ACY-1215 for Relapsed/Refractory Lymphoid Malignancies

Study Overview
=================
Brief Summary
-----------------
This will be an open-label, single agent, multi-institutional phase Ib/II study of ACY-1215 for the treatment of patients with relapsed or refractory lymphoid malignancies. The target population will include patients with histologically confirmed relapsed or refractory non-Hodgkin's lymphoma or Hodgkin's lymphoma, with an expansion cohort of patients with mantle cell lymphoma. The phase Ib will be conducted to determine the safety and tolerability of two dosing schedules of ACY-1215 monotherapy in patients with lymphoid malignancies. Patients will be accrued simultaneously to two dose cohorts (Arm A and Arm B) of ACY-1215. Selection into each cohort will occur by alternation. All patients will take the prescribed dose of ACY-1215 orally for 28 consecutive days. Patients enrolled into Arm A will take ACY-1215 160 mg daily (QD), whereas patients enrolled into Arm B will take ACY-1215 160 mg twice daily (BID). ACY-1215 will be supplied as a liquid for oral administration (PO). Each dose will be administered at least 1 hour after ingestion of food followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose. Frequency in phase II will be determined based on Phase Ib results.

Detailed Description
-----------------
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.

Official Title
-----------------
A Study of the Selective HDAC6 Inhibitor, ACY-1215, for the Treatment of Patients With Relapsed or Refractory Lymphoid Malignancies

Conditions
-----------------
Lymphoma, Lymphoid Malignancies

Intervention / Treatment
-----------------
* Drug: ACY-1215


Participation Criteria
=================
Eligibility Criteria
-----------------
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 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 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. 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

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase Ib: Arm A: ACY-1215 QD<br>Phase Ib: ACY-1215 160mg PO QD | Drug: ACY-1215<br>* All patients will take the oral ACY-1215 160mg for 28 consecutive days on a 28-day treatment cycle. Each dose will be administered at least 1 hour after ingestion of food and followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose.<br>* Other names: Ricolinostat;|
| Experimental: Phase Ib: Arm B: ACY-1215 BID<br>Phase Ib: ACY-1215 160mg PO BID | Drug: ACY-1215<br>* All patients will take the oral ACY-1215 160mg for 28 consecutive days on a 28-day treatment cycle. Each dose will be administered at least 1 hour after ingestion of food and followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose.<br>* Other names: Ricolinostat;|
| Experimental: Phase II: ACY-1215<br>Phase I dosing schedule has been determined. 160 mg BID dosing will be administered for Phase II. | Drug: ACY-1215<br>* All patients will take the oral ACY-1215 160mg for 28 consecutive days on a 28-day treatment cycle. Each dose will be administered at least 1 hour after ingestion of food and followed by at least 4 ounces of water. Patients will be instructed not to ingest food or other oral medication for at least 2 hours after each ACY-1215 dose.<br>* Other names: Ricolinostat;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Phase I: Number of patients who experience a dose-limiting toxicity (DLT) | This is designed to establish the safety of 2 dose schedules of ACY-1215 in patients with relapsed or refractory lymphoid malignancies treated with ACY-1215. If more than 1/3 or 2/6 patients experience a DLT, there will be no expansion. | Up to 1 year | 
| Phase II: Objective response rate | The anti-tumor activity of ACY-1215 will be measured by the number of subjects with the response rate: complete response [CR] and partial response [PR]. | Up to 3 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of Adverse Events (AEs) | To determine if ACY-1215 is safe and tolerated in patients with relapsed or refractory lymphoid malignancies, the number of AEs per patient, per cohort will be tabulated and reviewed. | Up to 1 year | 
| Progression free survival (PFS) | Time from start of study treatment until disease progression or death | Up to 3 years | 
| Duration of response (DoR) | Time from documentation of tumor response to disease progression | Up to 3 years | 

 Terms related to the study
=================
Keywords Provided by Centre Hospitalier Valida
-----------------
hematologic malignancies, hodgkin, hodgkins, non-hodgkin, non-hodgkins, mantle cell lymphoma, follicular, lymphoma, lymphoid malignancies