Phase I Platinum Based Chemotherapy Plus Indomethacin

Study Overview
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Brief Summary
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Mesenchymal stem cells (MSCs) are present in the circulation of cancer patients, and are recruited to the stroma of both the primary tumor and metastasis. Recent preclinical research has shown that in response to platinum-based chemotherapy, MSCs secrete two specific platinum-induced fatty acids (PIFAs) which induce resistance to a broad spectrum of chemotherapies. The secreted PIFAs are the fatty acid oxo-heptadecatetraenoic acid (KHT) and the omega-3 fatty acid hexadecatetraenoic acid (16:4). These PIFAs are produced via the COX-1 pathway. COX inhibitors, including indomethacin. This phase 1 study explores the safety of combining indomethacin with platinum containing chemotherapy.

Official Title
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Phase I Study Evaluating Indomethacin in Combination With Platinum-based Chemotherapy

Conditions
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Colorectal Neoplasms, Esophageal Neoplasms, Ovarian Neoplasms

Intervention / Treatment
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* Drug: Indomethacin


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects with a histological proven malignancy receiving cisplatin combined with gemcitabine or 5FU/capecitabine. (cisplatin dose range 60-80 mg/m2) (Arm I) or CAPOX (oxaliplatin, capecitabine) (Arm II) in a 21 day cycle. Age ≥ 18 years Platinum-based chemotherapy naïve for at least 6 months. Subjects with at least one evaluable lesion. WHO Performance Status of 0 or 1. Female participants should be of non-child bearing potential either physiologic or by using adequate contraception, have a negative serum pregnancy test, and refrain from breast feeding. Written informed consent. Exclusion Criteria: Known or suspected allergy or hypersensitivity to indomethacin or any agent given in association with this trial, in particular subjects who have a history of severe hypersensitivity reactions to anti-emetics (5-HT3 antagonists, metoclopramide or corticosteroids) and acetylsalicylic acid or other prostaglandin synthetase inhibitors. Symptomatic brain or meningeal tumors Subjects with seizure disorder requiring medication (such as corticosteroids or anti-epileptics). Any of the following concurrent severe and/or uncontrolled medical conditions which could compromise participation in the study: Uncontrolled high blood pressure, history of labile hypertension, or history of poor compliance with an antihypertensive regimen Unstable angina pectoris Symptomatic congestive heart failure NYHA class ≥ 3 (see appendix 13.6) Myocardial infarction ≤ 6 months prior to randomization Serious uncontrolled cardiac arrhythmia Active peptic ulcer disease, gastritis, inflammatory bowel disease. History of active gastrointestinal bleeding History of cerebrovascular disease Bleeding diathesis Chronic renal disease defined as GFR (MDRD) <60 ml/min Absolute Neutrophil Count (ANC) < 1.5 x 109/L (< 1500/mm3) Platelets (PLT) < 100 x 109/L (< 100,000/mm3) Hemoglobin (Hgb) < 6.0 mmol/l (patients may be transfused to achieve adequate Hb) Partial thromboplastin time (PTT) > 1,5 x ULN Serum bilirubin > 1.5 ULN Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase (ALT/SGPT) > 3.0 x ULN (> 5 x ULN if liver metastases present) Patients who are unable or unwilling to comply with the protocol Chronic treatment with a corticosteroid agent (nebulized corticosteroids are allowed) Patients who received radiation therapy within 4 weeks of the start of the study Patients who received an experimental agent less than 4 weeks before start of the study. Patients who used Omega-3/omega-6 containing products, including fish oil products less than 2 weeks before start of the study. Chronic use of NSAID's and/or acetylsalicylic acid and/or other prostaglandin synthetase inhibitors. Use of anticoagulant therapy

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Other
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Capecitabine/Oxaliplatin<br>Patients receiving Capecitabine/Oxaliplatin chemotherapy | Drug: Indomethacin<br>* 3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.<br>|
| Experimental: Cisplatin + Xeloda(Capecitabine) or Gemcitabine<br>Patients receiving Cisplatin regimen | Drug: Indomethacin<br>* 3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of dose limiting toxicities at each dosage cohort |  | From first dose of indomethacin until 28 days after last dose of indomethacin | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pharmacodynamics | Serum levels of mesenchymal stem cells and platinum induced fatty acids at T = pre-chemotherapy, one, two and four hours expressed in pmol/L. | During first 2 cycles of 3 weeks each | 
| Efficacy | Efficacy will be assessed according RECIST 1.1 criteria. Progression free survival is defined as time from baseline CT scan to progressive disease according RECIST 1.1 criteria. | From baseline to date of progressive disease according RECIST 1.1, approximately 9 to 18 weeks | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Colorectal, Esophageal, Indomethacin, PIFA