LBH589 in Combination With Capecitabine Plus/Minus (±) Lapatinib in Breast Cancer Patients
Condition: Breast Cancer
MeSH terms: Breast Neoplasms
Intervention: LBH589; Capecitabine; Lapatinib
Intervention description: 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.; Capecitabine will be administered orally twice daily for 14 days out of every 21 days.; Lapatinib, 1000 mg PO daily will be added to this combination.
Intervention MeSH terms: Capecitabine; Lapatinib; Panobinostat
Phase: Phase 1
Study type: Interventional
Primary purpose: Treatment
Allocation: Non-Randomized
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 20.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Refractory Malignancy; Breast Cancer; LBH589; Capecitabine; Lapatinib

Summary:

      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.
    

Eligibility criteria:

        Inclusion Criteria:

          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
             institutional normal.

          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
                  metastases

               -  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
             disease.

          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.

        Exclusion Criteria:

          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
                  prolongation.

          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