Model:
Parallel

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
EXPERIMENTAL: Arm I (erlotinib, gemcitabine, cixutumumab) Patients receive erlotinib hydrochloride PO once daily on days 1-28, gemcitabine hydrochloride 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	BIOLOGICAL: cixutumumab Given IV DRUG: erlotinib hydrochloride Given PO DRUG: gemcitabine hydrochloride Given IV
ACTIVE_COMPARATOR: Arm II (erlotinib, gemcitabine) Patients receive erlotinib hydrochloride and gemcitabine hydrochloride as in arm I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.	DRUG: erlotinib hydrochloride Given PO DRUG: gemcitabine hydrochloride Given IV

Participant Group/Arm

Intervention/Treatment

EXPERIMENTAL: Arm I (erlotinib, gemcitabine, cixutumumab)

Patients receive erlotinib hydrochloride PO once daily on days 1-28, gemcitabine hydrochloride 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

BIOLOGICAL: cixutumumab

Given IV

DRUG: erlotinib hydrochloride

Given PO

DRUG: gemcitabine hydrochloride

Given IV

ACTIVE_COMPARATOR: Arm II (erlotinib, gemcitabine)

Patients receive erlotinib hydrochloride and gemcitabine hydrochloride as in arm I. Treatment repeats every 28 days in the absence of disease progression or unacceptable toxicity.

DRUG: erlotinib hydrochloride

Given PO

DRUG: gemcitabine hydrochloride

Given IV

Primary Outcome Measures	Measure Description	Time Frame
Maximum Tolerated Dose Determination	Maximum dose of IMC-A12 (in combination with erlotinib and gemcitabine) at which 3/10 or fewer patients have dose-limiting toxicities (DLT). Toxicities graded according to the NCI Common Terminology Criteria for Adverse Events Version 3.0 (CTCAE 3.0). DLT apply only during cycle 1 and should be drug-related (possible, probable, or definite).	28 days
Progression-Free Survival	From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.	Up to 3 years

Secondary Outcome Measures	Measure Description	Time Frame
Overall Survival	From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.	Up to 3 years
Response	Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.	Up to 3 years
Toxicity	Number of patients with Grade 3 through 5 adverse events that are related to study drug. Only adverse events that are possibly, probably or definitely related to study drug are reported.	Up to 3 years

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Philip Philip, SWOG Cancer Research Network

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

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