This phase I study aims to define the MTD of the combination of cisplatin/hyperthermia/lapatinib, to confirm that the 2 agents combined with hyperthermia can be administered safely, and to recommend a dose for further clinical studies.
ID
Source
Brief title
Condition
- Reproductive neoplasms female malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
To establish a MTD of lapatinib in combination with a standard dose of
cisplatin (weekly 70 mg/m2) and local hyperthermia and to recommend a dose for
further clinical studies
Secondary outcome
To assess safety and tolerability of lapatinib in combination with cisplatin
and hyperthermia
To describe the activity of lapatinib in combination with cisplatin and
hyperthermia in patients with previously irradiated recurrent carcinoma of the
uterine cervix
Translational research: HER1/HER2 tumour tissue expression, Circulating
endothelial cells (CEC*s), Skin-biopsy: activation of HER1/2 mediated pathways
prior to and once during treatment.
Background summary
The combination of weekly systemic cisplatin and locoregional hyperthermia is
considered standard treatment in patients with local pelvic relapse from
previously irradiated carcinoma of the uterine cervix. In addition, this
combination of cisplatin and locoregional hyperthermia is used in patients with
distant metastases, who urgently need pain control from local relapse (Br J
Cancer; 1999; 80: 1387-91). The overall response rate of this treatment regimen
is about 50%, with a median duration of response of 6 months. Epidermal growth
factor receptor (EGFR) overexpression is negatively associated with overall
survival in patients with cancer of the uterine cervix (Gynecol Oncol; 2002;
87: 84-9, Int J Radiat Oncol Biol Phys; 2003; 56: 922-8). In addition,
preclinical studies have shown that a combination of cisplatin and an
EGFR-inhibitor acts synergistically (Anticancer Res; 2003; 23: 2577-83).
Preliminary safety data show that lapatinib can be safely combined with
cisplatin in patients undergoing chemoradiation because of head/neck carcinoma,
with acceptable toxicity.
Study objective
This phase I study aims to define the MTD of the combination of
cisplatin/hyperthermia/lapatinib, to confirm that the 2 agents combined with
hyperthermia can be administered safely, and to recommend a dose for further
clinical studies.
Study design
This is a Phase I, open-label, non-randomized, dose-escalation trial in
sequential cohorts of patients. Cohorts of 3 patients (to be expanded to 6 if 1
DLT is observed among the 3 patients) will be sequentially treated with
progressively higher dose levels of once daily lapatinib (1000 mg and 1500 mg)
in combination with weekly cisplatin 70 mg/m2 and locoregional hyperthermia. In
case of a DLT at the dose level of 1000 mg, the dose will be lowered to 750 mg
(=DL -1).The duration of the DLT period is 6 weeks.
In case of 2 DLTs at dose level 750 mg, the dose of lapatinib will be reduced
to 500 mg (=DL -2).
Intervention
Weekly hyperthermia combined with weekly cisplatin intravenously given at a
dose of 70 mg/m2 in combination with escalating dose of daily continuous
lapatinib for a total treatment period of 6 weeks.
Study burden and risks
The burden may be, if the patient agrees, the procedure of twice a skinbiopsy
and once a prolonged stay in the hospital for one day. The riscs may be
additional toxicity of the combination of lapatinib and cisplatin with
hyperthermia.
Groene Hilledijk 315
3075 EA Rotterdam
NL
Groene Hilledijk 315
3075 EA Rotterdam
NL
Listed location countries
Age
Inclusion criteria
Histologically proven pelvic recurrence of cervical cancer in previously irradiated area (with or without distant metastases), not amendable for surgery or additional radiotherapy, for which treatment with cisplatin/hyperthermia is indicated.
Age >= 18 years.
WHO performance of 0-1 and a predicted life expectancy of at least more than 12 weeks.
Adequate liver-, kidney- and bone marrow function
Left ventricular ejection fraction (LVEF) within normal range or above 50% based on MUGA/ECHO
Able to swallow and retain oral medication
Before patient registration, written informed consent must be given
Exclusion criteria
· Prior systemic chemotherapy for recurrent tumour
· Prior treatment with lapatinib
· Pacemaker
· Artificial hip
· Pre-existing motor or sensory neurotoxicity greater than WHO grade 1
· Untreated leptomeningeal or brain metastases.
· Class II, III or IV heart failure as defined by the NYHA functional classification system
· History of congestive heart failuire, clinically significant valvular disease, or poorly controlled hypertension
· Arterial or venous thrombosis
· Known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to lapatinib
· Any major surgery, hormonal therapy (other than replacement), chemotherapy or radiotherapy, immunotherapy or other investigational agent within the last 28 days and/or not recovered from prior therapy within the last 28 days have to wait 42 days before starting therapy.)
· History of malabsorption syndrome, disease significantly affecting gastrointestinal function or major resection of the stomach or small bowel that could affect absorption, distribution, metabolism or excretion of study drugs
· Any unresolved bowel obstruction or diarrhea
· Other concurrent serious disease, such as severe pulmonary conditions
· Psychological, familial, sociological, or geographical conditions that do not permit compliance with the protocol
· Is on any CYP3A4 inducing or inhibiting medication or requires any of these medications during treatment with lapatinib
· Has significant QTc prolongation (QTc interval greater than or equal to 480 msec) AND a prior history of cardiovascular disease, arrhythmias, or significant ECG abnormalities
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 | EUCTR2008-005083-13-NL |
| CCMO | NL24464.078.08 |