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Dasatinib in Preventing Oxaliplatin-Induced Peripheral Neuropathy in Patients With Colorectal Cancer Receiving FOLFOX and Bevacizumab

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ClinicalTrials.gov Identifier: NCT04164069
Recruitment Status : Recruiting
First Posted : November 15, 2019
Last Update Posted : July 31, 2020
Sponsor:
Collaborator:
National Cancer Institute (NCI)
Information provided by (Responsible Party):
Anne Noonan, Ohio State University Comprehensive Cancer Center

Tracking Information
First Submitted Date  ICMJE October 11, 2019
First Posted Date  ICMJE November 15, 2019
Last Update Posted Date July 31, 2020
Actual Study Start Date  ICMJE December 12, 2019
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: November 13, 2019)
  • Recommended phase II dose (RP2D) of dasatinib [ Time Frame: Up to 14 days ]
    The RP2D will be defined as the lowest intermittent dose of dasatinib that affects serum biomarkers of OCT2 without influencing the pharmacokinetic properties of oxaliplatin.
  • Incidence of adverse events [ Time Frame: At the end of Cycle 1 (cycle length is 28 days) ]
    The dose-limiting toxicity and toxicity profile will be based using the National Cancer Institute Common Terminology Criteria for Adverse Events version 5.0 and Chemotherapy-Induced Peripheral Neuropathy (CIPN) 20. Toxicity will be defined as adverse events deemed to be at least possibly related to dasatinib treatment. Adverse events and toxicities will be summarized by dose level, and will tabulate these events by type and severity. Will summarize the numbers of patients who required dose reductions in dasatinib or oxaliplatin and the cumulative doses received. The CIPN20 will be measured in these subjects, and will be summarized within and across dose levels, and will be used to support and inform assumptions for a subsequent phase 2 trial.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures
 (submitted: November 13, 2019)
Dasatinib on pharmacokinetics (PK) of oxaliplatin [ Time Frame: Baseline, days 1, 2, and 14 ]
Objective is to evaluate the influence of dasatinib on the pharmacokinetics of oxaliplatin and vice versa. Oxaliplatin PK will be measured at pre-dose, 1 hour, immediately prior to end of infusion of oxaliplatin, and 0.5, 1, 2, 4, and 24 hours after end of infusion on day 1; Dasatinib PK will be measured at pre-dose and 0.5, 1.5, 2.5, 3, 4.5, and 6.5 hours after taking dasatinib on day 14; PK of dasatinib and oxaliplatin will be measured on day 15 pre-dose of dasatinib, prior to starting oxaliplatin infusion, 1 hour after start of oxaliplatin infusion, immediately prior to end of infusion with oxaliplatin, and at 0.5, 1, 2, 4, and 24 hours after end of oxaliplatin infusion. PK parameters calculated using standard non-compartmental methods, and non-linear mixed effect models will be created to inform the use of limited-sampling strategies for subsequent confirmatory studies. Area Under the Curve [AUC] will be calculated for each drug Oxaliplatin - ug x h/ml and Dasatinib- ng x h/ml
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Dasatinib in Preventing Oxaliplatin-Induced Peripheral Neuropathy in Patients With Colorectal Cancer Receiving FOLFOX and Bevacizumab
Official Title  ICMJE A Phase Ib Adaptive Study Dasatinib for the Prevention of Oxaliplatin-Induced Neuropathy in Patients With Metastatic Colorectal Cancer Receiving FOLFOX Chemotherapy and Bevacizumab
Brief Summary This phase Ib trial studies side effects and best dose of dasatinib in preventing oxaliplatin-induced peripheral neuropathy in patients with stage IV colorectal cancer who are receiving FOLFOX regimen and bevacizumab. Drugs used in chemotherapy, such as leucovorin, fluorouracil, and oxaliplatin (FOLFOX regimen), 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. However, the buildup of oxaliplatin in the cranial nerves can result in damage or the nerves. Dasatinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Blocking these enzymes may reduce oxaliplatin-induced peripheral neuropathy.
Detailed Description

PRIMARY OBJECTIVES:

I. To determine the recommended phase 2 dose (RP2D) of dasatinib in combination with oxaliplatin and fluorouracil (5FU) (modified version 6 regimen of leucovorin, fluorouracil and oxaliplatin [mFOLFOX6]) with or without bevacizumab in patients with metastatic colorectal cancer, defined as the lowest intermittent dose of dasatinib that affects serum biomarkers of OCT2 without influencing the pharmacokinetic properties of oxaliplatin.

II. To determine the toxicity profile (based on Chemotherapy-Induced Peripheral Neuropathy [CIPN]20 and Common Terminology Criteria for Adverse Events [CTCAE] version [v.] 5.0) of dasatinib in combination with oxaliplatin/5-FU/bevacizumab in patients with colorectal cancer.

SECONDARY OBJECTIVES:

I. To evaluate the influence of dasatinib on the pharmacokinetics of oxaliplatin and vice versa in these patients.

OUTLINE: This is a dose-escalation study of dasatinib.

Patients receive oxaliplatin intravenously (IV) over 2 hours, leucovorin IV over 2 hours, fluorouracil slow IV push over 2-4 minutes followed by continuous infusion over 46 hours on days 1 and 15. Patients also receive dasatinib orally (PO) once daily (QD) on days 14, 15, and 28 of cycle 1 and day 1 of cycle 2. Patients may receive bevacizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to cycle 3 day 1 in the absence of disease progression or unacceptable toxicity.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: N/A
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Prevention
Condition  ICMJE
  • Advanced Colorectal Carcinoma
  • Metastatic Colorectal Carcinoma
  • Stage IV Colorectal Cancer AJCC v8
  • Stage IVA Colorectal Cancer AJCC v8
  • Stage IVB Colorectal Cancer AJCC v8
  • Stage IVC Colorectal Cancer AJCC v8
Intervention  ICMJE
  • Biological: Bevacizumab
    Given IV
    Other Names:
    • Anti-VEGF
    • Anti-VEGF Humanized Monoclonal Antibody
    • Anti-VEGF rhuMAb
    • Avastin
    • Bevacizumab awwb
    • Bevacizumab Biosimilar BEVZ92
    • Bevacizumab Biosimilar BI 695502
    • Bevacizumab Biosimilar CBT 124
    • Bevacizumab Biosimilar CT-P16
    • Bevacizumab Biosimilar FKB238
    • Bevacizumab Biosimilar HD204
    • Bevacizumab Biosimilar HLX04
    • Bevacizumab Biosimilar IBI305
    • Bevacizumab Biosimilar LY01008
    • Bevacizumab Biosimilar MIL60
    • Bevacizumab Biosimilar QL 1101
    • Bevacizumab Biosimilar RPH-001
    • Bevacizumab Biosimilar SCT501
    • BP102
    • BP102 Biosimilar
    • HD204
    • Immunoglobulin G1 (Human-Mouse Monoclonal rhuMab-VEGF Gamma-Chain Anti-Human Vascular Endothelial Growth Factor), Disulfide With Human-Mouse Monoclonal rhuMab-VEGF Light Chain, Dimer
    • Recombinant Humanized Anti-VEGF Monoclonal Antibody
    • rhuMab-VEGF
    • SCT501
  • Drug: Dasatinib
    Given PO
    Other Names:
    • BMS-354825
    • Dasatinib Hydrate
    • Dasatinib Monohydrate
    • Sprycel
  • Drug: Fluorouracil
    Given IV
    Other Names:
    • 5 Fluorouracil
    • 5 Fluorouracilum
    • 5 FU
    • 5-Fluoro-2,4(1H, 3H)-pyrimidinedione
    • 5-Fluorouracil
    • 5-Fluracil
    • 5-FU
    • 5FU
    • AccuSite
    • Carac
    • Fluoro Uracil
    • Fluouracil
    • Flurablastin
    • Fluracedyl
    • Fluracil
    • Fluril
    • Fluroblastin
    • Ribofluor
    • Ro 2-9757
    • Ro-2-9757
  • Drug: Leucovorin
    Given IV
    Other Name: Folinic acid
  • Drug: Leucovorin Calcium
    Given IV
    Other Names:
    • Adinepar
    • Calcifolin
    • Calcium (6S)-Folinate
    • Calcium Folinate
    • Calcium Leucovorin
    • Calfolex
    • Calinat
    • Cehafolin
    • Citofolin
    • Citrec
    • citrovorum factor
    • Cromatonbic Folinico
    • Dalisol
    • Disintox
    • Divical
    • Ecofol
    • Emovis
    • Factor, Citrovorum
    • Flynoken A
    • Folaren
    • Folaxin
    • FOLI-cell
    • Foliben
    • Folidan
    • Folidar
    • Folinac
    • Folinate Calcium
    • folinic acid
    • Folinic Acid Calcium Salt Pentahydrate
    • Folinoral
    • Folinvit
    • Foliplus
    • Folix
    • Imo
    • Lederfolat
    • Lederfolin
    • Leucosar
    • leucovorin
    • Rescufolin
    • Rescuvolin
    • Tonofolin
    • Wellcovorin
  • Drug: Oxaliplatin
    Given IV
    Other Names:
    • 1-OHP
    • Ai Heng
    • Aiheng
    • Dacotin
    • Dacplat
    • Diaminocyclohexane Oxalatoplatinum
    • Eloxatin
    • Eloxatine
    • JM-83
    • Oxalatoplatin
    • Oxalatoplatinum
    • RP 54780
    • RP-54780
    • SR-96669
  • Other: Quality-of-Life Assessment
    Ancillary studies
    Other Name: Quality of Life Assessment
Study Arms  ICMJE Experimental: Prevention (dasatinib, mFOLFOX, bevacizumab)
Patients receive oxaliplatin IV over 2 hours, leucovorin IV over 2 hours, fluorouracil slow IV push over 2-4 minutes followed by continuous infusion over 46 hours on days 1 and 15. Patients also receive dasatinib PO QD on days 14, 15, and 28 of cycle 1 and day 1 of cycle 2. Patients may receive bevacizumab IV over 30 minutes on days 1 and 15. Treatment repeats every 28 days for up to cycle 3 day 1 in the absence of disease progression or unacceptable toxicity.
Interventions:
  • Biological: Bevacizumab
  • Drug: Dasatinib
  • Drug: Fluorouracil
  • Drug: Leucovorin
  • Drug: Leucovorin Calcium
  • Drug: Oxaliplatin
  • Other: Quality-of-Life Assessment
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 Recruiting
Estimated Enrollment  ICMJE
 (submitted: November 13, 2019)
20
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 31, 2021
Estimated Primary Completion Date December 31, 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Confirmed stage IV (advanced/metastatic) colorectal cancer who are candidates for mFOLFOX6, with or without bevacizumab therapy. Pathological confirmation of colorectal cancer is required. Patients may have had prior therapy for metastatic colorectal cancer
  • Eastern Cooperative Oncology Group (ECOG) performance status =< 2
  • Absolute neutrophil count (ANC) >= 1.5 x 10^9/L
  • Platelets >= 100 x 10^9/L
  • International normalized ratio (INR) or prothrombin time (PT) =< 1.5 x upper limit of normal (ULN) unless subject is receiving anticoagulant therapy as long as PT or partial thromboplastin time (PTT) is within therapeutic range of intended use of anticoagulants
  • Activated partial thromboplastin time (aPTT) =< 1.5 x ULN unless subject is receiving anticoagulant therapy as long as PT or PTT is within therapeutic range of intended use of anticoagulants
  • Serum creatinine: =< 1.5 x upper limit of normal (ULN), or measured or calculated creatinine clearance (estimated by Cockcroft-Gault formula or measured ) >= 50 mL/min urine protein:creatinine (UPC) < 2
  • Total bilirubin =< 2 x ULN
  • Aspartate aminotransferase (AST, serum glutamic oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT, serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN, unless evidence of liver metastases, then AST/alanine aminotransferase (ALT) =< 5 x ULN
  • Blood pressure (if receiving bevacizumab): systolic blood pressure (SBP) > 150 or diastolic blood pressure (DBP) > 100
  • Serum potassium and magnesium within the institution normal range. Before starting therapy with dasatinib, hypokalemia and hypomagnesemia will be corrected to potassium >= 4.0 mmol/L, magnesium >= 2.0 mg/dL-supplementation is allowed
  • Corrected QT (QTc) interval =< 440 mSec
  • Women of child-bearing potential must agree to use adequate contraception prior to study entry, for the duration of study participation and for 3 months after completion of study treatment administration
  • Prior chemotherapy in the adjuvant (no prior exposure of oxaliplatin) or metastatic setting is allowed

Exclusion Criteria:

  • Prior exposure to any type of neurotoxic chemotherapy
  • Pre-existing neuropathy of any type or grade
  • Treatment with any other investigational agents within 4 weeks or 5 half-lives (whichever is longer) prior to the first dose of dasatinib
  • Gastrointestinal (GI) disease or impairment of GI function that is likely to significantly alter the absorption of dasatinib
  • Use of potent OCT2 and/or CYP3A4 inhibitors if treatment cannot be either safely discontinued or switched to a different medication prior to starting dasatinib
  • Concurrent cetuximab or panitumumab
  • Uncontrolled inter-current illness including, but not limited to, ongoing or active infection, known human immunodeficiency virus (HIV) diagnosis if receiving combination antiretroviral therapy, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations, including psychotic disorders, dementia and substance use disorders, that would limit compliance with study requirements
  • Because there is an unknown potential risk for adverse events in nursing infants secondary to treatment of the mother with dasatinib and/or oxaliplatin, breastfeeding should be discontinued
  • Inability to understand and sign informed consent
  • Any other condition that in the opinion of the investigators would make the study therapy unsafe
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: The Ohio State University Comprehensive Cancer Center 1-800-293-5066 OSUCCCClinicaltrial@osumc.edu
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04164069
Other Study ID Numbers  ICMJE OSU-19067
NCI-2019-04723 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
P30CA016058 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Anne Noonan, Ohio State University Comprehensive Cancer Center
Study Sponsor  ICMJE Anne Noonan
Collaborators  ICMJE National Cancer Institute (NCI)
Investigators  ICMJE
Principal Investigator: Anne M Noonan, MBBChBAO, MSc Ohio State University Comprehensive Cancer Center
PRS Account Ohio State University Comprehensive Cancer Center
Verification Date July 2020

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