Primary:To determine the effects of multiple-dose ketoconazole (Keto) on the pharmacokinetics of single-dose oral LBH589 in patients with advanced solid tumors.Secondary:In cancer patients with advanced solid tumors:* To assess the pharmacokinetic…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary variables that will be evaluated are AUC0-tlast, AUC0-*, and Cmax
of LBH589.
For the DDI analysis, the combination treatment (Keto + LBH589) will be the
test and LBH589 alone will be the reference.
Secondary outcome
The best overall response will be estimated by using the efficacy population
and devide this number by the total number of patients with confirmed complete
response (CR) or confirmed partial response (PR) divided.
Only treatment emergent adverse events (AE) will be summarized. Treatment
emergent AEs are defined as those that started on or after the study medication
but not after 28 days post the last dose of study medication, or those that
started before study medication but worsened.
Laboratory data, data from ECGs, vital signs and any other information
collected will be listed as appropriate.
Background summary
LBH589 is an oral histone deacetylase inhibitor (HDCAi) which has in vitro
activity
in low nM concentration against cutaneous T-cell lymphoma (CTCL), chronic
leukemia, multiple myeloma, prostate, colorectal, lung and breast cancer.
LBH589 also showed antitumor activity in murine xenograft models.
LBH589 is mutagenic, and therefore cannot be administered to healthy
volunteers. In animals, the primary target organs of toxicities were: bone
marrow (rats and dogs), thyroid (rats and dogs), GI (dogs), and male
reproductive system (dogs).
In vitro studies revealed a positive preclinical signal for QT prolongation.
LBH589 has been given i.v. and p.o. in separate phase I trials. In a phase I
study currently ongoing in which 15, 20, and 30 mg oral doses of LBH589 were
given Monday, Wednesday, and Friday every week dose limiting toxicities of
thrombocytopenia and diarrhea were observed at the 30 mg dose. Thus, the
maximum tolerated dose was established at 20 mg p.o. MWF every week.
Other toxicities include nausea, vomiting, and fatigue. No clear prolongation
of
QTc has been observed due to LBH589 on the 20 mg MWF regimen.
Complete and partial responses were observed in patients with cutaneous T-cell
lymphoma at 20 and 30 mg dose. Stable disease was observed in patients with
other solid tumors.
LBH589 was found to be metabolized in human liver, in part, by human cytochrome
P450s. CYP3A4 appears to be the main enzyme involved in the oxidative
metabolism of LBH589 (70-98%).
Ketoconazole is an antifungal agent used to treat fungal infections. It has
been used extensively as a standard probe to test for CYP3A4 inhibition.
Ketoconazole is a suitable potent inhibitor of CYP3A4 and is recommended
to test for CYP3A4 inhibition.
Study objective
Primary:
To determine the effects of multiple-dose ketoconazole (Keto) on the
pharmacokinetics of single-dose oral LBH589 in patients with advanced solid
tumors.
Secondary:
In cancer patients with advanced solid tumors:
* To assess the pharmacokinetic profile of LBH589 administered before
ketoconazole
* To assess the safety and tolerability of oral LBH589 when co-administered with
ketoconazole and oral LBH589 when administered on a MWF schedule
* To assess the best clinical response of oral LBH589 in patients with advanced
solid tumors
* To explore effects of oral LBH589 on biomarkers of angiogenesis and apoptosis
Study design
This study is an open-labelstudy design to investigate the effects of
ketoconazole, a CYP3A4 inhibitor, on oral LBH589, in patients with advanced
solid tumors.
The study comprises of a core phase (treatment days 1-14), followed by an
extension study (day 15-XX).
An interim analysis of PK data will be carried out when 12 patients have
completed the core phase. Based on the outcome of the analysis, either the
planned number of subjects will be enrolled or the enrollment will be halted.
All subjects enrolled before this interim analysis will proceed to the
extension phase regardless of the interim result.
Intervention
Core phase: On day 1 every patient will receive 20 mg LBH589 followed by
5 x 400 mg ketoconazole (day 5 - 9).
Extension phase: 3x weekly (Monday-Wednesday * Friday) 20 mg LBH589
Study burden and risks
Possible side effects of LBH589 alone and of ketoconazole + LBH589 when
administered in combination.
There will be additional visits and ECG assessments during the first 4 weeks of
treatment. These additional assessments and ECG monitoring are for reasons of
safety. In the 1st cycle (day 1 to 28) ECGs are performed before and after
administration of LBH589 and ketoconazole at several timepoints.
At all subsequent cycles one ECG will be performed pre-dose.
Regular laboratory assessments for safety will be done. During cycle 1 average
twice weekly hematology an biochemistry) and once weekly at subsequent cycles.
For pharmacokinetic evaluation 30 Blood samples will be drawn (total of 150
ml). Taking blood may cause pain, bleeding, and/or bruising.
Raapopseweg 1
6824 DP Arnhem
Nederland
Raapopseweg 1
6824 DP Arnhem
Nederland
Listed location countries
Age
Inclusion criteria
* Histologically proven solid tumor which is advanced or metastatic as documented by CT-scan or MRI
* Patients with non-Hodgkin*s lymphoma should have at least one measurable or evaluable lesions (Cheson response criteria for NHL )
* Patient*s disease must have progressed on or following standard therapies.
* ECOG performance status of * 2.
* Life expectancy of * 12 weeks.
* Patients must have the following lab results:
- Absolute neutrophil count (ANC) * 1.5 x 10 9/L
- Hemoglobin (Hgb) * 9g/dl
- Platelets (plt) * 100 x 109/L
- AST/SGOT and ALT/SGPT * 2.5 x upper limit of normal (ULN); if known with liver metastases: AST/SGOT and ALT/SGPT * 5.0 x (ULN)
- Serum bilirubin * 1.5 x ULN
- Calculated creatinine clearance * 50 ml/min
- Free T4 within normal limit (WNL) and TSH * ULN
- Serum potassium * the lower limit of normal (LLN)
- Serum total calcium, magnesium and phosphorus * LLN
* Screening ECG with a QTc * 450 msec.
* Negative serum or urine pregnancy test 72 hours prior to the administration of the first study treatment.
* Baseline LVEF * the lower limit of the institutional normal
Exclusion criteria
* CNS involvement or brain metastases.
* Chronic liver toxicity
* Impairment of gastrointestinal (GI) function or GI obstruction that may significantly alter the absorption of oral LBH589.
* Diarrhea >CTCAE grade 1
* Current chemotherapy, immunotherapy, or radio-therapy or within 4 weeks prior to study entry.
* Prior treatment with a HDAC inhibitor including valproic acid within 14 days prior to first dose of LBH589.
* Significant cardiac disease, including any one of the following:
- Congenital long QT syndrome, history of sustained ventricular tachycardia, history of ventricular fibrillation or torsades de pointes, bradycardia (<50 beats per minute), patients with pacemakers are eligible if HR*50 bpm, right bundle branch block and left anterior hemiblock, myocardial infarction or instable angina within 6 months of study entry, congestive heart failure (NY Heart Association class III or IV)
* Uncontrolled hypertension
* Concomitant use of drugs with a risk of causing torsades de pointes
* Concomitant use of CYP3A4/5 inhibitors or inducers (core phase only)
* Other concurrent severe and/or uncontrolled medical conditions
* Chemotherapy or major surgery * 4 weeks prior to starting study drug
* Targeted therapy * 2 weeks or * 5 half-lives of the active drug or active metabolites
* Wide-field radiotherapy * 4 weeks or limited-field radiation for palliation * 2 weeks prior to starting study drug
* Female patients who are pregnant, or have a positive serum pregnancy test during screening or breast feeding or patients of reproductive potential not using an effective method of birth control.
* Male patients whose sexual (childbearing potential) partners are not using effective birth control
* HIV or hepatitis C* Any active or uncontrolled severe infections.
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 | EUCTR2006-006637-40-NL |
| CCMO | NL17949.078.07 |