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

NCT04164069 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: OSU-19067NCI-2019-04723
• Study Type: interventional
• Target: 9
• Locations: 1 country
• Sites: 1

Brief Summary

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.

Conditions

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

Outcome Measures

Primary Outcomes (2)

• 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)

Other Outcomes (1)

• Dasatinib on pharmacokinetics (PK) of oxaliplatin

  Baseline, days 1, 2, and 14

Study Arms (1)

Prevention (dasatinib, mFOLFOX, bevacizumab)

EXPERIMENTAL

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.

Biological: Bevacizumab; Drug: Dasatinib; Drug: Fluorouracil; Drug: Leucovorin; Drug: Leucovorin Calcium; Drug: Oxaliplatin; Other: Quality-of-Life Assessment

Interventions

Bevacizumab BIOLOGICAL

Given IV

Also known as: 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

Prevention (dasatinib, mFOLFOX, bevacizumab)

Dasatinib DRUG

Given PO

Also known as: BMS-354825, Dasatinib Hydrate, Dasatinib Monohydrate, Sprycel

Prevention (dasatinib, mFOLFOX, bevacizumab)

Fluorouracil DRUG

Given IV

Also known as: 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

Prevention (dasatinib, mFOLFOX, bevacizumab)

Leucovorin DRUG

Given IV

Also known as: Folinic acid

Prevention (dasatinib, mFOLFOX, bevacizumab)

Leucovorin Calcium DRUG

Given IV

Also known as: 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

Prevention (dasatinib, mFOLFOX, bevacizumab)

Oxaliplatin DRUG

Given IV

Also known as: 1-OHP, Ai Heng, Aiheng, Dacotin, Dacplat, Diaminocyclohexane Oxalatoplatinum, Eloxatin, Eloxatine, JM-83, Oxalatoplatin, Oxalatoplatinum, RP 54780, RP-54780, SR-96669

Prevention (dasatinib, mFOLFOX, bevacizumab)

Quality-of-Life Assessment OTHER

Ancillary studies

Also known as: Quality of Life Assessment

Prevention (dasatinib, mFOLFOX, bevacizumab)

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• 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.

You may not qualify if:

• 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

Sponsors & Collaborators

• Anne Noonan: lead

Study Sites (1)

Ohio State University Comprehensive Cancer Center

Columbus, Ohio, 43210, United States

Location

Related Publications (1)

• 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.

  PMID: 33142018 DERIVED

Related Links

• The Jamesline

MeSH Terms

Conditions

Colorectal Neoplasms; Colonic Neoplasms; Rectal Neoplasms; Esophageal Neoplasms; Pancreatic Neoplasms; Bile Duct Neoplasms; Stomach Neoplasms; Gallbladder Neoplasms

Interventions

Bevacizumab; Immunoglobulin G; Disulfides; Dasatinib; Fluorouracil; dehydroftorafur; Leucovorin; Oxaliplatin

Condition Hierarchy (Ancestors)

Intestinal Neoplasms; Gastrointestinal Neoplasms; Digestive System Neoplasms; Neoplasms by Site; Neoplasms; Digestive System Diseases; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Rectal Diseases; Head and Neck Neoplasms; Esophageal Diseases; Endocrine Gland Neoplasms; Pancreatic Diseases; Endocrine System Diseases; Biliary Tract Neoplasms; Bile Duct Diseases; Biliary Tract Diseases; Stomach Diseases; Gallbladder Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Humanized; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Immunoglobulin Isotypes; Sulfides; Anions; Ions; Electrolytes; Inorganic Chemicals; Hydrogen Sulfide; Sulfur Compounds; Organic Chemicals; Thiazoles; Azoles; Heterocyclic Compounds, 1-Ring; Heterocyclic Compounds; Pyrimidines; Uracil; Pyrimidinones; Formyltetrahydrofolates; Tetrahydrofolates; Folic Acid; Pterins; Pteridines; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Coenzymes; Enzymes and Coenzymes; Coordination Complexes

Study Officials

• Anne M Noonan, MBBChBAO, MSc

  Ohio State University Comprehensive Cancer Center

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: PREVENTION
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: Principal Investigator

Study Record Dates

• First Submitted: October 11, 2019
• First Posted: November 15, 2019
• Study Start: September 2, 2020
• Primary Completion: June 22, 2023
• Study Completion: June 22, 2023
• Last Updated: December 27, 2024

Record last verified: 2024-04

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)