A Phase I Study of LBH589 in Combination With Paclitaxel and Carboplatin +/- Bevacizumab the Treatment of Solid Tumors
1. Histologically documented metastatic or locally advanced, incurable malignancy for
which paclitaxel and carboplatin is clinically appropriate for example, non-small
cell lung, breast, ovarian, head and neck cancer, and carcinoma of unknown primary.
2. Male or female patients aged >= 18 years old.
3. Maximum of 3 prior regimens in a metastatic setting allowed and may include other
targeted agents, immunotherapy and chemotherapy.
4. Measurable disease by RECIST criteria.
5. ECOG PS 0 or 1.
6. Laboratory values as follows:
ANC >= 1500/μL Hgb >= 9 g/dL Platelets >= 100,000/uL Bilirubin <= upper limit normal
(ULN) AST/SGOT and ALT/SGPT <= 2.5 x ULN or <= 5.0 x ULN in patients with liver
metastases Creatinine <= 2.0 mg/dL Or 24-hour Creatinine Clearance >= 50 ml/min
Albumin >= 3 g/dL Potassium >= lower limit normal (LLN) Phosphorous >= LLN Calcium >=
LLN Magnesium >= LLN PT/INR and PTT <= 1.5 x ULN
7. Peripheral neuropathy < grade 1.
8. Women of childbearing potential must have a negative serum or urine pregnancy test
performed within 7 days prior to start of treatment.
9. Life expectancy > 12 weeks.
10. Accessible for treatment and follow-up.
11. All patients must be able to understand the nature of the study and give written
informed consent prior to study entry.
1. Prior HDAC, DAC, HSP90 inhibitors or valproic acid for the treatment of cancer
Patients who will need valproic acid for any medical condition during the study or
within 5 days prior to first LBH589 treatment
2. Impaired cardiac function including any of the following:
- Screening ECG with a QTc > 450 msec.
- Congenital long QT syndrome.
- History of sustained ventricular tachycardia.
- Any history of ventricular fibrillation or torsades de pointes.
- Bradycardia defined as heart rate < 50 beats per minutes. Patients wit a
pacemaker and heart rate >= 50 beats per minute are eligible.
- Myocardial infarction or unstable angina within 6 months of study entry.
- Congestive heart failure (NY Heart Association class III or IV [See Appendix
- Right bundle branch block and left anterior hemiblock (bifasicular block).
- Atrial fibrillation or flutter.
3. Uncontrolled hypertension (systolic blood pressure [BP] 160 or diastolic BP >95mm Hg)
or uncontrolled cardiac arrhythmias.
4. Active CNS disease, including meningeal metastases.
5. Known diagnosis of human immunodeficiency virus (HIV) infection.
6. Unresolved diarrhea > CTCAE grade 1.
7. Chemotherapy, investigational drug therapy, major surgery < 4 weeks prior to starting
study drug or patients that have not recovered from side effects of previous therapy.
8. Patient is < 5 years free of another primary malignancy except if the other primary
malignancy is not currently clinically significant or requiring active intervention,
or if other primary malignancy is a basal cell skin cancer or a cervical carcinoma in
situ. Existence of any other malignant disease is not allowed.
9. Concomitant use of any anti-cancer therapy or radiation therapy.
10. Women who are pregnant or breast feeding or women of childbearing potential (WOCBP)
not willing to use a double barrier method of contraception during the study and 3
months after the end of treatment. One of these methods of contraception must be a
barrier method. WOCBP are defined as sexually mature women who have not undergone a
hysterectomy or who have not been naturally postmenopausal for at least 12
consecutive months (i.e., who has had menses any time in the preceding 12 consecutive
months). Women of childbearing potential (WOCBP) must have a negative serum or urine
pregnancy test within 7 days of the first administration of oral LBH589.
11. Male patients whose sexual partners are WOCBP not using a double method of
contraception during the study and 3 months after the end of treatment. One of these
methods must be a condom.
12. Patients with gastrointestinal (GI) tract disease, causing the inability to take oral
medication, malabsorption syndrome, a requirement for intravenous (IV) alimentation,
prior surgical procedures affecting absorption, uncontrolled inflammatory GI disease
(e.g., Crohn's disease, ulcerative colitis).
13. Other concurrent severe, uncontrolled infection or intercurrent illness, including
but not limited to ongoing or active infection, symptomatic congestive heart failure,
unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social
situations that would limit compliance with study requirements.
14. Patients with uncontrolled coagulopathy.
15. Abnormal thyroid function (TSH or free T4) detected at screening.Patients with known
hypothyroidism who are stable on thyroid replacement are eligible.
Exclusion Criteria (Part II portion)
1. Patients with tumor types other than advanced non-small cell lung cancer and patients
with squamous cell histology non-small cell lung cancer.
2. Patients who have had a major surgical procedure (not including mediastinoscopy),
open biopsy, or significant traumatic injury within 6--8 weeks of beginning
bevacizumab. Fine needle aspiration, core biopsy, mediastinoscopy or other minor
surgical procedure within 7 days of beginning bevacizumab.
3. Patients receiving full-dose oral or parenteral anticoagulation. Patients receiving
thrombolytic therapy within 10 days of starting bevacizumab are also ineligible.
Patients may receive anticoagulation therapy, (1 mg coumadin daily) for port clot
4. Patients with serious non-healing wound, ulcer, or bone fracture.
5. Patients with evidence of bleeding diathesis or coagulopathy.
6. Patients with history of hemoptysis (defined as bright red blood of ½ teaspoon or
more per episode) within 3 months prior to study enrollment.
7. History of myocardial infarction or unstable angina within 6 months of first
8. Patients with proteinuria at screening for as demonstrated by either:
a. Urine protein creatinine (UPC) ration >1.0 at screening OR b. Urine dipstick for
proteinuria > 2+ (patients discovered to have > 2+ proteinuria on dipstick
urinalysis at baseline should undergo a 24 hour urine collection and must demonstrate
< 1 g of protein in 24 hours to be eligible.
9. History of abdominal fistula, gastrointestinal perforation, or intra-abdominal
abscess within 6 months prior to beginning bevacizumab.
10. History of stroke or transient ischemic attack within 6 months prior to first