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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.
 
ClinicalTrials.gov Identifier: NCT02393755
Recruitment Status : Active, not recruiting
First Posted : March 19, 2015
Results First Posted : July 7, 2020
Last Update Posted : July 7, 2020
Sponsor:
Collaborators:
National Cancer Institute (NCI)
Boehringer Ingelheim
National Comprehensive Cancer Network
Information provided by (Responsible Party):
Roswell Park Cancer Institute

Tracking Information
First Submitted Date  ICMJE March 13, 2015
First Posted Date  ICMJE March 19, 2015
Results First Submitted Date  ICMJE July 12, 2019
Results First Posted Date  ICMJE July 7, 2020
Last Update Posted Date July 7, 2020
Actual Study Start Date  ICMJE May 8, 2015
Actual Primary Completion Date November 1, 2017   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 3, 2020)
  • To Examine the DLT [ Time Frame: At least 21 days. ]
    The recommended Phase II dose is of the Nintedanib and Capecitabine combination is defined as the dose level that causes dose limiting toxicities (DLTs) in ≤ 1 out of 6 patients at highest dose level below the maximally administered dose. Capecitabine is fixed dose at 2000 mg/m2; while Nintedanib is evaluated at 150mg (dose level 1) and 200 mg (dose level 2).
  • 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 ]
    Progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions (the sum must also demonstrate an absolute increase of at least 5 mm) or the appearance of new lesions. Will be summarized using standard Kaplan-Meier methods.
Original Primary Outcome Measures  ICMJE
 (submitted: March 13, 2015)
  • 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.
  • 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.
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 3, 2020)
  • Median PFS (Phase II) [ Time Frame: Up to 2 years ]
    Progressive disease is defined as at least a 20% increase in the sum of diameters of target lesions (the sum must also demonstrate an absolute increase of at least 5 mm) or the appearance of new lesions. Estimates of median PFS will be obtained with corresponding 90% confidence intervals.
  • Median OS (Phase II) [ Time Frame: From the date of enrollment to the time of death, assessed up to 2 years ]
    Overall survival is defined as time from date of subject enrollment to the date of death due to any cause. Estimates of median OS will be obtained with corresponding 90% confidence intervals.
  • Objective Response Rate [ Time Frame: After every 3 cycles (9 weeks) of therapy. ]
    Overall Response is defined as Complete Response: Disappearance of all target lesions and any lymph nodes must have a reduction in short axis to < 10 mm; or Partial Response: At least a 30% decrease in the sum of diameters of target lesions; or Stable Disease: Neither sufficient shrinkage to qualify for partial response, nor sufficient increase to qualify for progressive disease.
  • 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 ]
    Number of Participants with Adverse Events, Graded According to the CTEP NCI Common Terminology Criteria for Adverse Events (CTCAE Version 4.0).
Original Secondary Outcome Measures  ICMJE
 (submitted: March 13, 2015)
  • Median PFS (Phase II) [ Time Frame: Up to 2 years ]
    Estimates of median PFS will be obtained with corresponding 90% confidence intervals.
  • 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.
  • 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.
  • 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.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Nintedanib and Capecitabine in Treating Patients With Refractory Metastatic Colorectal Cancer
Official Title  ICMJE A Phase I/II Study of Nintedanib and Capecitabine in Refractory Metastatic Colorectal Cancer
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.
Detailed Description

PRIMARY OBJECTIVES:

  • 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)

SECONDARY OBJECTIVES:

  • 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)

TERTIARY OBJECTIVES:

  • 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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • 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
Intervention  ICMJE
  • 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
Study Arms  ICMJE
  • Experimental: Treatment (capecitabine, nintedanib)
    Patients received capecitabine PO BID (every 12 hours) on days 1-14 and nintedanib PO BID (every 12 hours) on days 1-21. Courses repeated every 21 days in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Capecitabine
    • Other: Laboratory Biomarker Analysis
    • Drug: Nintedanib
    • Other: Pharmacological Study
  • Experimental: Treatment (capecitabine , nintendanib)
    Patients receive the highest safe dose of the combination of nintedanib and capcitabine.
    Intervention: Drug: Nintedanib
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Active, not recruiting
Actual Enrollment  ICMJE
 (submitted: July 3, 2020)
42
Original Estimated Enrollment  ICMJE
 (submitted: March 13, 2015)
48
Estimated Study Completion Date  ICMJE January 1, 2021
Actual Primary Completion Date November 1, 2017   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02393755
Other Study ID Numbers  ICMJE 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 )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party Roswell Park Cancer Institute
Study Sponsor  ICMJE Roswell Park Cancer Institute
Collaborators  ICMJE
  • National Cancer Institute (NCI)
  • Boehringer Ingelheim
  • National Comprehensive Cancer Network
Investigators  ICMJE
Principal Investigator: Christos Fountzilas Roswell Park Cancer Institute
PRS Account Roswell Park Cancer Institute
Verification Date July 2020

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP