Original Article
Treatment of Advanced Thyroid Cancer With Axitinib: Phase 2 Study With Pharmacokinetic/Pharmacodynamic and Quality-of-Life Assessments Laura D. Locati, MD1; Lisa Licitra, MD1; Laura Agate, MD2; Sai-Hong I. Ou, MD, PhD3; Andree Boucher, MD4; Barbara Jarzab, MD, PhD5; Shukui Qin, MD6; Madeleine A. Kane, MD, PhD7; Lori J. Wirth, MD8; Connie Chen, PharmD9; Sinil Kim, MD10; Antonella Ingrosso, ScD11; Yazdi K. Pithavala, PhD12; Paul Bycott, DrPH10; and Ezra E. W. Cohen, MD13
BACKGROUND: In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient-reported outcomes were assessed. METHODS: Patients (N 5 52) with metastatic or unresectable, locally advanced medullary or differentiated thyroid cancer that was refractory or not amenable to iodine-131 received a starting dose of axitinib 5 mg twice daily. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progressionfree survival (PFS), overall survival (OS), safety, pharmacokinetic parameters, and patient-reported outcomes assessed with the MD Anderson Symptom Inventory questionnaire. RESULTS: The overall ORR was 35% (18 partial responses), and 18 patients had stable disease for 16 weeks. The median PFS was 16.1 months, and the median OS was 27.2 months. All-causality, grade 3 adverse events (>5%) were fatigue, dyspnea, diarrhea, decreased weight, pain in extremity, hypertension, decreased appetite, palmar-plantar erythrodysesthesia, hypocalcemia, and myalgia. Patients who had greater axitinib exposure had a longer median PFS. Quality of life was maintained during treatment with axitinib, and no significant deterioration in symptoms or interference in daily life caused by symptoms, assessed on MD Anderson Symptom Inventory subscales, were observed. CONCLUSIONS: Axitinib has activity and a manageable safety profile while maintaining quality of life, and it represents an additional treatment option for patients with advanced thyroid C 2014 American Cancer Society. cancer. Cancer 2014;000:000-000. V KEYWORDS: axitinib, MD Anderson Symptom Inventory, metastatic disease, pharmacokinetic, pharmacodynamic, quality of life, radioactive iodine-refractory, thyroid cancer, tyrosine kinase inhibitor.
INTRODUCTION Thyroid cancer incidence has increased in most populations worldwide.1 In 2008, thyroid cancer of any histology was diagnosed in approximately 212,000 individuals and was responsible for approximately 35,000 deaths worldwide.2 The 5-year survival rate varies by histology3 and stage,4 and the 10-year overall survival (OS) rate is 10% in patients with metastatic, iodine-131 (131I)-refractory, differentiated thyroid cancer (DTC).5 Because thyroid tumors have higher levels of vascular endothelial growth factor (VEGF) compared with normal thyroid tissue, the VEGF pathway is a potential therapeutic target.6 Several VEGF-receptor (VEGFR) inhibitors7-20 have been evaluated clinically in metastatic thyroid cancer. International thyroid cancer experts convened in September 2010 and agreed that, when considering VEGFR inhibitors for 131I-refractory DTC, their impact on quality of life (QoL) should be considered along with their potential for prolonging progression-free survival (PFS) or OS.21 To date, however, little research has investigated the impact of VEGFR inhibitors on QoL in patients with thyroid cancer.22
Corresponding author: Laura D. Locati, MD, Fondazione IRCCS, Istituto Nazionale dei Tumori, via Venezian 1, Milan, Italy; Fax: (011) 139-02-2390-3353; [email protected] 1 Head and Neck Medical Oncology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; 2Endocrine Unit, Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 3Chao Family Comprehensive Cancer Center-University of California Irvine Medical Center, Orange, California; 4Department of Medicine, University of Montreal Hospital Center, Montreal, Quebec, Canada; 5Oncology Center, Marii Sklodowskiej-Curie Institute, Gliwice, Poland; 6Nanjing Bayi Hospital, Nanjing, China; 7University of Colorado Cancer Center, Aurora, Colorado; 8Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts; 9Pfizer Oncology, New York, New York; 10Pfizer Oncology, San Diego, California; 11Pfizer Oncology, Milan, Italy; 12Clinical Pharmacology, Pfizer Oncology, San Diego, California; 13Department of Medicine, University of Chicago Medical Center, Chicago, Illinois
Sinil Kim was employed at Pfizer inc at the time of the study described here; current affiliation: MiRNA Therapeutics, Inc., Austin, Texas. Ezra E. W. Cohen’s current affiliation: University of California of San Diego Moores Cancer Center, La Jolla, CA. We thank Deborah Ostrosky-Womble (study manager) and Cynthia Kancler (statistician), previously employees of ExecuPharm Inc. and Rho Inc., respectively, who were paid consultants to Pfizer, for assistance with this study. DOI: 10.1002/cncr.28766, Received: February 28, 2014; Revised: April 16, 2014; Accepted: April 17, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
Month 00, 2014
1
Original Article
Axitinib, a potent, selective, second-generation inhibitor of VEGFRs,23 is approved in the United States,24 the European Union, and elsewhere for treatment of advanced renal cell carcinoma (RCC) after failure of prior systemic therapy. In a completed phase 2 trial, axitinib demonstrated activity and was well tolerated in patients (N 5 60) with various histologic subtypes of advanced thyroid cancer for whom 131I failed to control the disease or was inappropriate therapy.11 In the current phase 2 trial, we further evaluated the efficacy and safety of axitinib in patients with advanced thyroid cancer and assessed pharmacokinetic (PK)/pharmacodynamic relationships and patient-reported outcomes (PROs).
uptake (documented by radioiodine scan). Inclusion criteria also were expanded to include medullary or anaplastic histology. Other key eligibility criteria included age 18 years, 1 RECIST-defined target lesion, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate hepatic and renal function, and a baseline blood pressure (BP) 140/90 mm Hg. Hypertension controlled by antihypertensive medications was allowed. Exclusion criteria included prior antiangiogenic agents, hemoptysis in the week before enrollment, inability to take oral medications or malabsorption syndromes, use of strong cytochrome P450 3A4 inhibitors/inducers, active seizure disorder, or brain metastases.
MATERIALS AND METHODS Study Design
Study Treatments
In this multicenter, open-label, single-arm, phase 2 study, a starting dose of axitinib 5 mg twice daily was evaluated in patients with 131I-refractory (with or without doxorubicin-refractory disease) or 131I-inappropriate, metastatic or unresectable, locally advanced thyroid cancer. The primary objective was to determine the investigatorassessed objective response rate (ORR) according to version 1.0 of Response Evaluation Criteria in Solid Tumors (RECIST v.1.0).25 Secondary objectives were to determine PFS, duration of response, OS, and safety; to perform population PK analyses; and to evaluate PROs. This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guidelines on Good Clinical Practice, the study protocol, and applicable local regulatory requirements and laws. All participants provided written informed consent and agreed to comply with the study protocol. Study protocol and informed consent forms were approved by institutional review boards/independent ethics committees. The trial is registered on ClinicalTrials.gov (clinicaltrials.gov identifier NCT00389441).
Axitinib 5 mg twice daily (starting dose) was administered orally with food. Patients without grade >2 axitinibrelated adverse events (AEs) according to version 3.0 of Common Terminology Criteria for Adverse Events (CTCAE v3.0)26 for consecutive 2-week periods could have axitinib increased to 7 mg twice daily and then to 10 mg twice daily unless they were receiving antihypertensive medications or their BP was >150/90 mm Hg. In patients who experienced grade 3 AEs, axitinib was interrupted and/or reduced to 3 mg twice daily and then, if necessary, to 2 mg twice daily. Axitinib was continued until patients developed disease progression or unacceptable toxicity or withdrew consent. Subsequent therapy was at the investigator’s discretion.
Patients
Original eligibility criteria required histologically documented, metastatic or unresectable locally advanced, 131Irefractory (failure of prior 131I treatment as assessed by the investigator) DTC (papillary, follicular, or H€ urthle cell carcinoma) and anthracycline intolerance, contraindication, or refractoriness (RECIST-defined disease progression based on 2 sets of scans during therapy or within 6 months after the last dose). Because of slow accrual, the protocol was amended to also include DTC that was only 131 I-refractory (RECIST-defined disease progression within 12 months of enrollment) or that lacked iodine 2
Assessments
Patients were evaluated with physical examinations and laboratory tests at screening, predose (day 1, if >7 days since screening), every 4 weeks on treatment, and 28 days after the last axitinib dose. Radiologic tumor assessments were performed at screening (within 28 days of the first dose), every 8 weeks, at suspected disease progression, and 28 days after the last axitinib dose. RECIST-defined25 response required confirmation 4 weeks after first documentation. Safety was monitored throughout the study and until 28 days after the last axitinib dose; AEs were graded according to CTCAE v3.0.26 Blood pressure was measured at each clinic visit and at home twice daily by patients before each axitinib dose. Patients were to contact their physicians for a BP >150/100 mm Hg or for BPrelated symptoms (eg, headache, visual disturbance). The MD Anderson Symptom Inventory (MDASI) questionnaire was used to assess PROs on day 1 (predose), Cancer
Month 00, 2014
Axitinib in Thyroid Cancer: PK/PD & QoL/Locati et al
every 2 weeks during the first 8 weeks, every 4 weeks thereafter during treatment, and 28 days after the last axitinib dose. The MDASI, a validated, 19-item questionnaire, consists of 2 subscales assessing 1) the severity of 13 symptoms (pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, difficulty remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness/tingling) and 2) symptom interference in 6 areas of function (general activity, walking, work, mood, relations with people, enjoyment of life).27 Each item on the MDASI is rated from 0 to 10, and lower scores indicate less symptom severity or interference. The minimum important difference, defined as the smallest difference in score considered clinically important, ranges from 0.98 to 1.21. Plasma Pharmacokinetic Samples and Analysis
Population PK blood samples (7 mL) were collected 15 minutes before and 1 to 2 hours after the morning axitinib dose (day 1 and every 8 weeks). Axitinib plasma concentrations were measured using a validated, highperformance liquid chromatography, tandem massspectrometry detection method (Charles River Laboratories, Montreal, Quebec, Canada). After population PK analysis, the individual posthoc area under the plasma concentration-time curve at steady state (AUCss) was calculated as follows: AUCss-study 5 average total daily dose during entire time on study/CL, where CL is the systemic plasma clearance (individual post-hoc clearance estimated from population PK analysis), and AUCss-study is the average AUCss across the entire time on study. Statistical Analysis
Patients who received 1 axitinib dose were included in the intent-to-treat population for analyses of efficacy, safety, and PROs. The primary endpoint was investigator-assessed ORR. Assuming a true ORR 20% with axitinib, a study of 50 patients had 90% power to exclude an ORR 5% (with an overall 2-sided significance level of .05; exact binomial test). The 2-sided 95% exact confidence interval (CI) was provided for the ORR. Kaplan-Meier methods were used to estimate secondary endpoints (duration of response, PFS, and OS) and for post-hoc analyses of the time to response, and median event times and 2-sided 95% CIs were calculated. Subgroup analyses by histology were performed for ORR, PFS, and OS. Response was further evaluated according to the baseline site of metastasis, and PFS was further evaluated according to the AUCss using medians and quartiles Cancer
Month 00, 2014
TABLE 1. Patient Baseline Characteristics, N 5 52 Characteristic Sex Men Women Age: Mean [range], y Race White Asian Other ECOG PS 0 1 Histologic subtype Differentiated Papillary Folliculara Medullary Capsulated oncocytic Anaplastic 131 I-refractory Anthracycline-refractoryb Prior thyroidectomy Sites of diseasec Lung Lymph nodes Bone Liver Thyroid Otherd
No. of Patients (%)
28 (54) 24 (46) 57.6 [28-81] 44 (85) 7 (13) 1 (2) 20 (38) 32 (62) 45 (87) 28 (54) 17 (33) 6 (12) 1 (2) 0 (0) 46 (88) 22 (42) 50 (96) 44 (85) 26 (50) 14 (27) 12 (23) 7 (14) 26 (50)
Abbreviations: 131I, iodine-131; ECOG PS, Eastern Cooperative Oncology Group performance status. a These included H€ urthle cell (n 5 8) and non-H€ urthle cell (n 5 9) subtypes. b These were patients who received doxorubicin and/or epirubicin alone or with other chemotherapy and included follicular (n 5 8) and papillary (n 5 14) histology. Five patients were intolerant/had contraindications to anthracyclines. c These included all patients (regardless of post-baseline assessments) and both target and nontarget lesions. d Other disease sites were adrenal (n 5 3), brain (n 5 1), and pleural effusions (n 5 4).
as cutoff values. Landmark analyses at 8 weeks evaluated the association between diastolic BP and PFS or OS. For PROs (secondary endpoint), the MDASI subscales (symptom-severity and symptom-interference scores) were summarized according to the mean and median changes in scores from baseline by cycle and at the end of the study, and corresponding 95% CIs were calculated. Scoring was based on the MDASI validation manual.27 RESULTS Patients and Treatment
Baseline characteristics for 52 patients enrolled between December 2006 and September 2008 are reported in Table 1. The median duration of axitinib administration was 12.9 months (range, 0.07-56.2 months), and 28 patients remained on treatment 1 year. The median total daily axitinib dose was 10 mg (range, 4.1-18.8 mg). 3
Original Article TABLE 2. Investigator-Assessed Response to Axitinib No. of Patients (%)
All patients, N 5 52 Histologic subtype Papillary, n 5 28 Follicular, n 5 17e Medullary, n 5 6 Capsulated oncocytic, n 5 1 Site of metastasisg Lung, n 5 35 Lymph node, n 5 21 Bone, n 5 14 Liver, n 5 9 Thyroid, n 5 6
CR
PR
SDa
PD
Indeterminateb
Missingc
0 (0)
18 (35)d
18 (35)
5 (10)
8 (15)
3 (6)
0 0 0 0
(0) (0) (0) (0)
9 (32) 8 (47)f 0 (0) 1 (100)
8 (29) 5 (29) 5 (83) 0 (0)
4 (14) 1 (6) 0 (0) 0 (0)
6 (21) 1 (6) 1 (17) 0 (0)
1 (4) 2 (12) 0 (0) 0 (0)
0 1 1 0 0
(0) (5) (7) (0) (0)
14 (40) 7 (33) 0 (0) 1 (11) 2 (33)
14 (40) 7 (33) 10 (71) 5 (56) 1 (17)
1 (3) 2 (10) 3 (21) 2 (22) 0 (0)
6 (17) 4 (19) 0 (0) 1 (11) 3 (50)
— — — — —
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. a SD was defined as disease stability for 16 weeks. Sixteen patients had SD for 24 weeks. b For entire cohort and histologic subtypes, only 1 or 2 post-baseline scans were available, and for sites of metastasis, indeterminate and/or missing. c Reasons for missing data were study withdrawal because of protocol violation, loss to follow-up after treatment-related serious adverse event of jugular venous thrombosis, and refusal to continue the study (n 5 1 each). d For the entire cohort, the 95% confidence interval for PR rate was 22% to 49%. e These included H€ urthle cell subtype (n 5 8). f These included H€ urthle cell subtype (n 5 2). g These were patients who had 1 target lesion according to Response Evaluation Criteria in Solid Tumors and 1 post-baseline assessment. Bone as nontarget lesions were included because of clinical interest.
The axitinib dose was increased to >5 mg twice daily in 28 patients (54%) and was reduced to 74% of patients who were still receiving treat6
Figure 4. Common all-causality, all-grade adverse events (AEs) per year of therapy. aThe rate was calculated as: number of patients experiencing an AE/number of patients on therapy at the start of the year. Other AEs of interest included: bvomiting (n 5 2), anemia (n 5 1), peripheral artery thrombosis (n 5 1), cdysphonia (n 5 1), atrial thrombosis (n 5 1), and dgout (n 5 1).
ment completed all items. Herein, MDASI results are reported up to cycle 24 (when 12 patients were still receiving treatment). The baseline mean summary score was 2.24 for the symptom-interference subscale and 1.66 for the symptom-severity subscale. Mean scores for both subscales remained low (
Treatment of Advanced Thyroid Cancer With Axitinib: Phase 2 Study With Pharmacokinetic/Pharmacodynamic and Quality-of-Life Assessments Laura D. Locati, MD1; Lisa Licitra, MD1; Laura Agate, MD2; Sai-Hong I. Ou, MD, PhD3; Andree Boucher, MD4; Barbara Jarzab, MD, PhD5; Shukui Qin, MD6; Madeleine A. Kane, MD, PhD7; Lori J. Wirth, MD8; Connie Chen, PharmD9; Sinil Kim, MD10; Antonella Ingrosso, ScD11; Yazdi K. Pithavala, PhD12; Paul Bycott, DrPH10; and Ezra E. W. Cohen, MD13
BACKGROUND: In a previous phase 2 trial, axitinib was active and well tolerated in patients with advanced thyroid cancer. In this second phase 2 trial, the efficacy and safety of axitinib were evaluated further in this population, and pharmacokinetic/pharmacodynamic relationships and patient-reported outcomes were assessed. METHODS: Patients (N 5 52) with metastatic or unresectable, locally advanced medullary or differentiated thyroid cancer that was refractory or not amenable to iodine-131 received a starting dose of axitinib 5 mg twice daily. The primary endpoint was the objective response rate (ORR). Secondary endpoints included progressionfree survival (PFS), overall survival (OS), safety, pharmacokinetic parameters, and patient-reported outcomes assessed with the MD Anderson Symptom Inventory questionnaire. RESULTS: The overall ORR was 35% (18 partial responses), and 18 patients had stable disease for 16 weeks. The median PFS was 16.1 months, and the median OS was 27.2 months. All-causality, grade 3 adverse events (>5%) were fatigue, dyspnea, diarrhea, decreased weight, pain in extremity, hypertension, decreased appetite, palmar-plantar erythrodysesthesia, hypocalcemia, and myalgia. Patients who had greater axitinib exposure had a longer median PFS. Quality of life was maintained during treatment with axitinib, and no significant deterioration in symptoms or interference in daily life caused by symptoms, assessed on MD Anderson Symptom Inventory subscales, were observed. CONCLUSIONS: Axitinib has activity and a manageable safety profile while maintaining quality of life, and it represents an additional treatment option for patients with advanced thyroid C 2014 American Cancer Society. cancer. Cancer 2014;000:000-000. V KEYWORDS: axitinib, MD Anderson Symptom Inventory, metastatic disease, pharmacokinetic, pharmacodynamic, quality of life, radioactive iodine-refractory, thyroid cancer, tyrosine kinase inhibitor.
INTRODUCTION Thyroid cancer incidence has increased in most populations worldwide.1 In 2008, thyroid cancer of any histology was diagnosed in approximately 212,000 individuals and was responsible for approximately 35,000 deaths worldwide.2 The 5-year survival rate varies by histology3 and stage,4 and the 10-year overall survival (OS) rate is 10% in patients with metastatic, iodine-131 (131I)-refractory, differentiated thyroid cancer (DTC).5 Because thyroid tumors have higher levels of vascular endothelial growth factor (VEGF) compared with normal thyroid tissue, the VEGF pathway is a potential therapeutic target.6 Several VEGF-receptor (VEGFR) inhibitors7-20 have been evaluated clinically in metastatic thyroid cancer. International thyroid cancer experts convened in September 2010 and agreed that, when considering VEGFR inhibitors for 131I-refractory DTC, their impact on quality of life (QoL) should be considered along with their potential for prolonging progression-free survival (PFS) or OS.21 To date, however, little research has investigated the impact of VEGFR inhibitors on QoL in patients with thyroid cancer.22
Corresponding author: Laura D. Locati, MD, Fondazione IRCCS, Istituto Nazionale dei Tumori, via Venezian 1, Milan, Italy; Fax: (011) 139-02-2390-3353; [email protected] 1 Head and Neck Medical Oncology Unit, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy; 2Endocrine Unit, Clinical and Experimental Medicine, University of Pisa, Pisa, Italy; 3Chao Family Comprehensive Cancer Center-University of California Irvine Medical Center, Orange, California; 4Department of Medicine, University of Montreal Hospital Center, Montreal, Quebec, Canada; 5Oncology Center, Marii Sklodowskiej-Curie Institute, Gliwice, Poland; 6Nanjing Bayi Hospital, Nanjing, China; 7University of Colorado Cancer Center, Aurora, Colorado; 8Department of Medicine, Dana-Farber Cancer Institute, Boston, Massachusetts; 9Pfizer Oncology, New York, New York; 10Pfizer Oncology, San Diego, California; 11Pfizer Oncology, Milan, Italy; 12Clinical Pharmacology, Pfizer Oncology, San Diego, California; 13Department of Medicine, University of Chicago Medical Center, Chicago, Illinois
Sinil Kim was employed at Pfizer inc at the time of the study described here; current affiliation: MiRNA Therapeutics, Inc., Austin, Texas. Ezra E. W. Cohen’s current affiliation: University of California of San Diego Moores Cancer Center, La Jolla, CA. We thank Deborah Ostrosky-Womble (study manager) and Cynthia Kancler (statistician), previously employees of ExecuPharm Inc. and Rho Inc., respectively, who were paid consultants to Pfizer, for assistance with this study. DOI: 10.1002/cncr.28766, Received: February 28, 2014; Revised: April 16, 2014; Accepted: April 17, 2014, Published online Month 00, 2014 in Wiley Online Library (wileyonlinelibrary.com)
Cancer
Month 00, 2014
1
Original Article
Axitinib, a potent, selective, second-generation inhibitor of VEGFRs,23 is approved in the United States,24 the European Union, and elsewhere for treatment of advanced renal cell carcinoma (RCC) after failure of prior systemic therapy. In a completed phase 2 trial, axitinib demonstrated activity and was well tolerated in patients (N 5 60) with various histologic subtypes of advanced thyroid cancer for whom 131I failed to control the disease or was inappropriate therapy.11 In the current phase 2 trial, we further evaluated the efficacy and safety of axitinib in patients with advanced thyroid cancer and assessed pharmacokinetic (PK)/pharmacodynamic relationships and patient-reported outcomes (PROs).
uptake (documented by radioiodine scan). Inclusion criteria also were expanded to include medullary or anaplastic histology. Other key eligibility criteria included age 18 years, 1 RECIST-defined target lesion, an Eastern Cooperative Oncology Group performance status of 0 or 1, adequate hepatic and renal function, and a baseline blood pressure (BP) 140/90 mm Hg. Hypertension controlled by antihypertensive medications was allowed. Exclusion criteria included prior antiangiogenic agents, hemoptysis in the week before enrollment, inability to take oral medications or malabsorption syndromes, use of strong cytochrome P450 3A4 inhibitors/inducers, active seizure disorder, or brain metastases.
MATERIALS AND METHODS Study Design
Study Treatments
In this multicenter, open-label, single-arm, phase 2 study, a starting dose of axitinib 5 mg twice daily was evaluated in patients with 131I-refractory (with or without doxorubicin-refractory disease) or 131I-inappropriate, metastatic or unresectable, locally advanced thyroid cancer. The primary objective was to determine the investigatorassessed objective response rate (ORR) according to version 1.0 of Response Evaluation Criteria in Solid Tumors (RECIST v.1.0).25 Secondary objectives were to determine PFS, duration of response, OS, and safety; to perform population PK analyses; and to evaluate PROs. This study was conducted in accordance with the Declaration of Helsinki, the International Conference on Harmonization Guidelines on Good Clinical Practice, the study protocol, and applicable local regulatory requirements and laws. All participants provided written informed consent and agreed to comply with the study protocol. Study protocol and informed consent forms were approved by institutional review boards/independent ethics committees. The trial is registered on ClinicalTrials.gov (clinicaltrials.gov identifier NCT00389441).
Axitinib 5 mg twice daily (starting dose) was administered orally with food. Patients without grade >2 axitinibrelated adverse events (AEs) according to version 3.0 of Common Terminology Criteria for Adverse Events (CTCAE v3.0)26 for consecutive 2-week periods could have axitinib increased to 7 mg twice daily and then to 10 mg twice daily unless they were receiving antihypertensive medications or their BP was >150/90 mm Hg. In patients who experienced grade 3 AEs, axitinib was interrupted and/or reduced to 3 mg twice daily and then, if necessary, to 2 mg twice daily. Axitinib was continued until patients developed disease progression or unacceptable toxicity or withdrew consent. Subsequent therapy was at the investigator’s discretion.
Patients
Original eligibility criteria required histologically documented, metastatic or unresectable locally advanced, 131Irefractory (failure of prior 131I treatment as assessed by the investigator) DTC (papillary, follicular, or H€ urthle cell carcinoma) and anthracycline intolerance, contraindication, or refractoriness (RECIST-defined disease progression based on 2 sets of scans during therapy or within 6 months after the last dose). Because of slow accrual, the protocol was amended to also include DTC that was only 131 I-refractory (RECIST-defined disease progression within 12 months of enrollment) or that lacked iodine 2
Assessments
Patients were evaluated with physical examinations and laboratory tests at screening, predose (day 1, if >7 days since screening), every 4 weeks on treatment, and 28 days after the last axitinib dose. Radiologic tumor assessments were performed at screening (within 28 days of the first dose), every 8 weeks, at suspected disease progression, and 28 days after the last axitinib dose. RECIST-defined25 response required confirmation 4 weeks after first documentation. Safety was monitored throughout the study and until 28 days after the last axitinib dose; AEs were graded according to CTCAE v3.0.26 Blood pressure was measured at each clinic visit and at home twice daily by patients before each axitinib dose. Patients were to contact their physicians for a BP >150/100 mm Hg or for BPrelated symptoms (eg, headache, visual disturbance). The MD Anderson Symptom Inventory (MDASI) questionnaire was used to assess PROs on day 1 (predose), Cancer
Month 00, 2014
Axitinib in Thyroid Cancer: PK/PD & QoL/Locati et al
every 2 weeks during the first 8 weeks, every 4 weeks thereafter during treatment, and 28 days after the last axitinib dose. The MDASI, a validated, 19-item questionnaire, consists of 2 subscales assessing 1) the severity of 13 symptoms (pain, fatigue, nausea, disturbed sleep, distress, shortness of breath, difficulty remembering, lack of appetite, drowsiness, dry mouth, sadness, vomiting, and numbness/tingling) and 2) symptom interference in 6 areas of function (general activity, walking, work, mood, relations with people, enjoyment of life).27 Each item on the MDASI is rated from 0 to 10, and lower scores indicate less symptom severity or interference. The minimum important difference, defined as the smallest difference in score considered clinically important, ranges from 0.98 to 1.21. Plasma Pharmacokinetic Samples and Analysis
Population PK blood samples (7 mL) were collected 15 minutes before and 1 to 2 hours after the morning axitinib dose (day 1 and every 8 weeks). Axitinib plasma concentrations were measured using a validated, highperformance liquid chromatography, tandem massspectrometry detection method (Charles River Laboratories, Montreal, Quebec, Canada). After population PK analysis, the individual posthoc area under the plasma concentration-time curve at steady state (AUCss) was calculated as follows: AUCss-study 5 average total daily dose during entire time on study/CL, where CL is the systemic plasma clearance (individual post-hoc clearance estimated from population PK analysis), and AUCss-study is the average AUCss across the entire time on study. Statistical Analysis
Patients who received 1 axitinib dose were included in the intent-to-treat population for analyses of efficacy, safety, and PROs. The primary endpoint was investigator-assessed ORR. Assuming a true ORR 20% with axitinib, a study of 50 patients had 90% power to exclude an ORR 5% (with an overall 2-sided significance level of .05; exact binomial test). The 2-sided 95% exact confidence interval (CI) was provided for the ORR. Kaplan-Meier methods were used to estimate secondary endpoints (duration of response, PFS, and OS) and for post-hoc analyses of the time to response, and median event times and 2-sided 95% CIs were calculated. Subgroup analyses by histology were performed for ORR, PFS, and OS. Response was further evaluated according to the baseline site of metastasis, and PFS was further evaluated according to the AUCss using medians and quartiles Cancer
Month 00, 2014
TABLE 1. Patient Baseline Characteristics, N 5 52 Characteristic Sex Men Women Age: Mean [range], y Race White Asian Other ECOG PS 0 1 Histologic subtype Differentiated Papillary Folliculara Medullary Capsulated oncocytic Anaplastic 131 I-refractory Anthracycline-refractoryb Prior thyroidectomy Sites of diseasec Lung Lymph nodes Bone Liver Thyroid Otherd
No. of Patients (%)
28 (54) 24 (46) 57.6 [28-81] 44 (85) 7 (13) 1 (2) 20 (38) 32 (62) 45 (87) 28 (54) 17 (33) 6 (12) 1 (2) 0 (0) 46 (88) 22 (42) 50 (96) 44 (85) 26 (50) 14 (27) 12 (23) 7 (14) 26 (50)
Abbreviations: 131I, iodine-131; ECOG PS, Eastern Cooperative Oncology Group performance status. a These included H€ urthle cell (n 5 8) and non-H€ urthle cell (n 5 9) subtypes. b These were patients who received doxorubicin and/or epirubicin alone or with other chemotherapy and included follicular (n 5 8) and papillary (n 5 14) histology. Five patients were intolerant/had contraindications to anthracyclines. c These included all patients (regardless of post-baseline assessments) and both target and nontarget lesions. d Other disease sites were adrenal (n 5 3), brain (n 5 1), and pleural effusions (n 5 4).
as cutoff values. Landmark analyses at 8 weeks evaluated the association between diastolic BP and PFS or OS. For PROs (secondary endpoint), the MDASI subscales (symptom-severity and symptom-interference scores) were summarized according to the mean and median changes in scores from baseline by cycle and at the end of the study, and corresponding 95% CIs were calculated. Scoring was based on the MDASI validation manual.27 RESULTS Patients and Treatment
Baseline characteristics for 52 patients enrolled between December 2006 and September 2008 are reported in Table 1. The median duration of axitinib administration was 12.9 months (range, 0.07-56.2 months), and 28 patients remained on treatment 1 year. The median total daily axitinib dose was 10 mg (range, 4.1-18.8 mg). 3
Original Article TABLE 2. Investigator-Assessed Response to Axitinib No. of Patients (%)
All patients, N 5 52 Histologic subtype Papillary, n 5 28 Follicular, n 5 17e Medullary, n 5 6 Capsulated oncocytic, n 5 1 Site of metastasisg Lung, n 5 35 Lymph node, n 5 21 Bone, n 5 14 Liver, n 5 9 Thyroid, n 5 6
CR
PR
SDa
PD
Indeterminateb
Missingc
0 (0)
18 (35)d
18 (35)
5 (10)
8 (15)
3 (6)
0 0 0 0
(0) (0) (0) (0)
9 (32) 8 (47)f 0 (0) 1 (100)
8 (29) 5 (29) 5 (83) 0 (0)
4 (14) 1 (6) 0 (0) 0 (0)
6 (21) 1 (6) 1 (17) 0 (0)
1 (4) 2 (12) 0 (0) 0 (0)
0 1 1 0 0
(0) (5) (7) (0) (0)
14 (40) 7 (33) 0 (0) 1 (11) 2 (33)
14 (40) 7 (33) 10 (71) 5 (56) 1 (17)
1 (3) 2 (10) 3 (21) 2 (22) 0 (0)
6 (17) 4 (19) 0 (0) 1 (11) 3 (50)
— — — — —
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease. a SD was defined as disease stability for 16 weeks. Sixteen patients had SD for 24 weeks. b For entire cohort and histologic subtypes, only 1 or 2 post-baseline scans were available, and for sites of metastasis, indeterminate and/or missing. c Reasons for missing data were study withdrawal because of protocol violation, loss to follow-up after treatment-related serious adverse event of jugular venous thrombosis, and refusal to continue the study (n 5 1 each). d For the entire cohort, the 95% confidence interval for PR rate was 22% to 49%. e These included H€ urthle cell subtype (n 5 8). f These included H€ urthle cell subtype (n 5 2). g These were patients who had 1 target lesion according to Response Evaluation Criteria in Solid Tumors and 1 post-baseline assessment. Bone as nontarget lesions were included because of clinical interest.
The axitinib dose was increased to >5 mg twice daily in 28 patients (54%) and was reduced to 74% of patients who were still receiving treat6
Figure 4. Common all-causality, all-grade adverse events (AEs) per year of therapy. aThe rate was calculated as: number of patients experiencing an AE/number of patients on therapy at the start of the year. Other AEs of interest included: bvomiting (n 5 2), anemia (n 5 1), peripheral artery thrombosis (n 5 1), cdysphonia (n 5 1), atrial thrombosis (n 5 1), and dgout (n 5 1).
ment completed all items. Herein, MDASI results are reported up to cycle 24 (when 12 patients were still receiving treatment). The baseline mean summary score was 2.24 for the symptom-interference subscale and 1.66 for the symptom-severity subscale. Mean scores for both subscales remained low (
