A Phase 2 Study of Amrubicin in Relapsed or Refractory Thymic Malignancies

Amrubicin, a synthetic 9-aminoanthracycline, is structurally similar to doxorubicin, but has
a different primary mode of action. It acts primarily as an inhibitor of DNA topoisomerase
II, exerting its cytotoxic effects by stabilizing a topoisomerase II mediated cleavable
complex. This inhibition is significantly more than that seen in doxorubicin, which, in
contrast, tends to demonstrate more DNA intercalation than amrubicin.

It has not yet been evaluated for use in thymic malignancies, but given its efficacy in NSCLC
and small cell lung cancer (SCLC), as well as the known efficacy of other anthracyclines and
topoisomerase II inhibitors in first-line thymoma treatment, it warrants study for use in the
second line and beyond in refractory or relapsed patients. Unlike doxorubicin, amrubicin has
had minimal cardiotoxicity even with ongoing use, which also makes it a promising agent for
use in the second line even for patients who have previously been exposed to, and potentially
helped by, doxorubicin.

Inclusion Criteria:

- Histologically or cytologically confirmed invasive or metastatic thymoma or thymic
carcinoma. Locally invasive disease is acceptable, provided it is not resectable.

- Previous treatment with at least one prior chemotherapy regimen.

- Documented progressive disease after the most recent chemotherapy regimen.

- Presence of measurable disease on imaging within 4 weeks prior to first dose

- Completion of prior systemic therapy at least 4 weeks prior to first dose.

- Any prior immunotherapy therapy completed at least 8 weeks prior to first dose.

- Any prior surgery completed at least 4 weeks prior to first dose, with adequate
recovered from surgery.

- Any prior radiation therapy must have no residual toxic effects of therapy. Chest
radiotherapy with curative intent to the primary disease complex must have been
completed ≥ 28 days prior to first dose. Cranial radiation must have been completed ≥
21 days prior to first dose. Radiotherapy to all other areas must have been completed
≥ 7 days prior to first dose.

- Age ≥ 18 years.

- Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1.

- Leukocytes ≥ 3000/mm³

- Absolute neutrophil count ≥ 1500/mm³

- Platelets ≥ 100,000/mm³

- Hemoglobin ≥ 9 g/d

- Serum bilirubin < 1.5 x institutional upper limit of normal (ULN)

- Aspartate transaminase (AST) and alanine transaminase (ALT) ratio < 3 x ULN

- Serum creatinine < 1.5 times institutional upper limit of normal if serum creatinine
above institutional upper limit of normal, calculated serum creatinine clearance by
the Cockcroft Gault method > 60 mL/min

- Left ventricular ejection fraction (LVEF) ≥ 50% by transthoracic echocardiogram (TTE)
or multiple gated acquisition scan (MUGA)

- For females of childbearing potential, negative serum pregnancy test within 4 weeks of
first dose.

- For males and females of childbearing potential, use of effective contraceptive
methods during the study.

- Ability to understand and willingness to sign a written informed consent document.

Exclusion Criteria:

- Current use, or use within 4 weeks prior to first dose, of any other investigational
agents.

- Known history of allergic reactions attributed to compounds of similar chemical or
biologic composition to amrubicin.

- Active malignancy requiring treatment other than thymic malignancy.

- Pregnant or nursing females due to unknown toxic effects of amrubicin on the
developing fetus or in breast milk. Should a woman become pregnant or suspect she is
pregnant while participating in this study, she should inform her treating physician
immediately.

- Symptomatic central nervous system metastatic disease. Patients with asymptomatic
brain metastases allowed. If treated with surgical resection or radiation therapy, the
patient must be stable for >= 2 weeks after completion of therapy. If the patient is
on corticosteroids, the dose of corticosteroids, the dose of corticosteroids must have
been stable for >= 2 weeks prior to first dose of study treatment, or be in the
process of being tapered.

- Concurrent severe or uncontrolled medical disease (including but not limited to active
systemic infection, diabetes, hypertension, coronary artery disease, congestive hear
failure and mental illness) that in the opinion of the investigator would compromise
the safety of the patient or compromise the ability of the patient to complete the
study.

- Known history of seropositive human immunodeficiency virus (HIV) or use of
immunosuppressive medications for other conditions that would, in the opinion of the
investigator, increase the risk of serious neutropenic complications.