A Phase I Study of Pemetrexed, Carboplatin, and Concurrent

Cancer Therapy: Clinical

A Phase I Study of Pemetrexed, Carboplatin, and Concurrent Radiotherapy in Patients with LocallyAdvanced or Metastatic Non ^Small Cell Lung or Esophageal Cancer Tanguy Y.Seiwert,1Philip P. Connell,2 Ann M. Mauer,1Philip C. Hoffman,1Christopher M. George,1 Livia Szeto,1Ravi Salgia,1Katherine E. Posther,3 Binh Nguyen,3 Daniel J. Haraf,2 and Everett E.Vokes1

Abstract Purpose: The primary objective of this phase I study was to determine the maximum tolerated dose for pemetrexed, alone and in combination with carboplatin, with concurrent radiotherapy. Experimental Design: Patients with locally advanced or metastatic non ^ small cell lung cancer (NSCLC) or esophageal cancer were treated every 21 days for two cycles. Regimen 1 was pemetrexed (200-600 mg/m2); regimen 2 was pemetrexed (500 mg/m2) with escalating carboplatin doses (AUC = 4-6). Both regimens included concurrent radiation (40-66 Gy; palliative-intent doses were lower). Results: Thirty patients (18 locally advanced and 12 metastatic with dominant local symptoms) were enrolled, with an Eastern Cooperative Oncology Group performance status of 0/1/2 (n = 8/21/1). All dose levels were tolerable for regimen 1 (n = 18: 15 NSCLC and 3 esophageal cancers) and regimen 2 (n = 12: all NSCLC). In regimen 1, one dose-limiting toxicity (grade 4 esophagitis/anorexia) occurred (500 mg/m2). Grade 3 neutropenia (3 of 18 patients) was the main hematologic toxicity. In regimen 2, one dose-limiting toxicity (grade 3 esophagitis) occurred (500 mg/m2; AUC = 6); grade 3/4 leukopenia (4 of12patients) was the mainhematologic toxicity. Four complete responses (2 pathology proven) and eight partial responses were observed.When systemically active chemotherapy doses were reached, further dose escalation was discontinued, andaphase IIdose-range was established (pemetrexed 500 mg/m2 and carboplatin AUC = 5-6). Conclusions: The combination of pemetrexed (500 mg/m2)andcarboplatin(AUC=5or6) with concurrent radiation is well tolerated, allows for the administration of systemically active chemotherapy doses, and shows signs of activity. To further determine efficacy, safety profile, and optimal dosing, the Cancer and Leukemia Group B study 30407 is currently evaluating this regimen in patients with unresectable stage IIINSCLC.

Lung cancer is the leading cause of cancer-related death in the advanced stage III NSCLC, the majority of whom have United States and Europe for both men and women. Non– unresectable bulky disease or extensive mediastinal lymphade- small cell lung cancer (NSCLC) accounts for f87% of all lung nopathy, making curative treatment a challenge (1). The 5-year cancers. About one third of patients present with locally survival rate for these patients remains low (1). For patients with locally advanced unresectable disease, concurrent chemoradiotherapy offers a greater survival advan- tage than sequential chemotherapy and radiation. Concurrent 1 Authors’ Affiliations: Section of Hematology/Oncology, Department of chemoradiotherapy is now considered the standard therapeutic Medicine; 2Department of Radiation and Cellular Oncology, University of Chicago, Chicago, Illinois; and 3Eli Lilly and Company, Indianapolis, Indiana approach (2–8). However, both locoregional and distant Received 5/1/06; revised 10/12/06; accepted 10/26/06. failure remain a problem (8–11). Following treatment with Grant support: Eli Lilly and Company, Valda and Robert Svendsen Foundation, chemoradiotherapy, 70% to 75% of patients will develop and the University of Chicago Cancer Research Center. recurrent or progressive disease (failure of therapy): Roughly The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance one third of patients fail in the radiation field (local failure); with 18 U.S.C. Section 1734 solely to indicate this fact. one third of patients fail outside the irradiated field (distal Note: Presented in part at the American Society of Clinical Oncology 2005 Annual failure); and one third of patients fail both locally and distally Meeting, May 13-17, 2005, Orlando, Florida and the 11th World Conference on Lung (10–13). For patients with stage IV disease, radiotherapy is Cancer, July 3-6, 2005, Barcelona, Spain. also appropriate to relieve symptoms related to bulky chest Conflict of interest: E.Vokes has received research funding and honoraria from Eli Lilly and Company. K.E. Posther and B. Nguyen were employed by Eli Lilly and disease (6). Company at the time of preparation of this article. The combination of carboplatin, paclitaxel, and radiotherapy Requests for reprints: Everett E. Vokes, Section of Hematology/Oncology, (widely used in the United States) yielded disappointing results University of Chicago, 5841South Maryland Avenue, MC2115, Chicago, IL 60637. in a recent randomized cooperative group trial [Cancer and Phone: 773-702-9306; Fax: 773-702-3002; E-mail: evokes@ medicine. bsd.uchicago.edu. Leukemia Group B (CALGB) 39801], with median survival F 2007 American Association for Cancer Research. times of 11.4 and 13.7months (concurrent chemoradiotherapy doi:10.1158/1078-0432.CCR-06-1058 F induction chemotherapy; ref. 14). The Radiation Therapy

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Oncology Group 98-01 trial used the same chemotherapy I dose-finding study to determine the maximum tolerated dose plus accelerated, hyperfractionated radiotherapy and reported (MTD) of pemetrexed as a single agent and in combination better results (median survival time of 16 months; ref. 15). with carboplatin given with concurrent radiotherapy in patients Nevertheless, a clear need remains to explore novel therapies to with locally advanced or locally symptomatic metastatic improve survival in patients with locally advanced NSCLC. NSCLC or esophageal cancer. Secondary objectives were to Pemetrexed, a novel antimetabolite, acts as a multitargeted determine the dose-limiting toxicities (DLT) and the recom- antifolate by inhibiting several key enzymes involved in mended phase II dose of pemetrexed plus carboplatin and nucleotide synthesis: thymidylate synthetase, dihydrofolate radiotherapy for subsequent studies. reductase, and glycinamide ribonucleotide formyl transferase (16). Pemetrexed has activity in a wide range of cancers (17) and was approved by the U.S. Food and Drug Administration Patients and Methods for second-line, single-agent therapy in metastatic NSCLC (18) as well as first-line treatment of inoperable malignant Eligibility criteria. Inclusion and exclusion criteria are listed in mesothelioma in combination with cisplatin (19). Pemetrexed Table 1. This study was conducted according to good clinical practice shows single-agent activity similar to other active agents in guidelines and the Declaration of Helsinki. The local ethical review board approved the study, and patients gave written informed consent NSCLC (20, 21). In clinical trials for chemo-naive patients with before enrollment. advanced NSCLC, pemetrexed was evaluated in combination Treatment plan. This phase I trial was an open-label, nonrandom- with cisplatin, gemcitabine, vinorelbine, oxaliplatin, and ized, dose-finding cohort study using two sequential pemetrexed carboplatin (22–28). regimens and concurrent radiotherapy. Initially, patients with NSCLC In two phase II studies [one in Europe (N = 39) and one or esophageal cancer (regimen 1 only) received single-agent pemetrexed in the United States (N = 50)] in patients with locally with concurrent radiotherapy (regimen 1). Subsequently, the trial was advanced or metastatic NSCLC, the combination of pemetrexed amended to limit the inclusion criteria to NSCLC patients and combine (500 mg/m2) and carboplatin (AUC = 6) given every 3 weeks pemetrexed 500 mg/m2 with escalating doses of carboplatin plus produced response rates of 32% and 24%, median survival concurrent radiotherapy (regimen 2). times of 10.5 and 13.5 months, and 1-year survival rates of Pemetrexed (Alimta, LY231514, Eli Lilly and Company, Indian- apolis, IN) was administered as a 10-min i.v. infusion on day 1 every 44% and 56% (25, 29). 21 days for a maximum of two cycles or until disease progression or Furthermore, in preclinical studies, the combination of unacceptable toxicity occurred. In regimen 1, the initial dose level was pemetrexed with concurrent radiation showed synergistic pemetrexed 200 mg/m2, which was escalated in 100-mg/m2 incre- activity (30). An enhancement ratio of 1.6 was reported for a ments. During the conduct of the trial, published results established the lung cancer line (1.2-1.8 for other tumor types), with a pemetrexed dose for second-line treatment in NSCLC at 500 mg/m2 tendency towards higher ratios with increasing pemetrexed (18). The pemetrexed dose was therefore capped at 500 mg/m2, and concentrations. Based on these preclinical data, as well as the regimen 2 was started with an initial carboplatin dose of AUC = 4, evident activity of pemetrexed in NSCLC, we conducted a phase which was escalated in increments of 1. For patients on regimen 2,

Table 1. Eligibility/exclusion criteria and definition of DLT

Eligibility criteria . Histologic or cytologic diagnosis of locally advanced or metastatic NSCLC (regimen 1 or 2)or esophageal cancer (regimen 1) . Performance status (ECOG)of 0 or 1 . Adequate organ function: ANC z1.5 109/L, platelets z100 109/L, hemoglobin z9 g/dL, bilirubin V1.5 ULN, transaminases V3.0 ULN (V5.0 ULN if liver metastases were present), creatinine clearance z45 mL/min . Recovery from previous therapy effects (for postoperative patients who received adjuvant therapy more than 2 wks before enrollment) . Use of an approved contraception during and for 3 mos after the study (for patients with reproductive potential) Exclusion criteria . Active brain metastases and pleural or peritoneal effusions . Other serious concomitant systemic disorders . Inability to take folic acid or vitamin B12 supplementation . Inability to interrupt nonsteroidal anti-inflammatory drugs 2 d before and after pemetrexed dose . In regimen 1, prior pemetrexed-based chemotherapy or prior radiotherapy, except for whole-brain radiotherapy for metastases or for palliation of painful bony metastases . In regimen 2, prior chemotherapy for locally advanced or metastatic disease or prior thoracic radiotherapy; nonthoracic radiotherapy was allowed if completed 2 wks before enrollment with resolution of all toxicities DLT definition (occurring during cycle 1 for regimen 1 and during the course of radiation and up to 1 mo following the end of radiotherapy for regimen 2): . Grade 4 neutropenia (<0.5 109/L)lasting >5 d or febrile neutropenia . Grade 4 thrombocytopenia . Any grade 3 or 4 nonhematologic toxicity (excluding alopecia, nausea, or vomiting) . Grade 2 to 4 myelosuppression prohibiting treatment on day 22 . In regimen 1, grade 4 esophagitis prohibiting treatment on day 22 or grade 4 esophagitis occurring within 3 mos from the start of treatment . In regimen 2, grade 3 or 4 pulmonary or esophageal toxicity

Abbreviations: ECOG, Eastern Cooperative Oncology Group; ANC, absolute neutrophil count; ULN, upper limit of normal.

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Table 2. Treatment administration

Dose level No. patients Radiotherapy Completed fractions (n), Cumulative total dose (Gy), median (range) median (range) Regimen 1: pemetrexed (mg/m2)+ radiotherapy 200 3 25 (22-30)60 (44-60) 300 3 33 (30-33)66 (60-66) 400 3 33 (20-45)50 (40-66) 500 6 35 (26-35)70 (58-70) 600 3 25 (22-33)45 (44-66) All levels 18 33 (20-45)63 (40-70) Regimen 2: pemetrexed (mg/m2)/carboplatin (AUC) + radiotherapy 500/4 3 25 (22-30)50 (44-60) 500/5 3 29 (29-33)58 (58-66) 500/6 6 28 (22-33)56 (44-66) All levels 12 29 (22-33)58 (44-66)

a 30-min infusion of 100 mL saline was administered between the (1,000 Ag) and folate supplementation (350-600 Ag) were given f1to pemetrexed and carboplatin therapy, followed by a 30-min infusion of 2 weeks before the first pemetrexed dose. Folate was continued daily carboplatin. until the patient discontinued therapy. Radiotherapy started 30 to 60 min following chemotherapy on day 1. For both regimens, the absolute neutrophil count had to be above Patients received daily fractions of 2 Gy (using megavoltage equipment 1.5 109/L, and platelets had to be above 100 109/L, before the with a nominal energy of usually 6 and 18 MV if necessary to achieve start of any cycle; treatment was delayed up to a maximum of 3 weeks adequate dose homogeneity), 5 days per week to the isocenter of the to permit recovery. Pemetrexed was delayed until the patient received treatment field until the total cumulative dose of 40 to 70 Gy was vitamin B12 and folate for at least five of the 7days before cycle 1, or reached. Lower radiation doses were used in the palliative setting (stage until the patient took folate for at least 14 of the 21 days before cycle IV disease; typically between 40 and 55 Gy), whereas higher doses of 2. Pemetrexed was also held for creatinine clearance <45 mL/min. radiation were used in locally advanced disease (mean radiation dose: Both pemetrexed and carboplatin were held for Common Toxicity 61 Gy). The treatment volume generally consisted of two parts that were Criteria grade 3 or 4 mucositis or esophagitis and would not be irradiated sequentially: the original volume (included the primary restarted until recovery to grade V2. Any patient experiencing a lesion with a 2-cm margin and draining lymphatics for primary thoracic pulmonary or esophageal Common Toxicity Criteria grade 3 or 4 tumors) and the boost volume (included the entire pre-therapy toxicities did not receive cycle 2 treatment, unless it was considered to radiologically defined primary tumor volume and clinically involved be in the patient’s best interest to continue chemotherapy; if retreated, regional hilar and/or mediastinal nodes). Elective nodal regions were both study drugs were reduced by 50%. Radiotherapy was interrupted included in the ‘‘original volume’’ in most patients with IIIB NSCLC, for grade 4 esophagitis and was restarted when the patient recovered but this was not mandatory for all patients. Supraclavicular nodal to grade 2. regions were radiated only in a few selected patients due to concern for Dose-escalation schema. For regimen 1, five dose levels of peme- esophageal toxicity. Computed tomography–based planning and three- trexed were tested, starting at 200 mg/m2 (Table 2). The initial dose was dimensional dosimetry were used routinely, and dose-volume histo- given to the first three patients enrolled in the study. If none of the first grams for dose-limiting organs were established for all patients. three patients experienced a DLT, then escalation proceeded to the next All patients had custom immobilizations constructed and underwent dose level. If one of the first three patients experienced a DLT, then computed tomography–based simulation (with 3- to 5-mm image enrollment continued until six patients were enrolled, or a third DLT slices). Formal three-dimensional planning was done in all patients, occurred, whichever came first. If no or one additional DLT occurred and this was typically done using the PLUNC software package. (V2 DLTs in six patients), dose escalation continued. If z2 of the first Corrections for tissue density inhomogeneity were not used in the three patients or z3 of the six patients had DLTs, the MTD was reached, majority of cases. Weekly quality assurance port films were taken and and dose escalation stopped. reviewed by treating physicians. The initial treatment was delivered For regimen 2, pemetrexed was fixed at 500 mg/m2, and three dose using an AP/PA technique. Oblique field arrangements to boost levels of carboplatin were tested, starting at an AUC = 4 and increasing the mediastinum and areas with gross disease were instituted at the by 1 (Table 2). The protocol was amended to allow discontinuation of appropriate times to minimize the dose to normal lung and to keep the dose escalation once systemic doses of both pemetrexed and dose to the spinal cord under 46 Gy. The total radiation dose to grossly carboplatin were achieved. uninvolved mediastinum, supraclavicular fossa, or hilum was 40 to DLTs. All toxicities were assessed using the National Cancer 50 Gy. The total radiation dose to areas of gross disease was 40 to Institute-Common Toxicity Criteria 2.0 before each cycle.4 Following 70 Gy. No more than 40% of normal lung (with PTV subtracted) the expansion of the trial, the definition of DLT was broadened for received a dose >20 Gy based on three-dimensional dosimetry and regimen 2. The definition of DLTs for regimens 1 and 2 are shown in dose-volume histograms. Table 1. Patients were allowed to receive full supportive care. All patients were Baseline and treatment assessments. The assessment of disease status premedicated with oral dexamethasone 4 mg twice a day for 5 days, of each patient included medical history and physical examination, starting the day before treatment to reduce potential hypersensitivity evaluation of performance status, tumor measurement of palpable or reactions and nausea. Granulocyte colony-stimulating factor was used visible lesions, chest + abdomen computed tomography scan, for patients with absolute neutrophil count <0.5 109/L for at least electrocardiogram, and vital signs. Positron emission tomography 5 days, neutropenic fever, or documented infections with neutropenia. It was discontinued at least 24 h before the start of the next cycle. All 4 patients received vitamin supplementation (31): a vitamin B12 injection http://ctep.cancer.gov/forms/Hndbk.pdf (accessed July 25 2002).

www.aacrjournals.org 517 Clin Cancer Res 2007;13(2) January 15, 2007 Downloaded from clincancerres.aacrjournals.org on September 24, 2021. © 2007 American Association for Cancer Research. Cancer Therapy: Clinical scanning at the time of the initial study planning was not standard of population was significantly more homogeneous, with 83.3% care and was not included in staging studies. Mediastinoscopies were having locally advanced disease. Only two patients had done when clinically indicated, in particular, before surgical treatment metastatic disease (first and third patient enrolled). All nine when the study treatment was used neoadjuvantly. patients on the highest two dose levels had locally advanced Follow-up assessments included weekly hematology and blood NSCLC (stages IIIA and B; Table 3). chemistry monitoring (F3 days and up to 4 days before each cycle). Creatinine clearance was calculated (modified Cockcroft-Gault Recommended dose and DLTs. For both regimens, dose formula; ref. 32) within 4 days before the start of each cycle. Vitamin escalation was discontinued when full single-agent doses were metabolites were measured up to 4 days before both pemetrexed reached; accordingly, per the definition, the MTD was not doses. In addition, an outside laboratory (Covance, New York, NY) reached for either regimen (Table 4). However, two DLTs did blood chemistries and homocysteine levels and calculated occurred: one on each regimen. On regimen 1, at dose level creatinine clearance. All patients who received at least one dose of 500 mg/m2, one DLT (grade 4 esophagitis/anorexia) occurred chemotherapy were included in the analysis. Patients were then in a patient with metastatic NSCLC (radiation dose: 66 Gy). followed every 3 months until death, or until data was censored for This patient had a resected solitary brain metastasis and, in the disease progression, chemotherapy, surgery, and other treatments. absence of metastatic disease, was treated with curative Patients were closely followed for delayed toxicity for at least 30 days treatment doses for his remaining thoracic disease. This patient after completing therapy. Although efficacy was not an end point of this study, response was also experienced non-DLT toxicities of grade 3 dehydration, assessed per Southwest Oncology Group criteria (33). Baseline fatigue, and pain secondary to the esophagitis. Three additional computed tomography (chest + abdomen) was done within 4 weeks patients were enrolled, and pemetrexed was subsequently before starting therapy, and subsequent scans were obtained every 4 to escalated to 600 mg/m2. Parallel studies established the 6 weeks. All patients with bidimensionally measurable disease, who standard dose of single-agent pemetrexed for second-line received at least one dose of chemotherapy and radiotherapy, were treatment of NSCLC as 500 mg/m2 (18). Therefore, we chose evaluable for the efficacy analysis. Local response was assessed by 500 mg/m2 as the recommended dose for single-agent applying response criteria to lesions within the radiation field. Patients pemetrexed combined with radiotherapy and used this dose as who underwent surgery had pathologic response assessment. the basis for regimen 2. On regimen 2, one DLT (grade 3 esophagitis) occurred in a patient with locally advanced NSCLC 2 Results at the highest dose level (pemetrexed 500 mg/m and carboplatin AUC = 6; radiation dose, 66 Gy). Accordingly, Patient characteristics. A total of 30 patients were treated: 18 six patients were enrolled at this dose level. Further dose on regimen 1 and 12 on regimen 2 (Table 3). The median age escalation was discontinued at this point for multiple reasons was 65 years, and 60% of the patients were male. On regimen (i.e., achievement of systemically active doses, increased 1, the patient population was more heterogeneous, with 3 incidence of non-DLT toxicities, and absence of literature patients having esophageal cancer and 15 NSCLC. All patients supporting higher AUCs; see Discussion for further detail). on regimen 2 had advanced NSCLC. Overall, locally advanced Pemetrexed 500 mg/m2 with carboplatin with an AUC = 6 or disease was reported in 60% of patients. On regimen 2, the potentially 5 was recommended for phase II testing.

Table 3. Patient characteristics

Characteristic Regimen 1: Regimen 2: pemetrexed/ All patients pemetrexed + RT (n = 18) carboplatin + RT (n = 12) (N = 30) Gender, n (%) Female 7 (38.9)5 (41.7)12(40.0) Male 11 (61.1)7 (58.3)18(60.0) Median age (range), y 62.5 (32-80) 67 (42-77) 64.5 (32-80) ECOG performance status, n (%) 0 3 (16.7)5 (41.7)8(26.7) 1 14 (77.8)7 (58.3)21(70.0) 2 1 (5.6)* 0 1 (3.3)* Stage, n (%) Locally advanced (stage IIIB)8 (44.4) 10 (83.3) 18 (60.0) Metastatic (stage IV)10 (55.6) 2 (16.7)12(40.0) Histologic subtype, n (%) Lung cancer: NSCLC 15 (83.3)12 (100)27(46.7) Esophageal cancer 3 (16.7)0 3 (10) Prior therapy, n (%) Prior surgery 8 (44.4)3 (25.0)11(36.7) Curative intent 5 (27.8)2 (16.7)7(23.3) Diagnostic 3 (16.7)1 (8.3)4(13.3) Prior chemotherapy 8 (44.4)0 8 (26.7) Prior radiotherapy 3 (16.7)1 (8.3)4(13.3)

Abbreviations: ECOG, Eastern Cooperative Oncology Group; RT, radiotherapy. *Inclusion criteria of ECOG = 1 not fulfilled.

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Table 4. DLTs and selected treatment-related toxicities

Dose level No. patients DLT Selected CTC grade 3/4 toxicities Regimen 1: pemetrexed (mg/m2)+ radiotherapy 200 3 No DLT — 300 3 No DLT 1 patient: G3 leukopenia and neutropenia (66 Gy);G4 respiratory failure (60 Gy)*c 400 3 No DLT — 500 6 1 patient: G4 esophagitis/ 1 patient: G3 dehydration, fatigue, pain 2nd to anorexia* (66 Gy) esophagitis (66 Gy); 1 patient: G3 leukopenia and neutropenia (70 Gy); 1 patient: G3 leukopenia (70 Gy); 1 patient: G3 neutropenia (58 Gy) 600 3 No DLT 1 patient: G3 esophagitis (66 Gy)* Regimen 2: pemetrexed (mg/m2)/carboplatin (AUC) + radiotherapy 500/4 3 No DLT 1 patient: G3 leukopenia (60 Gy) 500/5 3 No DLT 1 patient: G4 leukopenia (66 Gy) 500/6 6 1 patient: G3 esophagitis (66 Gy)2 patients: G3 leukopenia (66 Gy; 58 Gy)

Abbreviations: CTC, Common Toxicity Criteria; G, grade. *Occurred within the first 30 d after the end of radiotherapy. cThe etiology remains unclear but was felt to be most consistent with an infectious etiology (see text).

Other non-DLT toxicities. Treatment-related grade 3 and 4 pemetrexed was 99.6% of the protocol planned dose intensity. toxicities are shown in Table 4. Overall, all dose levels were well One patient died due to disease progression before completing tolerated. On regimen 1, one patient at the 300 mg/m2 dose therapy. Five of 30 patients experienced dose delays due to level developed grade 4 respiratory failure (radiation dose; adverse events: decreased creatinine clearance in one patient on 60 Gy), which occurred within the first 30 days after the end of regimen 1 and hyperglycemia, dehydration, pulmonary embo- radiotherapy. The precise etiology remained unclear. Neverthe- lism, and atrial flutter each in one patient on regimen 2. On less, the clinical and radiological picture was suggestive of an regimen 2, one patient had cycle 2 doses reduced (both infectious etiology leading to acute respiratory distress syn- pemetrexed and carboplatin were reduced, by 50%) due to drome; therefore, the event was not primarily attributed to pulmonary embolism (radiation dose: 54 Gy). In regimen 2, study treatment or determined to qualify as a DLT. the weekly mean dose intensity for both pemetrexed and At 500 mg/m2, one patient developed grade 3 dehydration, carboplatin was 94.4% of the planned dose intensity. A total of fatigue, and pain [secondary to esophagitis (DLT, see above), three patients (two on regimen 1 and one on regimen 2) 66 Gy], and three patients had decreased blood counts developed pulmonary emboli (radiation doses: 60, 70, and (leukopenia or neutropenia). Furthermore, one case of grade 54 Gy); the patient on regimen 2 developed atrial fibrillation as 2 radiation pneumonitis occurred shortly after completion of a consequence. radiation at the 500 mg/m2 dose level (70 Gy). At 600 mg/m2, Efficacy. Although this was a phase I study, early signs of one patient developed grade 3 esophagitis (66 Gy), which per efficacy were visible. Four patients had a complete response: one definition (for regimen 1) was not a DLT. on regimen 1 (dose level: 500 mg/m2) and three on regimen 2 On regimen 2, at the 500 mg/m2 and AUC = 6 dose level, two (one on each dose level). Two of these patients had a patients had radiation pneumonitis [one grade 1 (58 Gy) and pathologically confirmed complete response after surgery one grade 2 (66 Gy)], which manifested in the month without any residual cancer cells (dose levels: 500 mg/m2, following radiation. After completion of therapy, the patient AUC = 5/6). One patient had an unclear initial assessment of with grade 2 pneumonitis had progressive disease and received partial response versus complete response by imaging; subse- docetaxel and dexamethasone within 30 days after the last quent pathologic examination of the specimen confirmed study drug administration. Withdrawal of dexamethasone led complete response, which was noted as the final response. After to immediate worsening of the previously stable symptoms 2 years of follow-up, this patient continues to be free of disease. (grade 3). Exacerbation was considered related to the docetaxel A total of five patients with borderline resectable disease and steroid withdrawal by the treating physician and the underwent curative intent surgery after neoadjuvant chemo- primary investigator; therefore, it was not considered to qualify radiotherapy (all on regimen 2). as a DLT for the previous study treatment. Although a remote Overall tumor response and in-field response are shown in possibility, the fulminant respiratory failure could also have Table 5. The overall response rate for both regimens combined been caused by pemetrexed and radiation. Careful further was 43%; this included two partial responders with esophageal testing in a larger cohort is necessary to clarify this further. In cancer on regimen 1. All responders on regimen 2 had locally the other patient, grade 1 radiation pneumonitis resolved over a advanced NSCLC. The overall in-field response rate was higher period of 2 months, and the patient subsequently underwent at 61% (63% for regimen 1 and 58% for regimen 2). curative intent surgery. The median survival time was 12.6 months (95% confidence There was no treatment discontinuation due to adverse interval, 6.9-18.8) overall. On regimen 2, seven of 12 patients events. In regimen 1, the weekly mean dose intensity for (58.3%) are still alive.

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Table 5. Overall response and in-field response rates

Regimen 1: Regimen 2: pemetrexed/ All (N = 28)c pemetrexed + RT (n = 16)* carboplatin + RT (n = 12)c Overall response rate 38% 50% 43% CR 1 3*b 4*b PR 5 3* 8* SD 5 4 9 PD 5 1 6 In-field response ratex 63% 58% 61% CR 1 3*b 4*b PR 9 4* 13* SD 6 4 10 PD 0 0 0

Abbreviations: RT, radiotherapy; CR, complete response; PR, partial response; SD, stable disease; PD, progressive disease. *Two patients were not evaluable for efficacy analysis because disease was not bidimensionally measurable. cBest response designation (per Southwest Oncology Group criteria)was unknown for one patient. bOne patient had an unclear response (PR versus CR)by imaging. Subsequent pathology confirmed CR and follow-up for 2 yrs did not reveal any evidence of disease recurrence. The patient is classified here as a CR. xDue to the small number of patients with metastatic disease (n = 2 in regimen 2), out-of-field response could not be calculated.

Discussion esophagitis were not a clinically significant problem with only three low-grade occurrences of pneumonitis (one grade 1 This phase I trial shows the tolerability of combining and two grade 2) and three cases of radiation esophagitis (two pemetrexed with thoracic radiotherapy as well as combining grade 3 and one grade 4; Table 4). pemetrexed, with carboplatin, and chest radiotherapy in The incidence of esophagitis as well as hematologic, skin, patients with NSCLC. Although limited by the small number and pulmonary toxicities is low in comparison with other of patients, our data suggest that pemetrexed can be adminis- established chemoradiotherapy platforms (14, 36). Two addi- tered at systemically active doses in combination with tional cases of pulmonary failure were not attributed to study radiotherapy, which is in contrast to several other active agents treatment. In the first case, the clinical picture was more in NSCLC [e.g., gemcitabine with prominent acute pulmonary suggestive of infectious origin, and in the second case, toxicity (34)], but similar to cisplatin/etoposide (35). complications associated with docetaxel consolidation and Overall, the toxicity profile seems favorable, in particular, steroid withdrawal were the likely cause. We caution that these given the enrollment of poor risk patients. Primarily hemato- pulmonary complications could remotely be attributed to logic toxicities were noted (i.e., grade 3/4 leukopenia/neutro- pemetrexed and radiation. Careful testing in a larger phase II penia) in up to one third of patients. On the other hand, cohorts is necessary to establish the safety profile of this in-field complications were mild. Radiation pneumonitis or regimen.

Fig. 1. Future direction. A follow-up phase II study (CALGB 30407: a randomized phase II study of radiotherapy, pemetrexed, and carboplatin with or without cetuximab in stage IIINSCLC). *, Cetuximab dose: week 1,400 mg/m2; weeks 2 to 7, 250 mg/m2.

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A limitation of this study is the heterogeneity with respect to single-agent administration for the treatment of NSCLC. The tumor types enrolled (esophageal and NSCLC), NSCLC stages protocol was amended to allow discontinuation of dose (stages IIIa, IIIb, and IV), and differences in radiation doses escalation once systemic doses of both pemetrexed and for curative (high dose) and palliative (lower dose) intent. This carboplatin were achieved. is particularly true for regimen 1, where general tolerability in Overall, the here presented data support phase II testing of thoracic malignancies was examined. Specifically, three patients the highest dose level: pemetrexed 500 mg/m2 and carboplatin (10%) with esophageal cancer were enrolled for regimen 1, and AUC = 6. However, the limited number of patients treated on there were several patients with metastatic disease (56%). In each dose level (typical for the phase I design) prevents us from contrast, regimen 2 enrollment was limited to NSCLC, and all drawing a final conclusion that carboplatin at an AUC = 6 is patients treated at the two highest dose levels had locally optimal. Additional data in a larger and homogenous cohort advanced NSCLC. are needed, evaluating both AUC = 5 and 6. Evidence of activity The average radiation dose for second highest dose level was was noted in several patients in this small phase I trial, with 60.7Gy (all locally advanced NSCLC) and for the highest dose four complete responses, two of which were based on the level was 57.0 Gy (all locally advanced NSCLC). There was only absence of tumor on pathology review of the surgical speci- one patient with locoregionally advanced disease (stage IIIb) mens. Furthermore, five patients with borderline resectable who received <50 Gy on the highest dose level. This was due to disease underwent curative-intent surgery after chemoradio- an unfavorable tumor location and large tumor burden. Tumor therapy. This suggests a good in-field activity, which is also coverage with high doses of radiotherapy would have been supported by the in-field response rate of 61%. prohibitively toxic and would have exceeded the tolerance of The choice of the second agent for combination with the normal lung tissue (no more than 40% of normal lung pemetrexed (carboplatin versus cisplatin) can be debated. could receive >20 Gy). All other radiation doses on the highest Carboplatin may have inferior efficacy when compared with two dose levels were consistent with curative intention. cisplatin-based combinations, although most studies suggest Given the overall study size and heterogeneity of this study similar efficacy for such doublet combinations (42–44). We population, its results are to be reviewed with caution. chose carboplatin over cisplatin as it offers a markedly better However, the apparent absence of severe toxicities when nonhematologic toxicity profile and showed good activity in administering pemetrexed and radiation (+/ carboplastin) is combination with pemetrexed in the previously mentioned encouraging and supports further testing in phase II trials in studies (25, 29). Furthermore, our results show activity with locally advanced NSCLC. Indeed, there are several ongoing four complete responses, which is encouraging, and support phase I and II trials examining regimens combining concurrent phase II testing of this combination of pemetrexed with pemetrexed, carboplatin or cisplatin, and radiation therapy as carboplatin and radiation (CALGB 30407). well as testing this combination with induction or consolida- We conclude that the combination of pemetrexed, carbo- tion chemotherapy. Specifically, the CALGB phase II study platin, and radiotherapy is promising for further testing as it 30407is currently enrolling patients (see Fig. 1). seems tolerable and achieves systemically active doses of Doublet chemotherapy has been shown to prolong survival chemotherapy, and preliminarily shows early signs of activity more than single-agent chemotherapy in metastatic NSCLC in the treatment of locally advanced NSCLC. Careful (37–41), and as mentioned earlier, the doses, systemic efficacy, monitoring of pulmonary toxicity is advised as this regimen and tolerability of pemetrexed/carboplatin without radiother- is further tested in phase II studies with locally advanced apy are substantiated in two phase II trials in stage IIIB and IV NSCLC, due to the two, likely unrelated cases, of pulmonary NSCLC (25, 29). In regimen 1, further dose escalation of failure reported here. pemetrexed beyond 500 mg/m2 was not pursued. Instead, we The recommended phase II dose range is pemetrexed 500 amended the protocol to determine if systemic doses of both mg/m2 and carboplatin AUC = 5 or 6. It is currently being pemetrexed and carboplatin could be administered with evaluated in a multicenter, randomized phase II trial (CALGB concurrent radiation in regimen 2. 30407; schema outlined in Fig. 1). CALGB 30407 and other Dose escalation of either agent beyond their recommended future trials will need to determine the optimal dose within the single-agent doses was considered to be of questionable value. given dose range and whether the systemic activity of this There is no data currently to support that doses of pemetrexed regimen will translate into lower rates of distal failure. higher than 500 mg/m2, or carboplatin higher than AUC = 6 (alone, in combination, or with radiotherapy), would be more efficacious in a similar NSCLC patient population. Similarly, Acknowledgments the authors are not aware of any chemotherapeutic agent with We thank the wonderful support of Noelle Gasco, Susan Sutton, Takashi radiosensitizing properties that is administered at a higher dose Nakamura, and Laura Oberthur (MedFocus consultant before publication) of Eli Lilly with concurrent radiation than the standard dose used in and Company as well asJulie Stein of the University of Chicago.

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Tanguy Y. Seiwert, Philip P. Connell, Ann M. Mauer, et al.

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