A Phase I Dose Escalation, Multi-center, Open-label Study of HSP990 Administered Orally in Adult Patients With Advanced Solid Malignancies
1. Patients with histologically confirmed, advanced malignant solid tumors whose disease
has progressed on standard therapy or for whom no standard therapy exists
2. All patients must have at least one measurable lesion as defined by RECIST.
Irradiated lesions are only evaluable for disease progression
3. All patients must have documented progressive disease before entering the study
4. Age ≥ 18 years
5. World Health Organization (WHO) Performance Status ≤ 2
6. Life expectancy of ≥ 12 weeks
7. Patients must have the certain laboratory values
8. Patients able and willing to swallow capsules
9. Ability to understand the patient information and informed consent form and comply
with the protocol
10. Signed and dated written informed consent is available
11. Only for patients enrolled at MTD: willing to provide a fresh pre-dose and post-dose
1. Patients with present or history of CNS metastasis.
2. Prior treatment with any Hsp90 or HDAC inhibitor compound.
3. Patients who have not recovered from side effects of previous systemic anticancer
therapy to < CTCAE Grade 2 prior to the first dose
4. Patients identified to be "poor or intermediate CYP2C9 metabolizers"
5. Patients who received systemic anti-cancer treatment prior to the first dose of
HSP990 within the following time frames:
- Patients who have received cyclical chemotherapy within a period of time that is
shorter than the cycle length used for that treatment (e.g., 6 weeks for
nitrosourea, mitomycin-C) prior to starting study drug or who have not recovered
from the side effects of such therapy
- Patients who have received biologic therapy (e.g., antibodies) within a period
of time that is ≤ 4 weeks prior to starting study drug or who have not recovered
from the side effects of such therapy
- Patients who have been treated with a continuous or intermittent small molecule
therapeutic within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks (whichever is
shorter) prior to starting study drug or who have not recovered from the side
effects of such therapy
- Patients who have received any other investigational agents within a period of
time that is ≤ 5 t1/2 or less than the cycle length used for that treatment or ≤
4 weeks (whichever is shorter) prior to starting study drug or who have not
recovered from the side effects of such therapy
- Patients who have received wide field radiotherapy (including therapeutic
radioisotopes such as strontium 89) ≤ 4 weeks or limited field radiation for
palliation ≤ 2 weeks prior to starting study drug or who have not recovered from
side effects of such therapy.
- Patients who have undergone major surgery ≤ 2 weeks prior to starting study drug
or who have not recovered from side effects of such therapy
6. Treatment with therapeutic doses of sodium warfarin (Coumadin).
7. Patients using medications that are CYP2C9 inhibitors and/or medications known to
have QT prolongation effect and cannot be switched or discontinued to an alternative
drug prior to commencing HSP990 dosing.
8. Unresolved diarrhea ≥ CTCAE grade 2
9. Patients who do not have either an archival tumor sample available or readily
obtainable in the course of the study or are unwilling to have a fresh tumor sample
collected at baseline.
10. Pregnant or lactating women.
11. Fertile women of childbearing potential (WCBP) not using adequate contraception
(abstinence, oral contraceptives, intrauterine device or barrier method of
contraception in conjunction with spermicidal jelly or surgically sterile). Male
patients whose partners are WCBP, not using adequate contraception.
12. Acute or chronic liver disease.
13. Acute or chronic renal disease.
14. Impairment of gastrointestinal (GI) function or GI disease that may significantly
alter the absorption of HSP990
15. Other concurrent severe and/or uncontrolled medical conditions (e.g., uncontrolled
diabetes, active or uncontrolled infection) that could cause unacceptable safety
risks or compromise compliance with the protocol.
16. Known diagnosis of HIV infection (HIV testing is not mandatory).
17. Patients with a history of another primary malignancy that is currently clinically
significant or currently requires active intervention
18. Cardiac exclusion criteria:
- History (or family history) of long QT syndrome.
- Mean QTcF ≥ 480 msec on screening ECG
- History of clinically manifest ischemic heart disease including myocardial
infarction, or unstable angina ≤ 3 months prior to study start.
- Left ventricular (LV) dysfunction (LVEF ≤ 45%) by MUGA or ECHO
- Clinically significant ECG abnormalities including one or more of the following:
left bundle branch block (LBBB), right bundle branch block (RBBB) with left
anterior hemiblock (LAHB), or 3rd degree AV block.
- History or presence of atrial fibrillation, atrial flutter or ventricular
arrhythmias including ventricular tachycardia or Torsades de Pointes.
- Clinically significant resting bradycardia (< 50 beats per minute).
- Patients who are currently receiving treatment with any medication which has a
relative risk or prolonging the QTcF interval or inducing Torsades de Pointes
(as listed in Post-text supplement 2) and cannot be switched or discontinued to
an alternative drug prior to commencing HSP990 dosing.
- Obligate use of a cardiac pacemaker.
- 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)
Other protocol-defined inclusion/exclusion criteria may apply