current trial

Treatment Rationale and Study Design for the PointBreak Study: A Randomized, Open-label Phase III Study of Pemetrexed/Carboplatin/Bevacizumab Followed by Maintenance Pemetrexed/Bevacizumab Versus Paclitaxel/Carboplatin/Bevacizumab Followed by Maintenance Bevacizumab in Patients with Stage IIIB or IV Nonsquamous NonSmall-Cell Lung Cancer
Jyoti D. Patel,1 Philip Bonomi,2 Mark A. Socinski,3 Ramaswamy Govindan,4 Shengyan Hong,5 Coleman Obasaju,6 Eduardo J. Pennella,6 Allicia C. Girvan,6 Susan C. Guba5
Abstract
We present the treatment rationale and study design of the PointBreak study, a phase III study of pemetrexed/ carboplatin/bevacizumab induction followed by pemetrexed/bevacizumab maintenance (arm A) compared with paclitaxel/carboplatin/bevacizumab induction followed by bevacizumab maintenance (arm B) in patients with advanced nonsquamous nonsmall-cell lung cancer (NSCLC). Treatment consists of up to 4 cycles of induction therapy followed by maintenance therapy until disease progression or treatment discontinuation in approximately 900 patients (450 per treatment arm). The efficacy objectives of this study are to compare overall survival (OS), response rates, disease control rates, progression-free survival, and time to progressive disease between the 2 treatment arms. In addition, safety, quality of life, pharmacokinetics, and translational research will be investigated for both treatment arms. If the primary objective (OS) is achieved, this study will provide robust results on an alternative treatment option, pemetrexed/carboplatin/bevacizumab followed by maintenance therapy with pemetrexed/bevacizumab, for patients with nonsquamous NSCLC. Clinical Lung Cancer, Vol. 10, No. 4, 252-256, 2009; DOI: 10.3816/CLC.2009.n.035 Keywords: Antifolate, Biomarkers, Induction therapy, Maintenance therapy

1Feinberg 2Rush

School of Medicine, Northwestern University, Chicago, IL University Medical Center, Chicago, IL 3Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill 4Washington University School of Medicine, St. Louis, MO 5Eli Lilly and Company, Indianapolis, IN 6Lilly USA, LLC, Indianapolis, IN ClinicalTrials.gov Identier: NCT00762034 Submitted: Mar 23, 2009; Revised: May 6, 2009; Accepted: May 13, 2009 Address for correspondence: Jyoti D. Patel, MD, Division of Hematology/Oncology, Feinberg School of Medicine, Northwestern University, 676 N. St. Claire, Ste 850, Chicago, IL, 60611 Fax: 312-695-6189; e-mail: jd-patel@northwestern.edu.

Rationale
Nonsmall-cell lung cancer (NSCLC) constitutes approximately 85% of all lung cancers.1 About 2/3 of patients are diagnosed with inoperable, locally advanced or metastatic stage IIIB or stage IV disease.2 Although innovations in the treatment of advanced or metastatic NSCLC have led to survival and quality-of-life benefits in recent years, the 5-year overall survival (OS) rate in the United States is relatively unchanged, supporting the need for further clinical trials.3 According to the American Society of Clinical Oncology (ASCO) and the European Society of Medical Oncology, patients with inoperable NSCLC who maintain good performance status are candidates for palliative chemotherapy consisting of standard induction therapy with 4-6 cycles of a platinum-based doublet.4,5

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Figure 1 Study Design

R A N D O M I Z A T I O N

Arm A* 450 Patients

Pemetrexed 500 mg/m2 I.V. every 21 days Carboplatin AUC of 6 I.V. every 21 days Bevacizumab 15 mg/kg I.V. every 21 days

Pemetrexed 500 mg/m2 I.V. every 21 days Bevacizumab 15 mg/kg I.V. every 21 days Postdiscontinuation Follow-up

Determination of Eligibility

Arm B 450 Patients

Paclitaxel 200 mg/m2 I.V. every 21 days Carboplatin AUC of 6 I.V. every 21 days Bevacizumab 15 mg/kg I.V. every 21 days

Bevacizumab 15 mg/kg I.V. every 21 days Patients with PD:

Follow-up every 90 days until death

Induction Therapy:
Up to four 21-day cycles Patients with CR, PR, or SD after 4 cycles of induction therapy continue on to maintenance therapy

Maintenance Therapy:
Until PD or treatment discontinuation

Patients without PD:

Follow-up every 6 weeks until PD; thereafter, follow-up every 90 days until death

patients on arm A should receive standard premedication (folic acid, vitamin B12, and dexamethasone) per the pemetrexed label. patients on arm B should receive standard premedication (dexamethasone, diphenhydramine, and cimetidine or ranitidine) per the paclitaxel label. rst dose of bevacizumab will be administered over 90 15 minutes. If the rst infusion is tolerated without infusion-associated adverse events (fever and/or chills), the second infusion may be delivered over 60 10 minutes. If the 60-minute infusion is well tolerated, subsequent infusions may be delivered over 30 10 minutes. Abbreviations: AUC = area under the curve; CR = complete response; I.V. = intravenous; PD = progressive disease; PR = partial response; RECIST = Response Evaluation Criteria in Solid Tumors; SD = stable disease
All The

*All

The Eastern Cooperative Oncology Group (ECOG) conducted a randomized study comparing 4 platinum-based doublets (cisplatin/paclitaxel, cisplatin/gemcitabine, cisplatin/docetaxel, and carboplatin/paclitaxel) in patients with advanced NSCLC. All 4 arms of the study demonstrated comparable median OS.6 The ECOG subsequently recommended carboplatin/paclitaxel as a reference regimen for future studies. In 2006, bevacizumab, in combination with carboplatin/ paclitaxel, received approval as an initial therapy for patients with advanced nonsquamous NSCLC on the basis of a 2-month improvement in OS. This triplet regimen was subsequently recommended by the National Comprehensive Cancer Network for first-line treatment of patients with nonsquamous NSCLC7,8 and has become a standard of care in that population. For maintenance therapy in the treatment of advanced NSCLC, studies with docetaxel, paclitaxel, gemcitabine, and bevacizumab have evaluated possible benefits from the use of single-agent treatment beyond the recommended 4-6 cycles of platinum-based chemotherapy.7,9-12 Randomized phase III clinical studies have demonstrated that pemetrexed is efficacious as a single agent in the second-line treatment of NSCLC, and in combination with cisplatin for the first-line treatment of nonsquamous NSCLC.13,14 In the first-line study, cisplatin/pemetrexed was compared with cisplatin/gemcitabine, and patients with advanced NSCLC with nonsquamous histology had superior OS.15 Preliminary data from another randomized phase III clinical trial demonstrated superior OS when pemetrexed was used in the maintenance setting following 4 cycles of non-pemetrexed induction therapy containing a platinum doublet.16 Activity was also observed in a phase II study of the combination of pemetrexed/carboplatin/bevacizumab followed by pemetrexed/bevacizumab maintenance.17-19 These results provide the basis for the current study design, which compares the induction combination of pemetrexed/

carboplatin/bevacizumab with a standard of care in nonsquamous advanced-stage NSCLC, paclitaxel/carboplatin/bevacizumab. The addition of pemetrexed to the carboplatin/bevacizumab induction doublet is intended to improve patient outcomes without significantly increasing toxicity. Maintenance therapy will be given in both arms of this study; the combination of pemetrexed/bevacizumab in the pemetrexed arm will be compared with bevacizumab alone in the paclitaxel arm to determine if patient benefit can be further augmented with pemetrexed maintenance therapy. The 2003 ASCO treatment guidelines recommend a maximum of 4-6 cycles of platinum-based therapy as initial treatment of patients with stage III and stage IV NSCLC.4 However, studies have shown that chemotherapy beyond 4 cycles does not improve median OS (though progression-free survival [PFS] is improved) and increases toxicity.1,20-25 In this superiority study of patients with advanced NSCLC and nonsquamous histology, induction will be stopped after 4 cycles to ensure that all nonprogressing patients will be able to tolerate subsequent maintenance therapy.

Study Objectives
The primary objective of this study is to compare OS between the 2 study arms. Secondary objectives include the following: Efficacyto compare the overall response rates, the disease control rates (complete response + partial response + stable disease)assessed according to Response Evaluation Criteria in Solid Tumors, version 1.0),26 PFS, and time to progressive disease between the 2 treatment arms. Safetyto investigate the safety and toxicity profile of study treatmentsgraded according to Common Terminology Criteria for Adverse Events, version 3.0,27 and to compare hospitalizations, transfusions, and concomitant medication use between the 2 treatment arms.

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Table 1 Patient Selection Criteria
Inclusion Criteria Signed informed consent document Histologic or cytologic diagnosis of advanced, nonsquamous NSCLC (stage IIIB with pleural eusions or IV disease) that is not amenable to curative therapy No previous systemic chemotherapy, immunotherapy, targeted therapy, or biologic therapy, including adjuvant therapy, for any stage of NSCLC Previous radiation therapy is allowed to < 25% of the bone marrow Measurable or nonmeasurable disease as dened by RECIST Men and women aged 18 years Performance status of 0 or 1 on the ECOG scale Adequate organ function Male and female patients with reproductive potential must use an approved contraceptive method Women with childbearing potential must have a negative serum or urine pregnancy test within 7 days before day 1 of cycle 1 Estimated life expectancy of 12 weeks Able to comply with study and/or follow-up procedures Exclusion Criteria Clinically signicant third-space uid collections Predominantly squamous cell histology NSCLC Known central nervous system disease, other than stable, treated brain metastasis Major surgical procedure, open biopsy, open pleurodesis, or signicant traumatic injury within 28 days before day 1 of cycle 1 Core biopsy or other minor surgical procedure within 7 days History of gastrointestinal stula, perforation, or abscess, inammatory bowel disease, or diverticulitis Currently ongoing treatment with full-dose warfarin or equivalent Signicant vascular disease Evidence of bleeding diathesis or coagulopathy Serious cardiac condition, such as myocardial infarction, angina, or heart disease Inadequately controlled hypertension Any previous history of hypertensive crisis or hypertensive encephalopathy Serious, nonhealing wound, active ulcer, or untreated bone fracture Another active malignancy, other than supercial basal cell and supercial squamous (skin) cell, or carcinoma in situ of the cervix within the past 5 years Treatment within the last 30 days before day 1 of cycle 1 with any drug that has not received regulatory approval for any indication at the time of study entry Pregnant or breast-feeding History of stroke or transient ischemic attack Known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab History of hemoptysis Unable to interrupt acetylsalicylic acid or other nonsteroidal anti-inammatory drugs, other than an acetylsalicylic acid dose 1.3 g per day, for a 5-day period Unable or unwilling to take folic acid or vitamin B12 supplementation Unable to take corticosteroids Serious concomitant systemic disorder
Abbreviations: ECOG = Eastern Cooperative Oncology group; NSCLC = nonsmall-cell lung cancer; RECIST = Response Evaluation Criteria in Solid Tumors

Quality of lifeto evaluate differences in patient-reported outcomes as assessed by the Functional Assessment of Cancer Therapy-Lung/ Neurotoxicity28,29 instrument between the 2 treatment arms. Pharmacokineticsto characterize pharmacokinetics of carboplatin (total and free platinum) and bevacizumab and compare between the 2 treatment arms, as well as to evaluate pemetrexed pharmacokinetics in patients randomized to arm A. Translational researchto assess biomarkers relevant to peme-

trexed, carboplatin, and bevacizumab, to investigate biomarkers relevant to the disease state, and to examine the correlation between biomarkers and clinical outcomes.

Study Design
This multicenter, randomized, open-label phase III study consists of eligible patients randomized in a 1:1 ratio to 1 of 2 treatment arms. Patients (n = 450) in arm A will receive intravenous

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Jyoti D. Patel et al
(I.V.) pemetrexed 500 mg/m2 + carboplatin area under the curve (AUC) of 6 + bevacizumab 15 mg/kg on the first day of up to four 21-day cycles, followed by I.V. pemetrexed 500 mg/m2 + bevacizumab 15 mg/kg for maintenance. Patients (n = 450) in arm B will receive I.V. paclitaxel 200 mg/m2 + carboplatin AUC of 6 + bevacizumab 15 mg/kg on the first day of up to four 21-day cycles, followed by I.V. bevacizumab 15 mg/kg for maintenance. Randomization will be stratified by the following factors: disease stage (IIIB with pleural effusions vs. IV), measurable versus nonmeasurable disease, ECOG performance status (0 vs. 1), and sex (male vs. female). As specified in the pemetrexed label, patients randomized to arm A will receive folic acid, vitamin B12, and dexamethasone.30 Patients assigned to arm B will receive premedication as specified in the paclitaxel label (dexamethasone, diphenhydramine, and cimetidine or ranitidine).31 Figure 1 illustrates the study design. population and by treatment arm. Associations between clinical endpoints and markers will be evaluated using data from patients who have a reported value for the marker measure of interest.

Impact of the Study

If the primary endpoint is achieved, this study will provide robust results on an alternative treatment option, pemetrexed/carboplatin/ bevacizumab followed by maintenance therapy with pemetrexed/ bevacizumab for patients with nonsquamous NSCLC.

Acknowledgements
The authors thank in advance all the patients, investigators, and institutions that will be involved in this study. They also thank Jayme L. Opolka and Patti Moore for assistance with manuscript preparation and Barbara J. McLean for editorial assistance.

Disclosures
This work was sponsored by Eli Lilly and Company, Indianapolis, IN. Drs. Obasaju, Pennella, Girvan, Guba, and Hong are full-time employees and minor stockholders of Eli Lilly and Company. Dr. Patel has a consultant/advisory relationship with and has received research funding from Eli Lilly and Company. Dr. Govindan reports a consultant/advisory relationship with Eli Lilly and Company; Genentech, Inc.; AstraZeneca, and ImClone Systems Incorporated. Dr. Socinski received research funding from and is on the Speakers Bureau for both Eli Lilly and Company and Genentech, Inc.; Dr. Bonomi has a consultant/advisory relationship, has received research funding from, and is on the Speakers Bureau for Eli Lilly and Company.

Study Population
The protocol will be approved by each participating institutional ethics review board. The study will be conducted in accordance with the ethical principles of the Declaration of Helsinki and good clinical practice. All patients will sign written informed consent before treatment. Inclusion criteria include a histologic or cytologic diagnosis of advanced, nonsquamous NSCLC (stage IIIB with pleural effusions or IV disease); measurable or nonmeasurable disease; age 18 years; adequate organ function; and stable brain metastases. Patients are ineligible for the study if they have predominantly squamous cell NSCLC histology or had any previous systemic chemotherapy, immunotherapy, targeted therapy, or biologic therapy, including adjuvant therapy, for any stage of NSCLC. Please see Table 1 for a full list of eligibility criteria.

References
1. Lustberg MB, Edelman MJ. Optimal duration of chemotherapy in advanced nonsmall cell lung cancer. Curr Treat Options Oncol 2007; 8:38-46. 2. Boulikas T, Vougiouka M. Recent clinical trials using cisplatin, carboplatin and their combination chemotherapy drugs. (review) Oncol Rep 2004; 11:559-95. 3. American Cancer Society. Cancer Facts and Figures 2008. Available at: http:// www.cancer.org/docroot/STT/stt_0.asp. Accessed February 20, 2009. 4. 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. 5. DAddario G, Felip E. Non-small-cell lung cancer: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol 2008; 19(suppl 2):ii39-40. 6. Schiller JH, Harrington D, Belani CP, et al. Comparison of four chemotherapy regimens for advanced non-small-cell lung cancer. N Engl J Med 2002; 346:92-8. 7. Sandler A, Gray R, Perry MC, et al. Paclitaxel-carboplatin alone or with bevacizumab for non-small cell lung cancer. N Engl J Med 2006; 355:2542-50. 8. National Comprehensive Cancer Network. NCCN clinical practice guidelines in oncology: non-small cell lung cancer. 2008. Available at: http://www.nccn. org/Registration/login/login.aspx. Accessed February 23, 2009. 9. Sekine I, Nokihara H, Sumi M, et al. Docetaxel consolidation therapy following cisplatin, vinorelbine, and concurrent thoracic radiotherapy in patients with unresectable stage III non-small cell lung cancer. J Thorac Oncol 2006; 1:810-5. 10. Fidias P, Dakhil S, Lyss A, et al. Phase III study of immediate versus delayed docetaxel after induction therapy with gemcitabine plus carboplatin in advanced non-small-cell lung cancer: updated report with survival. J Clin Oncol 2007; 25(suppl):388s (Abstract 7516). 11. Belani CP, Perry MC, La Rocca RV, et al. Maintenance therapy (MT) with weekly paclitaxel improves outcome for advanced non-small cell lung cancer (NSCLC) patients. J Clin Oncol 2005; 23(suppl):656s (Abstract 7143). 12. Brodowicz T, Krzakowski M, Zwitter M, et al. Cisplatin and gemcitabine first-line chemotherapy followed by maintenance gemcitabine or best supportive care in advanced non-small cell lung cancer: a phase III trial. Lung Cancer 2006; 52:155-63. 13. 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. 14. Scagliotti GV, Parikh P, von Pawel J, et al. Phase III study comparing cisplatin plus gemcitabine with cisplatin plus pemetrexed in chemotherapy-naive patients with advanced-stage non-small-cell lung cancer. J Clin Oncol 2008; 26:3543-51. 15. Scagliotti GV, Hanna N, Fossella F, et al. The differential efficacy of pemetrexed according to NSCLC histology: a review of two phase III studies. Oncologist 2009; 14:000-000.

Statistical Analysis Plan

The study will enroll approximately 900 patients (450 per arm), with the final analysis of OS to be performed after 676 deaths have occurred. An external Data Monitoring Committee (DMC) will be responsible for 4 planned interim analyses. The study will have the overall type I error of 1-sided 0.025 (or 2-sided 0.05) and overall power of 80%, assuming a true hazard ratio 0.80 of the pemetrexed-combination arm over the paclitaxel-combination arm. The efficacy analyses will be conducted on an intent-to-treat basis, and the safety analyses will include all enrolled patients receiving 1 dose of any of the study drugs. All tests of treatment effects will be conducted at a 2-sided level of 0.05, all tests of interactions will be conducted at a 2-sided level of 0.10, and all confidence intervals will be given at a 2-sided 95% level, unless otherwise stated. Log-rank tests32 and Kaplan-Meier estimations33 will be used for the OS, PFS, and time to progressive disease efficacy endpoints. Fisher exact tests will be performed for the other secondary efficacy endpoints, response rate and disease control rate. For the secondary translational research endpoint, the distributions of biomarkers with continuous measures, such as gene or protein expression, will be described for the total patient population and by treatment arm. Biomarkers with discrete measures, such as genotype locus or immunohistochemistry stainingassessed protein expression, will be summarized in frequency tables for the total

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16. Ciuleanu TE, Brodowicz T, Belani CP, et al. Maintenance pemetrexed plus best supportive care (BSC) versus placebo plus BSC: a phase III study. J Clin Oncol 2008; 26(15 suppl):426s (Abstract 8011). 17. Patel JD, Hensing TA, Rademaker A, et al. Phase II trial of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for advanced non-squamous nonsmall cell lung cancer. Poster presented at: Annual Meeting of the American Society of Clinical Oncology; 2008; Chicago, Il. 18. Patel JD, Hensing TA, Villafor V, et al. Pemetrexed and carboplatin plus bevacizumab for advanced non-squamous non-small cell lung cancer (NSCLC): preliminary results. J Clin Oncol 2007; 25(18 suppl):409s (Abstract 7601). 19. Patel JD, Hensing TA, Rademaker A, et al. Phase II study of pemetrexed and carboplatin plus bevacizumab with maintenance pemetrexed and bevacizumab as first-line therapy for non-small cell lung cancer. J Clin Oncol 2009; [in press]. 20. Larsen H, Sorensen JB, Nielsen AL, et al. Evaluation of the optimal duration of chemotherapy in phase II trials for inoperable non-small-cell lung cancer (NSCLC). Ann Oncol 1995; 6:993-7. 21. Smith IE, OBrien ME, Talbot DC, et al. Duration of chemotherapy in advanced non-small-cell lung cancer: a randomized trial of three versus six courses of mitomycin, vinblastine, and cisplatin. J Clin Oncol 2001; 19:1336-43. 22. Socinski MA, Schell MJ, Peterman A, et al. Phase III trial comparing a defined duration of therapy versus continuous therapy followed by second-line therapy in advanced-stage IIIB/IV non-small-cell lung cancer. J Clin Oncol 2002; 20:1335-43. 23. Park JO, Kim SW, Ahn JS, et al. Phase III trial of two versus four additional cycles in patients who are nonprogressive after two cycles of platinum-based chemotherapy in non small-cell lung cancer. J Clin Oncol 2007; 25:5233-9. 24. Socinski MA, Stinchcombe TE. Duration of first-line chemotherapy in advanced non small-cell lung cancer: less is more in the era of effective subsequent therapies. J Clin Oncol 2007; 25:5155-7. 25. Soon YY, Askie L, Stockler M, et al. Optimal duration of chemotherapy for advanced non-small cell lung cancer: a systematic review and meta-analysis. J Thorac Oncol 2007; 2(8 suppl 4):S450-S451. Abstract PD4-2-1. 26. Therasse P, Arbuck SG, Eisenhauer EA, et al. New guidelines to evaluate the response to treatment in solid tumors. J Natl Cancer Inst 2000; 92:205-16. 27. National Cancer Institute. Common Terminology Criteria for Adverse Events v3.0 (CTCAE). 2006. Available at: http://ctep.cancer.gov/reporting/ctc_v30. html. Accessed February 23, 2009. 28. Cella DF, Bonomi AE, Lloyd SR, et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Lung (FACT-L) quality of life instrument. Lung Cancer 1995; 12:199-220. 29. Calhoun EA, Welshman EE, Chang CH, et al. Psychometric evaluation of the Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (Fact/GOG-Ntx) questionnaire for patients receiving systemic chemotherapy. Int J Gynecol Cancer 2003; 13:741-8. 30. Alimta (pemetrexed). Indianapolis, IN: Eli Lilly and Company; 2008. [prescribing information]. 31. Taxol (paclitaxel). Princeton, NJ: Bristol-Myers Squibb Company; 2007. [prescribing information]. 32. Freedman LS. Tables of the number of patients required in clinical trials using the logrank test. Stat Med 1982; 1:121-9. 33. Kaplan EL, Meier P. Nonparametric estimation from incomplete observations. J Am Stat Assoc 1958; 53:457-81.

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