Primary objectiveTo determine the maximum tolerated dose (MTD) and characterize the dose-limiting toxicities (DLT) of LEQ506 when administered orally on a continuous daily dosing schedule.Secondary objectives* To characterize the safety and…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Frequency of dose-limiting toxicities (DLTs)
Secondary outcome
* Safety: Adverse drug reactions and serious adverse drug reactions, changes in
hematology and chemistry values (specifically those associated with hepatic and
renal function), assessment of physical examinations, vital signs and ECG's
* Pharmacokinetics parameters
* Pharmacodynamics: Post-treatment changes in Gli1 mRNA expression in normal
skin and tumor samples
* Efficacy: Tumor response using RECIST for patients with solid tumors and
using the Neuro-Oncology Criteria of Tumor Response for patients with Medullo
Blastoma
Background summary
LEQ506 is a potent and selective Smo (smoothened) antagonist. Smoothened (Smo)
is a Gprotein-coupled receptor (GPCR)-like molecule that positively regulates
the Hedgehog (Hh) signal transduction pathway.
Activation of the Hedgehog pathway without known mutations has been described
for a number of different tumor types. There is evidence of activating
mutations in Hh pathway genes in Medulloblastoma and Basel Cell Carcinoma
Growth of tumors driven by Hh signaling in xenograft models has been shown to
be inhibited by treatment with Smo antagonist. malignancies. Smo inhibitors may
therefore be useful in the treatment of a wide range of human malignancies. The
proof of concept for the potential clinical utility of this class of agents has
been established in patients with metastatic or locally advanced Basel Cell
Carcinoma.
Study objective
Primary objective
To determine the maximum tolerated dose (MTD) and characterize the
dose-limiting toxicities (DLT) of LEQ506 when administered orally on a
continuous daily dosing schedule.
Secondary objectives
* To characterize the safety and tolerability of LEQ506
* To characterize the PK of LEQ506 and any relevant metabolites
* To characterize the PD effects of LEQ506 by measuring Gli1 mRNA expression in
normal skin and tumor samples
* To characterize any anti-tumor activity associated with LEQ506 treatment
Study design
A phase I, multi-center, open label dose escalation study of LEQ506,
administered orally daily on a continuous 21-day dosing schedule.
The study starts with a PK run-in period, with administration of a single dose
(SD) of LEQ506 on day 1 followed by serial PK sampling over the subsequent 5
days, will be included in the dose escalation
phase of this trial in order to characterize the SD PK profile of LEQ506.
This will be followed by the dose escalation phase. 3 to 6 patients will be
enrolled in each cohort until MTD has been declared.
Individual patients may be considered for treatment at a dose of LEQ506.
After MTD has been declared enrollment to the safety expansion phase will be
restricted to patients with tumors that are characterized by Hedgehog pathway
activation, such as recurrent or refractory MB or locally advanced BCC.
Intervention
LEQ506, oral dosing, capsules
Starting dose: 80 mg/day
Study burden and risks
Side effects from LEQ506 seen in animal that might happen in human:.
* Abnormal laboratory findings in the kidneys and liver which could potentially
lead to
kidney or liver damage or failure.
* Nausea and vomiting, which can lead to dehydration
* Diarrhea, which can lead to dehydration
* Weakening of hair follicles leading to loss of hair
* Risk of inability to conceive and have children
* Risk of causing malformations in fetuses (unborn babies)
Taking blood and tumorbiopsies may cause pain, bleeding, and/or bruising.
Patients will be exposed to radiation (CT-scan, and X-rays). The radiation
exposure will not exceed the maximum ranges that are set within the
Netherlands.
Raapopseweg 1
6824 DP
NL
Raapopseweg 1
6824 DP
NL
Listed location countries
Age
Inclusion criteria
- Dose escalation phase: patients with a with a histologically or cytologically confirmed solid tumor, who have progressed despite standard therapy or for which no standard therapy exists. Patients with recurrent or refractory Medullo Blastoma (MB) and patients with metastatic or locally advanced Basel Cell Carcinoma (BCC) that cannot be with local therapy.
- Expansion phase: patients with tumors that are characterized by Hedgehog pathway activation, such as recurrent or refractory MB or metastatic or locally advanced BCC
- WHO performance status *2.
- Required baseline laboratory values:
*Absolute Neutrophil Count *1.5x109/L
*Hemoglobin * 9 g/dl <= 5.58 mmol/l
*Platelets * 80x109/L
*AST/SGOT and ALT/SGPT * 2.5 x Upper Limit of Normal (ULN) or * 5.0 x ULN if liver metastases are present
*Serum bilirubin * 1.5 x ULN
*Serum creatinine * 1.5 x ULN or 24-hour clearance * 50 ml/min.
- Patients must have fully recovered from the effects of prior major surgery and from any acute toxic effects of prior chemotherapy and radiotherapy.
- A negative serum pregnancy test * 72 hours before starting study treatment
Exclusion criteria
- History of primary central nervous system tumors or symptomatic brain metastases (except recurrent MB). However, patients with resected brain metastasis with no radiological evidence of disease or with stable brain metastasis with no evidence of progression are eligible. Such patients must have no need for treatment with steroids or anti-epileptic medications.
- Known diagnosis of HIV or Hepatitis C
- Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of LEQ506
- Any unresolved nausea, vomiting, or diarrhea CTCAE grade >1.
- Impaired cardiac function or clinically significant cardiac diseases, including any of the
following:
1) Acute myocardial infarction or angina pectoris * 3 months prior to starting study drug
2) QTcF > 450 msec for males and > 470 msec for females on screening ECG
3) Medical history of clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension)
- Any other concurrent severe and/or uncontrolled concomitant medical condition (e.g. uncontrolled diabetes, clinically significant pulmonary disease, clinically significant neurological disorder, active or uncontrolled infection).
- Systemic anti-cancer treatment or radiotherapy < 2 weeks before the first dose of study treatment
(* 4 weeks for monoclonal antibodies).
- Prior treatment with investigational agents * 4 weeks or * 5 x their half-lives (whichever is longer) before the first dose of study treatment.
- Treatment with medications that are known to be strong inhibitors or inducers of CYP3A4/5
- Treatment with medications that are known to be substrates of CYP3A4/5 or CYP2C9 and that have low therapeutic indices.
Design
Recruitment
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 | EUCTR2009-017969-30-NL |
| ClinicalTrials.gov | NCT01106508 |
| CCMO | NL32618.041.10 |