Phase I Platinum Based Chemotherapy Plus Indomethacin (PIFA)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT01719926
Recruitment Status : Completed
First Posted : November 1, 2012
Last Update Posted : August 18, 2017
Information provided by (Responsible Party):
Dr. F.Y.F.L. de Vos, UMC Utrecht

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
Colorectal Neoplasms Esophageal Neoplasms Ovarian Neoplasms Drug: Indomethacin Phase 1

Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 13 participants
Allocation: Non-Randomized
Intervention Model: Single Group Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Phase I Study Evaluating Indomethacin in Combination With Platinum-based Chemotherapy
Study Start Date : September 2012
Actual Primary Completion Date : August 2017
Actual Study Completion Date : August 2017

Resource links provided by the National Library of Medicine

U.S. FDA Resources

Arm Intervention/treatment
Experimental: Capecitabine/Oxaliplatin
Patients receiving Capecitabine/Oxaliplatin chemotherapy
Drug: Indomethacin
3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.
Experimental: Cisplatin + Xeloda(Capecitabine) or Gemcitabine
Patients receiving Cisplatin regimen
Drug: Indomethacin
3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.

Primary Outcome Measures :
  1. Number of dose limiting toxicities at each dosage cohort [ Time Frame: From first dose of indomethacin until 28 days after last dose of indomethacin ]

Secondary Outcome Measures :
  1. Pharmacodynamics [ Time Frame: During first 2 cycles of 3 weeks each ]
    Serum levels of mesenchymal stem cells and platinum induced fatty acids at T = pre-chemotherapy, one, two and four hours expressed in pmol/L.

  2. Efficacy [ Time Frame: From baseline to date of progressive disease according RECIST 1.1, approximately 9 to 18 weeks ]
    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.

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Ages Eligible for Study:   18 Years and older   (Adult, Senior)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

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

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT01719926

Meander Medisch Centrum
Amersfoort, Utrecht, Netherlands, 3813TZ
the Netherlands Cancer Institute
Amsterdam, Netherlands, 1066 CX
UMC Utrecht
Utrecht, Netherlands, 3584CX
Oncology Institute of Southern Switzerland
Bellinzona, Switzerland, CH-6500
Sponsors and Collaborators
UMC Utrecht
Principal Investigator: F.Y.F.L. de Vos, MD/PhD UMC Utrecht

Responsible Party: Dr. F.Y.F.L. de Vos, MD/PhD, UMC Utrecht Identifier: NCT01719926     History of Changes
Other Study ID Numbers: NL40487.041.12
First Posted: November 1, 2012    Key Record Dates
Last Update Posted: August 18, 2017
Last Verified: August 2017

Keywords provided by Dr. F.Y.F.L. de Vos, UMC Utrecht:

Additional relevant MeSH terms:
Colorectal Neoplasms
Ovarian Neoplasms
Esophageal Neoplasms
Intestinal Neoplasms
Gastrointestinal Neoplasms
Digestive System Neoplasms
Neoplasms by Site
Digestive System Diseases
Gastrointestinal Diseases
Colonic Diseases
Intestinal Diseases
Rectal Diseases
Endocrine Gland Neoplasms
Ovarian Diseases
Adnexal Diseases
Genital Diseases, Female
Genital Neoplasms, Female
Urogenital Neoplasms
Endocrine System Diseases
Gonadal Disorders
Head and Neck Neoplasms
Esophageal Diseases
Antimetabolites, Antineoplastic
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents
Anti-Inflammatory Agents, Non-Steroidal