Primary objective(s)Phase Ib:-Define the maximum tolerated dose (MTD) and/or recommended phase two dose (RPTD) of AUY922 in combination with Trastuzumab in patients with advanced or metastatic HER2-positive breast cancers.Phase II:-Evaluate…
ID
Source
Brief title
Condition
- Breast neoplasms malignant and unspecified (incl nipple)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase Ib:
- Incidence rate of Dose Limiting Toxicities (DLT)
Phase II:
- Overall response rate (ORR)
Secondary outcome
Phase Ib and II
- Safety: Adverse drug reactions , changes in hematology and chemistry values,
specifically those associated with hepatic and renal function; assessment of
physical examinations, neurological exams, vital signs and electrocardiograms.
- Pharmacokinetics: Cmax, Tmax, AUC0-tlast and AUC(0-infinity)
Phase Ib:
- Preliminary efficacy: Tumor response assessment using CT/MRI.
- Pre vs. serial post-treatment intracellular protein measurement of HSP70 in
PBMCs
Phase II:
- -PFS/OS as defined in RECIST guidelines.
-Temporal and magnitude changes in blood and tissue marker levels comparing
pre- vs. post-treatment.
Background summary
Breast cancer is the most common form of malignancy occurring in women. In the
US, approximately 182.460 new cases of invasive breast cancer have been
diagnosed in 2008. In the same year about 40.480 women have died from their
disease. In Europe approximately 13% (370.100) of all new cases of cancer that
were diagnosed were breast cancer. Approximately 40% of diagnosed patients will
eventually develop metastatic breast cancer. Treatment for metastatic breast
cancer is palliative and median life expectancy after recurrence is between 24
to 30 months.
HER-2 neu positive breast cancer accounts for approximately 20-25% of all cases
of breast cancer. This breast cancer type is characterized by high levels of
HER2 protein expression. These proteins and their associated signal
transduction pathways play a dominant role in cell growth and survival. These
HER-2 positive patients will have an aggressive form of breast cancer and
therefore a worse prognosis.
Study objective
Primary objective(s)
Phase Ib:
-Define the maximum tolerated dose (MTD) and/or recommended phase two dose
(RPTD) of AUY922 in combination with Trastuzumab in patients with advanced or
metastatic HER2-positive breast cancers.
Phase II:
-Evaluate preliminary anti-tumor activity of AUY922 in combination with
Trastuzumab in patients with advanced or metastatic HER2-positive breast
cancers.
Secondary objective(s)
- Safety and tolerability of AUY922 when administered in combination with
Trastuzumab.
- Pharmacokinetic profile of AUY922 and its metabolite BJP762 when given in
combination with Trastuzumab.
- Evaluate preliminary anti-tumor activity
- Assess the pharmacodynamic (PD) effect of AUY922 in combination with
Trastuzumab
- Characterize the relationship between PK and PD of the combination.
- Investigate the pharmaco dynamic effect of AUY922 in combination with
Trastuzumab on HSP90 client proteins in pre- and post-therapy tumor tissue
pairs and blood
Study design
Open-label, multicenter Phase Ib/II trial with a dose-escalation part with
AUY922 administered in combination with Trastuzumab (Phase Ib), followed by a
dose expansion part (Phase II).
The dose escalation will use an adaptive Bayesian logistic regression model to
find the MTD and/or the recommended phase II dose.
The phase II part will use a Bayesian design to estimate the overall response
rate (ORR).
One cycle is defined as 28 days.
Treatment should be continued as long as the patient does not have disease
progression and tolerates the treatment.
Tumor assessments using CT or MRI will be performed every 8 weeks, for 24
weeks, then every 12 weeks until progression or until a new anticancer therapy
is initiated. During the study, bone scans are to be performed only if
clinically indicated.
Follow-up: After the End of Treatment visit all patients will have their
follow-up visit 1 (FUP1) visit performed, 28 days after the last dose. Patients
who discontinued for any reason other than disease progression will continue to
have tumor assessments every 12 weeks until progression, death or until a new
anticancer therapy is initiated. All patients who have progressed during study
treatment will be followed every 3 months for survival. The follow-up period
will stop, in any case, 2 years after the last patient is enrolled in the
study.
Intervention
AUY922 - startdose 55mg/m2 - weekly infusion
Trastuzumab - 2mg/kg - weekly infusion
Study burden and risks
Side effects of AUY922 (especially vision toxicity, diarrhea, cardiac toxicity
and changes in adrenal glands) and side effects of trastuzumab.
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
- Confirmed HER2-positive, non-operable locally advanced or metastatic breast cancer
- Tumor samples must demonstrate HER2 over-expression based on either:
- Immunohistochemistry (IHC) 3+ or IHC 2+ confirmed by fluorescence in-situ hybridization (FISH).
- At least 1 but no more than 2 prior anti-HER2 based regimens including at least 1 regimen containing Trastuzumab.
- At least one measurable lesion as defined by RECIST.
-ECOG Performance Status of <= 1
• Patients must have the following laboratory values:
Absolute Neutrophil Count >=1.5x109/L
Hemoglobin >= 9 g/dl = 5.58 mmol/l
Platelets >=100x109/L
Potassium, total calcium and phosphorus within normal limits
Magnesium above LLN
Adequate liver function defined as:
AST/SGOT and ALT/SGPT <= 1.5 x Upper Limit of Normal or
AST/SGOT and ALT/SGPT <= 2.5 x Upper Limit of Normal (ULN) if <= 5.0 x ULN if liver metastases are present
Serum bilirubin <= 1.5 x ULN
Serum albumin > 2.5 g/dl
Serum creatinine <= 1.5 x ULN or 24-hour clearance >= 50 ml/min.
• Negative serum pregnancy test.
Exclusion criteria
• Patients with known CNS metastasis which are symptomatic or require treatment for symptom control and/or growing.
• Prior treatment with any HSP90 or HDAC inhibitor.
• Systemic anti-cancer treatment prior to the first dose of AUY922 within the following time frames:
- Palliative radiotherapy: within 2 weeks
- Nitrosoureas, mitomycin: within 6 weeks
• Unresolved diarrhea >= CTCAE grade 1
• Reversible side effects of previous systemic anticancer therapy (except for alopecia) to less than CTCAE grade 2 prior to the first dose.
• Therapeutic doses of sodium warfarin (Coumadin).
• Acute or chronic liver or renal disease.
• Patients with other concurrent severe and/or uncontrolled medical conditions that could cause unacceptable safety risks or compromise compliance with the protocol.
• Known hypersensitivity to any study medication.
• Impaired cardiac function, including any one of the following:
- History (or family history) of long QT syndrome.
- Mean QTcF >= 450 msec on screening ECG.
- History of clinically manifested ischemic heart disease <= 6 months prior to study start.
- (LVEF <= 45%) by MUGA or ECHO.
- Clinically significant ECG abnormalities
- History or presence of atrial fibrillation, atrial flutter or ventricular arrhythmias including ventricular tachycardia or Torsades de Pointes.
- Other clinically significant heart disease (e.g. congestive heart failure, uncontrolled hypertension, history of labile hypertension, or history of poor compliance with an antihypertensive regimen).
- Clinically significant resting bradycardia (< 50 beats per minute).
- Current treatment with any medication which has a relative risk of prolonging the QTcF interval or inducing Torsades de Pointes
- Obligate use of a cardiac pacemaker.
• 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 | EUCTR2009-015628-27-NL |
| CCMO | NL34231.031.10 |