Katherine Gano

Phase Ib/II trial of CYKLONE (cyclophosphamide, carfilzomib, thalidomide and dexamethasone) for newly diagnosed myeloma

Sixty‐four transplant‐eligible patients with newly diagnosed multiple myeloma (NDMM) received carfilzomib (days 1, 2, 8, 9, 15, 16), 300 mg/m2 cyclophosphamide (days 1, 8, 15), 100 mg thalidomide (days 1–28) and 40 mg dexamethasone (days 1, 8, 15, 22) in 28‐day cycles (CYKLONE regimen). Carfilzomib was dose‐escalated to 15/20, 20/27, 20/36 and 20/45 mg/m2 to determine the maximum tolerated dose (MTD), which was 20/36 mg/m2. Regardless of attribution, common Grade 3 or higher adverse events were lymphopenia (38%), neutropenia (23%) and anaemia (20%). All peripheral neuropathy (31%) was Grade 1 and considered most likely to be thalidomide‐related. Common cardiac or pulmonary events of any grade in ≥5% of patients included dyspnoea (20%) and cough (6%). Overall (N = 64), 91% of patients achieved a best response of partial response or better across all cycles of treatment, including five patients with complete responses. At the MTD (n = 29), 59% of patients achieved a very good partial response or better after four cycles (primary end point). Stem cell collection was successful in all patients in whom it was attempted (n = 42). Progression‐free survival and overall survival at 24 months was 76% and 96%, respectively (median follow‐up of 17·5 months). CYKLONE appears highly efficacious in NDMM patients, with manageable toxicities.

A Phase Ib Study of the combination of the Aurora Kinase Inhibitor Alisertib (MLN8237) and Bortezomib in Relapsed Multiple Myeloma

The proteasome inhibitor bortezomib is cornerstone of modern therapy for multiple myeloma (MM). When used in combination therapy at diagnosis, response rates are 80–90%, but as a single agent, in relapse, response rates are only 30– 40%. To better understand the molecular basis for response and resistance, we performed druggable genome-wide RNA interference studies (siRNA) to identify genes that, when suppressed, would synergistically enhance or abrogate the cytotoxicity of proteasome inhibition (Zhu et al, 2011; Tiedemann et al, 2012). AURKA (aurora kinase A) and AURKB (aurora kinase B) were identified as lethal targets in MM while suppression of these genes also sensitized MM cells to bortezomib. Alisertib (MLN8237) is an oral small molecule inhibitor of aurora kinase A (Carvajal et al, 2006). The safety and bioactivity of alisertib has been studied in several Phase I trials and has been generally well tolerated in patients with solid tumours (Cervantes et al, 2012; Dees et al, 2012; Falchook et al, 2014). With doses under 100 mg, the doselimiting toxicities have been largely mechanistic (haematological toxicities and mucositis) and manageable (Kelly et al, 2014). With supportive pre-clinical work, we conducted a Phase I open-label multicentre clinical trial testing the combination of alisertib and bortezomib. No corticosteroids were used. Patients who were aged ≥18 years with relapsed MM, measurable disease, good performance status and laboratory results demonstrating adequate blood, kidney and liver profiles were eligible. All patients provided written informed consent. Enrolment began on 5 February 2010 and expansion opened on 15 June 2012. The study was conducted in accordance with the Declaration of Helsinki and the International Conference on Harmonization Harmonized Tripartite Guideline for Good Clinical Practice and was approved by the relevant Regulatory and Institutional Review Boards. A standard ‘3 + 3’ design for dose escalation was utilized in Phase I. Alisertib initial dose level O was 25 mg PO daily and bortezomib was 1 3 mg/m IV on days 1, 4, 8, and 11 on a 28-day cycle. Data from concurrent Phase I trials prompted an addendum. Subsequently, alisertib was given twice daily at escalating doses from 20 mg to 50 mg PO BID days 1–7 on a 28-day cycle and bortezomib dosing was changed to the more convenient schedule of 1 5 mg/m weekly continuously. Amended dose level 0 was alisertib 20 mg PO BID with bortezomib 1 5 mg/m IV. Alisertib dosing was escalated from 20 mg to 50 mg PO BID in successive cohorts to determine the maximum tolerated dose (MTD) [level 0: 25 mg PO daily – 3 patients, amended level 0: 20 mg PO BID3 patients plus 1 (dosing error), level 1: 30 mg PO BID – 3 patients, level 2: 40 mg PO BID -3 patients, and level 3: 50 mg PO BID – 6 patients]. Patients were observed until the end of cycle 2 and assessed for toxicity. No dose limiting toxicities (DLT) were documented, although one patient (level 3 dose) did require platelet transfusion to proceed to cycle 2 on schedule. Doses were not further escalated as information from on-going trials indicated additional escalation would be associated with increased toxicity. If a patient failed to complete the initial cycle of therapy for reasons other than toxicity, the patient was regarded as treatment intolerant and was taken off study. All toxicity information was utilized in the analysis. The final cohort was expanded with an additional 7 patients receiving treatment. The initial planned maximum number of treatment cycles was 10, although responding patients were considered for additional cycles. Treatment was continued until progression, unacceptable toxicity, patient refusal, new primary malignancy or other medical problems. The primary endpoint was defining a MTD and describing toxicities of the combination of alisertib and bortezomib. The final dose cohort was expanded to evaluate overall response rate (ORR). All patients that received at least one dose of study drug were assessed for safety and response. Adverse events were monitored using the National Cancer Institute Common Toxicity Criteria for Adverse Events version 4.0 (http://evs.nci.nih.gov/ftp1/CTCAE/CTCAE_4.03_ 2010-06-14_QuickReference_8.5x11.pdf). Response was evaluated using the uniform response criteria established by the International Myeloma Working Group (Durie et al, 2006). Nineteen patients were treated during Phase I, with an additional 7 patients included in an expansion cohort (total 26 patients). Baseline characteristics are shown in Table SI. 14/26 (53 9%) patients were relapsed while 12 (46 1%) were relapsed and refractory. 96 2% (25/26) of patients had previous exposure to immunomodulatory drugs (IMiDs) and none were bortezomib-refractory. Median follow-up was 20 6 months (range 4 3–36 6). At last follow-up, 22 patients had progressed, while four had not. 12 patients were still alive and 14 had died. No patients Correspondence

A phase 2 study of lenalidomide, rituximab, cyclophosphamide, and dexamethasone (LR-CD) for untreated low-grade non-Hodgkin lymphoma requiring therapy

Patients with indolent non‐Hodgkin lymphoma (NHL) have multiple treatment options yet there is no consensus as to the best initial therapy. Lenalidomide, an immunomodulatory agent, has single agent activity in relapsed lymphoma. This trial was conducted to assess feasibility, efficacy, and safety of adding lenalidomide to rituximab, cyclophosphamide, and dexamethasone (LR‐CD) in untreated indolent NHL patients requiring therapy. This was a single institution phase II trial. Treatment consisted of IV rituximab 375 mg/m2 day 1; oral lenalidomide 20 mg days 1–21; cyclophosphamide 250 mg/m2 days 1, 8, and 15; and dexamethasone 40 mg days 1, 8, 15, and 22 of a 28‐day cycle. Treatment continued 2 cycles beyond best response for a maximum of 12 cycles without rituximab maintenance. Thirty‐three patients were treated. Median age was 68 (43–83 years). 39% had stage IV disease. Histologic subtypes included 8 follicular lymphoma (FL), 7 marginal zone lymphoma (MZL) (1 splenic, 2 extranodal, and 4 nodal), 15 Waldenströms macroglobulinemia (WM), 1 lymphoplasmacytic lymphoma, 1 small lymphocytic lymphoma, and 1 low‐grade B‐cell lymphoma with plasmacytic differentiation (unable to be classified better as MZL or LPL). Hematologic toxicity was the most common adverse event. Median time of follow‐up was 23.4 months (range 1.8–50.9). The overall response rate was 87.9%, with 30.3% complete response. The median duration of response was 38.7 months. The median progression free survival was 39.7 months, while median overall survival (OS) has not yet been reached. Lenalidomide can be safely added to a simple regimen of rituximab, oral cyclophosphamide, and dexamethasone and is an effective combination as initial therapy for low‐grade B‐cell NHL.

Multicenter phase 2 study of combination therapy with ruxolitinib and danazol in patients with myelofibrosis

Myelofibrosis is a myeloproliferative neoplasm that is characterized by splenomegaly, profound symptom burden, and cytopenias. JAK inhibitor therapy offers improvements in splenomegaly, symptom burden, and potentially survival; however, cytopenias remain a significant challenge. Danazol has previously demonstrated improvements in myelofibrosis-associated anemia. We conducted a phase II clinical trial evaluating the efficacy and tolerability of combination therapy with ruxolitinib, an oral JAK inhibitor, and danazol. Fourteen intermediate or high-risk MF patients were enrolled at 2 institutions. Responses per IWG-MRT criteria were stable disease in 9 patients (64.2%) clinical improvement in 3 (21.4%) all of which were spleen responses, partial response in 1 (7.1%) and progressive disease in 1 (7.1%). Despite limited IWG-MRT response, stabilization of anemia and thrombocytopenia was demonstrated. In JAK inhibitor naïve patients, 4/5 (80%) had stable or increasing hemoglobin. Of the 9 patients on prior JAK inhibitor, 5 patients (55.5%) and 8 patients (88.9%) had stable or increasing hemoglobin or platelet levels, respectively. Adverse events possibly related included grade 3 or greater hematologic toxicity in ten patients (71.4%) and non-hematologic toxicity in two patients (14.3%). Although combination therapy did not lead to increased hematologic response per IWG-MRT criteria, hematologic stabilization was observed and may be clinically useful.

A phase 2 study of rituximab, cyclophosphamide, bortezomib and dexamethasone (R-CyBorD) in relapsed low grade and mantle cell lymphoma

Abstract In this phase 2 trial, we sought to evaluate the efficacy and safety of rituximab, cyclophosphamide, bortezomib, and dexamethasone (R-CyBorD) in patients with low-grade NHL. The regimen included rituximab on day 1 with weekly cyclophosphamide, dexamethasone, and bortezomib 1.3 mg/m2 IV in a 28-day cycle. Twenty one patients were enrolled on the study. Median age was 69 years (range 51–80) and 17 (81%) patients had two or more prior treatments. Histologies included FL (n = 8), MCL (n = 8), and LPL/WM (n = 5). Hematologic toxicity and peripheral sensory neuropathy were the most common adverse events. With a median follow-up of 38.1 months, ORR was 13/21 (62%), with 4 (19%) CR. The ORR was 7/8 (88%) in FL and was 4/5 (80%) in LPL/WM. Median PFS and OS were 11.6 months and 54.8 months, respectively. R-CyBorD is an effective regimen in relapsed FL and LPL/WM patients with an acceptable safety profile.