Dose Finding, Safety and Tolerability Study for AC220 to Treat Advanced Solid Tumors

A phase 1 open-label, dose finding study of AC220 in patients with solid tumors.

Inclusion Criteria:

1. Males and females age ≥18 years

2. Understand and voluntarily sign the informed consent form for this study

3. Available for periodic follow-up at the investigative site

4. Able to swallow the liquid study drug

5. ECOG performance status of 0 - 2

6. Histological diagnosis of a primary solid tumor malignancy that meets the following
criteria:

- Evidence (radiographic or tissue confirmation) that the disease is metastatic
(locally advanced disease is allowable only if no surgical or local therapeutic
option exists); and

- Disease which has progressed on or following currently available standard
therapies or for which no curative therapy exists (Prior adjuvant, neoadjuvant,
and investigational therapies are permitted.)

7. Measurable disease by computer tomography (CT) or magnetic resonance imaging (MRI)
scans per RECIST.

8. Prior anticancer therapy, radiotherapy, hormonal, and immunotherapy are allowed.
Patients must have recovered from toxicity of prior therapy (ie, toxicity has resolved
to Grade 1, or to pre-treatment baseline, or is deemed irreversible). At least 4 weeks
must have elapsed since the last systemic therapy (6 weeks for nitrosoureas,
mitomycin-C, and liposomal doxorubicin), immunotherapy, or radiotherapy and the
beginning of study drug administration. For participants with GIST on approved
tyrosine kinase inhibitors (TKI), at least 2 weeks must have elapsed since the last
dose of TKI.

9. Adequate bone marrow function, defined as:

- Absolute neutrophil count (ANC) (neutrophils and bands) ≥1.5 x 10^9 cells/L

- Platelet count ≥ 100 x 10^9 cells/L

- Hemoglobin ≥ 9.0 g/dL

10. Adequate hepatic function, defined as:

- Total serum bilirubin ≤ 1.5 x the institutional upper limit of normal (ULN)

- Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x the
institutional ULN

11. Adequate renal function, defined as:

- Serum creatinine ≤ 1.5 x the institutional ULN

12. Prothrombin time or partial thromboplastin time (PT- PTT) ≤ 1.5 x the ULN

13. Serum potassium, magnesium, and calcium levels should be at least within institutional
normal limits, and every effort should be made to keep potassium concentrations above
4.0 mEq/dL, magnesium concentrations above 1.8 mg/dL, and serum calcium at normal
concentration with the administration of oral/IV potassium and/or magnesium and/or
calcium replacement during the study. If this is not possible, potassium and magnesium
(and calcium) concentrations should at least be kept within institutional normal
limits.

14. Fully recovered (≤ Grade 1 or returned to baseline or deemed irreversible) from the
acute effects of prior cancer therapy before initiation of study drug administration.

15. Baseline left ventricular ejection fraction (LVEF) ≥ 45% (or ≥ institutional lower
limit of normal if institutional lower limit of normal is below 45%) as assessed by
2-dimensional ECHO or MUGA as per institutional practice. If repeat LVEF assessment is
required, the same modality should be used throughout the duration of study, whenever
possible.

16. Women of childbearing potential (WOCBP) must be using an adequate method of
contraception to avoid pregnancy throughout the study and for at least 3 months after
the study in such a manner that the risk of pregnancy is minimized. WOCBP includes any
female who has experienced menarche and who has not undergone successful surgical
sterilization (hysterectomy, bilateral tubal ligation or bilateral oophorectomy) or is
not post menopausal (defined as amenorrhea > 12 consecutive months; or who is on
hormone replacement therapy [HRT] with documented serum follicle stimulating hormone
[FSH] level > 35 mIU/mL). Additionally, premenopausal women who are using oral,
implanted or injectable contraceptive hormones or mechanical products such as an
intrauterine device or barrier methods (diaphragm, condoms, spermicides) to prevent
pregnancy, are practicing abstinence, or whose partner is sterile (eg, vasectomy),
should be considered to be of childbearing potential.

17. WOCBP must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L
or equivalent units of human chorionic gonadotropin [hCG]) within 72 hours prior to
the start of study drug.

Exclusion Criteria:

1. WOCBP who are unwilling or unable to use an acceptable contraceptive method to avoid
pregnancy for the entire study period and for at least 3 months after the study.

2. Women who are pregnant or breastfeeding

3. WOCBP with a positive pregnancy test on enrollment prior to study drug administration

4. Men who are unwilling or unable to use an acceptable method of birth control if their
sexual partners are WOCBP for the entire study period and for at least 3 months after
completion of the study

5. Patients with known untreated, symptomatic or uncontrolled brain or central nervous
system (CNS) metastases. Patients with treated brain or CNS metastases that are
radiographically stable for 3 months or longer are eligible.

6. A serious uncontrolled medical disorder or active infection which would impair the
ability of the patient to receive study drug

7. Uncontrolled or significant cardiovascular disease, including:

- A myocardial infarction within 12 months prior to study entry

- Uncontrolled angina within 6 months prior to study entry

- Congestive heart failure (CHF) New York Heart Association (NYHA) class 3 or 4, or
patients with history CHF NYHA class 3 or 4 in the past, unless the screening
ECHO or MUGA within 14 days prior to study entry results in a LVEF that is ≥ 45%
(or ≥institutional lower limit of normal)

- Diagnosed or suspected congenital long QT syndrome

- Any history of clinically significant ventricular arrhythmias (such as
ventricular tachycardia, ventricular fibrillation, or Torsades de Pointes [TdP])

- Prolonged QTc interval on pre-entry ECG (≥ 450 ms)

- Any history of second or third degree heart block

- Uncontrolled hypertension

- Obligate need for a cardiac pacemaker

- Complete left bundle branch block

- Atrial fibrillation

8. Known infection with human immunodeficiency virus (HIV)

9. Known active hepatitis A, B, or C or other active liver disease

10. Dementia or altered mental status that would prohibit the understanding or rendering
of informed consent

11. Investigational agents during or within 4 weeks prior to the start of study drug

12. Use of drugs that are generally accepted to have a risk of causing prolonged QTc
and/or TdP and/or are CYP3A4 inhibitors. Patients who have discontinued any of these
medications must have a washout period of at least 5 days or at least 5 half-lives of
the drug (whichever is greater) prior to the first dose of study drug and should not
be allowed to take these medications during the study drug dosing.

13. Medical condition, serious intercurrent illness, or other extenuating circumstance
that, in the judgment of the Principal Investigator or Sponsor, could jeopardize
patient safety or interfere with the objectives of the study.