Dasatinib For The Prevention Of Oxaliplatin-Induced Neuropathy In Patients With Metastatic Gastrointestinal Cancer Receiving FOLFOX Chemotherapy With Or Without Bevacizumab

Study Overview

Dasatinib for the Prevention of Oxaliplatin-Induced Neuropathy in Patients With Metastatic Gastrointestinal Cancer Receiving FOLFOX Chemotherapy With or Without Bevacizumab

This phase Ib trial studies side effects and best dose of dasatinib in preventing oxaliplatin-induced peripheral neuropathy in patients with gastrointestinal cancers who are receiving FOLFOX regimen with or without 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.

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 colon, rectal or other GI 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 or other GI 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.

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
Stage II Colon Cancer
Stage II Rectal Cancer
Stage III Colon Cancer
Stage III Rectal Cancer
Esophageal Cancer
Pancreatic Cancer
Bile Duct Cancer
Gastric Cancer
Gall Bladder Cancer
Small Bowel Adenocarcinoma

BIOLOGICAL: Bevacizumab
DRUG: Dasatinib
DRUG: Fluorouracil
DRUG: Leucovorin
DRUG: Leucovorin Calcium
DRUG: Oxaliplatin
OTHER: Quality-of-Life Assessment

OSU-19067
NCI-2019-04723 (REGISTRY Identifier) (REGISTRY: CTRP (Clinical Trial Reporting Program))

Study Record Dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Registration Dates	Results Reporting Dates	Study Record Updates
First Submitted 2019-10-11	Results First Submitted N/A	Last Update Submitted that met QC Criteria 2024-12-21
First Submitted that Met QC Criteria 2019-11-13	Results First Submitted that Met QC Criteria N/A	Last Update Posted (ACTUAL) 2024-12-27
First Posted (ACTUAL) 2019-11-15	Results First Posted N/A	Last Verified 2024-04

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

Design Details

Primary Purpose:
Prevention

Allocation:
Na

Interventional Model:
Single Group

Masking:
None

Arms and Interventions

Participant Group/Arm	Intervention/Treatment
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 an	BIOLOGICAL: Bevacizumab Given IV DRUG: Dasatinib Given PO DRUG: Fluorouracil Given IV DRUG: Leucovorin Given IV DRUG: Leucovorin Calcium Given IV DRUG: Oxaliplatin Given IV OTHER: Quality-of-Life Assessment Ancillary studies

Participant Group/Arm

Intervention/Treatment

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 an

BIOLOGICAL: Bevacizumab

Given IV

DRUG: Dasatinib

Given PO

DRUG: Fluorouracil

Given IV

DRUG: Leucovorin

Given IV

DRUG: Leucovorin Calcium

Given IV

DRUG: Oxaliplatin

Given IV

OTHER: Quality-of-Life Assessment

Ancillary studies

Primary Outcome Measures	Measure Description	Time Frame
Recommended phase II dose (RP2D) of dasatinib	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.	Up to 14 days
Incidence of adverse events	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.	At the end of Cycle 1 (cycle length is 28 days)

Secondary Outcome Measures	Measure Description	Time Frame

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person’s general health condition or prior treatments.

Ages Eligible for Study:
ALL

Sexes Eligible for Study:
18 Years

Accepts Healthy Volunteers:

Confirmed confirmed stage II, III or IV colon or rectal cancer and other gastrointestinal (GI) cancers (e.g. pancreas, esophagogastric, bile duct, small bowel cancers etc) who are candidates for mFOLFOX6, with or without bevacizumab therapy. Pathological confirmation of colon,rectal or other GI cancer is required. Patients may have had prior therapy for GI 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.
Corrected QT (QTc) interval =< 450 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 or metastatic setting is allowed including prior exposure to oxaliplatin in the adjuvant setting for colorectal cancer or other GI cancer as long as neuropathy is grade 1 or less.
Pre-existing neuropathy is allowed as long as it is grade 1 or less.

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 panitumumab or any other biological/targeted agent.
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

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Investigators

PRINCIPAL_INVESTIGATOR: Anne M Noonan, MBBChBAO, MSc, Ohio State University Comprehensive Cancer Center

Publications

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Stage TB, Hu S, Sparreboom A, Kroetz DL. Role for Drug Transporters in Chemotherapy-Induced Peripheral Neuropathy. Clin Transl Sci. 2021 Mar;14(2):460-467. doi: 10.1111/cts.12915. Epub 2020 Nov 9.

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