A Phase 1/2 Study of ARRY-520 in Patients with Relapsed or Refractory Multiple Myeloma
Jatin J. Shah
The goal of the Phase I part of this clinical research study is to find the highest tolerable dose of ARRY-520 when given to patients with multiple myeloma or plasma cell leukemia who get ARRY-520 alone or ARRY-520 with Neupogen (filgrastim). The goal of the Phase II part of this study is to learn if ARRY-520 with or without dexamethasone can help to control multiple myeloma or plasma cell leukemia. The safety of this drug will be studied in both parts.
Disease Group: Myeloma
Treatment Agent: ARRY-520
Treatment Location: Both at MDACC & outside MDACC at one or more Collaborating Sites or Institutions
Estimatated Length of Stay in Houston: N/A
Sponsor: Array Biopharma
Return Visit: Screening cycle 1 days 1, 2, 3, 4 and 8. Cycle 2: Days 1, 2, 3, 4 and 8. The patient will return for a follow-up visit 30 days after the last treatment.
Home Care: N/A
In patients with relapsed or refractory Multiple Myeloma (MM) or Plasma Cell Leukemia (PCL) who have received at least two lines of prior treatment, which must have included bortezomib and an immunomodulatory agent (e.g., thalidomide and/or lenalidomide), unless patients were not eligible or refused to receive these treatments: PHASE 1 Primary To determine the Maximum Tolerated Dose (MTD) of ARRY-520 without and with G-CSF support. Secondary To assess the PK of ARRY-520 To obtain preliminary estimates of the efficacy of ARRY-520 in terms of response rate (RR), duration of response (DOR), progression-free survival (PFS), treatment-free interval (TFI) and time to next treatment (TNT) To explore potential markers for patient selection and obtain a preliminary assessment of the biological activity of Kinesin Spindle Protein (KSP) inhibition in hematological tumor cells. PHASE 2 Primary: To obtain preliminary estimates of the efficacy of ARRY-520 in terms of RR. Secondary: To obtain preliminary estimates of the efficacy of ARRY-520 in terms of PFS, DOR, TNT and TFI, and overall survival (OS) To further assess the safety of ARRY-520 To explore potential markers for patient selection and obtain a preliminary assessment of the biological activity of KSP inhibition in hematological tumor cells. Phase 2 with Dexamethasone In patients with refractory MM or PCL who have received at least two lines of prior treatment and who are refractory to their last myeloma treatment and refractory to prior lenalidomide, bortezomib and dexamethasone: Primary objectives: To obtain preliminary estimates of the efficacy of ARRY-520 with dexamethasone in terms of RR. Secondary objectives: To obtain preliminary estimates of the efficacy of ARRY-520 with dexamethasone in terms of DOR, PFS, TFI, TNT and OS To determine the safety of ARRY-520 when combined with dexamethasone To explore potential markers for patient selection and obtain a preliminary assessment of the biological activity of KSP inhibition in hematological tumor cells.
IRB Review and Approval Date: 12/29/2008
Recruitment Status: Not Accepting
Projected Accrual: 105
1) Confirmed relapsed or refractory MM or PCL. Patients should have
received at least two prior treatment regimens. Prior treatment must
have included bortezomib and an immunomodulatory agent (e.g.,
thalidomide and/or lenalidomide), unless patients were not eligible or
refused to receive these treatments. The disease should have progressed
during or after the last prior treatment regimen.
2) In the Phase 2 with dexamethasone: Pts should have received at least 2 prior treatment regimens; Pts must have refractory disease, defined as documented disease progression during or within 60 days of completing their last myeloma therapy; All pts must have received at least 2 consecutive cycles of prior treatment that included lenalidomide and bortezomib; All pts must be refractory to treatment including lenalidomide, bortezomib and dexamethasone, defined as documented progressive disease on therapy or within 60 days of completing treatment with these regimens. The required amount of dexamethasone administered in these combination regimens is defined as at least 40 mg per week on treatment weeks; Pts must have received adequate prior alkylator therapy, defined as autologous stem cell or bone marrow transplant with melphalan, or 2 cycles of either melphalan or cyclophosphamide, depending on the regimen.
3) Measurable MM disease, defined as one of the following: a) A monoclonal immunoglobulin (Ig) concentration on serum electrophoresis of >/= 0.5 g/dL for an IgG myeloma, 0.5 g/dL for an IgA myeloma, and 0.1 g/dL for an IgD myeloma; b) Measurable urinary light chain secretion by quantitative analysis of >/= 200 mg/24 hours; c) Involved serum Free Light Chain (FLC) level >/= 10 mg/dL, provided the serum FLC ratio is abnormal;
4) Male or female, >/= 18 years of age at time of signing consent.
5) Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
6) Adequate hematology laboratory values without transfusion support within two weeks of screening: a) Hemoglobin >/= 8 g/dL; b) Absolute Neutrophil Count (ANC) >/= 1.5 x 10^9/L; c) Platelets >/= 75 x 10^9/L. If the bone marrow contains >/= 50% plasma cells, a platelet count of >/= 5 x 10^9/L is allowed.
7) Adequate liver and renal function: a) Aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase (SGOT) and/or alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) </= 2.5 x the upper limit of normal (ULN); b) Total Bilirubin < 1.5mg/dL; c) Serum creatinine </= 2.5 mg/dL or a calculated creatinine clearance of at least 50 mL/min (using the Cockcroft and Gault method).
8) If patient is female and of childbearing potential, she must have a negative serum beta human chorionic gonadotropin (Beta-HCG) test.
9) Male patients and female patients of childbearing potential must agree to use an effective method of contraception per institutional standard. Female patients of childbearing potential must use an oral contraceptive, a double-barrier method of birth control, an intrauterine device, surgically sterilized, or the subject must be post-menopausal for a minimum of 12 months. Male patients must use a barrier method (i.e. condom w/ spermicidal jelly), be surgically sterilized or have a female partner using one of the above approved birth control methods.
10) Signed informed consent prior to initiation of any study-related procedures that are not considered standard of care.
1) Primary amyloidosis.
2) Concomitant malignancies or previous malignancies with less than a three-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.
3) Autologous or allogeneic stem cell or bone marrow transplant within 3 months prior to first dose of study drug.
4) Treatment with an investigational product or device within 28 days of initiating study drug.
5) Cytotoxic therapy or monoclonal antibodies within 21 days prior to first dose of study drug.
6) Radiotherapy within 21 days prior to first dose of study drug. However, if the radiation portal covered </= 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy.
7) Major surgery within two weeks prior to first dose of study drug.
8) Corticosteroid doses > 10 mg/day of prednisone or equivalent within two weeks prior to first dose of study drug.
9) Any serious medical or psychiatric disorder that would interfere with patient safety or informed consent.
10) Any severe concurrent disease or condition (including active systemic infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia), which, in the judgment of the Investigator, would make the patient inappropriate for study participation.
11) Known positive serology for the Human Immunodeficiency Virus (HIV), Hepatitis B and/or active Hepatitis C.
Information and next steps
Phase I/Phase II
Jatin J. Shah
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