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

A Phase Ib Adaptive Study 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.

Study Overview

• Status: Active, not recruiting
• Conditions: Gastric Cancer; Pancreatic Cancer; Esophageal Cancer; Bile Duct Cancer; Gall Bladder Cancer; 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; Advanced Colorectal Carcinoma; Small Bowel Adenocarcinoma
• Intervention / Treatment: Other: Quality-of-Life Assessment; Drug: Dasatinib; Biological: Bevacizumab; Drug: Fluorouracil; Drug: Leucovorin; Drug: Oxaliplatin; Drug: Leucovorin Calcium

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 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.

• Study Type: Interventional
• Enrollment (Estimated): 9
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • Ohio
    • Columbus, Ohio, United States, 43210
      • Ohio State University Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• 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.

Exclusion Criteria:

• 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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

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 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.

Other: Quality-of-Life Assessment; Ancillary studies; Other Names: Quality of Life Assessment; Drug: Dasatinib; Given PO; Other Names: BMS-354825; Dasatinib Hydrate; Dasatinib Monohydrate; Sprycel; Biological: Bevacizumab; Given IV; Other Names: Avastin; Anti-VEGF; Anti-VEGF Humanized Monoclonal Antibody; Anti-VEGF rhuMAb; 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: Fluorouracil; Given IV; Other Names: 5-FU; 5-Fluracil; Fluracil; 5 Fluorouracil; 5 Fluorouracilum; 5 FU; 5-Fluoro-2,4(1H, 3H)-pyrimidinedione; 5-Fluorouracil; 5FU; AccuSite; Carac; Fluoro Uracil; Fluouracil; Flurablastin; Fluracedyl; Fluril; Fluroblastin; Ribofluor; Ro 2-9757; Ro-2-9757; Drug: Leucovorin; Given IV; Other Names: Folinic acid; Drug: Oxaliplatin; Given IV; Other Names: 1-OHP; Dacotin; Dacplat; Eloxatin; Ai Heng; Aiheng; Diaminocyclohexane Oxalatoplatinum; Eloxatine; JM-83; Oxalatoplatin; Oxalatoplatinum; RP 54780; RP-54780; SR-96669; Drug: Leucovorin Calcium; Given IV; Other Names: Wellcovorin; citrovorum factor; folinic acid; Adinepar; Calcifolin; Calcium (6S)-Folinate; Calcium Folinate; Calcium Leucovorin; Calfolex; Calinat; Cehafolin; Citofolin; Citrec; Cromatonbic Folinico; Dalisol; Disintox; Divical; Ecofol; Emovis; Factor, Citrovorum; Flynoken A; Folaren; Folaxin; FOLI-cell; Foliben; Folidan; Folidar; Folinac; Folinate Calcium; Folinic Acid Calcium Salt Pentahydrate; Folinoral; Folinvit; Foliplus; Folix; Imo; Lederfolat; Lederfolin; Leucosar; leucovorin; Rescufolin; Rescuvolin; Tonofolin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	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)

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dasatinib on pharmacokinetics (PK) of oxaliplatin	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 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 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	Baseline, days 1, 2, and 14

Collaborators and Investigators

• Sponsor: Anne Noonan
• Investigators: Principal Investigator: Anne M Noonan, MBBChBAO, MSc, Ohio State University Comprehensive Cancer Center

Publications and helpful links

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.

Helpful Links

• The Jamesline

Study record dates

Study Major Dates

• Study Start (Actual): September 2, 2020
• Primary Completion (Actual): June 22, 2023
• Study Completion (Estimated): December 31, 2023

Study Registration Dates

• First Submitted: October 11, 2019
• First Submitted That Met QC Criteria: November 13, 2019
• First Posted (Actual): November 15, 2019

Study Record Updates

• Last Update Posted (Actual): December 12, 2023
• Last Update Submitted That Met QC Criteria: December 5, 2023
• Last Verified: December 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Gallbladder Diseases; Biliary Tract Diseases; Bile Duct Diseases; Biliary Tract Neoplasms; Carcinoma; Colorectal Neoplasms; Rectal Neoplasms; Gastrointestinal Neoplasms; Colonic Neoplasms; Gallbladder Neoplasms; Bile Duct Neoplasms; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Protective Agents; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Micronutrients; Protein Kinase Inhibitors; Vitamins; Bone Density Conservation Agents; Calcium-Regulating Hormones and Agents; Antidotes; Vitamin B Complex; Hematinics; Antibodies; Fluorouracil; Oxaliplatin; Immunoglobulins; Bevacizumab; Leucovorin; Calcium; Levoleucovorin; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Folic Acid; Calcium, Dietary; Dasatinib; Immunoglobulin G; Endothelial Growth Factors
• Other Study ID Numbers: OSU-19067; NCI-2019-04723 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No