A Phase I Trial of Sorafenib Combined with Cisplatin/Etoposide Or Carboplatin/Pemetrexed in Refractory Solid Tumor Patients

G Model LUNG-3604; No. of Pages 5 ARTICLE IN PRESS

Lung Cancer xxx (2010) xxx–xxx

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Lung Cancer

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A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients

Janine M. Davies a,b, Nirav S. Dhruva a, Christine M. Walko c, Mark A. Socinski a,b, Stephen Bernard a,b, D. Neil Hayes a,b, William Y. Kim a,b, Anastasia Ivanova b,d, Kimberly Keller b, Layla R. Hilbun b, Michael Chiu d,e, E. Claire Dees a,b, Thomas E. Stinchcombe a,b,∗ a Department of Medicine, Division of Hematology/Oncology, University of North Carolina at Chapel Hil, USA b Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA c UNC Eshelman School of Pharmacy, Institute of Pharmacogenomics and Individualized Therapy, University of North Carolina at Chapel Hill, USA d Department of Biostatistics, University of North Carolina at Chapel Hill, USA e Biostatistics and Data Management, Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, USA article info abstract

Article history: Introduction: Sorafenib has demonstrated single agent activity in non-small cell (NSCLC) and small cell Received 29 March 2010 lung cancer (SCLC). Carboplatin/pemetrexed (CbP) and cisplatin/etoposide (PE) are commonly used in Received in revised form 25 May 2010 the treatment of these diseases. Accepted 30 May 2010 Methods: A phase I trial escalating doses of sorafenib in combination with ﬁxed doses of PE (Arm A) or CbP (Arm B) was performed using a 3-patient cohort design to determine the maximum tolerated dose Keywords: (MTD) and dose-limiting toxicities (DLT); DLT were assessed in the ﬁrst cycle. The trial was subsequently Sorafenib amended with closure of Arm B and to include Arm C with a reduced dose of carboplatin. Non-small cell lung cancer Small cell lung cancer Results: Between 9/2007 and 9/2008, 20 pts were treated on the trial; median age 62 (range 42–73), Safety and toxicity male/female ratio 12/8, PS 0/1 ratio 6/14, and median number of prior therapies 2 (range 1–4). The most Phase I common tumor types were NSCLC and SCLC. On Arm A at dose level 0 (sorafenib 200 mg BID), 2 of 4 patients experienced DLT; 2 patients were enrolled at dose level −1 (sorafenib 200 mg QD) without DLT, but this arm was closed due to slow accrual. On Arm B, 2 of 3 patients experienced DLT at dose level 0 (sorafenib 200 mg BID). On Arm C at dose level 0 (sorafenib 200 mg BID), 1 of 6 patients experienced DLT, and at dose level +1 (sorafenib 400 mg BID) 2 of 5 patients experienced a DLT. Conclusions: The MTD of sorafenib was 200 mg BID continuously in combination with carboplatin (AUC of 5) and pemetrexed 500 mg/m2 every 3 weeks. However, only 6 patients were treated at this dose level, and the results should be interpreted cautiously. © 2010 Elsevier Ireland Ltd. All rights reserved.

1. Introduction oped, preliminary results of phase II trials had demonstrated single agent activity of sorafenib in non-small cell lung cancer (NSCLC) and In lung cancer, multiple signal pathways such as epidermal small cell lung cancer (SCLC) [3,4]. Phase II trials revealed promis- growth factor receptor (EGFR), vascular endothelial growth factor ing activity and favorable toxicity profile with the combination (VEGF), and vascular endothelial growth factor receptor (VEGFR) of carboplatin and pemetrexed (CbP) in advanced NSCLC [5,6].A are dysregulated [1]. The Ras/Raf pathway is an important mediator randomized phase II trial revealed a favorable toxicity profile of of angiogenesis and tumor proliferation [1]. Sorafenib is a multi- carboplatin and pemetrexed in SCLC, and a phase III trial comparing targeted tyrosine kinase inhibitor that inhibits Raf-1, VEGFR, and carboplatin and pemetrexed to carboplatin and etoposide in SCLC platelet derived growth factor receptor (PDGFR) pathways, and had been initiated [7,8]. An interim analysis of the phase III subse- the process of angiogenesis [2]. At the time this trial was devel- quently revealed that carboplatin and pemetrexed was inferior to carboplatin and etoposide, and trial enrollment was discontinued. The combination of cisplatin and etoposide (PE) is the standard first-line therapy for SCLC and an accepted therapy for advanced ∗ Corresponding author at: Multidisciplinary Thoracic Oncology Program, Divi- NSCLC [9–12]. We were interested in integrating sorafenib into two sion of Hematology-Oncology, University of North Carolina at Chapel Hill, 170 commonly used chemotherapy combinations for the treatment of Manning Drive, Physicians Office Building, 3rd Floor, CB 7305, Chapel Hill, NC, USA 27599–7305. Tel.: +1 919 966 4431; fax: +1 919 966 6735. NSCLC and SCLC. This interest led to the development of a two arm E-mail address: Thomas [email protected] (T.E. Stinchcombe). phase I trial to determine the dose-limiting toxicities (DLT) and

Please cite this article in press as: Davies JM, et al. A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients. Lung Cancer (2010), doi:10.1016/j.lungcan.2010.05.022 G Model LUNG-3604; No. of Pages 5 ARTICLE IN PRESS 2 J.M. Davies et al. / Lung Cancer xxx (2010) xxx–xxx maximum tolerated dose (MTD) of sorafenib in combination with Table 1 these chemotherapy combinations. Inclusion and exclusion criteria and dose-limiting toxicities. Inclusion criteria 1. Histologically or cytologically confirmed metastatic solid tumor 2. Materials and methods 2. Measurable disease by RECIST criteria 3. Progressed on at least one standard therapy or who have a disease for 2.1. Patient selection which there is no standard therapy 4. Age ≥ 18 years old 5. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1 Eligible patients included those with histologically or cytologically confirmed advanced solid tumors, with adequate organ 6. Adequate organ function defined as: ≥ ≥ × 9 function, good performance status, and able to provide informed - Bone marrow: hemoglobin 9.0 g/dL, ANC 1.5 10 /L, platelet count ≥ 100 × 109/L consent. The complete eligibility criteria are presented in Table 1. - Hepatic: total bilirubin ≤ 1.5 × ULN, ALT and AST ≤ 2.5 × ULN, INR < 1.5 or Study evaluations prior to each cycle included: complete blood a PT/PTT within normal limits. Patients receiving warfarin or heparin were count, electrolytes including magnesium, creatinine, and liver func- allowed to participate. For patients on warfarin, the INR should be measured tion tests (aspartate transaminase, alanine transaminase, alkaline prior to initiation of sorafenib and monitored at least weekly, or as defined by the local standard of care, until INR is stable phosphatase, and total bilirubin). Tumor response was assessed - Renal: Cockcroft calculated creatinine clearance (CrCL) ≥45 mL/min according to Response Evaluation Criteria in Solid Tumors (RECIST) ≥ [13] every two cycles with computed tomography (CT) or magnetic 7. Asymptomatic brain metastases were permitted if treated 6 months before study entry, and clinically stable without steroid treatment for 1 week resonance imaging (MRI) scans, and tumor markers, if applica- 8. Women of childbearing potential: negative serum pregnancy test ble. After trial enrolment had begun, the trial was amended to performed within 7 days prior to the start of treatment exclude patients with NSCLC with squamous histology. This trial 9. Women of childbearing potential and men must agree to use adequate was approved by the Protocol Review Committee of the Lineberger contraception (barrier method of birth control) prior to study entry and for the duration of study participation. Men and women should use adequate birth Comprehensive Cancer Center and the Institutional Review Board control for at least 2 weeks after the last administration of sorafenib of the University of North Carolina. The trial was registered 10. Able and willing to provide written informed consent with United States National Institutes of Health (trial number: NCT00573690). Exclusion criteria 1. Histological or cytological diagnosis of squamous cell carcinoma of the lung 2.2. Study design 2. Congestive heart failure > class II NYHA; unstable angina, new onset angina (began within the last 3 months), or myocardial infarction within the The primary objective of this phase I non-randomized single past 6 months 3. Cardiac ventricular arrhythmias requiring anti-arrhythmic therapy center clinical trial was to determine the MTD of sorafenib in com- 4. Uncontrolled hypertension (systolic blood pressure > 150 mmHg or bination with fixed doses of PE or CbP. The secondary objectives diastolic > 90 mmHg) despite optimal medical management were to identify the DLT and the efficacy of these combinations. 5. Known severe hypersensitivity to sorafenib or any of the excipients, The treatment arms were performed in parallel, with no intent to etoposide, pemetrexed, cisplatin, or carboplatin compare the two treatment arms. Toxicity was assessed after each 6. Known human immunodeficiency virus (HIV) infection or chronic Hepatitis B or C treatment cycle using the National Cancer Institute Common Ter- 7. Active clinically serious infection > CTCAE grade 2 minology Criteria for Adverse Events (NCI CTCAE) version 3.0. DLT 8. Thrombolic or embolic events within the past 6 months were assessed in cycle 1, defined as ≥grade 3 non-hematological 9. Pulmonary hemorrhage/bleeding event > CTCAE grade 2 or any other toxicities (except nausea, vomiting, and alopecia), grade 4 anemia hemorrhage/bleeding event > CTCAE grade 3 within the past 4 weeks 10. Serious non-healing wound, ulcer, or bone fracture or thrombocytopenia, grade 4 neutropenia lasting >7 days, and a 11. Evidence or history of bleeding diathesis or coagulopathy >2 weeks delay in initiating cycle 2 due to toxicities. 12. Major surgery, open biopsy or significant traumatic injury within the The initial study design included two treatment groups (Arms A past 4 weeks and B) with three dose levels of sorafenib (sorafenib 200 mg daily, 13. Use of St. John’s Wort or rifampin sorafenib 200 mg BID, sorafenib 400 mg BID) for each treatment 14. Any condition that impairs patient’s ability to swallow whole pills 15. Any malabsorption problem or uncontrolled inflammatory bowel disease arm. Sorafenib dose escalation was not pursued beyond the cur- or gastrointestinal disorder causing ≥5 bowel movements in 24 h period at rently approved single agent dose of 400 mg po BID. However, due baseline to toxicities attributed to the carboplatin dose of area under the 16. For Arms B/C (carboplatin/pemetrexed): curve (AUC) of 6 using the Calvert equation [14] in Arm B, the - Clinically relevant pleural effusions or ascites which cannot be controlled study was amended: Arm B was closed to accrual and Arm C was by drainage added with a lower dose of carboplatin (AUC = 5) while maintain- - Non-compliance or inability to take vitamin B12 and folic acid ing three sorafenib dose levels. Arm A included a pharmacokinetic supplementation - Inability to discontinue non-steroidal anti-inflammatory drugs (NSAIDs) evaluation of the sorafenib and etoposide. However, enrollment in for 2 days before (5 days for long-acting NSAIDs), the day of, and the 2 days that treatment arm was slow and the trial was amended to elimi- after pemetrexed administration nate the pharmacokinetic investigations in an attempt to facilitate 17. Prior exposure to >3 cytotoxic therapies for metastatic disease enrollment. A standard “3 + 3” trial design was used. Three patients were treated at the initial dose level for each treatment group, and if no 2.3. Study treatment DLTs were observed in cycle 1, then three patients were treated at the next dose level. If one of three patients experienced a DLT, then Patients on Arm A were treated with cisplatin 60 mg/m2 over three additional patients were enrolled at that dose level. If a DLT 1 h on day 1 and etoposide 120 mg/m2 over 30 min on days 1, 2 occurred in two or more patients at a given dose level (i.e. DLT rate and 3, in a 3-week cycle with sorafenib continuously. For cycle 1 ≥33%), the MTD would be exceeded and three additional patients only, cisplatin was given on day 2 in order to assess the pharma- were enrolled at the previous dose level. A maximum of six patients cokinetics of sorafenib and etoposide. Sorafenib was taken orally were enrolled at any dose level. The MTD (or recommended phase on a daily basis starting on day 2 for cycle 1, and taken continu- II dose) was defined as the highest dose with an observed toxicity ously thereafter. For all patients, dose level “0” (starting dose) was rate ≤1 in 6 patients. sorafenib 200 mg po BID, dose level “−1” was sorafenib 200 mg

Between September 2007 and September 2008, 31 patients pro- 3.2. Toxicities vided informed consent for trial participation and 20 patients were treated on the trial. Eleven patients did not participate in the trial At dose level 0 of Arm A, 2 of 4 patients experienced DLT (grade 4 due to decline in performance status related to disease progression thrombocytopenia, grade 3 fatigue, and grade 3 febrile neutropenia (n = 5), withdrawal of informed consent (n = 2), pursuit of hospice in one patient; grade 4 neutropenia for >7 days, grade 3 febrile neu- care (n = 1), ineligibility due to increased liver function tests (n = 1), tropenia, diarrhea, hypokalemia, and hyponatremia in the other). squamous histology (n = 1), and interval development of hemor- Two of the required six patients were then enrolled at dose level −1 rhagic brain metastases (n = 1). The median age was 62 (range without a DLT. However, this arm was closed due to slow accrual.

Table 3 Hematological toxicity per treatment arm.

Treatment cohort Patients (N) Cycles (N) Neutropenia Anemia Thrombocytopenia Febrile neutropenia

Grade Grade Grade Grade

1234123412341234

Arm A 6 10 0 0 0 6 1 2 1 0 1 0 1 1 0 0 2 0 ArmB 3 7 0120020000020010 ArmC 11 31 4141042022330000

Numbers represent episodes of toxicity observed during all cycles.

Table 4 Renal and electrolyte toxicities.

Treatment Patients Cycles Hyperglycemia Hypoglycemia Hypokalemia Hyponatremia Hypomagnesmia Hypophosphatemia Renal toxicity cohort (N) (N)

Grade Grade Grade Grade Grade Grade Grade

1234123412341234123412341234

Group A 6 10 0 0 0 0 0 0 0 0 1 0 1 0 0 0 1 0 0 1 0 0 0 0 0 0 1 0 0 0 Group B 3 7 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 00000 Group C 11 31 0 1 0 0 0 0 1 0 0 0 0 0 0 0 2 0 0 0 0 0 1 0 0 0 1 0 0 0

Numbers represent episodes of toxicity observed during all cycles.

Table 5 Select non-hematological toxicities.

Treatment Patients Cycles Fatigue Anorexia Dehydration Gastrointestinal Nausea Vomiting Diarrhea Hypertension cohort (N) (N) Perforation

Grade Grade Grade Grade Grade Grade Grade

12341234123412345123412341234

Group 6 10 01200000000000000300010100100 A Group 3 7 10100100000000000400000001000 B Group 11 31 16 3 0 31 3 0 02 1 0 00 0 0 1 81 0 0 30 000000 C

Numbers represent episodes of toxicity observed during all cycles.

On Arm B at dose level 0, two of three treated patients had with progressive solid tumors are candidates for cisplatin-based grade 4 thrombocytopenia attributed to carboplatin (AUC = 6). Sub- chemotherapy, physician and patient hesitancy about treatment sequently, on Arm C (carboplatin AUC = 5) at dose level 0, 1 of with a novel three drug combination, and restrictions related to trial 6 patients experienced DLT (grade 3 hyponatremia, dehydration, eligibility. The continuous schedule of sorafenib with cisplatin and and hypoglycemia). Enrollment continued at dose level +1, but etoposide may have contributed to the rate of toxicity observed, and 2 of 5 pts experienced DLT (both grade 3 fatigue and anorexia). investigations of an alternative schedule of sorafenib administra- As such, the MTD was exceeded and the recommended phase II tion may be considered for further investigation with appropriate dose was sorafenib 200 mg po BID continuously with carboplatin pharmacokinetic evaluation. AUC = 5 and pemetrexed 500 mg every 3 weeks. The hematologic An excessive rate of thrombocytopenia was observed with toxicities observed in each of the treatment arms are presented sorafenib 200 mg BID with the combination of carboplatin AUC = 6 in Table 3, electrolyte and renal toxicities in Table 4, and other and pemetrexed 500 mg/m2 every 3 weeks. The explanation of the non-hematological toxicities in Table 5. One grade 5 toxicity, gas- unexpectedly severe thrombocytopenia seen in Arm B is unclear. trointestinal perforation, was observed on Arm C after cycle 2 which Decreased excretion of sorafenib as a result of carboplatin is was possibly treatment-related. unlikely to explain this as less than 20% of sorafenib is excreted in the urine, predominantly as the inactive glucuronide metabo- 3.3. Treatment administration lite [18]. A potential explanation is the synergistic effect of both sorafenib and carboplatin on the platelets. Platelets and megakary- The median number of treatment cycles on all arms was 2; range ocytes express VEGFRs and VEGF, as well as other growth factors, for Arms A, B and C was 1–2, 1–4, and 1–4 respectively. The rea- which have been shown to be important in their production, matu- sons for treatment discontinuation were progressive disease (n = 5), ration, and function [19]. The current action of carboplatin causing adverse events (n = 9), and death (n = 1). Five patients received four direct toxicity to the platelets and sorafenib further inhibiting cycles of therapy and then discontinued treatment at the discretion production may have resulted in the more pronounced thrombocy- of the treating physician. After excessive toxicity was observed in topenia seen in these pretreated patients with lower megakaryocte Arm B, one patient who did not experience toxicity underwent a reserves. Episodes of grade 3 or 4 neutropenia were observed in dose reduction and received four cycles of treatment on Arm B. all arms, and three episodes of febrile neutropenia were observed. Four patients received four cycles on Arm C. Of the three patients who experienced febrile neutropenia, two patients did not receive any further therapy on trial and one patient 3.4. Response received growth colony stimulating factor on the following cycle and then discontinued treatment due to progressive disease. Since Of the 20 patients treated on the trial, 10 patients were evaluable only patient received colony growth factor for a single cycle it is for response. Two patients experienced a partial response (SCLC and not possible to determine the impact of colony growth stimulating squamous cancer of the head and neck) and three patients expe- factors on the rate of neutropenia or febrile neutropenia. rienced stable disease of ≥12 weeks duration (thymoma, atypical The combination of sorafenib 200 mg twice daily and carbo- carcinoid, and NSCLC). Five patients experienced progressive dis- platin AUC = 5 and pemetrexed 500 mg/m2 was moderately well ease. Of the remaining 10 patients, nine were not evaluable due to tolerated; however, excessive toxicity was observed with the the fact that they discontinued therapy related to toxicity, and one sorafenib 400 mg twice daily. It should be noted that the median patient died from a gastrointestinal perforation. Four of the patients number of cycles observed on this treatment arm was 2 (range 1–4). who experienced a partial response or stable disease received treat- The fact that a pretreated patient population with refractory dis- ment on Arm C, and one patient who had stable disease was treated ease was enrolled on this trial may have contributed to the low on Arm B. number of median cycles. If a phase II trial of this combination is pursued, then patients should be monitored for cumulative toxi- 4. Discussion city. It is possible that a treatment naïve patient population may better tolerate this three drug combination. An unacceptable rate of toxicity was observed in this previously While this trial was ongoing, the results of a phase III trial treated patient population with the combination of cisplatin and comparing carboplatin and paclitaxel with and without sorafenib etoposide with sorafenib 200 mg po BID. Enrollment at dose level revealed a similar overall survival in the intent-to-treat patient −1 was slow, and in order to facilitate accrual the trial was amended population, and a statistically signiﬁcant inferior survival among to eliminate the pharmacokinetic investigation, which required an patients with NSCLC with squamous histology on the sorafenib- inpatient admission to our clinical research center. However, this containing arm compared to the carboplatin and paclitaxel alone was not successful. Several factors probably contributed to the slow arm [20]. Subsequent to the development of this trial, the combina- accrual including the fact that only a limited number of patients tion of carboplatin and pemetrexed was found to be inferior to the

Please cite this article in press as: Davies JM, et al. A phase I trial of sorafenib combined with cisplatin/etoposide or carboplatin/pemetrexed in refractory solid tumor patients. Lung Cancer (2010), doi:10.1016/j.lungcan.2010.05.022 G Model LUNG-3604; No. of Pages 5 ARTICLE IN PRESS J.M. Davies et al. / Lung Cancer xxx (2010) xxx–xxx 5 combination of carboplatin and etoposide in patients with exten- carboplatin in the first-line treatment of advanced nonsmall cell lung cancer. sive stage SCLC [8], and the activity of pemetrexed in NSCLC was Cancer 2005;104:2449–56. [6] Scagliotti GV, Kortsik C, Dark GG, Price A, Manegold C, Rosell R, et al. Pemetrexed found to be limited to NSCLC tumors with non-squamous histology combined with oxaliplatin or carboplatin as first-line treatment in advanced [21]. non-small cell lung cancer: a multicenter, randomized, phase II trial. Clin Cancer The future development of sorafenib in combination with stan- Res 2005;11:690–6. 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