- Email: [email protected]
Vorinostat and Concurrent Stereotactic Radiosurgery for Non-Small Cell Lung Cancer Brain Metastases: A Phase 1 Dose Escalation Trial
Accepted Manuscript Vorinostat And Concurrent Stereotactic Radiosurgery For Non-Small Cell Lung Cancer Brain Metastases: A Phase I Dose Escalation Trial Clara Y.H. Choi, MD, PhD, Heather A. Wakelee, MD, Joel W. Neal, MD, PhD, Mary C. Pinder-Schenck, MD, Hsiang-Hsuan Michael Yu, MD, Steven D. Chang, MD, John R. Adler, MD, Leslie A. Modlin, MD, Griffith R. Harsh, MD, Scott G. Soltys, MD PII:
S0360-3016(17)30897-0
DOI:
10.1016/j.ijrobp.2017.04.041
Reference:
ROB 24241
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 18 January 2017 Revised Date:
18 April 2017
Accepted Date: 28 April 2017
Please cite this article as: Choi CYH, Wakelee HA, Neal JW, Pinder-Schenck MC, Michael Yu HH, Chang SD, Adler JR, Modlin LA, Harsh GR, Soltys SG, Vorinostat And Concurrent Stereotactic Radiosurgery For Non-Small Cell Lung Cancer Brain Metastases: A Phase I Dose Escalation Trial, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.04.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Vorinostat And Concurrent Stereotactic Radiosurgery For Non-Small Cell Lung Cancer Brain Metastases: A Phase I Dose Escalation Trial
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Authors: Clara Y. H. Choi MD, PhD1,4, Heather A. Wakelee MD2, Joel W. Neal MD, PhD2, Mary C. Pinder-Schenck MD5, Hsiang-Hsuan Michael Yu MD6, Steven D. Chang MD3, John R. Adler MD3, Leslie A. Modlin MD1, Griffith R. Harsh MD3*, Scott G. Soltys, MD1*
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Corresponding Author: Scott G. Soltys, MD Assistant Professor Department of Radiation Oncology Stanford University 875 Blake Wilbur Drive Stanford CA, 94305-5847 Phone: 650.724.1569 Email: [email protected]
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Affiliations: 1. Department of Radiation Oncology, Stanford University, Stanford CA 2. Department of Medicine, Division of Oncology, Stanford University, Stanford CA 3. Department of Neurosurgery, Stanford University, Stanford CA 4. Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose CA 5. Oncology, GlaxoSmithKline, Collegeville, PA 6. Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa FL
Running Title: Vorinostat and SRS for NSCLC Brain Metastases
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Conflicts of Interest: Mary C. Pinder-Schenck is an employee of GlaxoSmithKline. No other conflicts of interest.
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Funding Source: This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc. Notes: Presented, in part, at the ASTRO 57th Annual Meeting 2015 – San Antonio TX *Griffith R. Harsh and Scott G. Soltys contributed equally. Key Words: Stereotactic Radiosurgery, phase 1 trial, Vorinostat, brain metastases, lung cancer, prospective
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Number of Words in Abstract: 229 Number of Words in Text: 2210 Number of Tables: 3 Number of Figures: 0 Number of Appendices: 2
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Summary:
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Vorinostat, a histone deacetylase inhibitor, has been shown to be a radiosensitizer in preclinical models. We sought to investigate the concurrent use of vorinostat and stereotactic radiosurgery (SRS) in treatment of brain metastases. As a requisite first step, we conducted a phase I dose escalation study. The maximum tolerated dose of vorinostat with concurrent SRS was established as 400 mg once daily. A larger trial may confirm the safety and efficacy of this treatment.
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ABSTRACT Purpose:
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We sought to determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure (LF), distant intracranial failure (DF), and overall survival (OS) rates. Methods and Materials:
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In this multicenter study, patients with 1-4 NSCLC brain metastases, each <2 cm, were enrolled in a phase 1, 3+3 dose-escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any CTCAE v3.0 grade 3-5 acute non-hematologic adverse event (AE) related to vorinostat or SRS occurring within 30 days. Results:
Conclusions:
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From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. As no DLTs were observed, the MTD was established as 400 mg. Acute AEs were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n = 2), nausea (n = 1), and fatigue (n = 2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier OS was 13 months. There were no local failures. One (8%) patient at the 400 mg dose level with a 2.0 cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months following SRS.
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The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew prior to completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.
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INTRODUCTION
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Brain metastases are the most common intracranial tumors, occurring in approximately 25% of patients with cancer1. Lung cancer is the most common primary site of brain metastasis (ranging from 18 to 64%2). As even small brain metastases can cause neurologic symptoms or mortality, innovative treatments seeking to improve local tumor control are needed.
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Concurrent chemoradiotherapy improves locoregional control over radiotherapy alone by enhancing radiation-mediated cell kill3. Stereotactic radiosurgery (SRS) is an alternative to conventional radiotherapy, both for intracranial and extracranial tumors. Compared to conventional radiation, SRS has the advantages of shorter treatment and a higher biologically effective dose. Additionally, compared to whole brain radiotherapy, SRS better spares normal brain and has superior neurocognitive outcomes4. The safety and efficacy of combining SRS and chemotherapy, particularly radiosensitizers, needs further study.
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Epigenetic changes induced by histone acetylation have been implicated in tumorigenesis and cancer progression5. Vorinostat (suberanilohydroxamic acid), a histone deacetylase (HDAC) inhibitor, inhibits growth of a variety of transformed cell lines and of tumors in animal models of breast, lung, colon, and prostate cancers6. Clinically, vorinostat has been used to treat patients with cutaneous T-cell lymphoma (CTCL), breast cancer, glioblastoma, and NSCLC7. The appeal of vorinostat concurrent with intracranial SRS is threefold: First, it potentiates radiation-mediated cell kill8-12. Second, vorinostat crosses the blood brain barrier13. Finally, vorinostat is well tolerated as monotherapy, in combination with other chemotherapeutic agents, and with concurrent conventional radiotherapy7,14,15.
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This novel phase I study combining an HDAC inhibitor with SRS sought to determine the maximum tolerated dose (MTD) of vorinostat concurrent with SRS in treating NSCLC brain metastases.
PATIENTS AND METHODS Patient Characteristics
Patients ≥ 18 years of age with an ECOG performance status of 0-2 and pathologically confirmed non-small cell lung cancer with 1-4 brain metastases, each measuring ≤ 2.0 cm in diameter, were eligible. Informed consent was obtained for this IRB-approved study (clinicaltrials.gov: XXX). Adequate organ function, as defined in Appendix 1, was required. Patients were required to be off systemic cancer therapy for at least 7 days prior to SRS. Previous treatment of the target lesion with either SRS or WBRT was exclusionary.
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Treatment
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Vorinostat was taken orally, once per day, for 14 days. Single fraction SRS was delivered on Day 3 of vorinostat. On the day of SRS, Vorinostat was given 30 to 90 minutes prior to treatment, given its half-life of approximately 1.34 hours. SRS dose was based on the maximum tumor dimension as measured on axial T1 post-contrast MRI: diameter 0-1.0 cm: 24 Gy; 1.1-1.5 cm: 22 Gy; 1.6-2.0 cm: 20 Gy. The gross tumor volume (GTV) was defined by post-contrast MRI images. The planning target volume (PTV) was identical to the GTV. Dose limits were as follows: optic structure maximum dose <10 Gy; brain stem maximum dose <14 Gy. The prescribed dose covered ≥95% of the target. The RTOG conformity index (prescription isodose volume/target volume) was <1.7.
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The CyberKnife Robotic Radiosurgical System delivered the radiosurgical treatments in 15 patients at XXXXXX; 2 patients treated at XXXXXX were treated with a Novalis system. Supine patients were immobilized on the treatment table with an Aquaplast mask (WFT/Aquaplast Corp., Wyckoff, NJ). A high-resolution thin-slice (1 - 1.25 mm) computed tomogram was obtained after administration of intravenous contrast. For most patients, a post-contrast stereotactic magnetic resonance imaging (MRI) scan was obtained and fused to the stereotactic CT scan to improve target identification. Trial Design
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Vorinostat dose (given orally once daily for 14 days) was escalated as follows: Dose level 1: 200 mg; dose level 2: 300 mg; dose level 3: 400 mg. To address the possibility of unacceptable toxicity with dose level 1, the trial was designed with a dose level -1 of 100 mg, but this was not needed.
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Toxicity was graded using the NCI-CTCAE version 3.0. A dose-limiting toxicity (DLT) was defined as follows: Any Grade 3 or higher non-hematologic adverse event with the exception of alopecia, fatigue, anorexia; Grade 3 or higher nausea and/or vomiting that persists > 48 hours despite optimal medical management. Hematologic dose-limiting toxicity was defined as follows: Grade 4 neutropenia lasting for ≥ 7 days in duration, Grade > 3 febrile neutropenia with/without infection, any Grade 4 thrombocytopenia, or any Grade 5 hematologic toxicity. To be declared a dose-limiting toxicity, an adverse event had to be related (definitely, probably, or possibly) to study therapy. DLT was assessed as events that occurred before day 30. Dose escalation followed the standard 3+3 design (Appendix 2). There was a minimum waiting period of 30 days after the completion of SRS by the last patient enrolled at the dose level before proceeding to the next higher dose level.
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The maximum tolerated dose (MTD) was defined as the highest dose of vorinostat not causing unacceptable toxicity (i.e., MTD was to be designated as one dose level below the DLT dose). To confirm the safety of MTD, 3 additional patients were enrolled at the MTD for a total of 6 patients.
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Follow-up
Patients were seen in follow-up at 1-2 weeks and the 1st, 3rd, 6th, and 12th month following the date of radiosurgery. DLT was assessed at day 30. Patients continued to be monitored for late toxicity.
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Statistical Methods
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Local failure (LF) was defined as growth of a treated metastasis on imaging, utilizing metabolic imaging and pathologic information as needed to distinguish tumor growth from radionecrosis. Distant failure (DF) was defined as the appearance of new brain metastases outside the radiosurgical treatment volume. Time to recurrence was calculated from the date of SRS to that of the MRI showing local or distant tumor recurrence. Otherwise, patients were censored at the time of their last MRI. For patients receiving salvage whole brain radiotherapy (WBRT), failure rates were censored at the time of WBRT. Patients continued to be followed for survival and toxicity. Cumulative incidence rates16 of local failure and distant brain failure were calculated using R.2.11.0 (http://cran.r-project.org), with death as a competing risk.
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RESULTS
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The overall survival (OS) rate was calculated from the date of SRS to date of death; otherwise, patients were censored at the time of their last contact. Survival analyses were performed using Stat View, version 5.0.1 (SAS Institute Inc., Cary, NC). OS rate was calculated using the Kaplan-Meier (KM) product-limit method17.
Patient and Treatment Characteristics Between September 2009 and July 2014, 17 patients enrolled in the study (15 from XXXX and 2 from XXXXXX). Patient and treatment characteristics are shown in Table 1.
Dose Escalation Three patients were enrolled at dose level 1 (200 mg). All 3 patients tolerated treatment well, and no DLTs were observed.
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At dose level 2 (300 mg), 1 patient (patient 6, Table 2) reported an episode of dyspnea (grade 3) on day 11, which was considered unrelated to vorinostat. After this episode, he discontinued the study drug and withdrew from the study. Thus, 4 total patients were enrolled at dose level 2. No DLTs were observed.
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The first patient enrolled at dose level 3 (400 mg) (patient 8, Table 2) withdrew from the study after 1 day, citing Grade 1 nausea. Patients 9, 10, and 11 completed the study course without a DLT. Therefore, 400 mg was determined to be the MTD.
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Per protocol, 3 additional patients were needed to confirm safety. Because of the withdrawals, a total of 6 patients were enrolled during the expansion phase. Three patients (patient 12, 13, and 16) withdrew from the study, though none met the criteria for a DLT. Their AEs are listed in Table 2. Three other patients (patient 14, 15, and 17) completed the study course without significant AEs.
Adverse Events (AEs)
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Acute AEs for all patients are shown in Tables 2 and 3. Seven patients (41%) reported no acute AEs. Of the remaining 10 patients, the most common AEs were nausea (n=5) and fatigue (n=4). Other AEs experienced by more than 1 subject were dysgeusia, anorexia, headache, and dyspnea (n=2 each).
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Four of 5 patients who withdrew from the study were at the 400 mg level. Details on the 5 patients who withdrew from the study are in Table 2. The drug treatment duration in this group ranged from 1 to 11 days, and the most common reasons for withdrawal were nausea, fatigue, and dyspnea.
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There was one case (8%) of late AE. A patient at the 400 mg dose level (patient 17) developed grade 4 radionecrosis after completing treatment of a 2.0 cm lesion. He underwent a surgical resection 2 months after SRS.
Local Control, Distant Brain Failure, and Overall Survival Survival and control were analyzed for all 17 patients. The median follow up duration was 12 months (range, 1-64 months). There were no local failures. The 12-month cumulative incidence rate of distant failure, with death as a competing risk, was 42% (95% confidence interval, 10-72%). The Kaplan-Meier median OS was 13 months. OS for patients that completed the study course did not differ from that of those who withdrew.
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DISCUSSION
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By enhancing the cytotoxic effects of conventional radiation7, concurrent chemotherapy has the potential to improve clinical outcomes in patients with brain metastases. Use of hypoxic cell radiosensitizers with SRS for recurrent brain tumors18,19 suggests that this may pertain to radiosurgery as well.
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In the present study, we administered vorinostat, an HDAC inhibitor and a known radiosensitizer, concurrently with single fraction radiosurgery to brain metastases from NSCLC. Although multiple clinical studies have demonstrated the feasibility and safety of combining vorinostat with other systemic agents7, experience with vorinostat and concurrent radiation is limited to three studies, all of which used conventional radiation14,15.
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The first, a phase I dose escalation study, administered vorinostat with palliative pelvic radiation (3000 cGy in 300 cGy fractions) at doses ranging from 100 to 400 mg orally once a day14. Because 2 of 6 patients in the 400 mg group experienced DLTs (diarrhea, fatigue, anorexia, hyponatremia, and hypokalemia), the vorinostat MTD with whole pelvic radiation was deemed to be 300 mg once daily. Fatigue, nausea, anorexia, vomiting, and diarrhea were the most common AEs.
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In the second phase I study, vorinostat was used concurrently with whole brain radiation (3750 cGy in 250 cGy fractions) to treat brain metastases15. The vorinostat dose escalated from 200 to 400 mg once daily. The MTD for vorinostat with current WBRT was determined to be 300 mg once a day as one patient had a grade 3 pulmonary embolus and one other died within 30 days of treatment at the 400 mg dose level.
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Lastly, a phase I study investigated escalating doses of vorinostat from 100 to 400 mg per day concurrently with capecitabine and 30 Gy in 10 fractions in 21 patients with nonmetastatic pancreatic cancer20. Three DLTs occurred (2 gastrointestinal and 1 thrombocytopenia) and the MTD for vorinostat was concluded to be 400 mg per day. To our knowledge, there is no previous report of concurrent use of vorinostat and SRS. We thus conducted a phase I dose escalation study, using the standard 3+3 study design. We determined the MTD of vorinostat with concurrent SRS to be 400 mg orally once daily. As with vorinostat monotherapy at 400 mg once daily, the most common AEs in our study were nausea, fatigue, dysgeusia, anorexia, headache, and dyspnea21. The only exception was the higher rate of dyspnea in our study, perhaps more reflective of the lung disease of our patients with NSCLC than of vorinostat toxicity.
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Five patients discontinued vorinostat early and withdrew from the study. One withdrew after only 1 day of vorinostat. Three of the other four withdrawals occurred during the expanded phase I portion of the study during which additional patients were enrolled to confirm safety at 400 mg per day. The most common reasons for withdrawal were nausea, fatigue, and dyspnea. While the rate of AE-related withdrawal in our study was significantly higher than AE-related discontinuation reported in the vorinostat label (9.3% for patients with CTCL), this disparity may be related to the differences in disease, presence of brain metastases, concurrent SRS or a temporary masking by dexamethasone on the day of SRS of symptoms which later become apparent. Although none of the patients who withdrew met our studyspecific criteria for a DLT, AEs were more frequent at the 400 mg level. Furthermore 3 of the 5 patients had less than 4 days of medication left to complete the course of treatment. This finding was surprising, as patients tolerated 400 mg daily for a median of 118 days in the trial that led to the approval of vorinostat for cutaneous lymphoma22. The number of patients intolerant of this dose for 14 days on our study highlights the need for frequent assessment and early supportive intervention and encouragement upon initiation of Vorinostat at this dose level. Confirmation of tolerability with a larger patient cohort is needed.
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We chose to administer vorinostat for 14 days, but the optimal duration of vorinostat with concurrent SRS is not known. Because HDAC inhibition alters multiple pathways of tumor progression, no single biomarker adequately reports its affects. Most patients in this study tolerated the first week of vorinostat therapy relatively well. The second week of therapy, during which no radiation is delivered, may not be needed.
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The SRS doses used for this study were those found to be safe in the RTOG 9005 study23. The maximum size of each treated metastasis was 2 cm. In future experience, it will be important to determine whether larger tumors can be safely treated with concurrent SRS and vorinostat. More data are needed to verify if the relative early G4 radionecrosis and the 100% local control are signals of true radiosensitization with vorinostat.
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To our knowledge, this is the first study demonstrating that intracranial SRS can be safely delivered in combination with an HDAC inhibitor. Additional studies of larger groups of patients are needed to confirm safety and to determine efficacy. Outside the brain, stereotactic body radiotherapy is being used more commonly for tumors of various types, including lung and GI. Our study of concomitant use of a radiosensitizer and radiosurgery may thus have wide applicability.
CONCLUSION
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Stereotactic radiosurgery of brain metastases can be safely combined with the HDAC inhibitor, vorinostat. The MTD of vorinostat with concurrent SRS is 400 mg orally once per day. Additional studies are needed to determine the optimal vorinostat treatment duration, confirm safety, and determine efficacy.
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References:
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1. Kaal EC, Niel CG, Vecht CJ: Therapeutic management of brain metastasis. Lancet Neurol 4:289-98, 2005 2. Lassman AB, DeAngelis LM: Brain metastases. Neurol Clin 21:1-23, vii, 2003 3. Seiwert TY, Salama JK, Vokes EE: The concurrent chemoradiation paradigm-general principles. Nat Clin Pract Oncol 4:86-100, 2007 4. Chang EL, Wefel JS, Hess KR, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:1037-44, 2009 5. West AC, Johnstone RW: New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30-9, 2014 6. Emanuele S, Lauricella M, Tesoriere G: Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). Int J Oncol 33:637-46, 2008 7. Siegel D, Hussein M, Belani C, et al: Vorinostat in solid and hematologic malignancies. J Hematol Oncol 2:31, 2009 8. Zhang Y, Jung M, Dritschilo A, et al: Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat Res 161:667-74, 2004 9. Chinnaiyan P, Vallabhaneni G, Armstrong E, et al: Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 62:223-9, 2005 10. Munshi A, Kurland JF, Nishikawa T, et al: Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 11:4912-22, 2005 11. Munshi A, Tanaka T, Hobbs ML, et al: Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther 5:1967-74, 2006 12. Sonnemann J, Kumar KS, Heesch S, et al: Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. Int J Oncol 28:755-66, 2006 13. Palmieri D, Lockman PR, Thomas FC, et al: Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res 15:6148-57, 2009 14. Ree AH, Dueland S, Folkvord S, et al: Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol 11:459-64, 2010 15. Gondi V, Pugh SL, Tome WA, et al: Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 32:3810-6, 2014 16. Kim HT: Cumulative incidence in competing risks data and competing risks regression analysis. Clin Cancer Res 13:559-65, 2007 17. Kaplan E, Meier P: Nonparametric estimation for incomplete observation. J Am Stat Assoc 53:457-481, 1958 18. Drzymala RE, Wasserman TH, Won M, et al: A phase I-B trial of the radiosensitizer: etanidazole (SR-2508) with radiosurgery for the treatment of recurrent previously irradiated primary brain tumors or brain metastases (RTOG Study 95-02). Radiother Oncol 87:89-92, 2008
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19. Yamazaki H, Nakamura S, Nishimura T, et al: Hypofractionated stereotactic radiotherapy with the hypoxic sensitizer AK-2123 (sanazole) for reirradiation of brain metastases: a preliminary feasibility report. Anticancer Res 33:1773-6, 2013 20. Chan E, Arlinghaus LR, Cardin DB, et al: Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Radiother Oncol 119:312-8, 2016 21. Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109-15, 2007 22. Mann BS, Johnson JR, Cohen MH, et al: FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247-52, 2007 23. Shaw E, Scott C, Souhami L, et al: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291-8, 2000
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Appendix 1: Eligibility criteria included adequate organ function as defined by the following laboratory values. System
Laboratory Value ≥3,000 /µL
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥ 9 g/dL
Coagulation
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Prothrombin Time or INR
Partial thromboplastin time (PTT) Chemistry K levels
Normal limits
≤ 1.5 X ULN
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Calculated creatinine clearancea Hepatic
≥20 mL/min ≤ 1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN
Alkaline Phosphatase
≤ 2.5 X ULN
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Serum total bilirubin
a
Creatinine clearance should be calculated per institutional standard.
≤1.2 times the ULN unless the patient is receiving therapeutic anticoagulation. Normal limits
Renal Creatinine
≤1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation
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Mg levels
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Leukocytes
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Hematological
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Appendix 2. 3+3 study design dose escalation rules. Number of Patients with DLT at a Given Dose Level
>2
Enter 3 patients at the next dose level.
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0 out of 3
Escalation Decision Rule
Dose escalation will be stopped. Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose. Enter at least 3 more patients at this dose level. •
If 1 or more of this group suffer DLT, then dose escalation is stopped. Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose.
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•
If 0 of these 3 patients experience DLT, proceed to the next dose level.
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1 out of 3
<1 out of 6 at highest dose level This is the dose to be used in the expanded phase I below the maximally administered trial. At least 6 patients must be entered at this dose. dose
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Supplementary Figure 1: Overall Survival – Intent to Treat for all 17 patients
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Table 1. Patient and treatment characteristics Number/Value
%
7
41
Female Male
10
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Median
Number of metastases treated
Treatment volume (cm3)
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Dose (Gy)
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Disease-Specific Brain Metastases Grade Prognostic Assessment (GPA)
59
Range
62
49 - 76
80
60-90
1
1-4
GPA 3.5 – 4.0
0
GPA 2.5 – 3.0
27
GPA 1.5 – 2.0
60
GPA 0 - 1
13
0.61
0.03-5.92
24
20-24
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Age Karnofsky performance status (%)
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Sex
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Table 2. Details on each patient’s acute adverse events.
Oral Daily Adverse events Dose (mg)
Study completion
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Patient number
Dose Level 1 1
200 Grade 1 nausea
2
200 None
3
200 None
Completed
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Completed Completed
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Dose Level 2 4
300 None
Completed
5
300 None
Completed
6
300 Grade 3 dyspnea*
Withdrew after 11 days
7
300 Grade 2 dysgeusia
Completed
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Grade 2 anorexia Grade 1 sweating Dose Level 3
400 Grade 1 nausea
Withdrew after 1 days
9
400 None
Completed
400 Grade 2 diarrhea
Completed
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10
Grade 2 fatigue Grade 1 nausea Grade 1 headache
11
400 Grade 1 dysgeusia Dose Level 3 Expansion
Completed
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400 Grade 3 fatigue
Withdrew after 10 days
Grade 2 thrombocytopenia
Grade 1 nausea 13
400 Grade 2 dyspnea
Withdrew after 11 days
Grade 1 pain, chest wall
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Grade 1 arthralgia Grade 1 fatigue
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Grade 2 anorexia
400 None
15
400 Grade 1 headache
Completed
16
400 Grade 2 fatigue
Withdrew after 7 days
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14
Completed
Grade 2 pain, stomach
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Grade 2 abdominal distension/bloating Grade 2 nausea Grade 1 vomiting
400 None
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Completed
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Table 3. Treatment-emergent adverse events of any grade. Vorinostat Dose 300 mg Grade 1
2
3
1
2
Fatigue
-
-
-
-
-
Nausea
1
-
-
-
-
Dysgeusia
-
-
-
-
Anorexia
-
-
-
-
Dyspnea
-
-
-
Chest wall pain
-
-
Arthralgia
-
-
Sweating
-
-
1
2
3
-
1
2
1
-
3
1
-
-
1
-
-
1
-
-
1
-
-
-
1*
-
1
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
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1
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
1
-
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Diarrhea
3
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Adverse Event
400 mg
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200 mg
-
-
-
-
-
-
1
-
Headache Thrombocytopenia
-
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Abdominal distension/bloating Pain, stomach
-
-
-
-
-
-
-
1
-
Pain, chest wall
-
-
-
-
-
-
1
-
-
Vomiting
-
-
-
-
-
-
1
-
-
*Unrelated to vorinostat use.
S0360-3016(17)30897-0
DOI:
10.1016/j.ijrobp.2017.04.041
Reference:
ROB 24241
To appear in:
International Journal of Radiation Oncology • Biology • Physics
Received Date: 18 January 2017 Revised Date:
18 April 2017
Accepted Date: 28 April 2017
Please cite this article as: Choi CYH, Wakelee HA, Neal JW, Pinder-Schenck MC, Michael Yu HH, Chang SD, Adler JR, Modlin LA, Harsh GR, Soltys SG, Vorinostat And Concurrent Stereotactic Radiosurgery For Non-Small Cell Lung Cancer Brain Metastases: A Phase I Dose Escalation Trial, International Journal of Radiation Oncology • Biology • Physics (2017), doi: 10.1016/ j.ijrobp.2017.04.041. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Title: Vorinostat And Concurrent Stereotactic Radiosurgery For Non-Small Cell Lung Cancer Brain Metastases: A Phase I Dose Escalation Trial
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Authors: Clara Y. H. Choi MD, PhD1,4, Heather A. Wakelee MD2, Joel W. Neal MD, PhD2, Mary C. Pinder-Schenck MD5, Hsiang-Hsuan Michael Yu MD6, Steven D. Chang MD3, John R. Adler MD3, Leslie A. Modlin MD1, Griffith R. Harsh MD3*, Scott G. Soltys, MD1*
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Corresponding Author: Scott G. Soltys, MD Assistant Professor Department of Radiation Oncology Stanford University 875 Blake Wilbur Drive Stanford CA, 94305-5847 Phone: 650.724.1569 Email: [email protected]
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Affiliations: 1. Department of Radiation Oncology, Stanford University, Stanford CA 2. Department of Medicine, Division of Oncology, Stanford University, Stanford CA 3. Department of Neurosurgery, Stanford University, Stanford CA 4. Department of Radiation Oncology, Santa Clara Valley Medical Center, San Jose CA 5. Oncology, GlaxoSmithKline, Collegeville, PA 6. Department of Radiation Oncology, H. Lee Moffitt Cancer Center, Tampa FL
Running Title: Vorinostat and SRS for NSCLC Brain Metastases
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Conflicts of Interest: Mary C. Pinder-Schenck is an employee of GlaxoSmithKline. No other conflicts of interest.
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Funding Source: This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by Merck & Co., Inc. Notes: Presented, in part, at the ASTRO 57th Annual Meeting 2015 – San Antonio TX *Griffith R. Harsh and Scott G. Soltys contributed equally. Key Words: Stereotactic Radiosurgery, phase 1 trial, Vorinostat, brain metastases, lung cancer, prospective
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Number of Words in Abstract: 229 Number of Words in Text: 2210 Number of Tables: 3 Number of Figures: 0 Number of Appendices: 2
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Summary:
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Vorinostat, a histone deacetylase inhibitor, has been shown to be a radiosensitizer in preclinical models. We sought to investigate the concurrent use of vorinostat and stereotactic radiosurgery (SRS) in treatment of brain metastases. As a requisite first step, we conducted a phase I dose escalation study. The maximum tolerated dose of vorinostat with concurrent SRS was established as 400 mg once daily. A larger trial may confirm the safety and efficacy of this treatment.
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ABSTRACT Purpose:
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We sought to determine the maximum tolerated dose (MTD) of vorinostat, a histone deacetylase inhibitor, given concurrently with stereotactic radiosurgery (SRS) to treat non-small cell lung cancer (NSCLC) brain metastases. Secondary objectives were to determine toxicity, local failure (LF), distant intracranial failure (DF), and overall survival (OS) rates. Methods and Materials:
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In this multicenter study, patients with 1-4 NSCLC brain metastases, each <2 cm, were enrolled in a phase 1, 3+3 dose-escalation trial. Vorinostat dose levels were 200, 300, and 400 mg orally once daily for 14 days. Single-fraction SRS was delivered on day 3. A dose-limiting toxicity (DLT) was defined as any CTCAE v3.0 grade 3-5 acute non-hematologic adverse event (AE) related to vorinostat or SRS occurring within 30 days. Results:
Conclusions:
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From 2009 to 2014, 17 patients were enrolled and 12 patients completed study treatment. As no DLTs were observed, the MTD was established as 400 mg. Acute AEs were reported by 10 patients (59%). Five patients discontinued vorinostat early and withdrew from the study. The most common reasons for withdrawal were dyspnea (n = 2), nausea (n = 1), and fatigue (n = 2). With a median follow-up of 12 months (range, 1-64 months), Kaplan-Meier OS was 13 months. There were no local failures. One (8%) patient at the 400 mg dose level with a 2.0 cm metastasis developed histologically confirmed grade 4 radiation necrosis 2 months following SRS.
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The MTD of vorinostat with concurrent SRS was established as 400 mg. Although no DLTs were observed, 5 patients withdrew prior to completing the treatment course, a result that emphasizes the need for supportive care during vorinostat administration. There were no local failures. A larger, randomized trial may evaluate both the tolerability and potential local control benefit of vorinostat concurrent with SRS for brain metastases.
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INTRODUCTION
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Brain metastases are the most common intracranial tumors, occurring in approximately 25% of patients with cancer1. Lung cancer is the most common primary site of brain metastasis (ranging from 18 to 64%2). As even small brain metastases can cause neurologic symptoms or mortality, innovative treatments seeking to improve local tumor control are needed.
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Concurrent chemoradiotherapy improves locoregional control over radiotherapy alone by enhancing radiation-mediated cell kill3. Stereotactic radiosurgery (SRS) is an alternative to conventional radiotherapy, both for intracranial and extracranial tumors. Compared to conventional radiation, SRS has the advantages of shorter treatment and a higher biologically effective dose. Additionally, compared to whole brain radiotherapy, SRS better spares normal brain and has superior neurocognitive outcomes4. The safety and efficacy of combining SRS and chemotherapy, particularly radiosensitizers, needs further study.
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Epigenetic changes induced by histone acetylation have been implicated in tumorigenesis and cancer progression5. Vorinostat (suberanilohydroxamic acid), a histone deacetylase (HDAC) inhibitor, inhibits growth of a variety of transformed cell lines and of tumors in animal models of breast, lung, colon, and prostate cancers6. Clinically, vorinostat has been used to treat patients with cutaneous T-cell lymphoma (CTCL), breast cancer, glioblastoma, and NSCLC7. The appeal of vorinostat concurrent with intracranial SRS is threefold: First, it potentiates radiation-mediated cell kill8-12. Second, vorinostat crosses the blood brain barrier13. Finally, vorinostat is well tolerated as monotherapy, in combination with other chemotherapeutic agents, and with concurrent conventional radiotherapy7,14,15.
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This novel phase I study combining an HDAC inhibitor with SRS sought to determine the maximum tolerated dose (MTD) of vorinostat concurrent with SRS in treating NSCLC brain metastases.
PATIENTS AND METHODS Patient Characteristics
Patients ≥ 18 years of age with an ECOG performance status of 0-2 and pathologically confirmed non-small cell lung cancer with 1-4 brain metastases, each measuring ≤ 2.0 cm in diameter, were eligible. Informed consent was obtained for this IRB-approved study (clinicaltrials.gov: XXX). Adequate organ function, as defined in Appendix 1, was required. Patients were required to be off systemic cancer therapy for at least 7 days prior to SRS. Previous treatment of the target lesion with either SRS or WBRT was exclusionary.
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Treatment
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Vorinostat was taken orally, once per day, for 14 days. Single fraction SRS was delivered on Day 3 of vorinostat. On the day of SRS, Vorinostat was given 30 to 90 minutes prior to treatment, given its half-life of approximately 1.34 hours. SRS dose was based on the maximum tumor dimension as measured on axial T1 post-contrast MRI: diameter 0-1.0 cm: 24 Gy; 1.1-1.5 cm: 22 Gy; 1.6-2.0 cm: 20 Gy. The gross tumor volume (GTV) was defined by post-contrast MRI images. The planning target volume (PTV) was identical to the GTV. Dose limits were as follows: optic structure maximum dose <10 Gy; brain stem maximum dose <14 Gy. The prescribed dose covered ≥95% of the target. The RTOG conformity index (prescription isodose volume/target volume) was <1.7.
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The CyberKnife Robotic Radiosurgical System delivered the radiosurgical treatments in 15 patients at XXXXXX; 2 patients treated at XXXXXX were treated with a Novalis system. Supine patients were immobilized on the treatment table with an Aquaplast mask (WFT/Aquaplast Corp., Wyckoff, NJ). A high-resolution thin-slice (1 - 1.25 mm) computed tomogram was obtained after administration of intravenous contrast. For most patients, a post-contrast stereotactic magnetic resonance imaging (MRI) scan was obtained and fused to the stereotactic CT scan to improve target identification. Trial Design
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Vorinostat dose (given orally once daily for 14 days) was escalated as follows: Dose level 1: 200 mg; dose level 2: 300 mg; dose level 3: 400 mg. To address the possibility of unacceptable toxicity with dose level 1, the trial was designed with a dose level -1 of 100 mg, but this was not needed.
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Toxicity was graded using the NCI-CTCAE version 3.0. A dose-limiting toxicity (DLT) was defined as follows: Any Grade 3 or higher non-hematologic adverse event with the exception of alopecia, fatigue, anorexia; Grade 3 or higher nausea and/or vomiting that persists > 48 hours despite optimal medical management. Hematologic dose-limiting toxicity was defined as follows: Grade 4 neutropenia lasting for ≥ 7 days in duration, Grade > 3 febrile neutropenia with/without infection, any Grade 4 thrombocytopenia, or any Grade 5 hematologic toxicity. To be declared a dose-limiting toxicity, an adverse event had to be related (definitely, probably, or possibly) to study therapy. DLT was assessed as events that occurred before day 30. Dose escalation followed the standard 3+3 design (Appendix 2). There was a minimum waiting period of 30 days after the completion of SRS by the last patient enrolled at the dose level before proceeding to the next higher dose level.
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The maximum tolerated dose (MTD) was defined as the highest dose of vorinostat not causing unacceptable toxicity (i.e., MTD was to be designated as one dose level below the DLT dose). To confirm the safety of MTD, 3 additional patients were enrolled at the MTD for a total of 6 patients.
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Follow-up
Patients were seen in follow-up at 1-2 weeks and the 1st, 3rd, 6th, and 12th month following the date of radiosurgery. DLT was assessed at day 30. Patients continued to be monitored for late toxicity.
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Statistical Methods
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Local failure (LF) was defined as growth of a treated metastasis on imaging, utilizing metabolic imaging and pathologic information as needed to distinguish tumor growth from radionecrosis. Distant failure (DF) was defined as the appearance of new brain metastases outside the radiosurgical treatment volume. Time to recurrence was calculated from the date of SRS to that of the MRI showing local or distant tumor recurrence. Otherwise, patients were censored at the time of their last MRI. For patients receiving salvage whole brain radiotherapy (WBRT), failure rates were censored at the time of WBRT. Patients continued to be followed for survival and toxicity. Cumulative incidence rates16 of local failure and distant brain failure were calculated using R.2.11.0 (http://cran.r-project.org), with death as a competing risk.
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RESULTS
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The overall survival (OS) rate was calculated from the date of SRS to date of death; otherwise, patients were censored at the time of their last contact. Survival analyses were performed using Stat View, version 5.0.1 (SAS Institute Inc., Cary, NC). OS rate was calculated using the Kaplan-Meier (KM) product-limit method17.
Patient and Treatment Characteristics Between September 2009 and July 2014, 17 patients enrolled in the study (15 from XXXX and 2 from XXXXXX). Patient and treatment characteristics are shown in Table 1.
Dose Escalation Three patients were enrolled at dose level 1 (200 mg). All 3 patients tolerated treatment well, and no DLTs were observed.
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At dose level 2 (300 mg), 1 patient (patient 6, Table 2) reported an episode of dyspnea (grade 3) on day 11, which was considered unrelated to vorinostat. After this episode, he discontinued the study drug and withdrew from the study. Thus, 4 total patients were enrolled at dose level 2. No DLTs were observed.
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The first patient enrolled at dose level 3 (400 mg) (patient 8, Table 2) withdrew from the study after 1 day, citing Grade 1 nausea. Patients 9, 10, and 11 completed the study course without a DLT. Therefore, 400 mg was determined to be the MTD.
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Per protocol, 3 additional patients were needed to confirm safety. Because of the withdrawals, a total of 6 patients were enrolled during the expansion phase. Three patients (patient 12, 13, and 16) withdrew from the study, though none met the criteria for a DLT. Their AEs are listed in Table 2. Three other patients (patient 14, 15, and 17) completed the study course without significant AEs.
Adverse Events (AEs)
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Acute AEs for all patients are shown in Tables 2 and 3. Seven patients (41%) reported no acute AEs. Of the remaining 10 patients, the most common AEs were nausea (n=5) and fatigue (n=4). Other AEs experienced by more than 1 subject were dysgeusia, anorexia, headache, and dyspnea (n=2 each).
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Four of 5 patients who withdrew from the study were at the 400 mg level. Details on the 5 patients who withdrew from the study are in Table 2. The drug treatment duration in this group ranged from 1 to 11 days, and the most common reasons for withdrawal were nausea, fatigue, and dyspnea.
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There was one case (8%) of late AE. A patient at the 400 mg dose level (patient 17) developed grade 4 radionecrosis after completing treatment of a 2.0 cm lesion. He underwent a surgical resection 2 months after SRS.
Local Control, Distant Brain Failure, and Overall Survival Survival and control were analyzed for all 17 patients. The median follow up duration was 12 months (range, 1-64 months). There were no local failures. The 12-month cumulative incidence rate of distant failure, with death as a competing risk, was 42% (95% confidence interval, 10-72%). The Kaplan-Meier median OS was 13 months. OS for patients that completed the study course did not differ from that of those who withdrew.
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DISCUSSION
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By enhancing the cytotoxic effects of conventional radiation7, concurrent chemotherapy has the potential to improve clinical outcomes in patients with brain metastases. Use of hypoxic cell radiosensitizers with SRS for recurrent brain tumors18,19 suggests that this may pertain to radiosurgery as well.
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In the present study, we administered vorinostat, an HDAC inhibitor and a known radiosensitizer, concurrently with single fraction radiosurgery to brain metastases from NSCLC. Although multiple clinical studies have demonstrated the feasibility and safety of combining vorinostat with other systemic agents7, experience with vorinostat and concurrent radiation is limited to three studies, all of which used conventional radiation14,15.
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The first, a phase I dose escalation study, administered vorinostat with palliative pelvic radiation (3000 cGy in 300 cGy fractions) at doses ranging from 100 to 400 mg orally once a day14. Because 2 of 6 patients in the 400 mg group experienced DLTs (diarrhea, fatigue, anorexia, hyponatremia, and hypokalemia), the vorinostat MTD with whole pelvic radiation was deemed to be 300 mg once daily. Fatigue, nausea, anorexia, vomiting, and diarrhea were the most common AEs.
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In the second phase I study, vorinostat was used concurrently with whole brain radiation (3750 cGy in 250 cGy fractions) to treat brain metastases15. The vorinostat dose escalated from 200 to 400 mg once daily. The MTD for vorinostat with current WBRT was determined to be 300 mg once a day as one patient had a grade 3 pulmonary embolus and one other died within 30 days of treatment at the 400 mg dose level.
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Lastly, a phase I study investigated escalating doses of vorinostat from 100 to 400 mg per day concurrently with capecitabine and 30 Gy in 10 fractions in 21 patients with nonmetastatic pancreatic cancer20. Three DLTs occurred (2 gastrointestinal and 1 thrombocytopenia) and the MTD for vorinostat was concluded to be 400 mg per day. To our knowledge, there is no previous report of concurrent use of vorinostat and SRS. We thus conducted a phase I dose escalation study, using the standard 3+3 study design. We determined the MTD of vorinostat with concurrent SRS to be 400 mg orally once daily. As with vorinostat monotherapy at 400 mg once daily, the most common AEs in our study were nausea, fatigue, dysgeusia, anorexia, headache, and dyspnea21. The only exception was the higher rate of dyspnea in our study, perhaps more reflective of the lung disease of our patients with NSCLC than of vorinostat toxicity.
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Five patients discontinued vorinostat early and withdrew from the study. One withdrew after only 1 day of vorinostat. Three of the other four withdrawals occurred during the expanded phase I portion of the study during which additional patients were enrolled to confirm safety at 400 mg per day. The most common reasons for withdrawal were nausea, fatigue, and dyspnea. While the rate of AE-related withdrawal in our study was significantly higher than AE-related discontinuation reported in the vorinostat label (9.3% for patients with CTCL), this disparity may be related to the differences in disease, presence of brain metastases, concurrent SRS or a temporary masking by dexamethasone on the day of SRS of symptoms which later become apparent. Although none of the patients who withdrew met our studyspecific criteria for a DLT, AEs were more frequent at the 400 mg level. Furthermore 3 of the 5 patients had less than 4 days of medication left to complete the course of treatment. This finding was surprising, as patients tolerated 400 mg daily for a median of 118 days in the trial that led to the approval of vorinostat for cutaneous lymphoma22. The number of patients intolerant of this dose for 14 days on our study highlights the need for frequent assessment and early supportive intervention and encouragement upon initiation of Vorinostat at this dose level. Confirmation of tolerability with a larger patient cohort is needed.
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We chose to administer vorinostat for 14 days, but the optimal duration of vorinostat with concurrent SRS is not known. Because HDAC inhibition alters multiple pathways of tumor progression, no single biomarker adequately reports its affects. Most patients in this study tolerated the first week of vorinostat therapy relatively well. The second week of therapy, during which no radiation is delivered, may not be needed.
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The SRS doses used for this study were those found to be safe in the RTOG 9005 study23. The maximum size of each treated metastasis was 2 cm. In future experience, it will be important to determine whether larger tumors can be safely treated with concurrent SRS and vorinostat. More data are needed to verify if the relative early G4 radionecrosis and the 100% local control are signals of true radiosensitization with vorinostat.
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To our knowledge, this is the first study demonstrating that intracranial SRS can be safely delivered in combination with an HDAC inhibitor. Additional studies of larger groups of patients are needed to confirm safety and to determine efficacy. Outside the brain, stereotactic body radiotherapy is being used more commonly for tumors of various types, including lung and GI. Our study of concomitant use of a radiosensitizer and radiosurgery may thus have wide applicability.
CONCLUSION
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Stereotactic radiosurgery of brain metastases can be safely combined with the HDAC inhibitor, vorinostat. The MTD of vorinostat with concurrent SRS is 400 mg orally once per day. Additional studies are needed to determine the optimal vorinostat treatment duration, confirm safety, and determine efficacy.
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References:
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1. Kaal EC, Niel CG, Vecht CJ: Therapeutic management of brain metastasis. Lancet Neurol 4:289-98, 2005 2. Lassman AB, DeAngelis LM: Brain metastases. Neurol Clin 21:1-23, vii, 2003 3. Seiwert TY, Salama JK, Vokes EE: The concurrent chemoradiation paradigm-general principles. Nat Clin Pract Oncol 4:86-100, 2007 4. Chang EL, Wefel JS, Hess KR, et al: Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 10:1037-44, 2009 5. West AC, Johnstone RW: New and emerging HDAC inhibitors for cancer treatment. J Clin Invest 124:30-9, 2014 6. Emanuele S, Lauricella M, Tesoriere G: Histone deacetylase inhibitors: apoptotic effects and clinical implications (Review). Int J Oncol 33:637-46, 2008 7. Siegel D, Hussein M, Belani C, et al: Vorinostat in solid and hematologic malignancies. J Hematol Oncol 2:31, 2009 8. Zhang Y, Jung M, Dritschilo A, et al: Enhancement of radiation sensitivity of human squamous carcinoma cells by histone deacetylase inhibitors. Radiat Res 161:667-74, 2004 9. Chinnaiyan P, Vallabhaneni G, Armstrong E, et al: Modulation of radiation response by histone deacetylase inhibition. Int J Radiat Oncol Biol Phys 62:223-9, 2005 10. Munshi A, Kurland JF, Nishikawa T, et al: Histone deacetylase inhibitors radiosensitize human melanoma cells by suppressing DNA repair activity. Clin Cancer Res 11:4912-22, 2005 11. Munshi A, Tanaka T, Hobbs ML, et al: Vorinostat, a histone deacetylase inhibitor, enhances the response of human tumor cells to ionizing radiation through prolongation of gamma-H2AX foci. Mol Cancer Ther 5:1967-74, 2006 12. Sonnemann J, Kumar KS, Heesch S, et al: Histone deacetylase inhibitors induce cell death and enhance the susceptibility to ionizing radiation, etoposide, and TRAIL in medulloblastoma cells. Int J Oncol 28:755-66, 2006 13. Palmieri D, Lockman PR, Thomas FC, et al: Vorinostat inhibits brain metastatic colonization in a model of triple-negative breast cancer and induces DNA double-strand breaks. Clin Cancer Res 15:6148-57, 2009 14. Ree AH, Dueland S, Folkvord S, et al: Vorinostat, a histone deacetylase inhibitor, combined with pelvic palliative radiotherapy for gastrointestinal carcinoma: the Pelvic Radiation and Vorinostat (PRAVO) phase 1 study. Lancet Oncol 11:459-64, 2010 15. Gondi V, Pugh SL, Tome WA, et al: Preservation of memory with conformal avoidance of the hippocampal neural stem-cell compartment during whole-brain radiotherapy for brain metastases (RTOG 0933): a phase II multi-institutional trial. J Clin Oncol 32:3810-6, 2014 16. Kim HT: Cumulative incidence in competing risks data and competing risks regression analysis. Clin Cancer Res 13:559-65, 2007 17. Kaplan E, Meier P: Nonparametric estimation for incomplete observation. J Am Stat Assoc 53:457-481, 1958 18. Drzymala RE, Wasserman TH, Won M, et al: A phase I-B trial of the radiosensitizer: etanidazole (SR-2508) with radiosurgery for the treatment of recurrent previously irradiated primary brain tumors or brain metastases (RTOG Study 95-02). Radiother Oncol 87:89-92, 2008
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19. Yamazaki H, Nakamura S, Nishimura T, et al: Hypofractionated stereotactic radiotherapy with the hypoxic sensitizer AK-2123 (sanazole) for reirradiation of brain metastases: a preliminary feasibility report. Anticancer Res 33:1773-6, 2013 20. Chan E, Arlinghaus LR, Cardin DB, et al: Phase I trial of vorinostat added to chemoradiation with capecitabine in pancreatic cancer. Radiother Oncol 119:312-8, 2016 21. Olsen EA, Kim YH, Kuzel TM, et al: Phase IIb multicenter trial of vorinostat in patients with persistent, progressive, or treatment refractory cutaneous T-cell lymphoma. J Clin Oncol 25:3109-15, 2007 22. Mann BS, Johnson JR, Cohen MH, et al: FDA approval summary: vorinostat for treatment of advanced primary cutaneous T-cell lymphoma. Oncologist 12:1247-52, 2007 23. Shaw E, Scott C, Souhami L, et al: Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys 47:291-8, 2000
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Appendix 1: Eligibility criteria included adequate organ function as defined by the following laboratory values. System
Laboratory Value ≥3,000 /µL
Absolute neutrophil count (ANC)
≥1,500 /mcL
Platelets
≥100,000 / mcL
Hemoglobin
≥ 9 g/dL
Coagulation
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Prothrombin Time or INR
Partial thromboplastin time (PTT) Chemistry K levels
Normal limits
≤ 1.5 X ULN
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Calculated creatinine clearancea Hepatic
≥20 mL/min ≤ 1.5 X ULN
AST (SGOT) and ALT (SGPT)
≤ 2.5 X ULN
Alkaline Phosphatase
≤ 2.5 X ULN
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Serum total bilirubin
a
Creatinine clearance should be calculated per institutional standard.
≤1.2 times the ULN unless the patient is receiving therapeutic anticoagulation. Normal limits
Renal Creatinine
≤1.5x upper limit of normal (ULN) unless receiving therapeutic anticoagulation
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Mg levels
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Leukocytes
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Hematological
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Appendix 2. 3+3 study design dose escalation rules. Number of Patients with DLT at a Given Dose Level
>2
Enter 3 patients at the next dose level.
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0 out of 3
Escalation Decision Rule
Dose escalation will be stopped. Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose. Enter at least 3 more patients at this dose level. •
If 1 or more of this group suffer DLT, then dose escalation is stopped. Three (3) additional patients will be entered at the next lowest dose level if only 3 patients were treated previously at that dose.
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•
If 0 of these 3 patients experience DLT, proceed to the next dose level.
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1 out of 3
<1 out of 6 at highest dose level This is the dose to be used in the expanded phase I below the maximally administered trial. At least 6 patients must be entered at this dose. dose
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Supplementary Figure 1: Overall Survival – Intent to Treat for all 17 patients
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Table 1. Patient and treatment characteristics Number/Value
%
7
41
Female Male
10
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Median
Number of metastases treated
Treatment volume (cm3)
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Dose (Gy)
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Disease-Specific Brain Metastases Grade Prognostic Assessment (GPA)
59
Range
62
49 - 76
80
60-90
1
1-4
GPA 3.5 – 4.0
0
GPA 2.5 – 3.0
27
GPA 1.5 – 2.0
60
GPA 0 - 1
13
0.61
0.03-5.92
24
20-24
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Age Karnofsky performance status (%)
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Sex
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Table 2. Details on each patient’s acute adverse events.
Oral Daily Adverse events Dose (mg)
Study completion
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Patient number
Dose Level 1 1
200 Grade 1 nausea
2
200 None
3
200 None
Completed
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Completed Completed
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Dose Level 2 4
300 None
Completed
5
300 None
Completed
6
300 Grade 3 dyspnea*
Withdrew after 11 days
7
300 Grade 2 dysgeusia
Completed
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Grade 2 anorexia Grade 1 sweating Dose Level 3
400 Grade 1 nausea
Withdrew after 1 days
9
400 None
Completed
400 Grade 2 diarrhea
Completed
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10
Grade 2 fatigue Grade 1 nausea Grade 1 headache
11
400 Grade 1 dysgeusia Dose Level 3 Expansion
Completed
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12
400 Grade 3 fatigue
Withdrew after 10 days
Grade 2 thrombocytopenia
Grade 1 nausea 13
400 Grade 2 dyspnea
Withdrew after 11 days
Grade 1 pain, chest wall
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Grade 1 arthralgia Grade 1 fatigue
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Grade 2 anorexia
400 None
15
400 Grade 1 headache
Completed
16
400 Grade 2 fatigue
Withdrew after 7 days
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14
Completed
Grade 2 pain, stomach
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Grade 2 abdominal distension/bloating Grade 2 nausea Grade 1 vomiting
400 None
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Completed
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Table 3. Treatment-emergent adverse events of any grade. Vorinostat Dose 300 mg Grade 1
2
3
1
2
Fatigue
-
-
-
-
-
Nausea
1
-
-
-
-
Dysgeusia
-
-
-
-
Anorexia
-
-
-
-
Dyspnea
-
-
-
Chest wall pain
-
-
Arthralgia
-
-
Sweating
-
-
1
2
3
-
1
2
1
-
3
1
-
-
1
-
-
1
-
-
1
-
-
-
1*
-
1
-
-
-
-
-
-
-
-
-
-
-
-
1
-
-
-
-
1
-
-
-
-
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1
-
-
-
-
-
-
-
1
-
-
-
-
-
-
-
2
-
-
-
-
-
-
-
-
-
1
-
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Diarrhea
3
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Adverse Event
400 mg
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200 mg
-
-
-
-
-
-
1
-
Headache Thrombocytopenia
-
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Abdominal distension/bloating Pain, stomach
-
-
-
-
-
-
-
1
-
Pain, chest wall
-
-
-
-
-
-
1
-
-
Vomiting
-
-
-
-
-
-
1
-
-
*Unrelated to vorinostat use.