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- Copyright © 2020 Kristin Baird et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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Abstract
Hindawi Sarcoma Volume 2020, Article ID 7935475, 6 pages https://doi.org/10.1155/2020/7935475 Research Article Results of a Randomized, Double-Blinded, Placebo-Controlled, Phase 2.5 Study of Saracatinib (AZD0530), in Patients with Recurrent Osteosarcoma Localized to the Lung 1 2 3 4 5 KristinBaird , JohnGlod, SethM.Steinberg , DeniseReinke , JosephG.Pressey , 6 7 8 9 10 LeoMascarenhas, NoahFederman , NeyssaMarina, SantChawla, JoanneP.Lagmay, 11 12 13 14 John Goldberg, Mohammed Milhem , David M. Loeb, James E. Butrynski, 15 16 17 18 19 Brian Turpin, Arthur Staddon, Sheri L. Spunt, Robin L. Jones, Eve T. Rodler, 20 21 22 Scott M. Schuetze , Scott H. Okuno , and Lee Helman Center for Cancer Research, NCI, NIH, Building 10 CRC, Room 1W-3750, MSC 110410 Center Drive, Bethesda, MD 20892-1104, USA Center for Cancer Research, NCI, NIH, Building 10-CRC, Room 1-5750, Bethesda, MD 20892-1100, USA Center for Cancer Research, NCI, NIH, 9609 Medical Center Drive, Room 2W334, MSC 9716, Bethesda, MD 20892, USA SARC, 24 Frank Lloyd Wright Drive, Ann Arbor, MI 48106, USA Cincinnati Children’s Hospital Medical Center, 3333 Burnet Ave., MLC 7015, Cincinnati, OH 45229, USA Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California, 4650 Sunset Boulevard Mail Stop # 54, Los Angeles, CA 90027, USA Mattel Children’s Hospital, David Geffen School of Medicine, University of California, 10833 Le Conte Avenue, Los Angeles, CA 90095-6901, USA Stanford University School of Medicine, Palo Alto, CA 94305, USA Sarcoma Oncology Research Center, 2811 Wilshire Boulevard, Suite 411, Santa Monica, CA 90403, USA University of Florida Health Shands Children’s Hospital, 1600 SW Archer HD 204, Gainesville, FL 32610, USA Dana-Farber Cancer Institute, 450 Brookline Ave, Boston, MA 02215, USA University of Iowa Hospitals and Clinics, 200 Hawkins Drive C32 GH, Iowa City, IA 52242, USA Children’s Hospital at Montefiore, Albert Einstein College of Medicine, 3411 Wayne Ave., Room 910, Bronx, New York, NY 10467, USA Willamette Valley Cancer Institute and Research Center, 520 Country Club Road, Eugene, OR 97401, USA Cincinnati Children’s Hospital Medical Center, 3333 Burnett Avenue, Cincinnati, OH 45229, USA AbramsonCancerCenter,UniversityofPennsylvaniaHealthSystem,230W.WashingtonSquare,Philadelphia,PA19106,USA Stanford University School of Medicine, 1000 Welch Road Suite 300, MC 5798, Palo Alto, CA 94304, USA ?e Royal Marsden Hospital and Institute of Cancer Research, Fulham Road, London SW3 6JJ, UK Comprehensive Cancer Center University of California, Davis, 2279 45th Street, Sacramento, CA 95717, USA University of Michigan, 1500 East Medical Center Dr. Ann Arbor, Ann Arbor, MI 48109, USA Mayo Clinic, 200 First Street SW, Rochester, MN 55905, USA Children’s Hospital Los Angeles, Keck School of Medicine, University of Southern California Children’s Hospital Los Angeles, 4650 Sunset Blvd Mail Stop 57, Los Angeles, CA 90027, USA Correspondence should be addressed to Kristin Baird; kristin.baird@fda.hhs.gov Received 18 November 2019; Accepted 8 January 2020; Published 1 May 2020 Academic Editor: Eugenie S. Kleinerman Copyright © 2020 Kristin Baird et al. )is is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Purpose. Osteosarcoma is a rare cancer and a third of patients who have completed primary treatment will develop osteosarcoma recurrence. )e Src pathway has been implicated in the metastatic behavior of osteosarcoma; about 95% of samples examined 2 Sarcoma express Src or have evidence of downstream activation of this pathway. Saracatinib (AZD0530) is a potent and selective Src kinase inhibitor that was evaluated in adults in Phase 1 studies. )e primary goal of this study was to determine if treatment with saracatinib could increase progression-free survival (PFS) for patients who have undergone complete resection of osteosarcoma lung metastases in a double-blinded, placebo-controlled trial. Patients and Methods. Subjects with recurrent osteosarcoma localized to lung and who had complete surgical removal of all lung nodules were randomized within six weeks after complete surgical resection. Saracatinib, or placebo, was administered at a dose of 175 mg orally, once daily, for up to thirteen 28-day cycles. Results. )irty-seven subjects were included in the analyses; 18 subjects were randomized to receive saracatinib and 19 to receive placebo. Intent-to-treat analysis demonstrated a median PFS of 19.4 months in the saracatinib treatment group and 8.6 months in the placebo treatment group (p � 0.47). Median OS was not reached in either arm. Conclusions. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this double-blinded, placebo-controlled trial on OS, and Src inhibition alone may not be sufficient to suppress metastatic progression in osteosarcoma. )ere is a suggestion of potential clinical benefit as evidenced by longer PFS in patients randomized to saracatinib based on limited numbers of patients treated. 1.3. Src and Osteosarcoma. Due to its aberrant expression, 1. Introduction Src has been proposed to be important in signal transduction 1.1. Osteosarcoma. Osteosarcoma is the most common in human sarcomas, including osteosarcoma [13]. Total and malignant bone tumor in the United States and Europe and phosphorylated Src have been found to be increased in occurs frequently in adolescents and young adults, as well as several human sarcoma tissues including high-grade oste- older adults (>70 years of age). Data from the National osarcoma and various sarcoma cell lines (osteosarcoma, Cancer Institute’s (NCI) Surveillance, Epidemiology, and Ewing’s sarcoma, leiomyosarcoma, and rhabdomyosar- End Results (SEER) report an estimated osteosarcoma in- coma) [14]. Src activity has also been shown to be upre- cidence rate of 4.4 cases per 1 million in people aged 0 to 24 gulated in anoikis-resistant human osteosarcoma cells, years [1]. )e current 5-year survival rate is approximately SAOS-2, when compared with their parental population 65% [2], and there has not been a substantial improvement [15]. In mouse models of osteosarcoma, depletion of Src in survival since the 1980s [3, 4]. Approximately one-third of phosphorylation in SaOS-2 cells leads to decreased tumor patients who have completed primary therapy for localized growth [16]. More recently published data from Urciuoli osteosarcoma will develop recurrence and of those who et al. demonstrated high levels of total and phosphorylated develop recurrence, the five-year survival rate is approxi- Src protein expression in osteosarcoma tissue samples and mately 25% [5, 6]. found that the subcellular location of expression may pro- vide prognostic information [17]. 1.2. Src and Cancer. )e proto-oncogene c-SRC (SRC), a 1.4. Saracatinib and Osteosarcoma. Saracatinib (AZD0530) member of the SRC family of protein tyrosine kinases, is a is a highly selective, orally bioavailable, dual-specific Src/Abl nonreceptor tyrosine kinase that mediates signal trans- kinase inhibitor that has high potency against all Src family duction affecting various cellular functions, including pro- members tested [18]. In preclinical models and clinical liferation, differentiation, motility, adhesion, and survival studies, saracatinib modulates multiple key signaling [7–9]. Src can directly phosphorylate its substrates or act as a pathways in cancer and inhibits osteoclast-mediated bone docking site for the binding of other signaling proteins that resorption [19–28]. Additionally, in vitro data show that Src contain SH2 domains. )rough this dual mechanism, Src plays an important role in the motility of osteosarcoma cells, directly and indirectly impacts multiple signaling pathways, a function that can be abrogated by the use of Src inhibitors including PI3K/AKT/mTOR, Ras/Raf/MEK/MAPK, and [14]. More importantly, Src and other genes that are in- STAT3, all of which affect proliferation and survival of the volved in the Src pathway are activated in 95% of patients cell. Src also regulates adhesions by targeting substrates with osteosarcoma [14, 17]. )ese data suggest that sar- including focal adhesion kinase (FAK) and paxillin [10, 11]. acatinib may represent a promising therapy for the treat- Increased Src activity was first described in sarcomas and ment of patients with recurrence of osteosarcoma. is frequently implicated in cancer development. Examina- tion of sarcoma tumor samples showed that 33% had en- zyme activity levels that were 4- to 10-fold higher than that 2. Patients and Methods seen in normal tissue [12]. Similar findings were also found in mammary carcinomas [12]. Subsequently, increased ac- 2.1. Patients. From June 2009 to April 2014, subjects >15 tivity or expression of Src was found in many common solid years and <75 years of age with pulmonary recurrence of tumors, including the lung and several gastrointestinal tu- osteosarcoma who had complete surgical removal of all lung mors involving the esophagus, stomach, liver, pancreas, and nodules or with suspected recurrence of osteosarcoma but colon [8]. In some cancers, Src activity correlates with poor had not yet had surgery were eligible for enrollment on “A prognosis. Placebo-Controlled Study of Saracatinib (AZD0530) in Sarcoma 3 Patients With Recurrent Osteosarcoma Localized to the Resection of all remaining nodules, verification of recurrent osteosarcoma Lung” (NCT00752206), which was a double-blinded, pla- Randomized to receive saracatinib or placebo continuously cebo-controlled trial. Presence of metastases was evaluated (364 days/13 cycles) by CT chest and technetium bone scan. )ose who enrolled prior to surgery were not randomized until inclusion and Thoracic CT wk 3–4, 6–8; then every 3 months exclusion criteria were confirmed after surgery. )ose not confirmed were considered screen failures and were not Complete 13 cycles Recur in lung while on study randomized. Randomization occurred within six weeks after Study follow-up Unblinding patients on placebo may complete surgical resection of all tumor nodules. Ran- undergo another resection, and if fully st domization was stratified by the number of recurrences (1 resected, will be given option to nd vs. 2 vs. 3 or more) and lung metastases (1-2 vs. 3+). )e receive saracatinib for 13 cycles. Institutional Review Boards of all participating institutions Figure 1: Treatment design schema. Schema is for subjects enrolled approved the study, and all participants or their parent/ on NCT00752206, including the crossover design that was guardian, as appropriate, provided written informed con- implemented in 2012. sent. )e trial coordinating center was the SARC (Sarcoma Alliance for Research through Collaboration); all patients approximately a 0.0462 probability of failing each month were registered electronically, and all adverse events were when the 2-year PFS probability is 33%. If we assumed that reported to SARC. Histological diagnosis of osteosarcoma the 2-year PFS probability was 53% for the saracatinib arm, (osteoblastic, chondroblastic, fibroblastic, or telangiectatic the hazard rate is 0.0265, which then results in a hazard ratio subtypes) in the metastases was required. Subjects must have of 1.75. Forty-four patients were required to be randomized previously received standard chemotherapy including in each arm of the study, for a total of 88 patients, over a 48- doxorubicin, cisplatin, ifosfamide, and/or methotrexate. month accrual period to provide 80% power to detect a Subjects were excluded from enrollment if they had a re- difference between the two resulting actuarial curves with a currence at the primary site, metastatic disease in non- one-sided 0.10 alpha level log-rank test. pulmonary sites, or extensive disruption of the pleura by A secondary goal of this study was to determine whether tumor. the addition of saracatinib to surgery would result in an improvement in overall survival (OS). )e 3-year OS 2.2.StudyAimsandTreatment. )e primary objective was to probability is 45%, when a second surgical complete re- determine if the addition of saracatinib to pulmonary mission is achieved [5]. )e sample size selected to evaluate metastasectomy (S + PM) results in an increase in pro- PFS would be adequate to detect a 56% relative improvement gression-free survival in this selected patient population. (from 45% to 70%) in OS probability at three years. As- Additional secondary objectives were to determine if S + PM suming exponential survival curves, the hazard rate corre- results in an increase in overall survival and time to treat- sponding to this 3-year OS probability for the control arm is ment failure compared to placebo + PM. 0.0222, which is defined as approximately a 0.0222 proba- Saracatinib, or placebo, was administered as a once-daily bility of failing each month when the 3-year OS probability is oral dose of 175 mg for 28 days per 28-day cycle for up to 13 45%. If it was assumed that the 3-year OS probability may be cycles (364 days total) (Figure 1). Patients began cycle 1 after 70% for the saracatinib arm, the hazard is 0.0099, which then complete surgical resection of metastases. In February of results in a hazard ratio of 2.24. Evaluation of the 88 patients 2012, a crossover design was added to improve enrollment who were intended to be randomized over the same time after previous poor patient accrual. )is study amendment frame would have provided 85% power to detect a difference allowed unblinding of patients who experienced isolated between the two resulting actuarial curves with a one-sided pulmonary recurrence of osteosarcoma that were considered 0.10 alpha level log-rank test. to be amenable to complete surgical resection on study treatment. )ose patients who were receiving placebo then 3. Results had the option of receiving saracatinib following complete surgical resection. Saracatinib was administered similarly to 3.1. Efficacy. Forty-six subjects were enrolled during those patients initially randomized to saracatinib. 2009–2014. Eight subjects were screening failures; therefore, 38 subjects were randomized to receive therapy. One ran- 2.3. Statistical Methods. )e primary goal of this study was domized subject was subsequently taken off-study for to determine whether the addition of saracatinib to pul- pregnancy; therefore, 37 subjects were included in the monary metastasectomy would result in an improvement in analysis (Table 1). Most subjects were adolescent and young progression-free survival (PFS). )e 2-year PFS probability adults (AYA) with a median age of 22 years (range 15–55), was 33% when a second surgical complete remission was and five were<18 years of age. )e majority had osteoblastic assumed [5]. )e sample size was based on being able to subtype (n � 21), followed by chondroblastic (n � 9), telan- detect a 60% relative improvement (from 33% to 53%) in giectatic (n � 4), and fibroblastic (n � 3). )e median number PFS probability at two years. Assuming exponential survival of recurrences was 1 (mean � 1.75; range 1–3+), and the median number of lung nodules at enrollment was 1 curves, the hazard rate corresponding to this 2-year PFS probability for the control arm is 0.0462, which is defined as (mean � 1.62; range 1–3+). 4 Sarcoma Table 1: Patient characteristics. Male/female 19/18 90 Age (years) Median 22 (range 15–55) 15–17 5 18–39 27 >40 5 Race Asian 4 Black 1 White 25 Unknown 7 Osteosarcoma subtype Chondroblastic 9 12 24 36 48 60 Fibroblastic 3 Months Osteoblastic 21 Telangiectatic 4 Placebo Number of recurrences Saracatinib 1 19 Figure 2: Progression-free survival. Intent-to-treat analysis 2 8 demonstrated a median PFS of 19.4 months in the treatment group 3+ 10 and 8.6 months in the control group. Number of lung nodules 1 21 2 8 3+ 8 Eighteen subjects were randomized to receive sar- acatinib, and 19 were randomized to receive placebo. Nineteen subjects progressed while on study. Eighteen subjects completed therapy (saracatinib or placebo), 8 of those developed recurrence off therapy, while 10 remained disease-free at the time of analysis. Two subjects crossed over after progressing on placebo, and 2 withdrew from the study after progressing on placebo and declining crossover to saracatinib. With a data lock performed in October 12 24 36 48 60 2014, an intent-to-treat analysis demonstrated a median Months PFS of 19.4 months in the saracatinib treatment group and Placebo 8.6 months in the placebo treatment group, but no sta- Saracatinib tistical difference (p � 0.47 by log-rank test; Figure 2). Median OS was not reached in either group and the curves Figure 3: Overall survival. A median OS was not reached in either overlapped (p � 0.61; Figure 3). )e Data Safety Moni- group. A 5 yr OS of 62% versus 60% in the treatment versus the control group was observed. toring Board (DSMB) recommended study termination in 2014 for slow accrual and futility as no distinct impact of saracatinib on PFS or OS status postmetastasectomy was 4. Discussion observed. Although saracatinib was well tolerated in this patient population, there was no apparent impact of the drug in this 3.2.Safety. Overall, the regimen was well tolerated. A total double-blinded, placebo-controlled trial on OS. )is mirrors of 358 adverse events occurred in 26 patients. )ese were several studies that also showed no effect of saracatinib as a mostly grade 1-2 events of minimal clinical significance, single agent in other solid tumor types (non-small-cell lung and 50% of those events were graded as possibly related to cancer, colorectal cancer, thymic malignancies, and pros- drug (laboratory abnormalities, gastrointestinal com- tate) [29–32]. )e observed toxicity profile in the present plaints, and pain). )ere were two grade 4 events that were study was also similar to those observed in other published unrelated to study drug and resolved completely. )ere studies including hypophosphatemia requiring oral sup- were 20 grade 3 events reported: 11 were related to plementation [30, 31]. treatment and resolved completely. Of note, 4 subjects Despite preclinical data that implicate the Src pathway in experienced grade 3 hypophosphatemia deemed to be the development of pulmonary metastases in osteosarcoma, related to saracatinib and requiring supplementation. using Src tyrosine kinase inhibitors is likely insufficient to )ere were no deaths on study. prevent recurrent pulmonary metastases following complete Percent progression free Percent survival Sarcoma 5 placebo-controlled study design prematurely may have ad- resection. In 2009, Hingorani et al. published results of their study that examined the effects of dasatinib, a dual Src-Abl versely impacted study progression and drug development. )erefore, careful consideration of study designs in Phase 2 kinase inhibitor, on in vitro proliferation, adhesion, and invasion of osteosarcoma cell lines and in preventing the clinical trials is imperative to ensure adequate patient accrual development of spontaneous pulmonary metastases in an and retention to ultimately yield optimal data collection. orthotopic murine osteosarcoma model. )e authors found that although dasatinib inhibited Src and its downstream Data Availability targets and inhibited the adhesion and migration of oste- osarcoma cells in vitro, there was no impact on the devel- )e data used to support the findings of this study are opment of pulmonary metastases in the murine model. )ey available from SARC upon request. concluded that Src kinase activation might not be the pri- mary pathway involved in the development of pulmonary Disclosure metastases in osteosarcoma. However, they further con- Robin L. Jones was previously affiliated to University of cluded that Src inhibition combined with inhibition of one Washington/Fred Hutch Cancer Research Center, Seattle, or more alternative pathways that are also implicated in the metastatic behavior of osteosarcoma (ezrin, insulin-like Washington, USA. growth factor-I receptor pathway, and CXCR4) might be a rational approach for future clinical trials [33]. )is is Conflicts of Interest further supported by examples in the literature highlighting Dr. Neyssa Marina is currently employed by Synthorx. Dr. Sant the complex pathways associated with Src signaling, sum- Chawla has involvement in honoraria, consulting/advisory role, marized in a comprehensive review in 2015 by Liu et al. [34]. speakers’ bureau, and research funding with the following: )e authors conclude that the multifaceted role of Src in Amgen, Roche, GlaxoSmithKline, )reshold Pharmaceuticals, cancer metastasis and the relationship between Src and CytRx Corporation, Ignyta, Immune Design, TRACON metastasis suppressors must be considered concurrently. Pharma, Karyopharm )erapeutics, SARC, and Janssen. Dr. )ey suggest that key metastasis suppressors such as N-myc John Goldberg is currently employed by Oncorus, Inc. Dr. Lee downstream regulated gene 1 (NDRG1) play crucial roles in the effects of Src on the development of metastatic lesions Helman serves on advisory boards with Boehringer-Ingelheim, SpringWorks, and Roche; his wife is employed by Viela Bio. Dr. and that additional therapeutic intervention targeting such suppressors may be a necessary component in antimetastatic Robin Jones consults for Adaptimmune, Athenex, Blueprint, Clinigen, Eisai, Epizyme, Daichii, Deciphera, Helsinn, Immu- therapy [34]. )is is further evidenced by the results of a nedesign, Lilly, Merck, Pharmamar, Tracon, and UptoDate. Dr. Phase 2 study of dasatinib in patients with previously Mohammed Milhem consults for Blueprint Medicines, treated, high-grade, advanced sarcoma (NCT00464620) Immunocore, Amgen, Trieza, Array BioPharma, and BioNtech. where dasatinib failed to show activity as a single agent in the Dr. Leo Mascarenhas has received speaker fees from Bayer; majority of sarcoma subtypes, including osteosarcoma [35]. research grant from AstraZeneca to institution; clinical trial One of the unique aspects of this trial, which was novel at the time of initiation, was the inclusion of subjects as young as expenses from AstraZeneca, Bayer, Lilly, and Loxo Oncology to institution; consulting fees, travel expenses, meals, and ac- 15 years of age. In 2009, when this study opened, it was among the earliest trials to include adolescents<18 years of age upfront commodation from Bayer, Lilly, and AstraZeneca to institution; and travel and accommodation from )ermal Fisher Inc. and signaled the emerging acceptance of this approach from regulatory agencies, including Institutional Review Boards and the Food and Drug Administration (FDA). )e success of this Acknowledgments approach, in part due to this study, has led to several subse- )e authors are indebted to the patients and their families, quent SARC trials enrolling subjects <18 years of age. )is the referring physicians, and the clinical support teams who approach enables adolescents to have earlier access to drugs made this study possible. )e authors also thank Dr. Su that may be beneficial and can potentially improve study Young Kim and Dr. Melinda Merchant for their contri- accrual at sites that treat both adult and pediatric patients. butions to this study. 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Journal
Sarcoma – Hindawi Publishing Corporation
Published: May 1, 2020