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J Clin Oncol. Mar 1, 2011; 29(7): 839–844.
Published online Jan 24, 2011. doi:  10.1200/JCO.2010.30.7231
PMCID: PMC3068059
Pediatric Phase I Trial and Pharmacokinetic Study of Dasatinib: A Report From the Children's Oncology Group Phase I Consortium
Richard Aplenc, Susan M. Blaney, Lewis C. Strauss, Frank M. Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, John J. Wright, and Peter C. Adamson
From The Children's Hospital of Philadelphia; University of Pennsylvania School of Medicine, Philadelphia, PA; Baylor College of Medicine, Houston, TX; Bristol-Meyers Squibb, Wallingford, CT; Dana-Farber Cancer Center; Harvard Medical School, Boston, MA; Children's Oncology Group Statistics and Data Center, Arcadia, CA; University of Nebraska Medical Center, Omaha, NE; and Cancer Therapeutics and Evaluation Program, National Cancer Institute, Bethesda, MD.
Corresponding author: Richard Aplenc, MD, MSCE, The Children's Hospital of Philadelphia, Pediatric Oncology/Stem Cell Transplant, 4018 CTRB, 3501 Civic Center Blvd, Philadelphia, PA 19104-4318; e-mail: raplenc/at/mail.med.upenn.edu.
Received June 2, 2010; Accepted November 29, 2010.
Purpose
Dasatinib is an orally available tyrosine kinase inhibitor with low nanomolar activity against SRC family kinases, BCR-ABL, c-KIT, EPHA2, and the PDGF-β receptor. Dasatinib was found to have selective activity in several tumor models in the Pediatric Preclinical Testing Program.
Patients and Methods
A phase I study of dasatinib in pediatric patients with refractory solid tumors or imatinib-refractory, Philadelphia chromosome–positive leukemia was performed. Dose levels of 50, 65, 85, and 110 mg/m2/dose, administered orally twice daily for 28 days, with courses repeated without interruption, were studied. Pharmacokinetic studies were performed with the initial dose.
Results
A total of 39 patients (solid tumors, n = 28; chronic myeloid leukemia [CML], n = 9; acute lymphoblastic leukemia, n = 2) were enrolled. No dose-limiting toxicities (DLTs) were observed at the 50, 65, and 85 mg/m2 dose levels. At 110 mg/m2, two of six patients experienced DLT including grade 2 diarrhea and headache. In children with leukemia, grade 4 hypokalemia (50 mg/m2), grade 3 diarrhea (85 mg/m2), and grade 2 creatinine elevation (50 mg/m2) were observed. DLT in later courses included pleural effusions, hemangiomatosis, and GI hemorrhage. There were three complete cytogenetic responses, three partial cytogenetic responses, and two partial/minimal cytogenetic responses observed in evaluable patients with CML.
Conclusion
Overall, drug disposition and tolerability of dasatinib were similar to those observed in adult patients.
Dasatinib is currently approved for the treatment of adults with chronic-, accelerated-, or blast-phase chronic myeloid leukemia (CML) or adults with Philadelphia chromosome (Ph) –positive acute lymphoblastic leukemia, with resistance or intolerance to prior therapy. Through competitive inhibition of adenosine triphosphate binding sites,1 dasatinib inhibits multiple tyrosine kinases including BCR-ABL, SRC family kinases, c-KIT, EPHA2, and PDFG-β receptor. Dasatinib also inhibits tyrosine kinases that have been rendered insensitive to imatinib as a result of mutations in the tyrosine kinase binding domain.1 However, dasatinib, like imatinib and other currently available tyrosine kinase inhibitors, is not active against the T3151 BCR-ABL mutation.2
Recently published in vitro studies performed in the Pediatric Preclinical Testing Program demonstrated that dasatinib had activity at low nanomolar concentrations against a rhabdoid tumor cell line.3 In vivo studies demonstrated a two-fold extension of event-free survival in one of four mouse rhabdoid (KT016) models. Modest antitumor activity in other models, including ependymoma, glioblastoma, and osteosarcoma, was also observed.
Dasatinib can induce both hematologic and cytogenetic responses in adult patients with CML or BCR-ABL–positive acute lymphoblastic leukemia (ALL) refractory to imatinib.47 A phase I study in adults with Ph-positive leukemia did not define a maximum-tolerated dose (MTD) for dasatinib5; a similar study in adult patients with solid tumors demonstrated a similar toxicity profile.8 Common toxicities observed in adult patients include myelosuppression, thrombocytopenia, constitutional complaints, mild electrolyte abnormalities, and effusions.5 In adults, daily dosing has been found to be equally efficacious and less toxic than twice-daily dosing. However, these data were not available at the start of the pediatric phase I trial.
Therefore, we conducted a pediatric phase I trial and pharmacokinetic study of dasatinib. Dasatinib was administered orally twice daily for 28 consecutive days, with courses repeated without interruption in children with relapsed or refractory solid tumors and in select children with imatinib-resistant, Ph-positive leukemia. The trial was conducted by the Children's Oncology Group phase I consortium in 21 treatment centers throughout the United States and Canada.
Patient Eligibility
Patients with solid tumors refractory to standard therapy or imatinib-resistant, Ph-positive leukemia were eligible for the trial. Eligibility criteria included the following: age 1 to 21 years (inclusive); Karnofsky or Lanksy performance score of more than 50; recovery from the acute toxic effects of prior chemotherapy, radiotherapy, or immunotherapy with a minimum elapsed period of at least 7 days since the last dose of corticosteroids or hematopoietic growth factors; at least 3 months since stem-cell transplantation; at least 3 months since prior craniospinal radiation, pelvic radiation, or total-body irradiation; at least 2 weeks since local palliative radiation; and at least 6 weeks since other substantial radiation. Patients could not have evidence of active graft-versus-host disease. Patients were required to have adequate renal function (serum creatinine < the upper limit of normal for age or a glomerular filtration rate > 70 mL/min/1.73 m2), adequate liver function (serum bilirubin < 1.5 mg/dL × the upper limit of normal for age, ALT < 110 U/L, and albumin > 2 g/dL), adequate cardiac function, and adequate pulmonary function. Patients with solid tumors were required to have an absolute neutrophil count more than 1,000/μL, a platelet count more than 100,000/μL, and a hemoglobin level more than 8 g/dL. Patients with leukemia were required to have platelet count more than 20,000/μL and a hemoglobin level more than 8 g/dL. If necessary, platelet and RBC transfusions were allowed to meet these parameters on both treatment strata. One patient per cohort with bone marrow metastatic disease was permitted on protocol provided that the patient was not refractory to transfusion therapy. Administration of hydroxyurea was permitted up to 24 hours before the start of therapy if needed for cytoreduction of leukemia. Intrathecal therapy was permitted for patients with CNS leukemia.
Exclusion criteria included pregnancy or lactation in women of childbearing age; uncontrolled infection; receipt of concomitant enzyme-inducing anticonvulsant, antithrombotic, or antiplatelet agents; several CYP3A inhibitors (itraconazole, ketoconazole); HIV-positive patients whose highly active antiretroviral therapy regimen might interact with dasatinib; or concomitant use of other experimental agents.
Institutional review board approval was obtained at participating institutions. Informed consent was obtained from patients age ≥ 18 years or from parents/legal guardians of children age less than 18 years (with child assent when appropriate), according to individual institutional policies.
Dosage and Drug Administration
Dasatinib was administered orally twice daily either in tablet form or dissolved in a juice solution (1 oz of double-strength lemonade or preservative-free apple or orange juice).
Trial Design
The dose-finding component of this trial used a standard 3 + 3 dose-escalation design to define the toxicities and determine the MTD in children with relapsed or refractory solid tumors. Children with Ph-positive leukemia were enrolled at one dose level below the dose level under study in patients with solid tumors but were not included in the dose-finding cohorts. The starting study dose was 50 mg/m2/dose administered twice daily with planned escalations to 65, 85, and 110 mg/m2/dose. Courses were 28 days in length with no interruption between courses.
Safety Assessments
The National Cancer Institute Common Terminology Criteria for Adverse Events (version 3.0) was used to classify adverse events. Dose-limiting toxicity (DLT) was defined as any grade 3 or 4 adverse event that was possibly, probably, or definitely attributed to dasatinib in the first cycle of treatment. Patients not experiencing DLT during the first cycle must have received at least 85% of the prescribed dose to be considered fully evaluable for toxicity. Grade 2 nonhematologic toxicities were considered dose limiting if the toxicity duration was more than 7 days and necessitated removal from the trial. Patients enrolled onto the Ph-positive leukemia stratum were considered nonevaluable for hematologic toxicity. The following adverse events were excluded as DLTs: grade 3 nausea and vomiting of less than 3 days in duration with appropriate antiemetic therapy; grade 3 transaminases that return to levels that meet initial eligibility criteria within 7 days of study drug interruption and that do not recur on study rechallenge with study drug; grade 3 fever or infection of less than 5 days in duration; and grade 3 hypocalcemia responsive to oral calcium supplementation.
Efficacy Assessments
Response in patients with solid tumors was evaluated using Response Evaluation Criteria in Solid Tumors (RECIST) criteria.9 Patients with imatinib-resistant CML were assessed for hematologic and cytogenetic response using standard definitions.10 Patients with Ph-positive ALL were assessed by bone marrow response as follows: complete response (CR) was defined as an M1 (< 5% blasts) marrow with adequate cellularity; partial response was defined as an M2 (6% to 25% blasts) marrow; progressive disease (PD) was defined as increase of at least 25% in the absolute number of circulating leukemic cells, development of extramedullary disease, increase by ≥ 30% in Ph-positive bone marrow cells as assessed by standard cytogenetics, or other laboratory or clinical evidence of PD; and stable disease was defined as response other than a CR, partial response, or PD.
Pharmacokinetic Studies
Plasma pharmacokinetic studies of dasatinib were performed in consenting patients on day 1 of course 1. Plasma samples were obtained at 0, 15, 30, 60, and 90 minutes and 2, 4, 6 to 8, 9 to 12, and 24 to 28 hours after the oral dose, with the day 1 evening dose being withheld to allow for a better estimation of terminal half-life. Plasma samples were assayed for dasatinib using a validated liquid chromatography tandem mass spectrometry method.8 The dasatinib and metabolite plasma concentration-time data were analyzed using noncompartmental methods. The peak concentration (Cmax) and time to peak concentration (Tmax) were determined from the concentration-time curve for each patient. Area under the concentration curve to the last measured time point (AUC0-last) was calculated with the linear trapezoidal method and extrapolated to infinity (AUC0-∞) by adding the final measured plasma concentration divided by the terminal rate constant, which was derived from the slope of the natural log-transformed concentrations and times on the terminal elimination phase of the decay curve. The half-life was determined by dividing 0.693 by the terminal rate constant, and the apparent clearance was calculated from dose/AUC0-∞. Pharmacokinetic data past 9 hours were not used because of sparse data.
Patient Characteristics
A total of 39 patients were enrolled onto this trial, all of whom were eligible (Table 1). Twenty-eight patients (median age, 11.7 years; range, 2 to 20.9 years) were enrolled onto the solid tumor stratum, of whom 18 were fully evaluable for toxicity. Reasons for inevaluability were PD before completion of at least one cycle (n = 4), physician preference (n = 2), and withdrawal of consent for study participation (n = 4); none of these patients experienced DLT. Eleven patients (median age, 10 years; range, 2.7 to 17.6 years) were enrolled onto the leukemia stratum, all of whom were fully evaluable for toxicity. Data on BCR-ABL mutation status was not available for patients with CML.
Table 1.
Table 1.
Demographics and Clinical Characteristics of Eligible Patients
Toxicity
In the solid tumor stratum, the MTD was 85 mg/m2/dose, with two of six patients treated at 110 mg/m2/dose developing DLTs (Table 2); a 20-year-old woman with a leiomyosarcoma developed grade 2 headache that led to withdrawal from the study, and a 16-year-old girl with adenoid cystic carcinoma developed grade 2 diarrhea that was considered dose limiting. The headache and diarrhea resolved within 24 and 72 hours, respectively, of study drug discontinuation. Three other patients enrolled onto the solid tumor stratum at 110 mg/m2/dose experienced DLTs in subsequent courses, including development of grade 2 pleural effusions (n = 2), grade 3 chest pain (n = 1), and grade 3 pruritic, maculopapular rash (n = 1; Table 3). All toxicities reported are listed in Appendix Tables A1 and A2 (online only).
Table 2.
Table 2.
DLTs in Course 1
Although defining a separate MTD in the leukemia stratum was not an objective of the protocol, a number of toxicities were observed during the first and subsequent courses (Tables 2 and and3).3). One patient, a 3-year-old boy with recurrent CML after stem-cell transplantation, developed hemangiomatosis with a grade 3 GI hemorrhage during course 5 at the 65 mg/m2/dose level. These events were preceded by Escherichia coli H0157:H1 gastroenteritis 1 month before. Dasatinib was held, and the patient was treated with corticosteroids for a total of 4 weeks. Repeat endoscopy revealed resolution of the hemangiomas, and the patient subsequently tolerated a lower dose of dasatinib. The other observed DLTs included hypoalbuminemia secondary to proteinuria, diarrhea (two patients), grade 2 rash (with the patient electing to discontinue treatment), and hypokalemia.
Table 3.
Table 3.
DLTs After Course 1
Clinical Activity
No complete or partial objective responses were observed in patients with solid tumors. Two patients treated at 110 mg/m2/dose had prolonged stable disease (an 11-year-old girl with neuroblastoma who received five cycles of protocol therapy and a 15-year-old girl with neuroendocrine carcinoma who received nine cycles of protocol therapy). Both patients were removed from protocol therapy for toxicity rather than disease progression. None of the five patients with osteosarcoma experienced disease stabilization beyond the first course of therapy.
The first patient with Ph-positive ALL experienced disease progression during the first course of treatment. The second patient had a hypoplastic bone marrow at the end of course 1 and was taken off study after course 2 for dasatinib-associated diarrhea. Bone marrow evaluation was not performed at the end of course 2. Best response data for patients with CML are listed in Table 4. All nine evaluable patients had a response to therapy, although only two patients experienced reduction in bone marrow blasts and a minor or minimal cytogenetic response. The median number of courses was three (range, one to 20 courses), and the median time to best response was three cycles (range, one to three cycles) for patients who achieved a cytogenetic CR. Five patients with CML received stem-cell transplantation after dasatinib therapy. Two patients who went off study for unacceptable toxicity were treated at lower doses of dasatinib, and two patients did not have subsequent treatment data available.
Table 4.
Table 4.
Leukemia Response Data for Patients With CML
Pharmacokinetics
Dasatinib pharmacokinetic parameters after single-dose administration to 19 pediatric patients are listed in Table 5. Dasatinib was rapidly absorbed, with a median Tmax of 1.0 hours (range, 0.28 to 6.3 hours). Wide interpatient variability in half-life, AUC, and clearance was observed. The median terminal elimination half-life was 2.3 hours (range, 1.7 to 5.3 hours). AUC0-∞ was generally dose proportional. One metabolite contributing less than 10% of overall drug exposure was also observed (data not shown).
Table 5.
Table 5.
Dasatinib Pharmacokinetic Data
In pediatric patients with refractory solid tumors, the MTD of dasatinib was 85 mg/m2/dose administered twice daily. Overall, dasatinib was well tolerated, with headache and rash proving to be dose limiting. Pleural effusions, also seen in adult dasatinib trials, were observed in two patients who received multiple courses of dasatinib therapy. The other observed adverse effects were similar in distribution, frequency, and intensity with those seen in adults, with the notable exception of a single case of hemangiomatosis.47 Although the attribution of hemangiomatosis to dasatinib treatment is unclear, we could not exclude a possible drug relationship, especially with respect to bleeding from a previously undiagnosed lesion. All observed toxicities resolved without sequelae after discontinuation of dasatinib therapy.
The pediatric MTD of 85 mg/m2/dose is higher than the approved adult doses of 100 mg (approximately 60 mg/m2) daily for patients with chronic-phase (CP) CML or 140 mg (approximately 80 mg/m2/dose) administered daily for patients with advanced-phase CML or Ph-positive ALL.11 Dasatinib exposure seemed proportional to dose administered. The Cmax and AUCs in pediatric patients were similar to the Cmax and AUC observed in an adult pharmacokinetic study (Cmax, 104.5 ng/mL; coefficient of variation, 29%; AUC0-∞, 313.9 ng · h/mL; coefficient of variation, 42%).12
We opted not to attempt to define a separate MTD in patients with leukemia, in part because of the limited number of such patients potentially eligible for phase I investigation in the imatinib era. In an effort to gain initial experience with dasatinib in children with leukemia, the trial was designed to allow for accrual to the leukemia stratum, which lagged one dose level below the solid tumor stratum. One patient developed grade 4 hypokalemia at the 50 mg/m2/dose level but was clinically managed, and dose escalation was allowed for other patients. Similar to adult patients, the majority of children with CML achieved a cytogenetic CR. However, because most patients with CML proceeded to stem-cell transplantation, we were not able to estimate the duration of response.
On the basis of these results, a phase II trial in patients with select solid tumors is under consideration. A pediatric phase II trial of dasatinib for de novo CP-CML, imatinib-resistant CP-CML, advanced-phase CML, blast-phase CML, and Ph-positive ALL will use a dose of 60 mg/m2 daily for CP-CML and 80 mg/m2 daily for other leukemia strata. Additionally, Children's Oncology Group study AALL0662 is evaluating dasatinib 60 mg/m2 daily in combination with standard chemotherapy for patients with newly diagnosed Ph-positive ALL. Data from this phase I trial suggest that higher doses of dasatinib could be explored if necessary.
Appendix
Table A1.
Adverse Events Probably, Possibly, or Definitively Related to Dasatinib in Patients on the Solid Tumor Stratum
Toxicity and Dose Level (mg/m2)Toxicity Grade (No. of Patients)
Total No. of Patients With Adverse Events
1234
Otitis, middle ear (noninfectious)
    8511
Hemoglobin
    5011
    6511
    851113
    11022
Leukocytes (total WBC)
    50112
    6511
    85213
    110123
Lymphopenia
    5011
    8511
    1101113
Neutrophils/granulocytes (ANC/AGC)
    5011
    6511
    85134
    110314
Platelets
    5011
    6511
    85224
    110112
Blood/bone marrow, other (RBC)
    11011
Supraventricular and nodal arrhythmia, sinus tachycardia
    11011
Hypotension
    11011
International normalized ratio of prothrombin time
    11011
Partial thromboplastin time
    11011
Fatigue (asthenia, lethargy, malaise)
    85112
    110213
Fever (in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 × 109/L)
    85112
    11022
Weight loss
    11011
Rash/desquamation
    6533
    8511
    110213
Anorexia
    110213
Colitis
    11011
Diarrhea
    6511
    85213
    110213
Distension/bloating, abdominal
    11011
Dry mouth/salivary gland (xerostomia)
    11011
Flatulence
    11011
Heartburn/dyspepsia
    11011
Mucositis/stomatitis (clinical exam), oral cavity
    11011
Nausea
    8533
    11033
Vomiting
    8511
    110224
GI, other (reflux)
    11011
Hemorrhage/bleeding, other (hematuria)
    11011
Infection (documented clinically or microbiologically) with grade 3 or 4 neutrophils (ANC < 1.0 × 109/L), lung (pneumonia)
    8511
Infection with normal ANC or grade 1 or 2 neutrophils, lung (pneumonia)
    8511
Infection with normal ANC or grade 1 or 2 neutrophils, blood
    8511
Infection, other (Abiotrophia bacteremia)
    8511
Edema, head and neck
    11022
Edema, limb
    11011
Hypoalbuminemia
    8522
    110112
Alkaline phosphatase
    6511
ALT
    5011
    6511
    8511
    11022
Amylase
    8511
    11011
AST
    5011
    6533
    8533
    11033
Bicarbonate, serum low
    6511
Hypocalcemia
    8522
    11022
Hypercalcemia
    8511
Hypercholesterolemia
    8511
GGT
    8511
    11011
Hypomagnesemia
    8511
    11011
Hypophosphatemia
    8511
    11011
Hyperkalemia
    6511
Hypokalemia
    8511
    11011
Proteinuria
    8511
    11011
Hyponatremia
    8511
    11011
Hypertriglyceridemia
    8511
Metabolic/laboratory, other (total protein)
    8511
Metabolic/laboratory, other (urea)
    11011
Dizziness
    8511
Mood alteration, agitation
    11011
Neuropathy, sensory
    6511
Personality/behavioral
    11011
Pain, abdomen NOS
    11022
Pain, back
    11011
Pain, chest/thorax NOS
    11011
Pain, extremity/limb
    8522
    11022
Pain, head/headache
    8511
    110112
Pain, joint
    8511
    11011
Pain, neck
    8511
Pain, stomach
    11011
Cough
    11011
Dyspnea (shortness of breath)
    11011
Hypoxia
    11011
Pleural effusion (nonmalignant)
    11022
Abbreviations: ANC, absolute neutrophil count; AGC, absolute granulocyte count; GGT, γ-glutamyltransferase; NOS, not otherwise specified.
Table A2.
Adverse Events Probably, Possibly, or Definitively Related to Dasatinib in Patients on the Leukemia Stratum
Toxicity and Dose Level (mg/m2)Toxicity Grade (No. of Patients)
Total No. of Patients With Adverse Events
1234
Supraventricular and nodal arrhythmia sinus bradycardia
    6511
Hypotension
    6511
Fatigue (asthenia, lethargy, malaise)
    6511
    85112
Fever (in the absence of neutropenia, where neutropenia is defined as ANC < 1.0 × 109/L)
    8522
Dermatology/skin, flushing
    5011
Rash/desquamation
    5011
    6511
    8522
Rash, acne/acneiform
    8511
Dermatology/skin, other (hair on head and eyebrows turning gray)
    8511
Anorexia
    6511
Diarrhea
    8522
Nausea
    50112
    6511
    8522
Hemorrhage, GI/colon
    6511
Hemorrhage, GU/urinary NOS
    5011
Hemorrhage/bleeding, other (presence of blood in stool)
    8511
Hepatobiliary/pancreas, other (hepatomegaly, liver is palpable 4 cm below the costal margin)
    8511
Infection (documented clinically or microbiologically) with grade 3 or 4 neutrophils (ANC < 1.0 × 109/L), blood
    8511
Hypoalbuminemia
    5011
    8511
Alkaline phosphatase
    5022
ALT
    5011
    8522
AST
    5022
    6511
    85112
Bicarbonate, serum low
    6511
Hypocalcemia
    8511
Creatinine
    8511
Hyperglycemia
    8511
Hypoglycemia
    8511
Hypophosphatemia
    8511
Hypokalemia
    5011
Proteinuria
    5011
Extremity, lower (gait/walking)
    8511
Confusion
    6511
Pain, abdomen NOS
    6511
    8511
Headache
    5011
    85213
Pain, stomach
    8511
Vascular, other (hemangiomatosis)
    6511
Abbreviations: ANC, absolute neutrophil count; GU, genitourinary; NOS, not otherwise specified.
Footnotes
Supported by National Cancer Institute Grants No. U01 CA97452 and NCRR M01 RR00188.
Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
Clinical trial information can be found for the following: NCT00316953.
AUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST
Although all authors completed the disclosure declaration, the following author(s) indicated a financial or other interest that is relevant to the subject matter under consideration in this article. Certain relationships marked with a “U” are those for which no compensation was received; those relationships marked with a “C” were compensated. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Employment or Leadership Position: Lewis C. Strauss, Bristol-Myers Squibb (C); Shruti Agrawal, Bristol-Myers Squibb (C) Consultant or Advisory Role: None Stock Ownership: Lewis C. Strauss, Bristol-Myers Squibb Honoraria: None Research Funding: None Expert Testimony: None Other Remuneration: None
AUTHOR CONTRIBUTIONS
Conception and design: Richard Aplenc, Susan M. Blaney, Lewis C. Strauss, Suzanne Shusterman, Junfeng Sun, John J. Wright, Peter C. Adamson
Provision of study materials or patients: Richard Aplenc, Suzanne Shusterman
Collection and assembly of data: Richard Aplenc, Suzanne Shusterman, Ashish Mark Ingle
Data analysis and interpretation: Richard Aplenc, Susan M. Blaney, Lewis C. Strauss, Frank M. Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, Peter C. Adamson
Manuscript writing: Richard Aplenc, Susan M. Blaney, Lewis C. Strauss, Frank M. Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, John J. Wright, Peter C. Adamson
Final approval of manuscript: Richard Aplenc, Susan M. Blaney, Lewis C. Strauss, Frank M. Balis, Suzanne Shusterman, Ashish Mark Ingle, Shruti Agrawal, Junfeng Sun, John J. Wright, Peter C. Adamson
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