RationaleNon–small-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

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 Non–Small-Cell Lung CancerJyoti 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

AbstractWe 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 ad-vanced nonsquamous non–small-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 pa-tients (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 treat-ment 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 School of Medicine, Northwestern University, Chicago, IL2Rush University Medical Center, Chicago, IL3Multidisciplinary Thoracic Oncology Program, Lineberger Comprehensive Cancer Center, University of North Carolina, Chapel Hill4Washington University School of Medicine, St. Louis, MO5Eli Lilly and Company, Indianapolis, IN6Lilly USA, LLC, Indianapolis, IN ClinicalTrials.gov Identifier: 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, 60611Fax: 312-695-6189; e-mail: jd-patel@northwestern.edu.

This article might include the discussion of investigational and/or unlabeled uses of drugs and/or devices that might not be approved by the FDA.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. www.copyright.com 978-750-8400.

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Clinical Lung Cancer July 2009 | 253

The Eastern Cooperative Oncology Group (ECOG) conduct-ed 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 rec-ommended 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 mainte-nance 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 peme-trexed 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/peme-trexed 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 mainte-nance 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 de-sign, 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 signifi-cantly 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:

• Efficacy—to compare the overall response rates, the disease control rates (complete response + partial response + stable dis-ease)–assessed according to Response Evaluation Criteria in Solid Tumors, version 1.0),26 PFS, and time to progressive disease between the 2 treatment arms.

• Safety—to investigate the safety and toxicity profile of study treatments–graded according to Common Terminology Criteria for Adverse Events, version 3.0,27 and to compare hospitaliza-tions, transfusions, and concomitant medication use between the 2 treatment arms.

Study DesignFigure 1

Arm A*

450 Patients

*All patients on arm A should receive standard premedication (folic acid, vitamin B12, and dexamethasone) per the pemetrexed label.†All patients on arm B should receive standard premedication (dexamethasone, diphenhydramine, and cimetidine or ranitidine) per the paclitaxel label.‡The first dose of bevacizumab will be administered over 90 ± 15 minutes. If the first 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

Arm B†

450 Patients

Paclitaxel 200 mg/m2 I.V. every 21 daysCarboplatin AUC of 6 I.V. every 21 daysBevacizumab‡ 15 mg/kg I.V. every 21 days

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 with PD: Follow-up every 90

days until death

Patients without PD:

Follow-up every 6 weeks until PD;

thereafter, follow-up every 90 days

until death

Determinationof Eligibility

RANDOMIZATION

Pemetrexed 500 mg/m2 I.V. every 21 daysCarboplatin AUC of 6 I.V. every 21 daysBevacizumab‡ 15 mg/kg I.V. every 21 days

Pemetrexed 500 mg/m2 I.V. every 21 daysBevacizumab 15 mg/kg I.V. every 21 days

Bevacizumab 15 mg/kg I.V. every 21 days

Post-discontinuation

Follow-up

• Quality of life—to evaluate differences in patient-reported outcomes as assessed by the Functional Assessment of Cancer Therapy-Lung/Neurotoxicity28,29 instrument between the 2 treatment arms.

• Pharmacokinetics—to characterize pharmacokinetics of carbo-platin (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 research—to assess biomarkers relevant to peme-

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

Study DesignThis multicenter, randomized, open-label phase III study con-

sists of eligible patients randomized in a 1:1 ratio to 1 of 2 treat-ment arms. Patients (n = 450) in arm A will receive intravenous

Patient Selection CriteriaTable 1

Inclusion Criteria

Exclusion Criteria

Abbreviations: ECOG = Eastern Cooperative Oncology group; NSCLC = non–small-cell lung cancer; RECIST = Response Evaluation Criteria in Solid Tumors

• Signed informed consent document

• Histologic or cytologic diagnosis of advanced, nonsquamous NSCLC (stage IIIB with pleural effusions 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 defined 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

• Clinically significant third-space fluid 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 significant traumatic injury within 28 days before day 1 of cycle 1

• Core biopsy or other minor surgical procedure within 7 days

• History of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis

• Currently ongoing treatment with full-dose warfarin or equivalent

• Significant 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 superficial basal cell and superficial 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-inflammatory 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

The PointBreak Study

254 | Clinical Lung Cancer July 2009

Jyoti D. Patel et al

Clinical Lung Cancer July 2009 | 255

(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 + bevaci-zumab 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 non-measurable 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 pre-medication as specified in the paclitaxel label (dexamethasone, diphenhydramine, and cimetidine or ranitidine).31 Figure 1 il-lustrates the study design.

Study PopulationThe 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 cyto-logic 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 pre-dominantly squamous cell NSCLC histology or had any previous systemic chemotherapy, immunotherapy, targeted therapy, or bio-logic therapy, including adjuvant therapy, for any stage of NSCLC. Please see Table 1 for a full list of eligibility criteria.

Statistical Analysis PlanThe 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 peme-trexed-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 re-ceiving ≥ 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 oth-erwise 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 second-ary efficacy endpoints, response rate and disease control rate.

For the secondary translational research endpoint, the distribu-tions 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 staining–assessed protein expression, will be summarized in frequency tables for the total

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 StudyIf 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.

AcknowledgementsThe 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.

DisclosuresThis 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 consul-tant/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 con-sultant/advisory relationship, has received research funding from, and is on the Speaker’s Bureau for Eli Lilly and Company.

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