Phase I Platinum Based Chemotherapy Plus Indomethacin (PIFA)

This study is currently recruiting participants. (see Contacts and Locations)
Verified February 2014 by UMC Utrecht
Sponsor:
Information provided by (Responsible Party):
Martijn P. Lolkema, UMC Utrecht
ClinicalTrials.gov Identifier:
NCT01719926
First received: October 30, 2012
Last updated: February 24, 2014
Last verified: February 2014
  Purpose

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 Intervention Phase
Colorectal Neoplasms
Esophageal Neoplasms
Ovarian Neoplasms
Drug: Indomethacin
Phase 1

Study Type: Interventional
Study Design: Allocation: Non-Randomized
Endpoint Classification: Safety Study
Intervention Model: Single Group Assignment
Masking: Open Label
Official Title: Phase I Study Evaluating Indomethacin in Combination With Platinum-based Chemotherapy

Resource links provided by NLM:


Further study details as provided by UMC Utrecht:

Primary Outcome Measures:
  • Number of dose limiting toxicities at each dosage cohort [ Time Frame: From first dose of indomethacin until 28 days after last dose of indomethacin ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:
  • Pharmacodynamics [ Time Frame: During first 2 cycles of 3 weeks each ] [ Designated as safety issue: No ]
    Serum levels of mesenchymal stem cells and platinum induced fatty acids at T = pre-chemotherapy, one, two and four hours expressed in pmol/L.

  • Efficacy [ Time Frame: From baseline to date of progressieve disease according RECIST 1.1, approximately 9 to 18 weeks ] [ Designated as safety issue: No ]
    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.


Estimated Enrollment: 18
Study Start Date: September 2012
Estimated Study Completion Date: July 2016
Estimated Primary Completion Date: February 2016 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
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(Capecitabin) or Gemcitabin
Patients receiving Cisplatin regimen
Drug: Indomethacin
3 times per day from 2 days before until 5 days after chemotherapy. Escalating dosage each cohort.

  Eligibility

Ages Eligible for Study:   18 Years to 70 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

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 and < 70 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
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT01719926

Contacts
Contact: G.A. Cirkel, MD +31 (0)88 75 55 555 ext 4773 g.a.cirkel-2@umcutrecht.nl

Locations
Netherlands
Meander Medisch Centrum Recruiting
Amersfoort, Utrecht, Netherlands, 3813TZ
Principal Investigator: H.j. Bloemendal, MD/PhD         
UMC Utrecht Recruiting
Utrecht, Netherlands, 3584CX
Principal Investigator: E.E. Voest, MD/PhD         
Switzerland
Oncology Institute of Southern Switzerland Recruiting
Bellinzona, Switzerland, CH-6500
Principal Investigator: C. Sessa, MD/PhD         
Sponsors and Collaborators
UMC Utrecht
Investigators
Principal Investigator: M.P.J.K. Lolkema, MD/PhD UMC Utrecht
  More Information

No publications provided

Responsible Party: Martijn P. Lolkema, MD/PhD, UMC Utrecht
ClinicalTrials.gov Identifier: NCT01719926     History of Changes
Other Study ID Numbers: NL40487.041.12
Study First Received: October 30, 2012
Last Updated: February 24, 2014
Health Authority: Netherlands: The Central Committee on Research Involving Human Subjects (CCMO)

Keywords provided by UMC Utrecht:
Colorectal
Esophageal
Indomethacin
PIFA

Additional relevant MeSH terms:
Neoplasms
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
Indomethacin
Anti-Inflammatory Agents, Non-Steroidal
Analgesics, Non-Narcotic
Analgesics
Sensory System Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs

ClinicalTrials.gov processed this record on September 16, 2014