Primary objective:To assess the puncture free survival after start of treatment with cediranib (time to first need for paracentesis or thoracentesis or time to death, which event occurred first)Secondary objectives:-To assess the palliative effects…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
If the puncture free survival after start of treatment with cediranib (time to
first need for paracentesis or thoracentesis or time to death, which event
occurred first) is more than 44 days the treatment of ascites and/or pleural
effusion with cediranib is effective.
Secondary outcome
n.a.
Background summary
Malignant ascites is a difficult clinical problem. Increasing intra-abdominal
pressure resulting from fluid accumulation may cause anorexia, sleep
disturbance, pain, dyspnoea, abdominal distension, fatigue, nausea vomiting and
reduced mobility. The main complaints of pleural effusion are dyspnoea and
cough. Paracentesis and thoracentesis provide relief for a very limited period.
Studies have shown high concentrations of VEGF in malignant ascites and pleural
effusion. Beneficial effects of treatment with an intravenous or
intraperitoneal antibody against VEGF on malignant ascites have been reported.
In the recent past we have treated two patients with symptomatic malignant
ascites (colorectal cancer and ovarian cancer, respectively) in a phase I study
with cediranib. Shortly after start of cediranib, within a couple of days, the
ascites disappeared. However, after stopping cediranib for progressive disease
on other sites the ascites reappeared within days. Therefore, one of those
patients was treated with cediranib as palliative treatment until two days
before his death, which was beneficial for this patient.
In this phase II study we would like to investigate the effects of treatment
with cediranib as palliative treatment on malignant ascites or pleural
effusion.
Study objective
Primary objective:
To assess the puncture free survival after start of treatment with cediranib
(time to first need for paracentesis or thoracentesis or time to death, which
event occurred first)
Secondary objectives:
-To assess the palliative effects of cediranib on ascites and ascites related
symptoms or to assess the palliative effects of cediranib on pleural effusion
and pleural effusion related symptoms
-The effect of treating ascites and/or pleural effusion with cediranib on the
quality of life
-Toxicity profile of cediranib (acute and late adverse events) in this group of
patients
-Tumour response
-Overall survival
Study design
This will be an open label, randomized phase II single centre study. Sixteen
patients with ascites and 16 patients with pleural effusion will be randomized
between immediate start with cediranib or best supportive care and start with
cediranib after 4 weeks. Cross-over from the control group to the cediranib
arm is permitted when paracentesis or thoracentesis is necessary before start
of Cediranib on day 29.
Intervention
The start dosage of cediranib will be 30 mg oid. The dose will be titrated to
have the most beneficial effect on the ascites or pleural effusion and the
fewest adverse events. Special in this study is the possibility to decrease (to
minimal 15 mg oid) or increase the dose (to a maximum of 30 mg oid) during the
study to get an individualised optimal palliative treatment with cediranib. The
patient will continue cediranib as long as a clinical benefit is experienced.
Half of the patients start with cediranib 30 mg once a day and best supportive
care, the other half will have the first 28 days of the study just best
supportive care and will start after 28 days with cediranib 30 mg once a day
Study burden and risks
For the exact burden of the study see the table in the protocol on page 18 and
19.
In former studies, doses of 30 mg cediranib were well tolerated in patients
with advanced cancer.
We think that cediranib can be an effective drug in the palliative treatment of
malignant ascites or pleural effusion and that it can improve the quality of
life of this group of patients. We specifically chose in this study for a lower
dose cediranib than used in former studies because we expect that cediranib is
also effective in a lower dose and that with the lower dose the side effects
will restricted.
P.O. Box 9101
6500 HB Nijmegen
NL
P.O. Box 9101
6500 HB Nijmegen
NL
Listed location countries
Age
Inclusion criteria
-symptomatic malignant ascites and/or pleural effusion (from a histological proven solid malignancy which is refractory to standard anti-tumour therapy of for which no standard therapy exists)
-Karnofsky score >= 50 if the low performance score is due to ascites and/or pleural effusion, otherwise >= 60;-written informed consent
Exclusion criteria
Contraindications for treatment with cediranib:
-The presence of a pleural or peritoneal tap
-Untreated unstable brain or meningeal metastases.
-Previous treatment with chemotherapeutic agents or tyrosine kinase inhibitors (TKIs) within 14 days prior to the first dose of cediranib, with cetuximab within 30 days prior to the first dose of cediranib, or with bevacizumab within 60 days prior to the first dose of cediranib
-Inadequate bone marrow reserve as demonstrated by an absolute neutrophil count <=1.5 x 109/L or platelet count <=100 x 109/L
-Alanine aminotransferase (ALT) or aspartate aminotransferase (AST) >= 2,5 x ULN
-Serum creatinine > 1.5 x ULRR or a creatinine clearance of <= 50mL/min calculated by Cockcroft-Gault
-Greater than +1 proteinuria on two consecutive dipsticks taken no less than 1 week apart unless urinary protein < 1.5g in a 24 hr period
-Prothrombin time (PT) and activated partial thromboplastin time (APTT) > 2 x ULN History of significant gastrointestinal impairment, as judged by the Investigator, that
would significantly affect the absorption of cediranib, including the ability to swallow the tablet whole. Patients with an ileostoma.
- Patients with a history of poorly controlled hypertension with resting blood pressure >150/100 in the presence or absence of a stable regimen of anti-hypertensive therapy. Patients who are currently receiving maximal doses of calcium channel blockers or more than 1 antihypertensive for the treatment of hypertension are also ineligible.
-Any evidence of severe or uncontrolled diseases e.g., unstable or uncompensated respiratory, cardiac, hepatic or renal disease.
-Unresolved toxicity > CTC grade 1 from previous anti-cancer therapy (including radiotherapy) except alopecia (if applicable) or polyneuropathy.
-Mean QTc with Bazetts correction >470msec in screening ECG or history of familial long QT syndrome
-Significant haemorrhage (>30mL bleeding/episode in previous 3 months) or haemoptysis (>5mL fresh blood in previous 4 weeks)
-Recent (<14 days) major surgery prior to entry into the study, or a surgical incision that is not fully healed
-Pregnant or breast-feeding women or women of childbearing potential with a positive pregnancy test prior to receiving study medication
-Known risk of the patient transmitting HIV, hepatitis B or C via infected blood
-Treatment with an investigational (non-registered) drug within 30 days prior to the first dose of cediranib
-Other concomitant anti-cancer therapy (including LHRH agonists) except steroids
-Concomitant use of any medication that may significantly affect hepatic cytochrome P450 drug metabolising activity by way of enzyme induction (e.g., phenytoin) or inhibition (e.g., ketoconazole, ritonavir, erythromycin) within 2 weeks if the first dose of cediranib and throughout the study period
-Patients being treated with anticoagulants (with the exception of low molecular weight heparin).
-Patients previously treated with antracyclines (total of > 550 mg/m2 doxorubicine) and an ejection fraction on the MUGA scan below 40%
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
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In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2010-018275-20-NL |
| CCMO | NL31254.091.10 |