- Email: [email protected]
A Randomized Phase II Study of Pemetrexed or RAD001 as Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer in Elderly Patients: Treatment Rationale and Protocol Dynamics
c urrent trial A Randomized Phase II Study of Pemetrexed or RAD001 as Second-Line Treatment of Advanced Non–Small-Cell Lung Cancer in Elderly Patients: Treatment Rationale and Protocol Dynamics Cesare Gridelli,1 Antonio Rossi,1 Floriana Morgillo,2 Maria Anna Bareschino,2 Paolo Maione,1 Massimo Di Maio,3 Fortunato Ciardiello2 Abstract In the current clinical trial summary, we present a randomized phase II trial of pemetrexed or RAD001 as second-line treatment of elderly patients with advanced non–small-cell lung cancer. The molecular and clinical rationale is reviewed. The primary endpoint is progression-free survival, and secondary endpoints include objective tumor response rates, disease control rates, safety, tolerability, and overall survival. Based on the statistical design, the investigators plan to enroll 92 elderly patients, 46 per arm. Clinical Lung Cancer, Vol. 8, No. 9, 568-571, 2007
Key words: Chemotherapy, Everolimus, Mammalian target of rapamycin, Targeted therapy
Rationale
mentioned conditions, very few trials have been performed in this subset of patients, and a disproportionately low number of elderly participants have been included in clinical trials.4,5 Based on the results of a limited number of large, phase III, randomized trials,3,6 the American Society of Clinical Oncology guidelines recommend single-agent chemotherapy as the standard of comparison for first-line therapy for elderly patients with advanced NSCLC.7 An International Experts Panel on elderly patients with advanced NSCLC confirmed this as a main recommendation.8 To date, 2 chemotherapeutic drugs and 1 new targeted agent have been licensed for the treatment of recurrent NSCLC. Second-line chemotherapy with docetaxel can prolong survival after platinum agent–based therapy.9,10 Furthermore, pemetrexed has been approved for second-line treatment since it was demonstrated that it is not inferior in terms of clinical efficacy compared with docetaxel, but pemetrexed has significantly fewer side effects.11 Among the new targeted agents, erlotinib, an oral small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK), is the first biologic drug registered for the treatment of pretreated NSCLC.12 To date, there is a lack of prospective data in second-line treatment of elderly patients with advanced NSCLC. An interesting retrospective analysis performed in 86 elderly (aged ≥ 70 years) of 571 patients enrolled in a randomized phase III trial comparing
Lung cancer is the leading cause of cancer death throughout the world. Non–small-cell lung cancer (NSCLC), including squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma, represents approximately 80%-85% of all lung cancers. Approximately 30%-40% of all lung cancers are diagnosed in patients aged ≥ 70 years.1 Aging decreases physiological hepatic, renal, and bone marrow (BM) functions, which has a negative impact on the degree of toxicity.2 Furthermore, concomitant diseases, frequently present in this patient population, can significantly compromise functional status and general health and exacerbate tumor symptoms.3 Because most patients with NSCLC have advanced disease at diagnosis, chemotherapy is the mainstay of treatment; yet, for the previously 1Division 2Division
of Medical Oncology, “S.G. Moscati” Hospital, Avellino of Medical Oncology, Department of Clinical and Experimental Medicine and Surgery “F. Magrassi and A. Lanzara,” Second University of Naples, School of Medicine 3Division of Medical Oncology, “N. Giannettasio” Hospital, Rossano Italy Submitted: Aug 28, 2007; Revised: Sep 24, 2007; Accepted: Sep 24, 2007 Address for correspondence: Cesare Gridelli, MD, Division of Medical Oncology, “S.G. Moscati” Hospital, Città Ospedaliera, Contrada Amoretta, 83100 Avellino, Italy Fax: 39-0825-203556; e-mail: [email protected]
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
568
Clinical Lung Cancer November 2007
second-line pemetrexed with docetaxel showed no significant difference in outcome between elderly and younger patients, but pemetrexed produced a more favorable toxicity profile with less febrile neutropenia and no toxic deaths.13 These data showed that pemetrexed was a safe and active chemotherapeutic agent in this subset of patients. Our increasing understanding of cancer biology has allowed the development of several potential molecular targets for NSCLC treatment essential for the acquisition of a cancer phenotype. Better toxicity profile and tolerability than chemotherapy, better target selectivity, availability for chronic treatment, and, in some cases, oral administration have marked these new targeted compounds among the most promising investigational drugs in elderly patients with advanced NSCLC. Among the several targeted agents introduced into clinical trials in NSCLC, RAD001 (everolimus) is one of the most promising. RAD001 is a novel and unique, orally available, small-molecule rapamycin analogue able to selectively inhibit the mammalian target of rapamycin (mTOR).
Biochemical and Molecular Background The mTOR is a key protein kinase which regulates cell growth, proliferation, and survival. The mTOR belongs to a family of kinases with a C terminus domain similar to the catalytic region of the phosphatidylinositol 3-kinase (PI3K), which are known as PI3K-related kinases and which also include mTOR.14 After the activation of membrane receptors by a variety of growth factors, the PI3K pathway is activated. This activation is mediated by activated K-ras or directly by some TK receptors, under the control of several growth factors and cytokines. Downstream to PI3K, protein kinase B, also named AKT, affects cell survival at multiple levels. Among substrates of AKT, mTOR is also included.15 The phosphatase and tensin homologue gene (PTEN) is a tumor suppressor gene involved in the regulation of the PI3K pathway. PTEN negatively regulates the PI3K/AKT/mTOR pathway, and cancer cells (in which the PTEN gene is deleted or its expression downregulated) exhibit constitutively activated PI3K signaling, which contributes to lung carcinogenesis.16,17 Therefore, mTOR activity can be related to loss of tumor suppressor gene PTEN and activation of AKT. Frequent AKT activation and mTOR phosphorylation were found in 51% of samples of patients with NSCLC and in 74% of NSCLC cell lines, respectively.18 The mTOR pathway is a central sensor for nutrient/energy availability, and is further modulated by PI3K/Akt-dependent mechanisms. In the presence of mitogenic stimuli and sufficient nutrients and energy, mTOR modulates translation of specific messenger RNAs through the phosphorylation state of translation proteins such as p70s6k, 4E-binding protein 1 (4E-BP1), and eukaryotic elongation factor 2. The inhibition of mTOR by starvation or targeted agents causes early G1 cell cycle arrest mediated by an inactivation of p70s6k and hypophosphorylation of 4E-BP1 (the main downstream effectors of mTOR).19-21 Preclinical studies showed that the antitumor activity of RAD001 is related to its inhibitory effects of p70s6k in tumor tissue and peripheral blood mononuclear cells.22,23
Clinical Background Recently, RAD001 has been administered at an oral dose of 10 mg per day until progression to 85 patients with refractory advanced NSCLC. All patients were “platinum refractory” and were enrolled in 2 separate treatment arms: patients previously treated with ≤ 2 chemotherapies (arm 1); and patients previously treated with ≤ 2 chemotherapies and small-molecule EGFR TK inhibitors (TKIs), such as erlotinib or gefitinib (arm 2). In arm 1, 42 patients were treated; a partial response (PR) rate of 4.8% was reported with a stable disease (SD) rate of 47.6% and a progression-free survival (PFS) time of 2.6 months. In arm 2, 45 patients were treated; a PR rate of 2.3% was reported with an SD rate of 37.2% and a PFS time of 2.23 months. Treatment was very well tolerated with primary grade 3/4 toxicities including fatigue (11.9%) and dyspnea (4.8%) in arm 1, and mucositis (7%), hypokalemia (4.7%), and hyponatremia (4.7%) in arm 2. The investigators concluded that RAD001 10 mg daily was active and safe in pretreated patients with advanced NSCLC.24 Based on the considerations discussed herein, we are launching a phase II randomized trial. In this study, pretreated elderly patients aged ≥ 70 years with advanced NSCLC will be randomized to receive second-line treatment, with pemetrexed or RAD001.
Objectives The primary endpoint of the present study is PFS, and secondary objectives include activity response rate (RR) and disease control rate, toxicity, and overall survival (OS) time for patients treated with pemetrexed or RAD001.
Eligibility Criteria The main selection criteria include: patients aged ≥ 70 years with Eastern Cooperative Oncology Group performance status of 0-2 and histologically or cytologically documented, measurable, unresectable stage IIIB (with pleural effusion or supraclavicular lymph node metastases)/IV NSCLC who received 1 previous chemotherapy and who have radiologic evidence of disease progression. Adequate BM, renal, and liver function are required. Patients with symptomatic brain metastases, history of cardiac disease, uncontrolled diabetes mellitus, or patients with other currently active malignancies, with the exception of nonmelanomatous skin cancer or carcinoma in situ of the cervix, are not eligible. All patients must sign institutional review board–approved informed consent forms.
Treatment Plan At the time of study registration, patients will be randomized to 1 of 2 study arms (Figure 1). Patients treated on arm A will receive pemetrexed (500 mg/m2 on day 1 every 3 weeks) for a maximum of 6 cycles. Vitaminic supplementation with vitamin B12 1000 μg, via intramuscular injection every 9 weeks, and folic acid 350-600 μg orally daily, beginning approximately 1-2 weeks before the first dose of pemetrexed is administered. Dexamethasone 4 mg orally twice daily the day before, the day of, and the day after pemetrexed, as a prophylactic measure against
Clinical Lung Cancer November 2007
569
Pemetrexed or RAD001 in Pretreated Elderly Patients with NSCLC Figure 1
Table 1 Methods of Judgment of Results Between Calibration and Experimental Arms
Treatment Schema Pemetrexed 500 mg/m2, I.V. on day 1 every 3 weeks for a maximum of 6 cycles
Elderly, aged q 70 years, patients with pretreated NSCLC
3 " / % 0 . * ; &
Vitamin B12 1000 μg via intramuscular injection every 9 weeks and folic acid 350-600 μg orally daily, beginning approximately 1-2 weeks before the first dose of Pemetrexed. Dexamethasone 4 mg orally twice daily the day before, the day of, and the day after Pemetrexed RAD001 10 mg orally daily from day 1 to day 21 of each cycle, and after 6 cycles of therapy until disease progression
rash will be administered. Patients treated on arm B will receive RAD001 (10 mg once daily orally) until disease progression. Before protocol therapy commences, patients will undergo a brain, chest, and abdomen computed tomography scan, a 12lead echocardiogram, and a bone scan. Further examinations will be performed, if necessary. Tumor response and disease progression will be evaluated based on investigator-assessed Response Evaluation Criteria in Solid Tumors.
Expected Results and Toxicities This is the first phase II randomized trial assessing pemetrexed or RAD001 as second-line therapy in patients with stage IIIB-IV NSCLC. In this trial, we attempt to prospectively confirm the interesting retrospective results reported with secondline pemetrexed in patients with advanced NSCLC.13 In this context, we will also determine if RAD001 is sufficiently active and well tolerated to warrant further exploration of the secondline treatment in this special patient population, which is often unsuitable for treatment. This phase II randomized, calibrated, 2-arm, parallel study25 consists of random allocation of patients to the investigational treatment (RAD001) or to a control arm (pemetrexed) that is known to have had activity at a certain level in the previous trial (median time to progression, 4.6 months).13 Patients assigned to the pemetrexed arm establish the “calibration” group. The calibration group is not a control group in the traditional sense, and a formal efficacy comparison between the investigational treatment group and the calibration group is not planned. Primary endpoint of the study is the rate of patients without progression at 6 months. In the calibration arm (pemetrexed), 30% of patients is expected. The sample size of the experimental arm has been calculated assuming a P0 (minimum acceptable proportion of patients without progression at 6 months) of 25%, P1 (auspicated proportion of patients without progression at 6 months) of 45%, α error (risk of false-positive result) 0.05, and power of 90%. According to these parameters, a total of 92 patients, 46 per arm, need to be randomized. At least 16 patients have to be progression free at 6 months to consider the results “positive” enough to warrant further exploration. Results obtained in the calibration arm will be used to judge the results obtained in the experimental arm, as reported in Table 1. All subjects who are enrolled and who receive study treatment will be considered in the intent-to-treat (ITT) population. The
570
Clinical Lung Cancer November 2007
Calibration Arm
Experimental Arm Positive Result
Negative Result
Better than Expected
High risk of false result; second trial recommended
Negative result
As Expected
Positive result
Negative result
Worse than Expected
Positive result
High risk of false result; second trial recommended
analysis population for all efficacy outcome variables will be the ITT population. Durations of PFS and OS will be analyzed and summarized by Kaplan-Meier methods. The objective RR for each arm will be calculated. Tolerability will be summarized by the appropriate standard summary statistics. All adverse events will be reported and graded according to National Cancer Institute Common Terminology Criteria, version 3.0. If the primary endpoint of the present phase II randomized trial should be reached, future trials could investigate RAD001 in combination with pemetrexed or an EGFR TKI, such as erlotinib or gefitinib.
References 1. Jemal A, Siegel R, Ward E, et al. Cancer statistics, 2007. CA Cancer J Clin 2007; 57:43-66. 2. Gridelli C, Shepherd F. Chemotherapy for elderly patients with non-small-cell lung cancer: a review of the evidence. Chest 2005; 128:947-57. 3. Gridelli C, Perrone F, Gallo C, et al. Chemotherapy for elderly patients with advanced non-small-cell lung cancer: the Multicenter Italian Lung cancer in the Elderly Study (MILES) phase III randomized trial. J Natl Cancer Inst 2003; 95:362-72. 4. Lewis JH, Kilgore ML, Goldman DP, et al. Participation of patients 65 years of age or older in cancer clinical trials. J Clin Oncol 2003; 21:1383-9. 5. Hutchins LF, Unger JM, Crowley JJ, et al. Underrepresentation of patients 65 years of age or older in cancer-treatment trials. N Engl J Med 1999; 341:2061-7. 6. Elderly Lung Cancer Vinorelbine Italian Study (ELVIS) Group. Effects of vinorelbine on quality of life and survival of elderly patients with advanced non-small-cell lung cancer. J Natl Cancer Inst 1999; 91:66-72. 7. Pfister DG, Johnson DH, Azzoli CG, et al. American Society of Clinical Oncology treatment of unresectable non-small-cell lung cancer guideline: update 2003. J Clin Oncol 2004; 22:330-53. 8. Gridelli C, Aapro M, Ardizzoni A, et al. Treatment of advanced non small cell lung cancer in the elderly: results of an international expert panel. J Clin Oncol 2005; 23:3125-37. 9. Shepherd FA, Dancey J, Ramlau R, et al. A prospective randomized trial of docetaxel versus best supportive care in patients with non-small-cell lung cancer previously treated with platinum-based chemotherapy. J Clin Oncol 2000; 18:2095-103. 10. Fossella FV, DeVore R, Kerr RN, et al. Randomized phase III trial of docetaxel versus vinorelbine or ifosfamide in patients with advanced non-small-cell lung cancer previously treated with platinum-containing chemotherapy regimens. The TAX 320 Non-Small Cell Lung Cancer Study Group [published correction appears in J Clin Oncol 2004; 22:209]. J Clin Oncol 2000; 18:2354-62. 11. Hanna N, Shepherd FA, Fossella FV, et al. Randomized phase III trial of pemetrexed versus docetaxel in patients with non-small-cell lung cancer previously treated with chemotherapy. J Clin Oncol 2004; 22:1589-97. 12. Shepherd FA, Pereira JR, Ciuleanu T, et al. Erlotinib in previously treated nonsmall-cell lung cancer. N Engl J Med 2005; 353:123-32. 13. Weiss GJ, Langer C, Rosell R, et al. Elderly patients benefit from second-line cytotoxic chemotherapy: a subset analysis of a randomized phase III trial of pemetrexed compared with docetaxel in patients with previously treated advanced non-small-cell lung cancer. J Clin Oncol 2006; 24:4405-11. 14. Schmelzle T, Hall MN. TOR, a central controller of cell growth. Cell 2000; 103:253-62. 15. Kozma SC, Thomas G. Regulation of cell size in growth, development and human disease: PI3K, PKB and S6K. Bioassays 2002; 24:65-71. 16. Tang JM, He QY, Guo RX, et al. Phosphorylated Akt overexpression and loss of PTEN expression in non-small cell lung cancer confers poor prognosis. Lung
• ••••••• ••• •••••••••• Cancer 2006; 51:181-91. 17. Soria JC, Lee HY, Lee JL, et al. Lack of PTEN expression in non-small cell lung cancer could be related to promoter methylation. Clin Cancer Res 2002; 8:1178-84. 18. Balsara BR, Pei J, Mitsuuchi Y, et al. Frequent activation of AKT in nonsmallcell lung carcinomas and preneoplastic bronchial lesions. Carcinogenesis 2004; 25:2053-9. 19. Proud CG. Regulation of mammalian translation factors by nutrients. Eur J Biochem 2002; 269:5338-49. 20. Peng T, Golub TR, Drenan R, et al. The immunosuppressant rapamycin mimics a starvation-like signal distinct from amino-acid and glucose deprivation. Mol Cell Biol 2002; 22:5575-84. 21. Beugnet A, Tee AR, Taylor PM, et al. Regulation of targets of mTOR (mammalian target of rapamycin) signalling by intracellular amino acid availability. Biochem J
2003; 372:555-66. 22. Schuler W, Sedrani R, Cottens S, et al. SDZ RAD, a new rapamycin derivative: pharmacological properties in vitro and in vivo. Transplantation 1997; 64:36-42. 23. O’Reilly T, Vaxelaire J, Muller M, et al. In vivo activity of RAD001, an orally active rapamycin derivative, in experimental tumor models. Proc Am Soc Cancer Res 2002; 43:17 (Abstract 359). 24. Papadimitrakopoulou V, Soria JC, Douillard JY, et al. A phase II study of RAD001 (everolimus) monotherapy in patients with advanced non-small cell lung cancer (NSCLC) failing prior platinum-based chemotherapy (C) or prior C and EGFR inhibitors. J Clin Oncol 2007; 25(18 suppl):406s (Abstract 7589). 25. Herson J, Carter SK. Calibrated phase II clinical trials in oncology. Stat Med 1986; 5:441-7.
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Key words: Chemotherapy, Everolimus, Mammalian target of rapamycin, Targeted therapy
Rationale
mentioned conditions, very few trials have been performed in this subset of patients, and a disproportionately low number of elderly participants have been included in clinical trials.4,5 Based on the results of a limited number of large, phase III, randomized trials,3,6 the American Society of Clinical Oncology guidelines recommend single-agent chemotherapy as the standard of comparison for first-line therapy for elderly patients with advanced NSCLC.7 An International Experts Panel on elderly patients with advanced NSCLC confirmed this as a main recommendation.8 To date, 2 chemotherapeutic drugs and 1 new targeted agent have been licensed for the treatment of recurrent NSCLC. Second-line chemotherapy with docetaxel can prolong survival after platinum agent–based therapy.9,10 Furthermore, pemetrexed has been approved for second-line treatment since it was demonstrated that it is not inferior in terms of clinical efficacy compared with docetaxel, but pemetrexed has significantly fewer side effects.11 Among the new targeted agents, erlotinib, an oral small-molecule inhibitor of the epidermal growth factor receptor (EGFR) tyrosine kinase (TK), is the first biologic drug registered for the treatment of pretreated NSCLC.12 To date, there is a lack of prospective data in second-line treatment of elderly patients with advanced NSCLC. An interesting retrospective analysis performed in 86 elderly (aged ≥ 70 years) of 571 patients enrolled in a randomized phase III trial comparing
Lung cancer is the leading cause of cancer death throughout the world. Non–small-cell lung cancer (NSCLC), including squamous cell carcinoma, adenocarcinoma, and large-cell carcinoma, represents approximately 80%-85% of all lung cancers. Approximately 30%-40% of all lung cancers are diagnosed in patients aged ≥ 70 years.1 Aging decreases physiological hepatic, renal, and bone marrow (BM) functions, which has a negative impact on the degree of toxicity.2 Furthermore, concomitant diseases, frequently present in this patient population, can significantly compromise functional status and general health and exacerbate tumor symptoms.3 Because most patients with NSCLC have advanced disease at diagnosis, chemotherapy is the mainstay of treatment; yet, for the previously 1Division 2Division
of Medical Oncology, “S.G. Moscati” Hospital, Avellino of Medical Oncology, Department of Clinical and Experimental Medicine and Surgery “F. Magrassi and A. Lanzara,” Second University of Naples, School of Medicine 3Division of Medical Oncology, “N. Giannettasio” Hospital, Rossano Italy Submitted: Aug 28, 2007; Revised: Sep 24, 2007; Accepted: Sep 24, 2007 Address for correspondence: Cesare Gridelli, MD, Division of Medical Oncology, “S.G. Moscati” Hospital, Città Ospedaliera, Contrada Amoretta, 83100 Avellino, Italy Fax: 39-0825-203556; e-mail: [email protected]
Electronic forwarding or copying is a violation of US and International Copyright Laws. Authorization to photocopy items for internal or personal use, or the internal or personal use of specific clients, is granted by CIG Media Group, LP, ISSN #1525-7304, provided the appropriate fee is paid directly to Copyright Clearance Center, 222 Rosewood Drive, Danvers, MA 01923 USA 978-750-8400.
568
Clinical Lung Cancer November 2007
second-line pemetrexed with docetaxel showed no significant difference in outcome between elderly and younger patients, but pemetrexed produced a more favorable toxicity profile with less febrile neutropenia and no toxic deaths.13 These data showed that pemetrexed was a safe and active chemotherapeutic agent in this subset of patients. Our increasing understanding of cancer biology has allowed the development of several potential molecular targets for NSCLC treatment essential for the acquisition of a cancer phenotype. Better toxicity profile and tolerability than chemotherapy, better target selectivity, availability for chronic treatment, and, in some cases, oral administration have marked these new targeted compounds among the most promising investigational drugs in elderly patients with advanced NSCLC. Among the several targeted agents introduced into clinical trials in NSCLC, RAD001 (everolimus) is one of the most promising. RAD001 is a novel and unique, orally available, small-molecule rapamycin analogue able to selectively inhibit the mammalian target of rapamycin (mTOR).
Biochemical and Molecular Background The mTOR is a key protein kinase which regulates cell growth, proliferation, and survival. The mTOR belongs to a family of kinases with a C terminus domain similar to the catalytic region of the phosphatidylinositol 3-kinase (PI3K), which are known as PI3K-related kinases and which also include mTOR.14 After the activation of membrane receptors by a variety of growth factors, the PI3K pathway is activated. This activation is mediated by activated K-ras or directly by some TK receptors, under the control of several growth factors and cytokines. Downstream to PI3K, protein kinase B, also named AKT, affects cell survival at multiple levels. Among substrates of AKT, mTOR is also included.15 The phosphatase and tensin homologue gene (PTEN) is a tumor suppressor gene involved in the regulation of the PI3K pathway. PTEN negatively regulates the PI3K/AKT/mTOR pathway, and cancer cells (in which the PTEN gene is deleted or its expression downregulated) exhibit constitutively activated PI3K signaling, which contributes to lung carcinogenesis.16,17 Therefore, mTOR activity can be related to loss of tumor suppressor gene PTEN and activation of AKT. Frequent AKT activation and mTOR phosphorylation were found in 51% of samples of patients with NSCLC and in 74% of NSCLC cell lines, respectively.18 The mTOR pathway is a central sensor for nutrient/energy availability, and is further modulated by PI3K/Akt-dependent mechanisms. In the presence of mitogenic stimuli and sufficient nutrients and energy, mTOR modulates translation of specific messenger RNAs through the phosphorylation state of translation proteins such as p70s6k, 4E-binding protein 1 (4E-BP1), and eukaryotic elongation factor 2. The inhibition of mTOR by starvation or targeted agents causes early G1 cell cycle arrest mediated by an inactivation of p70s6k and hypophosphorylation of 4E-BP1 (the main downstream effectors of mTOR).19-21 Preclinical studies showed that the antitumor activity of RAD001 is related to its inhibitory effects of p70s6k in tumor tissue and peripheral blood mononuclear cells.22,23
Clinical Background Recently, RAD001 has been administered at an oral dose of 10 mg per day until progression to 85 patients with refractory advanced NSCLC. All patients were “platinum refractory” and were enrolled in 2 separate treatment arms: patients previously treated with ≤ 2 chemotherapies (arm 1); and patients previously treated with ≤ 2 chemotherapies and small-molecule EGFR TK inhibitors (TKIs), such as erlotinib or gefitinib (arm 2). In arm 1, 42 patients were treated; a partial response (PR) rate of 4.8% was reported with a stable disease (SD) rate of 47.6% and a progression-free survival (PFS) time of 2.6 months. In arm 2, 45 patients were treated; a PR rate of 2.3% was reported with an SD rate of 37.2% and a PFS time of 2.23 months. Treatment was very well tolerated with primary grade 3/4 toxicities including fatigue (11.9%) and dyspnea (4.8%) in arm 1, and mucositis (7%), hypokalemia (4.7%), and hyponatremia (4.7%) in arm 2. The investigators concluded that RAD001 10 mg daily was active and safe in pretreated patients with advanced NSCLC.24 Based on the considerations discussed herein, we are launching a phase II randomized trial. In this study, pretreated elderly patients aged ≥ 70 years with advanced NSCLC will be randomized to receive second-line treatment, with pemetrexed or RAD001.
Objectives The primary endpoint of the present study is PFS, and secondary objectives include activity response rate (RR) and disease control rate, toxicity, and overall survival (OS) time for patients treated with pemetrexed or RAD001.
Eligibility Criteria The main selection criteria include: patients aged ≥ 70 years with Eastern Cooperative Oncology Group performance status of 0-2 and histologically or cytologically documented, measurable, unresectable stage IIIB (with pleural effusion or supraclavicular lymph node metastases)/IV NSCLC who received 1 previous chemotherapy and who have radiologic evidence of disease progression. Adequate BM, renal, and liver function are required. Patients with symptomatic brain metastases, history of cardiac disease, uncontrolled diabetes mellitus, or patients with other currently active malignancies, with the exception of nonmelanomatous skin cancer or carcinoma in situ of the cervix, are not eligible. All patients must sign institutional review board–approved informed consent forms.
Treatment Plan At the time of study registration, patients will be randomized to 1 of 2 study arms (Figure 1). Patients treated on arm A will receive pemetrexed (500 mg/m2 on day 1 every 3 weeks) for a maximum of 6 cycles. Vitaminic supplementation with vitamin B12 1000 μg, via intramuscular injection every 9 weeks, and folic acid 350-600 μg orally daily, beginning approximately 1-2 weeks before the first dose of pemetrexed is administered. Dexamethasone 4 mg orally twice daily the day before, the day of, and the day after pemetrexed, as a prophylactic measure against
Clinical Lung Cancer November 2007
569
Pemetrexed or RAD001 in Pretreated Elderly Patients with NSCLC Figure 1
Table 1 Methods of Judgment of Results Between Calibration and Experimental Arms
Treatment Schema Pemetrexed 500 mg/m2, I.V. on day 1 every 3 weeks for a maximum of 6 cycles
Elderly, aged q 70 years, patients with pretreated NSCLC
3 " / % 0 . * ; &
Vitamin B12 1000 μg via intramuscular injection every 9 weeks and folic acid 350-600 μg orally daily, beginning approximately 1-2 weeks before the first dose of Pemetrexed. Dexamethasone 4 mg orally twice daily the day before, the day of, and the day after Pemetrexed RAD001 10 mg orally daily from day 1 to day 21 of each cycle, and after 6 cycles of therapy until disease progression
rash will be administered. Patients treated on arm B will receive RAD001 (10 mg once daily orally) until disease progression. Before protocol therapy commences, patients will undergo a brain, chest, and abdomen computed tomography scan, a 12lead echocardiogram, and a bone scan. Further examinations will be performed, if necessary. Tumor response and disease progression will be evaluated based on investigator-assessed Response Evaluation Criteria in Solid Tumors.
Expected Results and Toxicities This is the first phase II randomized trial assessing pemetrexed or RAD001 as second-line therapy in patients with stage IIIB-IV NSCLC. In this trial, we attempt to prospectively confirm the interesting retrospective results reported with secondline pemetrexed in patients with advanced NSCLC.13 In this context, we will also determine if RAD001 is sufficiently active and well tolerated to warrant further exploration of the secondline treatment in this special patient population, which is often unsuitable for treatment. This phase II randomized, calibrated, 2-arm, parallel study25 consists of random allocation of patients to the investigational treatment (RAD001) or to a control arm (pemetrexed) that is known to have had activity at a certain level in the previous trial (median time to progression, 4.6 months).13 Patients assigned to the pemetrexed arm establish the “calibration” group. The calibration group is not a control group in the traditional sense, and a formal efficacy comparison between the investigational treatment group and the calibration group is not planned. Primary endpoint of the study is the rate of patients without progression at 6 months. In the calibration arm (pemetrexed), 30% of patients is expected. The sample size of the experimental arm has been calculated assuming a P0 (minimum acceptable proportion of patients without progression at 6 months) of 25%, P1 (auspicated proportion of patients without progression at 6 months) of 45%, α error (risk of false-positive result) 0.05, and power of 90%. According to these parameters, a total of 92 patients, 46 per arm, need to be randomized. At least 16 patients have to be progression free at 6 months to consider the results “positive” enough to warrant further exploration. Results obtained in the calibration arm will be used to judge the results obtained in the experimental arm, as reported in Table 1. All subjects who are enrolled and who receive study treatment will be considered in the intent-to-treat (ITT) population. The
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Clinical Lung Cancer November 2007
Calibration Arm
Experimental Arm Positive Result
Negative Result
Better than Expected
High risk of false result; second trial recommended
Negative result
As Expected
Positive result
Negative result
Worse than Expected
Positive result
High risk of false result; second trial recommended
analysis population for all efficacy outcome variables will be the ITT population. Durations of PFS and OS will be analyzed and summarized by Kaplan-Meier methods. The objective RR for each arm will be calculated. Tolerability will be summarized by the appropriate standard summary statistics. All adverse events will be reported and graded according to National Cancer Institute Common Terminology Criteria, version 3.0. If the primary endpoint of the present phase II randomized trial should be reached, future trials could investigate RAD001 in combination with pemetrexed or an EGFR TKI, such as erlotinib or gefitinib.
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