ACY-1215 for Relapsed/Refractory Lymphoid Malignancies

The emergence of epigenetic therapies has identified pan-class deacetylase (DAC) inhibitors
as effective therapeutic agents for the treatment of lymphoma. While pan-class DAC
inhibitors have led to FDA indications, clinical activity has been limited to the T-cell
derived malignancies. The mechanism of action remains largely unknown and off-target effects
lead to side effects including fatigue, gastrointestinal disturbances, and cytopenias.
Recently, the development of isoform selective DAC inhibitors have opened the opportunity to
investigate their mechanism. It is now recognized that DAC inhibitors not only have
epigenetic properties, but have direct effects on transcription factors (p53), oncogenes
(Bcl6), and protein degradation pathways (aggresome). Proteolysis occurs primarily through
the ubiquitin-proteosome pathway. In states where this pathway is physiologically
overwhelmed or therapeutically inhibited, the aggresome sequesters proteins for degradation.
DAC6 is a class IIb deacetylase that facilitates misfolded protein transport to the
aggresome for proteosome-independent proteolysis. Inhibition of the aggresome activates the
unfolded protein response (UPR) pathway, a cellular quality control mechanism with two
primary functions: (1) to promote survival during cellular endoplasmic reticulum (ER) stress
by chaperoning proteins back for re-folding and halting further transcription until
homeostasis is restored and (2) to signal CCAAT/enhancer binding protein (C/EBP)-homologous
protein (CHOP) mediated apoptosis when homeostasis cannot be reestablished[9]. While most
cells depend on both branches of the UPR to coordinate protein folding, lymphocytes
physiologically down-regulate the UPR-apoptosis pathway, specifically CHOP, to allow for
generation of high affinity antibodies. In addition to initiating genetic abnormalities
(translocations and point mutations) lymphomas inherit this biology, and thus gain a
survival advantage.

It has been shown ACY-1215, an Histone Deacetylase 6 (HDAC6)-selective, orally active
small-molecule enzyme inhibitor has had single agent activity in a panel of lymphoma cell
lines and mouse models, and marked synergistic activity with several agents such as
bortezomib, carfilzomib, and ibrutinib, unpublished data. ACY-1215 has been studied in vivo
in models of multiple myeloma and lymphoma with marked activity both as a single agent and
in combination with bortezomib. Therefore ACY-1215 will be investigated for treatment of
lymphoma as a single agent leading to future studies evaluating its effects in combination
with other targeted agents known to be active in lymphoma and synergistic with ACY-1215.

Inclusion Criteria:

- Patients must have histologically confirmed relapsed or refractory non-Hodgkin's
lymphoma or Hodgkin's lymphoma (World Health Organization criteria), for which they
are unwilling or unable to undergo an autologous stem cell transplant. Patients may
have relapsed after prior stem cell transplant.

- Must have received first line chemotherapy. No upper limit to number of prior
therapies.

- Patients must have measurable disease.

- Patients must be age ≥ 18.

- Patient has a Karnofsky Performance Status score of ≥70 or Eastern Cooperative
Oncology Group (ECOG) performance status score of ≤2

- The patient or the patient's legal representative is able to understand the risks of
the study and provide signed informed consent and authorization to use protected
health information (in accordance with national and local privacy regulations).

- Patient has adequate bone marrow reserve, as evidenced by:

- Absolute neutrophil count (ANC) of ≥1.0x109/L.

- Platelet count of ≥50x109/L.

- Patient has adequate renal function, as evidenced by a creatinine within the
institutional limits of normal or a calculated creatinine clearance of ≥30 mL/min
according to the Cockcroft-Gault equation.

- Patient has adequate hepatic function, as evidenced by serum bilirubin values <2.0
mg/dL and serum alanine transaminase (ALT) and/or aspartate transaminase (AST) values
<3 × the upper limit of normal (ULN) of the local laboratory reference range.
(Patients with isolated elevations in alkaline phosphatase (ALP) <5 × ULN in the
presence of bony disease are not excluded from participating in the study.)

- Females of childbearing potential must have a negative urine or serum pregnancy test
within 7 days of (C1D1) and have adequate contraception. (A female is considered to
be not of childbearing potential if she has undergone bilateral oophorectomy or if
she has been menopausal without a menstrual period for 12 consecutive months.)

Exclusion Criteria:

- Prior Therapy

1. Patients who have had chemotherapy or radiotherapy within 2 weeks of study drug
treatment or those who have not recovered from adverse events due to agents
administered

2. Systemic steroids that have not been stabilized to the equivalent of ≤10 mg/day
prednisone during the 7 days prior to the start of the study drugs.

3. No monoclonal antibody within 3 months unless evidence of disease progression.

- Patients may not be receiving any other investigational agents.

- Patients with known central nervous system metastases, including lymphomatous
meningitis

- Any known cardiac abnormalities such as:

- Congenital long QT syndrome

- Corrected QT (QTc) interval ≥ 500 milliseconds;

- Uncontrolled inter-current illness

- Pregnant or nursing women

- Patient is known to be Human Immunodeficiency Virus (HIV)-positive

- Active Hepatitis A, Hepatitis B, or Hepatitis C infection

- Patient has a history of surgery that would interfere with the administration or
absorption of the oral study drugs