Clinical Trials /

ACY-1215 for Relapsed/Refractory Lymphoid Malignancies

NCT02091063

Description:

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.

Related Conditions:
  • Hodgkin Lymphoma
  • Mantle Cell Lymphoma
  • Non-Hodgkin Lymphoma
Recruiting Status:

Completed

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: ACY-1215 for Relapsed/Refractory Lymphoid Malignancies
  • Official Title: A Phase Ib/II, Open-label, Multicenter Study of the Selective HDAC6 Inhibitor, ACY-1215, for the Treatment of Patients With Relapsed or Refractory Lymphoid Malignancies

Clinical Trial IDs

  • ORG STUDY ID: AAAM4054
  • NCT ID: NCT02091063

Conditions

  • Lymphoma
  • Lymphoid Malignancies

Interventions

DrugSynonymsArms
ACY-1215RicolinostatPhase Ib: Arm A: ACY-1215 QD

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase Ib: Arm A: ACY-1215 QDExperimentalPhase Ib: ACY-1215 160mg PO QD
  • ACY-1215
Phase Ib: Arm B: ACY-1215 BIDExperimentalPhase Ib: ACY-1215 160mg PO BID
  • ACY-1215
Phase II: ACY-1215ExperimentalPhase I dosing schedule has been determined. 160 mg BID dosing will be administered for Phase II.
  • ACY-1215

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

               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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase I: Number of patients who experience a dose-limiting toxicity (DLT)
Time Frame:Up to 1 year
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure:Number of Adverse Events (AEs)
Time Frame:Up to 1 year
Safety Issue:
Description: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.
Measure:Progression free survival (PFS)
Time Frame:Up to 3 years
Safety Issue:
Description:Time from start of study treatment until disease progression or death
Measure:Duration of response (DoR)
Time Frame:Up to 3 years
Safety Issue:
Description:Time from documentation of tumor response to disease progression

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Jennifer Amengual

Trial Keywords

  • hematologic malignancies
  • hodgkin
  • hodgkins
  • non-hodgkin
  • non-hodgkins
  • mantle cell lymphoma
  • follicular
  • lymphoma
  • lymphoid malignancies

Last Updated

May 16, 2017