Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients with Recurrent/Refractory Multiple Myeloma

Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients with Recurrent/Refractory Multiple Myeloma

Original Article A Phase 1 Dose-Escalation Study of Filanesib Plus Bortezomib and Dexamethasone in Patients With Recurrent/Refractory Multiple Myeloma Ajai Chari, MD1; Myo Htut, MD2; Jeffrey A. Zonder, MD3; Joseph W. Fay, MD4; Andrzej J. Jakubowiak, MD5; Joan B. Levy, PhD6; Kenneth Lau, BA1; Steven M. Burt, MSN, NP-C3; Brian J. Tunquist, PhD7; Brandi W. Hilder, PhD7; Selena A. Rush, BS7; Duncan H. Walker, PhD7; Mieke Ptaszynski, MD7; and Jonathan L. Kaufman, MD8 BACKGROUND: Filanesib is a kinesin spindle protein inhibitor that has demonstrated encouraging activity in patients with recurrent/ refractory multiple myeloma. Preclinical synergy with bortezomib was the rationale for the current phase 1 study. METHODS: The cur- rent study was a multicenter study with an initial dose-escalation phase to determine the maximum tolerated dose of 2 schedules of filanesib plus bortezomib with and without dexamethasone, followed by a dose-expansion phase. RESULTS: With the addition of pro- phylactic filgastrim, the maximum planned dose was attained: 1.3 mg/m2/day of bortezomib plus 40 mg of dexamethasone on days 1, 8, and 15 of a 28-day cycle, with filanesib given intravenously either at a dose of 1.5 mg/m2/day (schedule 1: days 1, 2, 15, and 16) or 3 mg/m2/day (schedule 2: days 1 and 15). The most common adverse events (assessed for severity using version 4.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events) were transient, noncumulative neutropenia and thrombocytopenia with grade 3/4 events reported in 44% (16% in cycle 1 with filgastrim) and 29% of patients, respectively. A low (11%) overall rate of nonhematological grade 3/4 toxicity was observed. With a median of 3 prior lines of therapy and 56% of patients with disease that was refractory to proteasome inhibitors, the overall response rate was 20% (55 patients), and was 29% in 14 patients with proteasome inhibitors-refractory disease receiving filanesib at a dose of 1.25 mg/m2 (duration of response, 5.2 to 21.2 months). CONCLUSIONS: The current phase 1 study established a dosing schedule for the combination of these agents that demonstrated a favorable safety profile with a low incidence of nonhematologic toxicity and manageable hematologic toxicity. The combination of filanesib, bortezo- mib, and dexamethasone appears to have durable activity in patients with recurrent/refractory multiple myeloma. Cancer 2016;000:000–000. VC 2016 American Cancer Society. KEYWORDS: bortezomib, dexamethasone, filanesib, multiple myeloma, neoplasm recurrence, proteasome inhibitors, recurrent/ refractory. INTRODUCTION Despite improvements in the survival of patients with multiple myeloma (MM) over the last decade with the introduction of proteasome inhibitors (PIs) and immunomodulatory agents (IMiDs), patients eventually develop disease recurrence.1,2 An emerging treatment strategy to combat acquired drug resistance and induce durable responses is the incorporation of novel drugs with unique mechanisms of action. Kinesin spindle proteins (KSPs) are critical for normal mitosis. KSP inhi- bition results in the formation of a monopolar spindle, causing mitotic arrest and apoptosis, particularly in cells that ex- hibit rapid, sustained depletion of Mcl-1 (myeloid cell leukemia 1), an antiapoptotic member of the Bcl-2 family.3 Because MM cells are Mcl-1-dependent, KSP inhibition represents a novel therapeutic approach in patients with MM.4,5 Filanesib (ARRY-520) is a highly selective, first-in-class targeted KSP inhibitor. Due to its novel mechanism of action, filanesib is expected to overcome PI and/or IMiD resistance. In addition, no additive peripheral neuropathy is expected, due to the absence of KSP expression in neurons. Single-agent filanesib already has demonstrated efficacy and safety in patients with recurrent/refractory MM (RRMM) (unpublished data). In preclinical models, the combination of bortezomib and filanesib has demonstrated additive apoptosis, and filane- sib appears to have significant antitumor activity in bortezomib-resistant MM cell lines.6 Furthermore, MM cells in Corresponding author: Ajai Chari, MD, Mount Sinai School of Medicine, 1 Gustave Levy Pl, Box 1185, New York, NY 10029; Fax: (212) 241-3908; ajai.chari@mssm. edu 1Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York; 2City of Hope, Duarte, California; 3Department of Oncology, Karmanos Cancer Institute, Wayne State University, Detroit, Michigan; 4Baylor Research Institute, Dallas, Texas; 5University of Chicago Medical Center, Chicago, Illinois; 6Multi- ple Myeloma Research Consortium, Norwalk, Connecticut; 7Array BioPharma Inc, Boulder, Colorado; 8Winship Cancer Institute, Emory University, Atlanta, Georgia We thank our patients, their families, and the Multiple Myeloma Research Consortium. DOI: 10.1002/cncr.30174, Received: February 11, 2016; Revised: April 26, 2016; Accepted: May 3, 2016, Published online Month 00, 2016 in Wiley Online Library (wileyonlinelibrary.com) Cancer Month 00, 2016 1 Original Article mitotic arrest also are rendered more sensitive to dexa- methasone; therefore, the addition of dexamethasone is hypothesized to enhance filanesib activity.3,7 Bortezomib in combination with dexamethasone was the first PI approved for the treatment of RRMM.8 Therefore, the current phase 1 study was designed to establish the maxi- mum tolerated dose (MTD) of filanesib in combination with bortezomib and dexamethasone in patients with Figure 1. Treatment schedules. DEX indicates dexamethasone; G-CSF, granulocyte colony-stimulating factor. RRMM. MATERIALS AND METHODS Treatment Schedules Dose escalations were conducted using 2 filanesib treat- The current study was a phase 1 multicenter study with an ment schedules within 28-day cycles (Fig. 1). initial dose-escalation phase to determine the MTD of 2 Schedule 1 first determined the MTD of filanesib schedules of filanesib plus bortezomib with and without administered on days 1, 2, 15, and 16 in combination dexamethasone, followed by a dose-expansion phase. with bortezomib on days 1, 8, and 15, followed by a sec- Additional objectives in the dose-escalation phase were to ond dose escalation starting at 1 dose level below the obtain preliminary estimates of efficacy and possible bio- established MTD of the combination with the addition of markers to predict response. Because data analyses cur- dexamethasone on the same dosing days as bortezomib. rently are ongoing in the expansion cohorts, the current Filanesib was administered at escalating doses starting at study focused on the completed dose-escalation phase. 0.5 mg/m2/day as a 1-hour intravenous (iv) infusion and bortezomib was administered at a dose of 1.0 or 1.3 mg/ 2 Patients m /day according to the assigned dose level. Bortezomib Patients aged 18 years with measurable RRMM or administration was initially iv, but the protocol was plasma cell leukemia were eligible for participation in the amended to allow for subcutaneous (SC) dosing in ac- 9 current study. Patients had received 2 prior regimens cordance with current clinical practice. Dexamethasone including a PI (eg, bortezomib, carfilzomib) and an IMiD was administered orally at a standard dose of 40 mg/day (eg, thalidomide, lenalidomide), with disease progression (20 mg/day for patients aged 75 years). (PD) during or after the last prior regimen. Patients with Schedule 2 determined the MTD of filanesib PI-refractory disease were eligible. Patients had an Eastern administered on days 1 and 15 plus bortezomib and dexa- Cooperative Oncology Group performance status of 0 or methasone on days 1, 8, and 15. A weekly bortezomib 1, adequate liver function, serum creatinine 2.5 mg/dL schedule was used primarily so that all drugs would be or calculated creatinine clearance 50 mL/minute, a neu- given on both day 1 and day 15, thereby allowing for opti- trophil count 1.5 3 109/L, and a platelet count 75 3 mal in vivo synergy. 109/L (or 50 3 109/L if bone marrow contained 50% Due to the exacerbated neutropenia observed in the plasma cells) without transfusion or growth factor support first 2 dosing cohorts, the protocol was amended to add for 2 weeks before screening. Key exclusion criteria prophylactic filgastrim. Patients received or self- included primary amyloidosis and any stem cell transplan- administered concurrent filgastrim as a daily SC injection tation performed within 3 months before initiating the for a total of 5 to 7 days after each filanesib dosing. Vari- study drug. cella zoster virus prophylaxis was prescribed as per stand- The current study was conducted in accordance with ard of care, and gram-negative antibiotic prophylaxis was International Conference on Harmonisation of Technical prescribed if patients were neutropenic. Requirements for Registration of Pharmaceuticals for Patients received study drug(s) in continuous cycles Human Use Good Clinical Practice guidelines and all ap- until unacceptable toxicity or PD occurred. plicable regulatory requirements. The study was approved by the Institutional Review Boards of all participating Determination of the MTD centers, and patients provided written informed consent. A standard 313 design was used to determine the MTD, This study was registered at www.ClinicalTrials.gov with defined as the dose below that which resulted in dose- identifier NCT01248923. limiting toxicities (DLTs) in 33% of patients. A DLT 2 Cancer Month 00, 2016 Filanesib1Bortezomib1Dexamethasone in MM/Chari et al was defined as an adverse event (AE) in cycle 1 that was they received

View Full Text

Details

  • File Type
    pdf
  • Upload Time
    -
  • Content Languages
    English
  • Upload User
    Anonymous/Not logged-in
  • File Pages
    9 Page
  • File Size
    -

Download

Channel Download Status
Express Download Enable

Copyright

We respect the copyrights and intellectual property rights of all users. All uploaded documents are either original works of the uploader or authorized works of the rightful owners.

  • Not to be reproduced or distributed without explicit permission.
  • Not used for commercial purposes outside of approved use cases.
  • Not used to infringe on the rights of the original creators.
  • If you believe any content infringes your copyright, please contact us immediately.

Support

For help with questions, suggestions, or problems, please contact us