Nintedanib and Capecitabine in Treating Patients With Refractory Metastatic Colorectal Cancer

A Phase I/II Study of Nintedanib and Capecitabine in Refractory Metastatic Colorectal Cancer

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.

Study Overview

• Status: Completed
• Conditions: Recurrent Colon Carcinoma; Recurrent Rectal Carcinoma; Rectal Adenocarcinoma; Colon Adenocarcinoma; Stage IVA Colon Cancer; Stage IVA Rectal Cancer; Stage IVB Colon Cancer; Stage IVB Rectal Cancer
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Nintedanib; Drug: Capecitabine

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: Interventional
• Enrollment (Actual): 42
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• United States
  • California
    • Duarte, California, United States, 91010
      • City of Hope Comprehensive Cancer Center
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
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.	Other: Laboratory Biomarker Analysis; Correlative studies; Other: Pharmacological Study; 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; Drug: Capecitabine; Given PO; Other Names: Xeloda; Ro 09-1978/000
Experimental: Treatment (capecitabine , nintendanib); Patients receive the highest safe dose of the combination of nintedanib and capcitabine.	Drug: Nintedanib; Given PO; Other Names: BIBF 1120; BIBF-1120; Intedanib; Multitargeted Tyrosine Kinase Inhibitor BIBF 1120; tyrosine kinase inhibitor BIBF 1120; Vargatef

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
To Examine the DLT	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).	At least 21 days.
Progression Free Survival (PFS) Rate, Defined as the Proportion of Patients Who Survive Without Disease Progression Via the RECIST Version 1.1 (Phase II)	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.	At 18 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Median PFS (Phase II)	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.	Up to 2 years
Median OS (Phase II)	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.	From the date of enrollment to the time of death, assessed up to 2 years
Objective Response Rate	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.	After every 3 cycles (9 weeks) of therapy.
Aggregate Rates of Adverse Events Measured by CTCAE Version 4.0 (Phase II)	Number of Participants with Adverse Events, Graded According to the CTEP NCI Common Terminology Criteria for Adverse Events (CTCAE Version 4.0).	Up to 30 days after the last dose of study drug

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: National Cancer Institute (NCI); Boehringer Ingelheim; National Comprehensive Cancer Network
• Investigators: Principal Investigator: Christos Fountzilas, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): May 8, 2015
• Primary Completion (Actual): November 1, 2017
• Study Completion (Actual): May 18, 2021

Study Registration Dates

• First Submitted: March 13, 2015
• First Submitted That Met QC Criteria: March 13, 2015
• First Posted (Estimate): March 19, 2015

Study Record Updates

• Last Update Posted (Actual): July 8, 2021
• Last Update Submitted That Met QC Criteria: July 6, 2021
• Last Verified: July 1, 2021

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Pathologic Processes; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Disease Attributes; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms; Carcinoma; Recurrence; Adenocarcinoma; Rectal Neoplasms; Colonic Neoplasms; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Protein Kinase Inhibitors; Capecitabine; Nintedanib
• Other Study ID Numbers: I 265514 (Other Identifier: Roswell Park Cancer Institute); P30CA016056 (U.S. NIH Grant/Contract); NCI-2015-00223 (Registry Identifier: CTRP (Clinical Trial Reporting Program))