Combination Chemotherapy with or without Regorafenib in Treating Patients with Metastatic Colorectal Cancer

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Basic Trial Information

PhaseTypeAgeTrial IDs
Phase IIBiomarker/Laboratory analysis, Treatment18 and overLCCC 1029
NCI-2013-00954, 10-2176, NCT01298570

Trial Description

Summary

This randomized phase II trial studies how well combination chemotherapy with or without regorafenib works in treating patients with colorectal cancer that has spread to other areas of the body. Drugs used in chemotherapy, such as leucovorin calcium, fluorouracil, and irinotecan hydrochloride, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Regorafenib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It is not yet known whether combination chemotherapy is more effective with or without regorafenib in treating colorectal cancer.

Further Study Information

PRIMARY OBJECTIVES:

I. To compare progression-free survival (PFS) between regorafenib + leucovorin calcium, fluorouracil, and irinotecan hydrochloride (FOLFIRI) chemotherapy (ARM A) versus placebo + FOLFIRI (ARM B) in patients failing one prior oxaliplatin-containing regimen for metastatic colorectal cancer (mCRC).

SECONDARY OBJECTIVES:

I. To compare overall response (OR) rates (OR; complete response [CR] + partial response [PR]) between ARM A and ARM B as defined via Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).

II. To compare the disease control (DC) rate (DC; CR + PR + stable disease [SD]) between ARM A and ARM B as defined via RECIST 1.1.

III. To compare overall survival (OS) between ARM A and ARM B.

IV. To evaluate the effect of regorafenib on the pharmacokinetic (PK) profile of irinotecan (irinotecan hydrochloride) and liposomal SN-38 (SN-38).

V. To further evaluate the safety and tolerability of regorafenib in combination with FOLFIRI.

TERTIARY OBJECTIVES:

I. To explore potential correlations between blood and tissue biomarkers and clinical benefit.

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM A: Patients receive irinotecan hydrochloride intravenously (IV) over 90 minutes, leucovorin calcium IV over 2 hours, and fluorouracil IV over 46 hours on days 1 and 15 and regorafenib orally (PO) once daily (QD) on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM B: Patients receive irinotecan hydrochloride, leucovorin calcium, and fluorouracil as in Arm A and placebo PO QD on days 4-10 and 18-24. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, and then every 3 months for 2 years and every 6 months for 3 years.

Eligibility Criteria

Inclusion Criteria:

Progression during or within 6 months following administration of a standard regimen for treatment of metastatic disease that included oxaliplatin with any of the following agents with or without bevacizumab:

5-fluorouracil (5-FU) with or without leucovorin or levoleucovorin

Capecitabine

NOTE: in patients receiving FOLFOX, oxaliplatin is sometimes discontinued due to toxicity or as part of maintenance therapy strategy; if such patients progress while on 5-FU alone, they are eligible for this trial; as an example, a patient who is begun on FOLFOX or CapeOx (with or without bevacizumab), whose oxaliplatin is held for neurotoxicity and who is switched to capecitabine monotherapy or capecitabine with bevacizumab, would be considered to have had ONE prior therapy OR patients who develop metastatic disease within 9 months of adjuvant FOLFOX for stage II or III colon cancer

Signed, Institutional Review Board (IRB)-approved written informed consent

The subject is capable of understanding and complying with parameters as outlined in the protocol

Women of childbearing potential and male subjects must agree to use adequate contraception for the duration of study participation and up to 6 months following completion of therapy; adequate contraception is defined as any medically recommended method (or combination of methods) as per standard of care

International normalized ratio (INR)/partial thromboplastin time (PTT) =< 1.5 x ULN

Patients who are therapeutically treated with an agent such as warfarin or heparin will be allowed to participate provided that no prior evidence of underlying abnormality in coagulation parameters exists; close monitoring of at least weekly evaluations will be performed until INR/PTT is stable based on a measurement that is pre-dose as defined by the local standard of care

Alkaline phosphatase =< 3 x ULN (=< 5 x ULN with liver involvement of their cancer)

Bilirubin =< 1.5 x ULN

Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) =< 3 x ULN (=< 5.0 x ULN for patients with liver involvement of their cancer)

Glomerular filtration rate (GFR) >= 30 ml/min/1.73m^2

Serum creatinine =< 1.5 x upper limit of normal (ULN)

Hemoglobin >= 9.0 g/dL

Platelets >= 100,000/mm^3

Absolute neutrophil count (ANC) >= 1,500/mm^3

Life expectancy of at least 3 months

Eastern Cooperative Oncology Group (ECOG) performance status =< 1

Measurable disease, defined as at least 1 unidimensionally measurable lesion on a computed tomography (CT) scan as defined by RECIST 1.1

Metastatic disease not amenable to surgical resection with curative intent

Archived, paraffin-embedded tissue block (primary or metastatic) available for genomic studies required

Histological or cytological documentation of adenocarcinoma of the colon or rectum

Spot urine must not show 1+ or more protein in urine or the patient will require a repeat urinalysis; if repeat urinalysis shows 1+ protein or more, a 24-hour urine collection will be required and must show total protein excretion < 1000 mg/24 hours

Amylase and lipase =< 1.5 x ULN

Exclusion Criteria:

Unwilling to avoid vaccinations with live vaccine and concomitant use of attenuated live vaccines

Patients unable or unwilling to discontinue (and substitute if necessary) use of prohibited drugs for at least 30 days prior to day 1 of FOLFIRI initiation

Unresolved toxicity higher than CTCAE v. 4.0 grade 1 attributed to any prior therapy/procedure excluding alopecia and oxaliplatin-induced neurotoxicity (which must be =< grade 2)

Any malabsorption condition

Inability to swallow oral medications

Interstitial lung disease with ongoing signs and symptoms at the time of informed consent

Known hypersensitivity to any of the study drugs, study drug classes, or excipients in the formulation

Substance abuse, medical, psychological, or social conditions that may interfere with the patient’s participation in the study or evaluation of the study results

Dehydration according to NCI-Common Toxicity Criteria (CTC) v 4.0 grade >= 1

Renal failure requiring hemo- or peritoneal dialysis

Non-healing wound, ulcer, or bone fracture

Evidence or history of bleeding diathesis; any hemorrhage or bleeding event >= grade 4 within 4 weeks of start of FOLFIRI

History of organ allograft

Symptomatic metastatic brain or meningeal tumors unless the patient is > 6 months from definitive therapy, has a negative imaging study within 4 weeks of FOLFIRI initiation, and is clinically stable with respect to the tumor at the time of study entry; also, the patient must not be undergoing acute steroid therapy or taper (chronic steroid therapy is acceptable provided that the dose is stable for one month prior to and following screening radiographic studies)

Known history of chronic hepatitis B or C

Known history of human immunodeficiency virus (HIV) infection

Ongoing infection > grade 2 according to National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events version 4.0 (CTCAE v. 4.0)

Arterial thrombotic or embolic events such as cerebrovascular accident (including transient ischemic attacks), or pulmonary embolism within the 6 months before start of FOLFIRI

Patients with pheochromocytoma

Active cardiac disease including any of the following:

Congestive heart failure (New York Heart Association [NYHA]) >= class 2

Unstable angina (angina symptoms at rest), new-onset angina (begun within the last 3 months); myocardial infarction less than 6 months before start of day 1 of FOLFIRI

Cardiac arrhythmias requiring anti-arrhythmic therapy (beta blockers or digoxin are permitted)

Uncontrolled hypertension; (systolic blood pressure > 150 mmHg or diastolic pressure > 90 mmHg despite optimal medical management)

Radiotherapy within 4 weeks prior to first dose of FOLFIRI

Major surgical procedure, open biopsy, or significant traumatic injury within 28 days before start of day 1 of treatment with FOLFIRI

Pernicious anemia or other anemias due to vitamin B12 deficiency (due to potential masking of deficiency with leucovorin)

Known dihydropyrimidine dehydrogenase (DPD) deficiency

History of Gilbert’s syndrome

Pregnant or breastfeeding patients; women of childbearing potential must have a pregnancy test performed a maximum of 7 days before start of FOLFIRI treatment, and a negative result must be documented before start of treatment

Known history of or concomitant malignancy likely to affect life expectancy in the judgment of the investigator

More than 1 prior chemotherapy regimen for mCRC; previous adjuvant FOLFOX based chemotherapy is allowed; prior FOLFIRI or single agent irinotecan is prohibited

Prior treatment with regorafenib

Any chronic inflammatory bowel disease and/or chronic bowl obstruction

Unwilling to provide consent for genetic studies of tumor, whole blood, or plasma specimens

Patients with seizure disorder requiring medication

Trial Contact Information

Trial Lead Organizations / Sponsors / Collaborators

University of North Carolina at Chapel Hill

  • National Cancer Institute
Hanna Kelly Sanoff, Principal Investigator

Trial Sites

U.S.A.

Colorado
Denver

Rocky Mountain Cancer Centers-Midtown

Allen Lee Cohn
Ph: 303-388-4876
Email: allen.cohn@usoncology.com

Allen Lee Cohn
Principal Investigator

Florida
Miami Beach

Mount Sinai Medical Center

Joseph Frank Pizzolato
Ph: 305-535-3300
Email: JPizzolato@aptiumoncology.com

Joseph Frank Pizzolato
Principal Investigator

Tampa

Moffitt Cancer Center

Richard D. Kim
Ph: 813-745-1277
Email: richard.kim@moffitt.org

Richard D. Kim
Principal Investigator

Georgia
Sandy Springs

Georgia Cancer Specialists- Northside

Mansoor N. Saleh
Ph: 404-256-4777
Email: mns@uab.edu

Mansoor N. Saleh
Principal Investigator

Illinois
Evanston

NorthShore University HealthSystem-Evanston Hospital

Robert de Wilton Marsh
Ph: 847-570-2112
Email: rmarsh@northshore.org

Robert de Wilton Marsh
Principal Investigator

Indiana
Indianapolis

IU Health Central Indiana Cancer Centers-East

Paul R. Helft
Ph: 317-948-6942
Email: phelft@iu.edu

Paul R. Helft
Principal Investigator

Kentucky
Louisville

Baptist Health Louisville

Wangjian Zhong
Ph: 502-897-1166
Email: wzhong@bhsi.com

Wangjian Zhong
Principal Investigator

The James Graham Brown Cancer Center at University of Louisville

Rebecca A. Redman
Ph: 502-562-4370
Email: raredm01@louisville.edu

Rebecca A. Redman
Principal Investigator

New Jersey
New Brunswick

Rutgers Cancer Institute of New Jersey

Rebecca A. Moss
Ph: 732-235-8663
Email: mossr1@umdnj.edu

Rebecca A. Moss
Principal Investigator

New York
New Hyde Park

Long Island Jewish Medical Center

Craig E. DeVoe
Ph: 516-734-8874
Email: edevoe@nshs.edu

Craig E. DeVoe
Principal Investigator

New York

Laura and Issac Perlmutter Cancer Center at NYU Langone

Theresa Ryan
Ph: 212-731-5430
Email: Theresa.Ryan@nyumc.org

Theresa Ryan
Principal Investigator

North Carolina
Boone

Seby B. Jones Cancer Center

Anna Sobol
Ph: 828-265-5008
Email: asobol@apprhs.org

Anna Sobol
Principal Investigator

Burlington

Cone Health Cancer Center at Alamance Regional

Timothy John Finnegan
Ph: 336-538-7725
Email: finntimo@armc.com

Timothy John Finnegan
Principal Investigator

Chapel Hill

University of North Carolina at Chapel Hill

Hanna Kelly Sanoff
Ph: 919-966-4431
Email: hanna_sanoff@med.unc.edu

Hanna Kelly Sanoff
Principal Investigator

Goldsboro

Southeastern Medical Oncology Center-Goldsboro

Samer S. Kasbari
Ph: 919-580-0000
Email: skasbari@cancersmoc.com

Samer S. Kasbari
Principal Investigator

Greensboro

Cone Health Cancer Center

Gary Bradley Sherrill
Ph: 336-832-1100
Email: gary.sherrill@mosescone.com

Gary Bradley Sherrill
Principal Investigator

Greenville

East Carolina University

Prashanti Atluri
Ph: 252-744-3326
Email: atlurip@ecu.edu

Prashanti Atluri
Principal Investigator

New Bern

New Bern Cancer Care

W. Chris Taylor
Ph: 252-636-5135
Email: ctaylor@cchealthcare.com

W. Chris Taylor
Principal Investigator

Pinehurst

FirstHealth of the Carolinas-Moore Regional Hosiptal

Todd Anthony Moore
Ph: 910-715-3517
Email: tamoore@firsthealth.org

Todd Anthony Moore
Principal Investigator

Raleigh

Rex Cancer Center

Oludamilola Abidemi Olajide
Ph: 919-784-6818
Email: Lola.Olajide@rexhealth.com

Oludamilola Abidemi Olajide
Principal Investigator

Rocky Mount

Nash General Hospital

Xiang Sean Wang
Ph: 252-937-0249
Email: swang@boice-willis.com

Xiang Sean Wang
Principal Investigator

Washington

Marion L Shepard Cancer Center at Vidant Beaufort Hospital

John Joseph Inzerillo
Ph: 252-975-4308
Email: John.Inzerillo@VidantHealth.com

John Joseph Inzerillo
Principal Investigator

Winston-Salem

Comprehensive Cancer Center of Wake Forest University

George Yacoub
Ph: 336-716-6846
Email: gyacoub@wakehealth.edu

George Yacoub
Principal Investigator

Ohio
Cincinnati

University of Cincinnati

Olugbenga Olowokure (Gbenga)
Ph: 513-584-6131
Email: olowokoo@ucmail.uc.edu

Olugbenga Olowokure (Gbenga)
Principal Investigator

Columbus

Ohio State University Comprehensive Cancer Center

Richard Miles Goldberg
Ph: 614-366-6355
Email: Jamesline@osumc.edu

Richard Miles Goldberg
Principal Investigator

South Carolina
Charleston

Medical University of South Carolina

Harry A. Drabkin
Ph: 843-792-4271
Email: drabkin@musc.edu

Harry A. Drabkin
Principal Investigator

Florence

Carolina Health Care

Asim Amin
Ph: 704-355-4162
Email: asim.amin@carolinashealthcare.org

Asim Amin
Principal Investigator

Virginia
Charlottesville

University of Virginia Cancer Center

Geoffrey Roger Weiss
Ph: 434-243-0066
Email: Grw3k@virginia.edu

Geoffrey Roger Weiss
Principal Investigator

Portsmouth

Naval Medical Center - Portsmouth

Karen Bullock Russell
Ph: 757-953-7278
Email: Karen.Russell@med.navy.mil

Karen Bullock Russell
Principal Investigator

Washington
Tacoma

MultiCare Regional Cancer Center - Tacoma

Yoshio Inoue
Ph: 253-403-1677
Email: Yoshio.inoue@multicare.org

Yoshio Inoue
Principal Investigator

Ireland

Dublin

Ireland Cooperative Oncology Research Group

John Kennedy
Ph: 353-749-1237
Email: jkennedy@stjames.ie

John Kennedy
Principal Investigator

Link to the current ClinicalTrials.gov record.
NLM Identifer NCT01298570

Note: Information about participating sites on pharmaceutical industry trials may be incomplete. Please visit the ClinicalTrials.gov record via the link above for more information about participating sites.