Study of ACY-1215 Alone and in Combination With Bortezomib and Dexamethasone in Multiple Myeloma

A Phase 1/2, Open-Label, Multicenter Study of ACY-1215 Administered Orally as Monotherapy and in Combination With Bortezomib and Dexamethasone for the Treatment of Relapsed or Relapsed/Refractory Multiple Myeloma

Phase 1(a & b): To evaluate the side effects and determine the best dose of oral ACY-1215 as monotherapy, and also in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma.

Phase 2a: To determine the objective response rate of oral ACY-1215 in combination with bortezomib and dexamethasone in patients with relapsed or relapsed/refractory multiple myeloma.

Inclusion Criteria:

• Patient has relapsed or relapsed/refractory MM with measurable disease parameters according to the International Myeloma Working Group (IMWG) Criteria

  • Refractory is defined as experiencing less than minimal response (MR) to or progressive disease (PD) within 60 days after completion of the most recent anti-MM regimen
  • Relapsed is defined as experiencing PD that requires therapy but which is not refractory following the achievement of stable disease (SD) or better to the most recent anti-MM regimen.

• Patient received at least 2 prior regimens for MM.

• Patient received prior treatment for MM with a proteasome inhibitor and an immunomodulatory drug, unless not a candidate for a proteasome inhibitor or an immunomodulatory drug.

• Patient either is not a candidate for autologous stem cell transplant (ASCT), has declined the option of ASCT, or has relapsed after prior ASCT.

• Patient is ≥18 years of age.

• Patient has a Karnofsky Performance Status score of ≥70

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

  • Absolute neutrophil count (ANC) of ≥1.0x109/L.
  • Platelet count of ≥ 75x109/L in patients in whom <50% of bone marrow nucleated cells are plasma cells and ≥50x109/L in patients in whom more than 50% of bone marrow nucleated cells are plasma cells.

• Patient has adequate renal function (calculated creatinine clearance of ≥30 mL/min according to the Cockroft-Gault)

• Patient has adequate hepatic function (serum bilirubin values <2.0 mg/dL and ALT and/or AST values <3 × the upper limit of normal ULN).

• Patient has a corrected serum calcium ≤ULN.

Exclusion Criteria

• Patient has received any of the following therapies:

  • Radiotherapy or systemic therapy within 2 weeks of baseline
  • Prior peripheral autologous stem cell transplant within 12 wks of Baseline.
  • Prior allogeneic stem cell transplant.
  • Prior treatment with an HDAC inhibitor.

• Patient has an active systemic infection requiring treatment.

• Patient has a history of other malignancies unless has undergone definitive treatment more than 5 yrs prior to study and without evidence of recurrent malignant disease (excluding basal cell carcinoma of the skin; superficial carcinoma of the bladder; carcinoma of the prostate with a current prostate-specific antigen <0.1 ng/mL; or cervical intraepithelial neoplasia).

• Patient has known or suspected HIV, positive for hepatitis B or is known or suspected to have active hepatitis C infection.

• Patient has a history of significant cardiovascular, neurological, endocrine, gastrointestinal, respiratory, or inflammatory illness including recent myocardial infarction (within 6 months)or stroke; hypertension requiring >2 medications for adequate control; diabetes mellitus with >2 episodes of ketoacidosis in the preceding 12 months; or chronic obstructive pulmonary disease (COPD) requiring >2 hospitalizations in the preceding 12 months.

• Patient has a QTcF value of >480 msec; family or personal history of long QTc syndrome or ventricular arrhythmias including ventricular bigeminy; previous history of drug-induced QTc prolongation

• Patient has > Grade 2 painful neuropathy or peripheral neuropathy

• Patient has a history of allergic reaction attributable to bortezomib or other compounds containing boron or mannitol (Phase 1b and 2a only)