The primary objective of this study is to proof the concept that cisplatin-induced ototoxicity can be prevented by transtympanic STS containing gel application, through inserted grommets.The STS containing and blank gel formulations will be provided…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Audiometric tests after each cycle will be compared to baseline audiometric
tests to measure the development of the occurence of ototoxicity and 4 weeks en
3 months after the last cycle of cisplatin.
Secondary outcome
To determine the feasibility and safety of repeated application of a STS
containing or placebo gel formulation to the middle ear through a grommet (arm
A)
To determine the feasibility and safety of repeated application of STS
containing gel formulation by direct puncture of the ear drum (arm B).
To determine the pharmacokinetics of platinum in plasma (bound and unbound) in
these patients.
On exploratory basis patients will be screened for genetic variants in the
TPMT, COMT, LRP2, GSTP1, GSTM1 and OCT2. Previous prospective studies performed
and prescirbed in literature have shown a possible relation of genetic
variations in these genes to the development of ototoxicity in patients treated
with cisplatin.
Background summary
Platinum drugs are effective chemotherapeutic agents widely used for the
treatment of various types of adult and pediatric cancers. Clinical application
of cisplatin however causes severe and irreversible toxicity including
neurotoxicity, nephrotoxicity and ototoxicity. Nephrotoxicity is limited with
forced diuresis pre- and post-infusion. Ototoxicity however can not be cured
and is permanent in the majority of patients treated with cisplatinum. It
affects the inner ear which is essential in both hearing and balance.
Platinum-induced toxicity is caused by high doses of administered cisplatin
intravenously or intraperitoneally. Cisplatin induces dose-dependant death of
cochlear cells, mostly outer hair cells (OHC*s). It targets DNA of
proliferating cells to achieve anti-tumor activity. Cisplatin is activated by
the replacement of one of its two chloride groups by a water molecule.
Activated mono-aqua cisplatin binds to DNA which forms intra- and interstrand
complexes that lead to inhibition of DNA synthesis, suppression of RNA
transcription, cell cycle arrest and ultimately apoptosis.
Study objective
The primary objective of this study is to proof the concept that
cisplatin-induced ototoxicity can be prevented by transtympanic STS containing
gel application, through inserted grommets.
The STS containing and blank gel formulations will be provided by the pharmacy
department of the Slotervaart Hospital. Patients with advanced cancer treated
with cisplatin according to standard of care will be consented for this
clinical proof of concept study. In total six evaluable patients will be
included. The investigational medicinal products consist of a 0.1M STS in a
0.5% w/w HYA in PBS gel formulation and the blank gel, consisting of the same
formulation without STS. A volume of 1.0 ml of the STS containing and blank
gel will be injected into the middle ear of the consented patients. Patients
will be treated with cisplatin at a minimal dose of 75 mg/m2 or more, for a
minimum of three cycles (q=3weeks), if in the best interest of the patient. The
transtympanic injection will take place three hours prior to the start of each
cycle of cisplatin treatment. Patients will be randomized whereby right and
left ear will be injected with the STS containing gel or blank gel. Every next
cycle the STS containing gel and blank gel, respectively, will be administered
to the same ear as during the first cycle.
Study design
A pharmaceutical, pharmacological, otological, audiological, randomized
clinical phase 1 study
Intervention
Arm A
In order to prevent the development of ototoxicity STS containing transtympanic
injections will be applied three hours prior to each first administration of
cisplatin treatment in each cycle. Through randomization it will be decided in
which ear patients will receive the STS containing gel or blank gel.
Arm B
By randomization it will be decided which ear will be treated with
natriumthiosulfate in this ear a grommet will be placed. Via direct puncture of
the ear drum the natriumthiosulfate will be injected (in arm A this was done
via the grommet). The non randomized ear will remain untreated.
Study burden and risks
After written informed consent, grommets will be inserted prior to start of the
study after which the transtympanic injections will be performed.
Physical examiniation, laboratory assessments, audiometric tests will be
performed prior to start of each cycle. Patients will visit the hospital weekly
for physical examination. On cycle 1 day 1 patients will be hospitalized for
one day on wich pharmacokinetic sampling will be performed. In total 8 blood
samples will be taken on different time point during the day. Also after 2
cycles a CT scan will be performed. Genetic sampling will take place during the
pharmacokinetic sampling.
Plesmanlaan 121
Amsterdam 1066 CX
NL
Plesmanlaan 121
Amsterdam 1066 CX
NL
Listed location countries
Age
Inclusion criteria
1. Histological or cytological proof of advanced cancer for which cisplatin treatment at a minimal dose of 75 mg/m2 per 21 days is considered of benefit; for example non-small cell lung cancer; patients with a head and neck malignancy of the oropharynx, hypofarynx, oral cavity and larynx with blue or brown eyes.
2. Age * 18 years;
3. Able and willing to give written informed consent;
4. WHO performance status of 0, 1 or 2;
5. No relevant otological history; (presbyacusis, conductive hearing loss, air-bone gap (ABG), complaints of tinnitus or vertigo, ototoxic co-medication (see appendix VI), chronic middle ear infections, trauma, operations, or hearing aid) ,
6. Able and willing to undergo blood sampling for PK analysis and genetic analysis for specific SNPs;
7. Minimal acceptable safety laboratory values;
a. ANC of * 1.5 x 109 /L
b. Platelet count of * 100 x 109 /L
c. Hepatic function as defined by serum bilirubin * 1.5 x ULN, ALAT and ASAT * 2.5 x ULN or *5 x ULN in case of liver metastases
d. Renal function as defined by serum creatinine * 2.5 x ULN or creatinine clearance * 60 ml/min (by Cockcroft-Gault formula).
8. Negative pregnancy test (urine/serum) for female patients with childbearing potential;
9. Combined treatment of cisplatin with other cytostatic, cytotoxic or radiation therapy according to local treatment guidelines is permitted. However, radiation therapy to the head and neck region is excluded.
Exclusion criteria
1. Any treatment with investigational drugs or other antineoplastic therapy within 21 days prior to receiving the first dose of investigational treatment;
2. Patients who have had previous systemic treatment with cisplatin or oxaliplatin; (HIPEC and other local non systemic therapy are allowed)
3. Known hypersensitivity to STS containing HYA gel formulation;
4. Patients with symptomatic brain metastases, carcinomatous leptomeningitis at start;
5. Woman who are pregnant or breast feeding;
6. Uncontrolled infectious disease or known Human Immunodeficiency Virus HIV-1 or HIV-2 type patients;
7. Patients with a known history of hepatitis B or C;
8. Patients with a head and neck malignancy other than; oropharynx, hypopharynx, oral cavity and larynx or patients with a head and neck malignancy green eyes.
9. Any condition that would, in the investigator judgement contraindicate the patients participation in the clinical study due to safety concerns or compliance with clinical study procedures
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 | EUCTR2012-004653-80-NL |
| CCMO | NL42566.031.12 |