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Nintedanib and Capecitabine in Treating Patients With Refractory Metastatic Colorectal Cancer

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02393755
Recruitment Status : Active, not recruiting
First Posted : March 19, 2015
Last Update Posted : January 15, 2019
National Cancer Institute (NCI)
Boehringer Ingelheim
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Brief Summary:
This phase I/II trial studies the side effects and best dose of nintedanib when given together with capecitabine and to see how well they work in treating patients with colorectal cancer that has not responded to previous treatment (refractory) and has spread to other places in the body (metastatic). Nintedanib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. It may also block the growth of new blood vessels necessary for tumor growth. Drugs used in chemotherapy, such as capecitabine, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving nintedanib with capecitabine may be a better treatment for colorectal cancer.

Condition or disease Intervention/treatment Phase
Colon Adenocarcinoma Rectal Adenocarcinoma Recurrent Colon Carcinoma Recurrent Rectal Carcinoma Stage IVA Colon Cancer Stage IVA Rectal Cancer Stage IVB Colon Cancer Stage IVB Rectal Cancer Drug: Capecitabine Other: Laboratory Biomarker Analysis Drug: Nintedanib Other: Pharmacological Study Phase 2

Detailed Description:


I. To estimate the maximum tolerated dose (MTD) and examine the dose-limiting toxicities of nintedanib when administered with capecitabine within the study population and, establish the recommended phase II dose (RP2D). (Phase I) II. To assess progression free survival at 18 weeks. (Phase II)


I. To assess median progression free survival. (Phase II) II. To assess median overall survival from the date of enrollment to the time of death will be documented. (Phase II) III. To assess the objective response rate as measured by Response Evaluation Criteria in Solid Tumors (RECIST) version (v) 1.1. (Phase II) IV. To assess the toxicity of dose regimen using the Cancer Therapy Evaluation Program (CTEP) National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE version 4.0). (Phase II)


I. Measurement of circulating angiogenic cytokines (CAFs): vascular endothelial growth factor (VEGF), soluble vascular endothelial growth factor receptor (sVEGFR) 1/2, placental growth factor (PlGF), granulocyte macrophage colony-stimulating factor (GMCSF), leptin, interleukin (IL)-1 alpha (a), IL-8, IL-6, fibroblast growth factor basic (FGFb), osteopontin and pentraxin-3. (Phase II) II. Measurement of drug levels and pharmacokinetic (PK)/pharmacodynamic (PD) modeling. (Phase II)

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

Patients receive capecitabine orally (PO) twice daily (BID) (every 12 hours) on days 1-14 and nintedanib PO BID (every 12 hours) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days, every 28 days until resolution or satisfactory stabilization of persistent drug-related toxicity, and then every 6 months thereafter.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 39 participants
Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase I/II Study of Nintedanib and Capecitabine in Refractory Metastatic Colorectal Cancer
Actual Study Start Date : May 8, 2015
Actual Primary Completion Date : November 1, 2017
Estimated Study Completion Date : April 1, 2019

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Treatment (capecitabine, nintedanib)
Patients receive capecitabine PO BID (every 12 hours) on days 1-14 and nintedanib PO BID (every 12 hours) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Drug: Capecitabine
Given PO
Other Names:
  • Ro 09-1978/000
  • Xeloda

Other: Laboratory Biomarker Analysis
Correlative studies

Drug: Nintedanib
Given PO
Other Names:
  • BIBF 1120
  • BIBF-1120
  • Intedanib
  • Multitargeted Tyrosine Kinase Inhibitor BIBF 1120
  • tyrosine kinase inhibitor BIBF 1120
  • Vargatef

Other: Pharmacological Study
Correlative studies

Primary Outcome Measures :
  1. Progression free survival (PFS) rate, defined as the proportion of patients who survive without disease progression via the RECIST version 1.1 (Phase II) [ Time Frame: At 18 weeks ]
    Will be summarized using standard Kaplan-Meier methods.

  2. RP2D of nintedanib in combination with capecitabine (Phase I) [ Time Frame: 21 days ]
    The RP2D will be considered tolerable if dose-limiting toxicities are observed in at most 1 of 6 patients completing at least 2 treatment cycles at that dose level. Toxicity will be graded according to the CTCAE version 4.0.

Secondary Outcome Measures :
  1. Aggregate rates of adverse events measured by CTCAE version 4.0 (Phase II) [ Time Frame: Up to 30 days after the last dose of study drug ]
    The frequency of toxicities will be tabulated by grade across all dose levels and cycles. The frequency of toxicities will also be tabulated for the dose estimated to be the MTD. The observed toxicities and adverse events will be reported as frequencies and relative frequencies, with toxicity rates estimated by 90% Wilson confidence intervals.

  2. Median OS (Phase II) [ Time Frame: From the date of enrollment to the time of death, assessed up to 2 years ]
    Estimates of median OS will be obtained with corresponding 90% confidence intervals.

  3. Median PFS (Phase II) [ Time Frame: Up to 2 years ]
    Estimates of median PFS will be obtained with corresponding 90% confidence intervals.

  4. Overall survival (OS) [ Time Frame: Time from treatment until the survival event or censoring, assessed up 2 years ]
    Will be summarized using standard Kaplan-Meier methods.

Information from the National Library of Medicine

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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Have an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1
  • Hemoglobin >= 9 g/dL
  • Absolute neutrophil count >= 1500/mm^3
  • Platelet count >= 100,000/mm^3
  • Creatinine =< 1.5 upper limit of normal (ULN) AND creatinine clearance (CrCl) > 50 mL/min by Cockcroft-Gault equation
  • Males = (140 -age (yrs) (body weight (kg)/(72) (serum creatinine) (mg/dL)
  • Females = 0.85 * (140-age (yrs) (body weight (kg)/(72)(serum creatinine (mg/dL)
  • Bilirubin < ULN
  • Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) =< 1.5 ULN if without liver metastases
  • AST/ALT =< 2.5 x ULN if with liver metastases
  • Coagulation parameters: international normalized ratio (INR) =< 2, prothrombin time (PT) and partial thromboplastin time (PTT) < 1.5 X institutional ULN
  • Have measurable disease per RECIST 1.1 criteria
  • Histologically or cytologically proven adenocarcinoma of the colon or rectum
  • Prior progression following a fluoropyrimidine-based therapy and progression following or intolerance to irinotecan and oxaliplatin, as well as anti-epidermal growth factor receptor (EGFR) therapy (e.g., panitumumab or cetuximab) for rat sarcoma viral oncogene homolog (RAS) wild-type patients
  • Ability to swallow and retain oral medication
  • Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry and for three months following completion of therapy; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
  • Participant or legal representative must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

  • Prior treatment with nintedanib
  • Prior treatment with regorafenib
  • Major injuries or surgery within the 4 weeks prior to initiation of therapy with incomplete wound healing or planned surgery during the on-study treatment period
  • Uncontrolled hypertension: systolic blood pressure >= 160, diastolic blood pressure >= 90
  • Urine protein/creatinine ratio >= 1.0
  • History of clinically significant hemorrhagic or thrombotic event within the past 6 months, not including uncomplicated catheter-associated venous thrombosis; patients on anti-coagulation are not permitted to be on any oral formulations (warfarin, rivaroxaban, dabigatran, etc.) due to concern for drug-drug interaction
  • Unstable angina, symptomatic congestive heart failure or cardiac arrhythmia requiring anti-arrhythmic therapy (beta-blockers, calcium channel blockers and digoxin are allowed)
  • History of cerebrovascular or myocardial ischemia within 6 months of initiation
  • Known inherited predisposition to bleeding or thrombosis
  • Known active or chronic hepatitis B or C or human immunodeficiency virus (HIV)
  • Untreated brain metastases
  • History of second primary malignancy diagnosed within 3 years prior to enrollment, excluding:

    • In-situ cervical carcinoma
    • Superficial bladder cancer
    • Non-melanoma skin cancer
    • Stage I breast cancer
    • Low grade (Gleason =< 6) localized prostate cancer
    • Any additional malignancy which has been in clinical remission for at least 1 year
  • Pregnant or nursing female participants
  • Unwilling or unable to follow protocol requirements
  • Any condition which in the Investigator's opinion deems the participant an unsuitable candidate to receive study drug
  • Received an investigational agent within 4 weeks prior to enrollment
  • PHASE I: History of intolerance to capecitabine at doses =< 1000 mg/m^2 BID, as defined by documented >= grade 3 hand-foot syndrome, documented severe diarrhea requiring hospitalization, or other documented severe adverse events (AEs) attributable to capecitabine
  • PHASE II: History of intolerance to capecitabine at doses below 1000 mg/m^2 BID, as defined by documented >= grade 3 hand-foot syndrome; documented severe diarrhea requiring hospitalization; or other documented severe AEs attributable to capecitabine

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02393755

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United States, California
City of Hope Comprehensive Cancer Center
Duarte, California, United States, 91010
United States, New York
Roswell Park Cancer Institute
Buffalo, New York, United States, 14263
Sponsors and Collaborators
Roswell Park Cancer Institute
National Cancer Institute (NCI)
Boehringer Ingelheim
National Comprehensive Cancer Network
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Principal Investigator: Patrick Boland Roswell Park Cancer Institute
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Responsible Party: Roswell Park Cancer Institute Identifier: NCT02393755    
Other Study ID Numbers: I 265514
NCI-2015-00223 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
I 265514 ( Other Identifier: Roswell Park Cancer Institute )
P30CA016056 ( U.S. NIH Grant/Contract )
First Posted: March 19, 2015    Key Record Dates
Last Update Posted: January 15, 2019
Last Verified: January 2019
Additional relevant MeSH terms:
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Rectal Neoplasms
Colonic Neoplasms
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Colorectal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Enzyme Inhibitors