Phase I Study of LBH589 & Erlotinib for Advanced Aerodigestive Tract Cancers

• Number of Participants With Progression Free Survival (PFS) [ Time Frame: 6 Months ] [ Designated as safety issue: Yes ]
  Evaluate safety of erlotinib/LBH589B, pharmacokinetic drug levels of Erlotinib, full profile of single agent vs. combination; biomarkers of acetylation; objective response rate; 6-mo. progression free survival rate; time-to-event variables.
• Duration of Stable Disease (SD) [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  Participants' duration of stable disease up to 1 year.
• Number of Participants With Overall Survival (OS) [ Time Frame: 1 Year ] [ Designated as safety issue: No ]
  Overall survival time up to 1 year.

The purpose of the study is to:

• Find out if Erlotinib and LBH589 can be safely given together in patients with advanced non-small cell lung cancer (NSCLC) or Head and Neck (H&N) Cancer.
• Learn more about the side effects of these two drugs when combined together.
• Learn how these two drugs work in cancer cells when they are combined.
• Learn how this combination affects the ways in which they are absorbed by the body and eliminated.
• Find the highest doses of Erlotinib and LBH589 that can be safely given without causing serious side effects.

Patients will be asked to remain on the study for a minimum of 3 months unless the study doctor decides the patient should be taken off the study or the patient withdraws from the study. Each cycle of treatment is 21 days in length and there is a 30 day follow-up after the patient receives their last dose of study drug. Scans will be repeated to see how their cancer is doing after two cycles of treatment. These scans wil be repeated every 2 cycles for the first 6 cycles and then every 3 cycles for as long as the patient remains on the study. The patient may continue on therapy as long as they are responding or have stable disease.

• Lung Cancer
• Head and Neck Cancer

• Drug: LBH589

  During the study, LBH589 will be administered orally as biweekly dose of 20-40 mg (20 mg and 5 mg capsules are available) on Mondays and Thursday, one week off, then two weeks on.

  Cycle # 1 week 2 dosing will be the exception. The LBH589 for cycle 1 week 2 will be given on day 9 and 12 (Tuesday and Friday) due to the pharmacokinetic (PK) sampling for that week.

  Patients may continue treatment with oral LBH589 until they experience unacceptable toxicity that precludes further treatment, disease progression, and/or at the discretion of the investigator.

  Other Names:

  • histone deacetylase inhibitor
  • HDAC
  • pabinostat
• Drug: erlotinib
  Erlotinib will be self-administered in an open-label, unblinded manner to all patients enrolled in the study. During the treatment period, patients will receive single-agent erlotinib, 100-150 mg/day (dose will depend upon which dose level that patient is enrolled in. Tablets should be taken at the same time each day with 200 mL of water at least 1 hour before or 2 hours after a meal. Patients who are unable to swallow tablets may dissolve the tablets in distilled water for administration.
  Other Names:

  • Tarceva
  • quinazoline

Inclusion Criteria:

• Histologically or cytologically documented diagnosis of advanced/metastatic NSCLC or Head and Neck cancer.
• Male or female patients aged ≥ 18 years old
• Ability to provide written informed consent obtained prior to participation in the study and any related procedures being performed
• Have progressive and measurable disease that can be measured by Response Evaluation Criteria in Solid Tumors (RECIST) criteria
• Patients must have discontinued prior systemic chemotherapy by 14 days.

• Patients must meet the following laboratory criteria:

  1. Serum albumin ≥ 3g/dL
  2. Aspartic transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT) ≤ 2.5 x upper limit of normal (ULN)or ≤ 5.0 x ULN if the transaminase elevation is due to leukemic involvement
  3. Serum bilirubin ≤ 1.5 x ULN
  4. Serum creatinine ≤ 1.5 x ULN or 24-hour creatinine clearance ≥ 50 ml/min
  5. Serum potassium ≥ lower limit of normal (LLN) and ≤ ULN
  6. Serum phosphorous ≥ LLN
  7. Serum total calcium (corrected for serum albumin) or serum ionized calcium ≥ LLN
  8. Serum magnesium ≥ LLN
  9. Absolute neutrophil count (ANC)(ANC: segmented and bands) ≥ 1.5 X10^9/L
  10. Platelets ≥ 100 X 10^9/L
• Baseline multiple gated acquisition imaging (MUGA) or echocardiogram (ECHO) must demonstrate left ventricular ejection fraction (LVEF) ≥ the lower limit of the institutional normal
• Eastern Cooperative Oncology Group (ECOG) Performance Status of ≤ 1
• Reproductive potential must be either terminated (by surgery, radiation, or menopause) or attenuated by the use of an approved contraceptive method during and for 3 to 6 months following the study.
• Patient instructed that intravenous (IV) bisphosphonates will be withheld for the first 8 weeks of LBH589 therapy due to risk of hypocalcemia.

Exclusion Criteria:

• Impaired cardiac function including any one of the following:

  1. Screening electrocardiogram (ECG) with a corrected QT (QTc) > 450 msec confirmed by central laboratory prior to enrollment to the study
  2. Patients with congenital long QT syndrome
  3. History of sustained ventricular tachycardia
  4. Any history of ventricular fibrillation or torsades de pointes
  5. Bradycardia defined as heart rate < 50 beats per minute. Patients with a pacemaker and heart rate ≥ 50 beats per minute are eligible.
  6. Patients with a myocardial infarction or unstable angina within 6 months of study entry
  7. Congestive heart failure - New York Heart Association (NYHA) class III or IV
  8. Right bundle branch block and left anterior hemiblock (bifascicular block)
  9. Patients with a history of uncontrolled or chronic atrial fibrillation.
• Uncontrolled hypertension, blood pressure (BP) >180/110 on 3 separate occasions despite oral antihypertensive medications
• Concomitant use of drugs with a risk of causing torsades de pointes Concomitant use of CYP3A4 inhibitors
• Patients with documented central nervous system or leptomeningeal metastasis (brain metastasis) at the time of study entry. Patients with prior brain metastasis may be considered if they have completed their treatment for brain metastasis, no longer require corticosteroids, and are asymptomatic.
• Patients with unresolved diarrhea > Common Terminology Criteria for Adverse Events (CTCAE) grade 1
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral LBH589
• Other concurrent severe and/or uncontrolled medical conditions
• Patients who have received chemotherapy < 14 days, any investigational drug < 14 days or undergone major surgery < 4 weeks prior to starting study drug or who have not recovered from side effects of such therapy.
• Concomitant use of any anti-cancer therapy (except erlotinib) or radiation therapy.
• Female patients who are pregnant or breast feeding or patients of reproductive potential not using two effective methods of birth control. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 7 days of the first administration of oral LBH589
• Male patients whose sexual partners are WOCBP not using effective birth control
• Patients with known positivity for human immunodeficiency virus (HIV) or hepatitis C; baseline testing for HIV and hepatitis C is not required
• Patients with any significant history of non-compliance to medical regimens or with inability to grant a reliable informed consent
• Patients who are not willing to refrain from wearing contact lenses during study participation will be excluded.

• Genentech
• Novartis