A Phase 1/2 Study of the Oral ALK/EGFR Inhibitor AP26113

Patients must meet all the criteria for the cohort for which their entry is proposed.

PART 1: Dose Escalation Phase:

1. Histologically confirmed advanced malignancies. All histologies except leukemia
2. Refractory to available therapies or for whom no standard or available curative treatments exist
3. Tumor tissue available for analysis.

PART 2: Expansion cohorts (4 additional cohorts):

1. Expansion cohort 1: Non-small cell lung cancer (NSCLC) patients whose tumors exhibit anaplastic lymphoma kinase (ALK) rearrangements and who have not been treated with previous ALK inhibitors.

   • Histologically confirmed NSCLC
   • Tumor tissue available for analysis
   • ALK rearrangement by fluorescence in situ hybridization (FISH)
   • No prior ALK inhibitor therapy.

2. Expansion cohort 2: NSCLC patients whose tumors exhibit ALK rearrangements and who are resistant to crizotinib:

   • Histologically confirmed NSCLC
   • Tumor tissue available for analysis
   • ALK rearrangement by FISH
   • Resistant to crizotinib.

3. Expansion cohort 3: NSCLC patients whose tumors exhibit epidermal growth factor receptor (EGFR) activating mutations and who are resistant to at least one (1) prior EGFR inhibitor:

   • Histologically confirmed NSCLC
   • Tumor tissue available for analysis;
   • Activating mutation in EGFR including point mutation or activating deletion;
   • Resistant to at least one (1) prior EGFR inhibitor.

4. Expansion cohort 4: Patients with any cancers with abnormalities in ALK or other targets against which AP26113 is active. Examples include, but are not limited to, anaplastic large cell lymphoma (ALCL), diffuse large-cell lymphoma (DLCL), inflammatory myofibroblastic tumors (IMT), and other cancers with ALK abnormalities, or tumors with ROS fusions:

   • Histologically confirmed lymphomas and other cancers except for leukemias
   • Tumor tissue available for analysis.

General Eligibility Criteria:

All patients (irrespective of whether they are enrolled in PART 1 or PART 2) must meet all the following eligibility criteria for study entry.

• All patients must have tumor tissue available for analysis. If sufficient tissue is not available, patients must undergo a biopsy to obtain adequate samples.
• In the expansion cohorts, for which failure of prior therapy is specified (expansion cohorts 2 and 3), tumor tissue must be obtained following failure to prior therapy.
• Must have measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST).
• Male or female patients ≥ 18 years old.
• Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
• Minimum life expectancy of 3 months or more.
• Adequate renal and hepatic function.
• Adequate bone marrow function.
• Normal QT interval on screening electrocardiogram (ECG) evaluation.
• For females of childbearing potential, a negative pregnancy test must be documented prior to enrollment.
• Female and male patients who are of childbearing potential must agree to use an effective form of contraception with their sexual partners throughout study participation.
• Signed and dated informed consent indicating that the patient has been informed of all pertinent aspects of the study.
• Willingness and ability to comply with scheduled visits and study procedures.

Main Exclusion Criteria:

• Received an investigational agent within 14 days prior to initiating AP26113.
• Received systemic anticancer therapy or radiation therapy within 14 days prior to initiating AP26113. (Except for FDA-approved TKIs targeted against EGFR or ALK, which are allowed up to 72 hours prior to initiating AP26113 if the patient is free of treatment-related toxicity)
• Received any prior agents targeted against ALK, with the exception of crizotinib.
• Major surgery within 28 days prior to initiating AP26113.
• Central nervous system metastases that are symptomatic or require steroid or anticonvulsant use (unless discussed with and otherwise agreed to by the sponsor).
• Significant uncontrolled or active cardiovascular disease.
• Uncontrolled hypertension (diastolic blood pressure [BP] > 100 mm Hg; systolic > 150 mm Hg).
• Prolonged QT interval, or being treated with medications known to cause Torsades de Pointes.
• History or presence of pulmonary interstitial disease.
• Ongoing or active infection. The requirement for intravenous (IV) antibiotics is considered active infection.
• Known history of human immunodeficiency virus (HIV). Testing is not required in the absence of history.
• Pregnant or breastfeeding.
• Malabsorption syndrome or other gastrointestinal illness that could affect oral absorption of AP26113.
• Any condition or illness that, in the opinion of the Investigator, would compromise patient safety or interfere with the evaluation of the safety of the drug.