A Study of ARRY-520 and Bortezomib Plus Dexamethasone in Patients With Relapsed/Refractory Multiple Myeloma

• Characterize the safety profile of the study drug in combination with bortezomib ± dexamethasone + G-CSF in terms of adverse events, clinical laboratory tests and electrocardiograms. [ Time Frame: Until MTD is reached ] [ Designated as safety issue: Yes ]
• Establish the maximum tolerated dose (MTD) of the study drug in combination with bortezomib ± dexamethasone + G-CSF. [ Time Frame: Until MTD is reached ] [ Designated as safety issue: Yes ]

• Characterize the safety profile of ARRY-520 when combined with bortezomib and dexamethasone as determined by adverse events, dose limiting toxicities, clinical laboratory tests, physical examination, body weight and electrocardiograms [ Time Frame: Until MTD is reached ] [ Designated as safety issue: Yes ]
• Establish the maximum tolerated dose of ARRY-520 when combined with bortezomib and dexamethasone [ Time Frame: Until MTD is reached ] [ Designated as safety issue: Yes ]

• Assess the efficacy of ARRY-520 when combined with bortezomib and dexamethasone as determined by serum/urine protein and immunofixation electrophoresis, serum free light chain, bone marrow aspirate/biopsy, CRP, LDH and beta-2 microglobulin [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
• Assess the efficacy of ARRY-520 when combined with bortezomib and dexamethasone as determined by best overall response, time to progression, treatment-free interval, and time to next treatment [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]
• Assess potential markers for patient selection and measurement of the biological activity of ARRY-520 when combined with bortezomib and dexamethasone in hematological tumor cells and peripheral blood [ Time Frame: Every 4 weeks ] [ Designated as safety issue: No ]

This is a Phase 1 study during which patients with relapsed or refractory multiple myeloma (MM) or plasma cell leukemia (PCL) will receive investigational study drug ARRY-520 and bortezomib, with or without dexamethasone, with granulocyte-colony stimulating factor (G-CSF) support.

This study has 2 parts. In the first part, patients will receive increasing doses of study drug (2 dosing schedules will be evaluated) in combination with (1) bortezomib with G-CSF support or (2) bortezomib and dexamethasone with G-CSF support, in order to achieve the highest dose of study drug possible that will not cause unacceptable side effects. Approximately 45 patients from the US will be enrolled in Part 1 (Recruiting).

In the second part of this study, patients will receive the best dose(s) and schedule(s) of study drug, in combination with bortezomib ± dexamethasone + G-CSF, determined from the first part of the study and will be followed to see what side effects the combination causes and what effectiveness the combination has, if any, in treating the cancer. Approximately 42 patients from the US will be enrolled in Part 2 (Not yet recruiting).

• Drug: ARRY-520, KSP(Eg5) inhibitor; intravenous
  Part 1: multiple dose, escalating; Part 2: multiple dose, single schedule.
• Drug: Bortezomib, proteasome inhibitor; intravenous or subcutaneous
  Part 1: standard of care; Part 2: standard of care determined in Part 1.
• Drug: Dexamethasone, steroid; oral
  Part 1: standard of care; Part 2: standard of care determined in Part 1.
• Drug: Filgrastim, granulocyte-colony stimulating factor (G-CSF); subcutaneous
  Part 1: standard of care; Part 2: standard of care.

• Experimental: ARRY-520 (Schedule 1) + bortezomib + G-CSF
  Interventions:

  • Drug: ARRY-520, KSP(Eg5) inhibitor; intravenous
  • Drug: Bortezomib, proteasome inhibitor; intravenous or subcutaneous
  • Drug: Filgrastim, granulocyte-colony stimulating factor (G-CSF); subcutaneous
• Experimental: ARRY-520 (Schedule 1) + bortezomib + dexamethasone + G-CSF
  Interventions:

  • Drug: ARRY-520, KSP(Eg5) inhibitor; intravenous
  • Drug: Bortezomib, proteasome inhibitor; intravenous or subcutaneous
  • Drug: Dexamethasone, steroid; oral
  • Drug: Filgrastim, granulocyte-colony stimulating factor (G-CSF); subcutaneous
• Experimental: ARRY-520 (Schedule 2) + bortezomib + dexamethasone + G-CSF
  Interventions:

  • Drug: ARRY-520, KSP(Eg5) inhibitor; intravenous
  • Drug: Bortezomib, proteasome inhibitor; intravenous or subcutaneous
  • Drug: Dexamethasone, steroid; oral
  • Drug: Filgrastim, granulocyte-colony stimulating factor (G-CSF); subcutaneous

Key Inclusion Criteria (Part 1 and Part 2):

• Confirmed relapsed or refractory MM (measurable disease) or PCL.
• Prior treatment regimens for Part 1: Patients should have received at least 2 prior treatment regimens. Prior treatment must have included at least one full cycle of a proteasome inhibitor (e.g., bortezomib or carfilzomib) and at least one full cycle of an IMiD (e.g., thalidomide, lenalidomide or pomalidomide).
• Prior treatment regimens for Part 2: Patients should have received 1 to 3 prior treatment regimens. Prior treatment could have included bortezomib only if the disease was not refractory to treatment with bortezomib (refractory defined as documented progression on therapy or within 60 days of completing treatment with bortezomib).
• The disease should have progressed per IMWG criteria during or after the last prior treatment regimen.
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• Adequate hematology laboratory values without transfusion support and without hematological growth factor support within 2 weeks of screening.
• Adequate liver and renal function.
• Additional criteria exist.

Key Exclusion Criteria (Part 1 and Part 2):

• Primary amyloidosis.
• Peripheral neuropathy ≥ Grade 2 or neuropathy with pain, regardless of grade.
• Concomitant malignancies or previous malignancies with less than a 3-year disease free interval at the time of enrollment (patients with adequately resected basal or squamous cell carcinoma of the skin, carcinoma in situ of the cervix or Stage A low grade prostate cancer may enroll irrespective of the time of diagnosis).
• Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to first dose of study drug.
• Treatment with an investigational medicinal product or device within 28 days prior to first dose of study drug.
• Cytotoxic therapy or monoclonal antibodies within 21 days prior to first dose of study drug.
• Radiotherapy within 21 days prior to first dose of study drug (if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy).
• Major surgery within 14 days and minor surgery within 7 days prior to first dose of study drug.
• Corticosteroid doses > 10 mg/day of prednisone or equivalent within 14 days prior to first dose of study drug.
• Known positive serology for the human immunodeficiency virus (HIV), hepatitis B and/or active hepatitis C.
• Additional criteria exist.