Phase I study to investigate safety of the combination indomethacin and two platinum-based chemotherapy regimens in patients with advanced cancers.
ID
Source
Brief title
Condition
- Gastrointestinal neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints: Safety of the combination of platinum-based therapy and
indomethacin.
Secondary outcome
Secondary endpoints: Pharmacodynamics of the combination of platinum-based
chemotherapy and indomethacin. Efficacy. Tolerability.
Background 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, but not
selective COX-2 inhibitors, prevented the MSC induced resistance and enhance
chemotherapy efficacy in preclinical studies.
Study objective
Phase I study to investigate safety of the combination indomethacin and two
platinum-based chemotherapy regimens in patients with advanced cancers.
Study design
Phase I, non-randomized, dose-escalation study for the combination of
platinum-based chemotherapy and indomethacin is comprised of two arms:
arm I : patients with advanced carcinoma receiving cisplatin combined with
gemcitabine or 5FU/capecitabine. (cisplatin dose range 60-80 mg/m2).
arm II : patients receiving CAPOX (oxaliplatine, capecitabine).
The dose of indomethacin will be escalated in each arm to a maximum of 225 mg
per day, in a 3+3 design.
Intervention
All patients will receive their first chemotherapy cycle according standard of
care without addition of indomethacin. If no toxicity as defined in table 3.1.1
is observed Indomethacin will be administered orally 8 days around the
chemotherapy infusion from the second cycle and beyond, starting 2 days before
until 5 days after. Dosage of indomethacin will be escalated between cohorts if
no DLT criteria are met. Indomethacin starting dose in the first cohort will be
three times 25 mg per day and escalated in a second cohort to three times 50mg
per day, and a third cohort of 3 times 75 mg per day. All patients will use
proton pump inhibition (PPI) from 1 week before start of the 2nd cycle and
continue during the remainder of the study protocol to prevent gastric stress
ulcers. Per treatment arm each cohort consists of 3 patients, which can be
expanded to 6 patients if indicated according dose escalation rules.
Study burden and risks
Potential risks:
The potential risks follow from the known toxicity of cisplatin, oxaliplatin
and indomethacin and a potential enhancement of these toxicities due to the
combination of the two agents.
Both cisplatin, oxaliplatin and indomethacin are registered in The Netherlands
and the toxicity profiles, contra-indications and interactions are extensively
investigated and described.
Our department has broad experience with the administration of cisplatin and
oxaliplatin. Indomethacin is a very well established drugs used for a broad
range of indications in and outside the hospital.
Due to the combination of both agents the risk of nephrotoxicity, mainly with
cisplatin, bone marrow depressions and gastro-intestinal side effects might be
increased and this will be monitored very carefully as described in section
7.4.2.
It should be noted however that indomethacin is only administered 7 days of
each cycle, were usually, eg in patients with rheumatic arthritis, indomethacin
is taken for a prolonged period in row.
Potential benefits:
Given the results of our preclinical studies, as described in the introduction,
we expect that the addition of indomethacin will enhance the chemotherapy
efficacy and prevent the development of resistance of platinum-based
chemotherapy, and will therefore lead to an enhanced progression free and
overall survival.
Concluding, the preclinical data generated till now did provide evidence for a
beneficial effect for the addition of indomethacin to cisplatin or oxaliplatin.
The preclinical and clinical data available and safety assessments as part of
this study provide confidence that this trial can be safely executed.
Heidelberglaan 100
Utrecht 3584 CX
NL
Heidelberglaan 100
Utrecht 3584 CX
NL
Listed location countries
Age
Inclusion criteria
- Subjects with a histological proven malignancy receiving cisplatinum combined with gemcitabine or 5FU/capecitabin (dose range cisplatin 60-80 mg/m2) (Arm I) or CAPOX (oxaliplatin, capecitabine) (Arm II) in a 21 day cycle.
- Platinum*based chemotherapy naïve for at least 6 months.
- Age * 18 years.
- 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 synthethase inhibitors.
- Symptomatic brain or meningeal tumors
- Subjects with seizure disorder requiring medication (such as steroids 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 gastro-intestinal bleeding
- History of cerebro-vascular 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 synthethase inhibitors.
- Use of anticoagulant therapy
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2012-001860-32-NL |
| ClinicalTrials.gov | NCT01719926 |
| CCMO | NL40487.041.12 |