This single center Phase I dose escalation trial will evaluate the safety, tolerability and
efficacy of LBH589 when combined with capecitabine and lapatinib in three parts. Part 1
will determine the maximum tolerated doses (MTD) of LBH589 when combined with capecitabine.
Parts 2 and 3 will be limited to locally recurrent or metastatic breast cancer patients,
ICH 3+ overexpression or FISH amplification documented locally. Part 2 will evaluate the
safety of the MTD of LBH589 determined in Part 1 when paired with lapatinib 1000 mg by mouth
(PO) daily. Parts 2 and 3 will be limited to locally recurrent or metastatic breast cancer
patients, ICH 3+ overexpression or FISH amplification documented locally. Part 3 will
evaluate the tolerability and effectiveness of the triplet combination, LBH589, capecitabine
and lapatinib in breast cancer patients.
LBH589 will be evaluated when administered twice weekly at the following possible dose
levels: 20 mg, 30 mg, 45 mg, and 60 mg. Capecitabine will be paired with LBH589 and will
range in dose from 825 mg/m2 to 1250 mg/m2 orally BID 14 of every 21 days. Treatment
cycles will be 21 days in length. Once determined safe, 10 additional patients will be
treated at the determined MTD to further assess safety.
The second portion of this study will assess QTc prolongation with the LBH589 and lapatinib
combination. A subset of 6 patients will be treated with the LBH589 one dose below the MTD
determined during Part I. If tolerated, 6 additional patients will receive LBH589 at the
MTD established in Part I with lapatinib (capecitabine will not be administered in this
subset of patients).
If there are no clinically significant findings in the LBH589 and lapatinib subset, the
study will advance to a third portion which combines the three drugs LBH589, capecitabine,
The triple combination will initially administer lapatinib 1000 mg orally daily with LBH589
and capecitabine at one dose level below the established MTD. If tolerated, LBH589 and
capecitabine doses will be escalated to the MTD.
Toxicity assessments will be ongoing and disease assessments will be repeated every 2
treatment cycles. If all dose level combinations are explored, a total of 45-55 patients
will be required to accommodate for the additional patients enrolled in the QTc subset and
to establish the recommended phase II dose of the combination regimen.
1. Histologically documented metastatic or locally unresectable, incurable malignancy
for which capecitabine is clinically appropriate.
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 Response Evaluation Criteria in Solid Tumors (RECIST) criteria.
5. Eastern Cooperative Oncology Group performance status (ECOG PS) 0 or 1.
6. Baseline MUGA or ECHO must demonstrate LVEF > than the lower limits of the
7. Laboratory values as follows:
- ANC > 1500/μL
- Hgb > 9 g/dL
- Platelets > 100,000/uL
- Bilirubin < 1.5 mg/dL
- AST/SGOT < 2.5 x ULN or < 5.0 x ULN and ALT/SGPT in patients with liver
- Creatinine < 1.5 mg/dL or calculated creatinine clearance > 50 ml/min
- Albumin > 3 g/dL
- Potassium > lower limit of normal (LLN)
- Phosphorous > LLN
- Calcium > LLN
- Magnesium > LLN
8. Women of childbearing potential must have a negative serum or urine pregnancy test
performed within 7 days prior to start of treatment and must commit to begin two
acceptable methods of birth control, one highly effective method of birth control and
one additional effective method at the same time before starting 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.
Additional Breast Cancer Patient Subset (Part 2 and Part 3) Inclusion Criteria:
1. Incurable carcinoma of the breast, with measurable locally recurrent or metastatic
2. ICH 3+ overexpression or FISH amplification documented by a local laboratory in
primary or metastatic tumor tissue.
3. Prior treatment with an anthracycline, taxane, and trastuzumab or not a candidate for
such treatment. Patient may have received these drugs in combination or in sequence
for the treatment of locally advanced or metastatic disease and/or adjuvant therapy.
1. Prior treatment with an HDAC inhibitor or current treatment with valproic acid.
2. Previous treatment with capecitabine.
3. 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 minute. Patients with 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).
- Right bundle branch block and left anterior hemiblock (bifascicular block).
- Atrial fibrillation or flutter.
- Ongoing therapy with antiarrhythmics or other medications associated with QTc
4. Uncorrected hypokalemia or hypomagnesaemia.
5. Uncontrolled hypertension (systolic blood pressure [BP] 180 or diastolic BP > 100 mm
Hg) or uncontrolled cardiac arrhythmias.
6. Active CNS disease, including meningeal metastases.
7. Known diagnosis of human immunodeficiency virus (HIV) infection.
8. Unresolved diarrhea > CTCAE grade 1.
9. Concomitant requirement for medication classified as CYP3A4 inducers or inhibitors.
10. Patients with a history of allergic reactions attributed to compounds of similar
chemical or biologic composition to lapatinib.
11. Patients with known hypersensitivity to 5-fluorouracil 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.
12. 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.
13. Concomitant use of any anti-cancer therapy or radiation therapy.
14. Pregnant or breast feeding or female of reproductive potential not using two
effective methods of birth control.
15. Male patients whose sexual partners are women of childbearing potential not using
effective birth control.
16. 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).
17. 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.
18. Patients taking any medications listed in "Prohibited Medications" for both
capecitabine and lapatinib .
19. Patients with uncontrolled coagulopathy (PT and/or PTT > 1.2 x ULN; patient must also
be on stable dose of anticoagulant for a defined medical indication).
20. Abnormal thyroid function (TSH or free T4) detected at screening. Patients with
known hypothyroidism who are stable on thyroid replacement are eligible.
Additional Breast Cancer Patient Subset (Part 2 and Part 3) Exclusion Criteria:
1. Prior treatment with lapatinib