Primary objective (dose escalation arm): To determine the MTD of AUY922 as a single agent.Primary objective (phase II): At the MTD two further arms will be expanded to assess response (breast cancer)
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase I: to determine the MTD of AUY922 as a single agent, administered once
weekly. Estimation of the MTD will be based upon the estimation of the
probability of DLT in cycle 1.
Phase II only (breast cancer)
Efficacy: responders (CR/PR), non-responders with stable disease for at least 6
months (SD * 6 months), progressive disease within 6 months from study start or
others
Secondary outcome
* Safety: Type, frequency and severity of adverse events (CTCAE Version 3.0)
* Efficacy: In the dose-escalation arm response will be also assessed by RECIST.
* PK: Cmax, Tmax, AUC0-24 and AUC0-T
* PD: PET response, blood and tumor biomarkers at baseline and post-AUY922
dosing.
Background summary
AUY922 is a Heat shock protein (HSP) inhibitor. Heat shock proteins (HSP) are
molecular chaperones that assist in the structural formation and folding of a
wide variety of client proteins such as HER2 and ER. HSP90 is the most abundant
molecular chaperone and is essential for cell survival.
AUY922 is an isoxazole that competitively inhibits the ATPase activity of
HSP90. In doing so, the client proteins of HSP90 begin to undergo cellular
degradation and the regulation of cell survival, proliferation and apoptosis
are therefore affected. HSP90 is an important target for cancer
chemotherapeutics because tumor cells, especially those with mutations, exist
in a stressful environment and depend on HSP90 to grow and survive. For this
reason, HSP90 inhibitors such as AUY922 are considered to be agents with
significant therapeutic potential in a wide variety of tumor types.
Study objective
Primary objective (dose escalation arm): To determine the MTD of AUY922 as a
single agent.
Primary objective (phase II): At the MTD two further arms will be expanded to
assess response (breast cancer)
Study design
The study is designed as a phase I/II trial. During the phase I dose escalation
component,
patients with advanced solid malignancies will be enrolled into cohorts to
establish the MTD.
An adaptive Bayesian logistic regression model for dose escalation will guide
the phase I dose escalation component to determine the MTD. Once the MTD has
been confirmed, the cohort will be expanded to become the MTD expansion arm of
the trial enrolling a total of 22 patients (advanced solid tumors) for safety
and tolerability including patients from the MTD cohort.
The phase II component can start in parallel to the MTD expansion arm it will
enroll only patients with locally advanced or metastatic breast cancer at the
MTD and will have two arms: one for patients with HER2 positive disease and the
other for those with ER positive disease.
Intervention
AUY922 administered intravenously, once weekly as single agent.
Study burden and risks
Side effects of AUY922.
The risks of taking blood and an intravenous catheter.
Risks of a tumor biopsy depend on the area of the biopsy.
Radiation exposure of CT-scan). The exposure to radiation in these scans is
within the standard limits in this country.
Raapopseweg 1
6824 DP Arnhem
NL
Raapopseweg 1
6824 DP Arnhem
NL
Listed location countries
Age
Inclusion criteria
Breast cancer phase II expansion arms only
1a. Female patients with ER positive HER2 positive locally advanced non-operable metastatic breast cancer with history of trastuzumab resistance
1b. Female patients with ER positive non-operable locally advanced or metastatic breast
cancer who received endocrine therapy and whose disease has
progressed on at least one line of endocrine therapy for advanced disease.
2. At least one measurable lesion as defined by RECIST.
3. All patients must have progressive disease before entering to the study.
4. (WHO) Performance Status of * 2.
5. Life expectancy of * 12 weeks.
6. Patients must have the following laboratory values:
* Absolute Neutrophil Count (ANC) * 1.5 x 109/L
* Hemoglobin (Hgb) * 9 g/dl
* Platelets (plt) * 100 x 109/L
* Potassium, calcium, magnesium and phosphorus within normal limits or correctable with supplements
* Liverfunctiontests * 2.5 x Upper Limit of Normal (ULN) or * 5.0 x ULN if liver metastases are present
* bilirubin and creatinin * 1.5 x ULN or 24-hour clearance * 50 ml/min
* albumin * 2.5g/dl
Exclusion criteria
Main Exclusion criteria
1. CNS metastasis.
2. Prior treatment with any HSP90 or HDAC inhibitor compound.
3a. Radiotherapy within 4 weeks or palliative radiotherapy within 2 weeks
3b. Nitrosoureas, mitomycin and monoclonal antibodies, such as trastuzumab: within 6 weeks
3c. Systemic anticancer treatment for which the recovery period
is not known, or investigational drugs within a duration of * 5 half lives of the agent and their active metabolites (if any)
4. Patients who have not recovered from side effects of previous systemic anticancer therapy to less than grade 2 prior to the first dose of study treatment
5. Treatment with therapeutic doses of sodium warfarin (Coumadin). Low doses of
Coumadin (e.g. * 2mg/day for line patency) are permitted.
6. Patients using medications that are substrates, inhibitors or inducers of CYP3A4,
CYP2C8, CYP2C9 and CYP2C19 and cannot be switched or discontinued to an
alternative drug prior to commencing AUY922 dosing
7. Unresolved diarrhea * CTCAE grade 2.
8. Patients who do not have either an archival tumor sample available or are unwilling to have a fresh tumor sample collected at baseline.
9. Acute or chronic liver disease.
10. Acute or chronic renal disease.
11. Other concurrent severe and/or uncontrolled medical conditions
12. Clinical significant cardiac disease e.g:
* History of long QT syndrome or Mean QTc * 450 msec
* History of clinically manifest ischemic heart disease * 6 months prior to
study start.
* History of heart failure or left ventricular (LV) dysfunction (LVEF * 45%) by MUGA
or ECHO.
* Clinically significant ECG abnormalities
* History of atrial fibrillation, atrial flutter or ventricular arrhythmias
* Clinically significant resting bradycardia (< 50 beats per minute).
* Any medication which has a relative risk or prolonging the QTcF interval or inducing Torsades de Pointes
* Pacemaker.
13. Patients with known disorders due to a deficiency in bilirubin glucuronidation
14. Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention.
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 | EUCTR2006-0027660-2-NL |
| ClinicalTrials.gov | NCT00526045AphaseIdoseescalation,multi-center,open-labelstudyof |
| CCMO | NL24551.042.08 |