Phase I trial of ARRY-520 in relapsed/refractory multiple myeloma (RR MM).
Abstract:
Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. ARRY-520 is a potent, selective inhibitor of KSP, arresting cells in mitosis with subsequent onset of apoptosis. Malignancies, such as MM, depending on the survival protein MCL-1 rapidly undergo apoptosis following treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease Methods: This phase I study was designed to evaluate the safety, pharmacokinetics and pharmacodynamics of ARRY-520 administered intravenous (IV) on D1 and D2 q 14 days without/with granulocyte colony stimulating factor (G-CSF). Patients (pts) with RR MM or plasma cell leukemia with ≥ 2 prior lines of therapy (including a bortezomib and IMiD-based regimen, unless refusing or ineligible for this therapy) were eligible. Cohorts of at least 3 pts are being enrolled in a classical 3+3 dose escalation design. Pts are treated for 2 cycles for safety evaluation prior to dose escalation. Results: 13 pts have been treated to date, with a median age of 55 years (range 44-78) and a median of 4 prior regimens (range 3-13). All pts received prior bortezomib, 9 pts prior lenalidomide, 5 pts prior thalidomide, and 10 pts had an autologous stem cell transplant. Pts received ARRY- 520 without G-CSF at 1 mg/m2/day (n=3), and at 1.25 mg/m2/day (n=7). Dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose without G-CSF. As neutropenia was the DLT, dose escalation with G-CSF support was initiated, and 3 pts have been treated to date at 1.5 mg/m2/day with G-CSF. The most commonly reported (> 1 pt) treatment-related adverse events include anemia, neutropenia and thrombocytopenia as well as fatigue and nausea. No mucositis or peripheral neuropathy were noted. The median number of cycles is 4 (range 1-15+). One pt experienced a partial response (ongoing in Cycle 15 at 1 mg/m2/day, 8 prior regimens, decrease of % plasma cells in the bone marrow from 30 to 0%). Conclusions: ARRY-520 shows promising signs of clinical activity and has been well tolerated in pts with MM. Enrollment is ongoing at 1.5 mg/m2/day with G-CSF support.
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A phase I study of ARRY-520 in solid tumors.
Abstract:
Background: Antimitotic therapy stabilizes microtubule polymers and inhibits tubulin polymerization, but is nonselective and causes neurotoxicity. Kinesin Spindle Protein (KSP) is responsible for centrosome separation, required for formation and maintenance of a bipolar spindle. As a target, KSP has been validated preclinically and its inhibition avoids negative effects in nontarget cells where KSP is not expressed. Methods: This phase I study is designed to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of ARRY-520, a potent, selective KSP inhibitor, administered intravenously (IV) in 2 dose schedules (S1 and S2). S1: D1 q 21 days (dose levels [DL] 2.5 and 3.3 mg/m2) with an expansion at the maximum tolerated dose (MTD). In the expansion, tumor biopsies were performed post-dose for PD markers. S2: D1 and D2 q 14 days without granulocyte colony stimulating factor (G-CSF) (DL 1.25 and 1.6 mg/m2/day) and with G-CSF support (DL to date: 1.6 mg/m2/day, with an expansion planned at the MTD, including biopsies). Results: A total of 34 patients (pts) have been treated to date. The median age was 61 years (range 40-79), the median number of prior treatments 3 (range 0-12). The MTD for both S1 and S2 without G- CSF was 2.5 mg/m2 per cycle. Dose-limiting toxicities (DLTs) in S1: Grade 3 febrile neutropenia, sepsis, and Grade 4 thrombocytopenia. DLTs in S2: Grade 3 febrile neutropenia, increased aspartate aminotransferase, hyponatremia, and anorexia. The most common (≥ 10% of pts) adverse events (AEs) considered at least possibly related to ARRY-520 included hematologic AEs (leukopenia, lymphopenia, neutropenia), nausea, vomiting, anorexia and fatigue. One pt each experienced Grade 1 and Grade 2 mucositis at the DL above the MTD in S1. As neutropenia was the most common DLT, dose escalation with G-CSF support was initiated. Three pts (melanoma, ovarian cancer, and mesothelioma) experienced prolonged stable disease at 42, 22, and 13 weeks respectively. Monopolar spindles were observed in tumor biopsies, indicating that systemic exposure sufficient to elicit biological activity was achieved. PK results will be presented. Conclusions: S2 enrollment is ongoing at 2 mg/m2/day with G-CSF. Preliminary data support further disease-directed development of ARRY-520.
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Clinical responses to AZD6244 (ARRY-142886)-based combination therapy stratified by gene mutations in patients with metastatic melanoma.
Abstract:
Background: BRAF and NRAS mutations (mut) occur in 50-60% and 15-20% of melanomas, respectively. As a consequence, MAPK signaling is frequently activated. To correlate clinical benefit of a MEK inhibitor with the mut status, we performed a genomic study using tumors of patients (pts) enrolled in a clinical study of AZD6244 (a selective MEK inhibitor)-containing combination regimens. Methods: Pts ≥ 18 years of age with advanced solid tumors and a WHO performance status 0-1 were enrolled in a phase I trial of AZD6244 in combination with one of 3 drugs in 3-week (q3w) treatment cycles: dacarbazine (DTIC) 1000 mg/m2 iv q3w or docetaxel (Doc) 75 mg/m2 iv q3w or temsirolimus (Tems) 25 mg iv weekly. Oral AZD6244 was given at 50-75 mg twice daily continuously. Responses were assessed every 2 cycles per RECIST. In pts with available archived tumor samples, BRAF and NRAS were genotyped by pyrosequencing. Results: Among 25 pts with metastatic melanoma who received one of the combination regimens, tumor samples from 18 pts (14 in DTIC, 3 in Doc, 1 in Tems arms) were analyzed. NRAS sequencing on one sample was unsuccessful. Median age was 58 and, among these pts, 5 (28%) and 9 (50%) pts had a response and stable disease, respectively. Overall, 9 (50%) pts harbored BRAF mut (8 V600E; 1 nonclassical R600 nonsense mut), and 4 (22%) harbored NRAS mut (2 Q61R; 1 Q61K; 1 G12S). These muts were mutually exclusive in each case. Of interest, all 5 responders had BRAF mut, and none of the pts with BRAF mut had early disease progression. Presence of BRAF mut was significantly associated with both clinical responses and increased time to progression (TTP). While the number of patients analyzed is small, the trend toward clinical benefit in pts with BRAF mut is inferred. Conclusions: Our analyses showed a trend toward response and clinical benefit in patients who harbor a BRAF gene mut.
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Phase II study and tissue correlative studies of AZD6244 (ARRY-142886) in iodine-131 refractory papillary thyroid carcinoma (IRPTC) and papillary thyroid carcinoma (PTC) with follicular elements.
Abstract:
Background: There is no standard treatment for IRPTC. AZD6244 is an oral, small molecule inhibitor of the mitogen-activated protein kinase, MEK-1/2. Thyroid cancers appear to be dependent on RAF/MEK/ERK (MAPK) signaling. A multicenter, open-label, phase II trial was conducted to evaluate the efficacy, safety, and tolerability of AZD6244 in IRPTC. Correlative studies were performed to include the tumor genotype for BRAF a potent activator of the MAP kinase pathway. Methods: Patients with objective evidence of disease progression within the last 12 months were eligible. AZD6244 was administered as a free base suspension at a dose of 100 mg twice daily for 28-day cycles. The primary end point was objective response rate. The secondary end points were safety, overall survival, and time to progression. 32 evaluable patients were required. Radiologic response was assessed every 8 weeks and determined using RECIST. Correlative studies were performed to include the tumor genotype for BRAF. Results: 39 subjects were enrolled. The median age was 59 years. The population was predominantly men (75%) and Caucasian (88%). Only 19% of subjects had received prior systemic therapy. The most common drug-related adverse events included rash (69%), fatigue (49%), diarrhea (49%), and peripheral edema (36%). Grade 3-4 toxicities included rash (18%), fatigue (8%), diarrhea (5%), and peripheral edema (5%). Best response in 32 evaluable patients who completed at least two cycles was 1 partial response (3%), 21 with stable disease (66%), and 10 with progressive disease (31%). The mean progression free survival (PFS) was 53.6 weeks with a 95% confidence interval of 37.8-69.5 weeks. The median PFS was 32 weeks. Seven patients remain on study with PFS up to 53 weeks. Data on BRAF mutation status will be presented. Conclusions: In the treatment of IRPTC, AZD6244 is well-tolerated. One partial response was reported, along with PFS greater than 1 year in a patient population with previously documented progressive disease and few therapeutic options. These observations suggest that AZD6244 offers benefit in some patients with IRPTC.
