Pediatr Blood Cancer 2014;61:1754–1760 A Phase 2 Study of Bortezomib Combined with Either Idarubicin/Cytarabine or Cytarabine/Etoposide in Children with Relapsed, Refractory or Secondary Acute Myeloid Leukemia: A Report from the Children’s Oncology Group 1 2 3 4,5 Terzah M. Horton, MD, PhD, John P. Perentesis, MD, Alan S. Gamis, MD, MPH, Todd A. Alonzo, PhD, 5 6 7 8 9 Robert B. Gerbing, MS, Jennifer Ballard, RN, Kathleen Adlard, MSN, Dianna S. Howard, MD, Franklin O. Smith, MD, 1 10 10 6 Gaye Jenkins, BS, Angele´ Kelder, MSc, Gerrit J. Schuurhuis, PhD, and Jeffrey A. Moscow, MD * Background. This Phase 2 study tested the tolerability and were closed after failure to meet predetermined efficacy thresholds efficacy of bortezomib combined with reinduction chemotherapy for during the first stage of the two-stage design. The complete response pediatric patients with relapsed, refractory or secondary acute (CR þ CRp) rates were 29% for Arm A and 43% for Arm B. Counting myeloid leukemia (AML). Correlative studies measured putative AML additional CRi responses (CR with incomplete neutrophil recovery), leukemia initiating cells (AML-LIC) before and after treatment. the overall CR rates were 57% for Arm A and 48% for Arm B. The 2- Procedure. Patients with <400 mg/m2 prior anthracycline received year overall survival (OS) was 39 Æ 15%. Correlative studies showed bortezomib combined with idarubicin (12 mg/m2 days 1–3) and low- that LIC depletion after the first cycle was associated with clinical dose cytarabine (100 mg/m2 days 1–7) (Arm A). Patients with response. Conclusion. Bortezomib is tolerable when added to 400 mg/m2 prior anthracycline received bortezomib with etopo- chemotherapy regimens for relapsed pediatric AML, but the regimens side (100 mg/m2 on days 1–5) and high-dose cytarabine (1 g/m2 every did not exceed preset minimum response criteria to allow continued 12 hours for 10 doses) (Arm B). Results. Forty-six patients were treated accrual. This study also suggests that AML-LIC depletion has prognostic with 58 bortezomib-containing cycles. The dose finding phase of value. Pediatr Blood Cancer 2014;61:1754–1760. Arm B established the recommended Phase 2 dose of bortezomib at # 2014 Wiley Periodicals, Inc. 1.3 mg/m2 on days 1, 4, and 8 with Arm B chemotherapy. Both arms Key words: AML; AraC; pediatric oncology; relapse; Velcade INTRODUCTION 71%. A second study treated 95 newly diagnosed, older adult AML patients with daunorubicin (60 mg/m2 days 1–3), cytarabine Bortezomib (PS-341, Velcade), is a selective inhibitor of the 26S (100 mg/m2, days 1–7), and bortezomib (1.3 mg/m2 days 1, 4, 8, and proteasome, is involved in protein degradation and is an integral 11), followed by two courses of consolidation chemotherapy with part of the ubiquitin proteasome pathway [1,2]. Several studies cytarabine (2 g/m2 days 1–5) and bortezomib [11]. The CR rate in have shown that proteasome number and activity are increased this population was 65%. in hematologic malignancies, including AML and ALL [3–5]. In addition to its activity in multiple myeloma [6,7] and lymphoma [8], bortezomib has shown promising activity against leukemias in the pediatric preclinical testing program (PPTP) [9] and has been Additional Supporting Information may be found in the online version shown to be an effective adjuvant in two adult AML clinical of this article. trials [10,11]. Bortezomib appears to also specifically sensitize 1Texas Children’s Cancer and Hematology Centers at Baylor College of AML cells to cytarabine and anthracyclines, two agents commonly Medicine, Houston, Texas; 2Cincinnati Children’s Hospital Medical used in induction chemotherapy [12–14]. In addition, a clinical trial Center, Cincinnati, Ohio; 3Children’s Mercy Hospitals & Clinics, of bortezomib in relapsed ALL done by Messinger et al. [15,16] Kansas City, Missouri; 4Keck School of Medicine, University of showed that bortezomib was effective in this difficult to treat Southern California, Los Angeles, California; 5Children’s Oncology population. Group—Operations Center, Monrovia, California; 6Department of 7 Previous studies have shown that AML originates from rare, Pediatrics, University of Kentucky, Lexington, Kentucky; Children’s 8 self-renewing leukemia initiating cells (LIC) that differ from their Hospital of Orange County, Orange, California; Division of progenitors in several respects, including their capacity for Hematology and Oncology, Wake Forest University, Winston-Salem, NC; 9Division of Hematology/Oncology, Department of Internal extensive growth and self-renewal [17–20]. LIC have unique Medicine, University of Cincinnati Cancer Institute, Cincinnati, stem cell gene expression signatures [21–23], dysregulated protein Ohio; 10Department of Hematology, VU University Medical Center, expression [24], and altered response to the bone marrow (BM) Amsterdam, the Netherlands microenvironment [25]. Studies have shown that high AML stem Grant sponsor: Takeda/Millenium Pharmaceuticals; Grant sponsor: cell frequency and AML-LIC engraftment in NOD/SCID mice National Cancer Insititute; Grant numbers: K12CA90433-04; correlates with high minimal residual disease (MRD) and poor K23CA113337; Grant sponsor: NCI Children’s Oncology Group; event-free survival (EFS) [26,27]. Patients with relapsed AML Grant number: U10CA098543; Grant sponsor: DanceBlue often have increased LIC at diagnosis, a feature reported to be Conflict of interest: Nothing to report. associated with poor prognosis [26]. Attar et al. [11] treated 31 adult patients with either relapsed Clinical Trial information: Identification number: NCT00666588. Trial AML (n ¼ 9) or adults >60 years with newly diagnosed AML Registry: clinicaltrials.gov (n ¼ 22) on a Phase 1 dose escalation study of bortezomib with ÃCorrespondence to: Jeffrey A. Moscow, Department of Pediatrics, idarubicin and cytarabine. This study reported a complete response University of Kentucky, Lexington, KY. E-mail: [email protected] (CR) of 61%, with an overall response rate (ORR; CR þ CRp) of Received 10 March 2014; Accepted 5 May 2014 C 2014 Wiley Periodicals, Inc. DOI 10.1002/pbc.25117 Published online 29 June 2014 in Wiley Online Library (wileyonlinelibrary.com). Bortezomib With Reinduction in Pediatric AML 1755 Two pediatric Phase 1 studies have established the dose of of circulating blasts or extramedullary disease, and with recovery of bortezomib as 1.3 mg/m2 in both solid tumors and leukemia [28,29]. peripheral blood counts (ANC 1,000/mL and platelet count Bortezomib was well tolerated; possible bortezomib-related grades 100,000/mL). CRp was defined as CR without platelet transfusion 3 and 4 toxicities included myelosuppression, bacteremia, zoster independence (defined as no platelet transfusions  1 week). CR with or without neuralgia, and peripheral sensory neuropathy [30]. with incomplete blood count recovery (CRi) required an ANC Based on data from both adults and children, bortezomib was added <1,000/mL with or without platelet recovery. Partial response (PR) to chemotherapy for pediatric patients with relapsed AML using; required at least 50% decrease in the percentage of blasts to 5–25% (i) idarubicin and cytarabine (Arm A); or (ii) high-dose cytarabine myeloblasts in the bone marrow aspirate (M2 marrow) with (1 g/m2) and etoposide (Arm B). adequate marrow cellularity (>15%). Treatment failure was defined as any M2 or M3 marrow that did not qualify for PR. METHODS Study Population Trial Design and Therapy The Children’s Oncology Group (COG) study AAML07P1 was Patients were nonrandomly assigned to either Arm A or Arm B open from April 2008 through December 2011. The eligibility based on prior anthracycline exposure. Those with a prior 2 criteria for the study included refractory, relapsed or treatment- cumulative anthracycline dose of 400 mg/m were eligible for Arm A, which consisted of idarubicin (12 mg/m2 on days 1–3), related AML. The dose finding phase was limited to relapsed 2 patients without favorable cytogenetics (t(8;21) or inv16), while the cytarabine (100 mg/m on days 1–7 by continuous IV infusion), and 2 > efficacy phases were limited to patients with refractory, treatment- bortezomib (1.3 mg/m on days 1, 4, and 8). Patients with 400 mg/ m2 prior anthracycline exposure were eligible for Arm B, consisting related, or first relapse AML. Other eligibility criteria included: age 2 > of high-dose cytarabine (1 g/m q12 hours on days 1–5), etoposide 12 months and 30 years; 5% marrow myeloblasts; no prior 2 reinduction chemotherapy (efficacy phase), <5/mL myeloblasts in (150 mg/m on days 1–5) and bortezomib using the same schedule. In the dose finding phase of Arm B, bortezomib was administered at CSF (CNS1 or CNS2), performance level (Lansky/Karnofsky) 2 two dose levels (1 and 1.3 mg/m ) on days 1, 4, and 8. In the efficacy 50; no prior cytotoxicity therapy in 2 weeks; no prior steroids in 2 7 days; no prior radiation for 2 weeks (small port), 6 weeks, or phase, bortezomib was administered at a dose of 1.3 mg/m . 8 weeks (pelvis or cransiospinal); at least 2 months from stem cell For the efficacy phase of both arms, the study employed a two- transplant with no evidence of graft versus host disease; and stage design that considered both response and toxicity [33]. The adequate organ function including adequate renal, cardiac, liver, two-stage design was constructed to test the null hypothesis that and pulmonary function (pulse oximetry >94% with normal the ORR was 40% versus the alternative hypothesis that the ORR respiratory rate, normal pulmonary function tests). Patients with a was 60%, based on a previous study of relapsed AML (CCG- þ seizure disorder could be enrolled if seizures were well controlled 2951) [34], and required CR CRp of 6 or more of the first 14 on a non-enzyme inducing anticonvulsant and if CNS toxicity had patients for Arm A and 11 or more of the first 24 patients in Arm B.