Study of Participants With Advanced Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00948675
• Recruitment Status: Completed
• First Posted: July 29, 2009
• Results First Posted: April 2, 2014
• Last Update Posted: October 29, 2021
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: July 28, 2009
• First Posted Date: July 29, 2009
• Results First Submitted Date: January 14, 2014
• Results First Posted Date: April 2, 2014
• Last Update Posted Date: October 29, 2021
• Actual Study Start Date: September 1, 2009
• Actual Primary Completion Date: January 31, 2013 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: March 4, 2014)

Progression Free Survival Without Grade 4 Toxicity (G4PFS) as Measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0 [ Time Frame: Randomization to measured progressive disease or treatment discontinuation up to 39.49 months ]

G4PFS was defined as the duration from the date of randomization to the earliest occurrence date of one of the following three events: Common Terminology Criteria (CTC) grade 4 adverse events (G4AEs), or progressive disease (PD) or death from any cause, whichever occurred earlier. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD is ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants who had no G4AEs, or PD, or death at the time of the data inclusion cutoff, PFS was censored at their last objective progression-free disease assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy.

• Original Primary Outcome Measures (submitted: July 28, 2009): Progression free survival without grade 4 toxicity as measured by the Common Terminology Criteria for Adverse Events (CTCAE) Version 3.0. [ Time Frame: Baseline to measured progressive disease or treatment discontinuation, assessed at 3 years. ]

Current Secondary Outcome Measures (submitted: October 18, 2021)

• Progression Free Survival (PFS) [ Time Frame: Randomization to measured progressive disease up to 39.49 months ]
  PFS was defined as the duration from the date of randomization to the date of progressive disease (PD) or death from any cause. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. PD was ≥20% increase in sum of longest diameter of target lesions or the appearance of new lesions. For participants who had no PD or death at the time of the data inclusion cutoff, PFS was censored at their last objective progression-free disease assessment prior to the cutoff date or the date of initiation of subsequent systemic anticancer therapy.
• Overall Survival (OS) [ Time Frame: Randomization to date of death from any cause up to 39.49 months ]
  OS was defined as the duration from the date of randomization to the date of death from any cause. For participants who were alive at the time of the data inclusion cutoff, OS was censored at the last date the participant was known to be alive.
• Percentage of Participants With Complete Response or Partial Response (Overall Tumor Response Rate) [ Time Frame: Baseline to date of objective progressive disease up to 39.49 months ]
  Overall Response rate (ORR) was the percentage of participants with a confirmed complete response (CR) or partial response (PR), as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR was the disappearance of all target and non-target lesions; PR was a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesions. ORR was calculated as a total number of participants with CR or PR from the start of study treatment until disease progression or recurrence divided by the total number of participants treated, then multiplied by 100.
• Disease Control Rates Defined as Complete Response (CR), Partial Response (PR), and Stable Disease (SD) [ Time Frame: Baseline to date of objective progressive disease up to 39.49 months ]
  Disease control rate was the percentage of participants with a confirmed CR, PR or SD, as classified by the investigators according to the Response Evaluation Criteria In Solid Tumors (RECIST) criteria version 1.0. CR was the disappearance of all target and non-target lesions; PR was a ≥30% decrease in sum of longest diameter of target lesions without new lesion and progression of non-target lesion; SD was neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive disease. Disease control rate was calculated as a total number of participants with CR or PR or SD divided by the total number of participants treated, then multiplied by 100.

Original Secondary Outcome Measures (submitted: July 28, 2009)

• Progression free survival [ Time Frame: Baseline to measured progressive disease, assessed at 3 years. ]
• Overall survival [ Time Frame: Baseline to date of death from any cause, assessed at 3 years. ]
• Overall Tumor Response rate [ Time Frame: Baseline to date of confirmed response, assessed at every other 21 day cycle. ]
• Disease control rates defined as complete response, partial response, and stable disease [ Time Frame: Baseline to date of confirmed response, assessed at every other 21 day cycle. ]

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: Study of Participants With Advanced Non-Small Cell Lung Cancer
• Official Title: A Study of Pemetrexed Plus Carboplatin Followed by Maintenance Pemetrexed vs Paclitaxel Plus Carboplatin and Bevacizumab Followed by Maintenance Bevacizumab in Patients With Advanced NCSLC of Nonsquamous Histology
• Brief Summary: The purpose of this study is to compare the regimens of pemetrexed, carboplatin with pemetrexed maintenance and paclitaxel, carboplatin, bevacizumab with bevacizumab maintenance in participants with Stage IV nonsquamous non-small cell lung cancer.
• Detailed Description: This is a multicenter, randomized, open-label, Phase III trial. Eligible participants will be randomized in a 1:1 ratio to receive pemetrexed and carboplatin followed by pemetrexed or paclitaxel, carboplatin, and bevacizumab followed by bevacizumab as their study treatment. Participants randomized to Pemetrexed + Carboplatin + Pemetrexed will receive folic acid, vitamin B12, and dexamethasone as stated in the pemetrexed label. Before administration of paclitaxel, participants randomized to Paclitaxel + Carboplatin + Bevacizumab will receive premedication (dexamethasone, diphenhydramine, and cimetidine or ranitidine) as recommended in the paclitaxel label.
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Condition: Advanced Non-Small Cell Lung Cancer

Intervention

• Drug: Pemetrexed
  Induction therapy: 500 milligrams/square meter (mg/m²) given intravenously every 21 days for 4 cycles. Maintenance therapy: 500 mg/m² given intravenously every 21 days until disease progression or treatment discontinuation.
  Other Name: ALIMTA, LY231514
• Drug: Carboplatin
  Induction Therapy (every 21 days for 4 cycles): Area Under the Curve (AUC) 6 [maximum possible dose of 900 milligrams (mg)] intravenously infused over 30 minutes.
• Drug: Paclitaxel
  Induction Therapy (every 21 days for 4 cycles): 200 mg/m² intravenously infused over 3 hours
• Biological: Bevacizumab
  Induction therapy: 15 milligrams/kilogram (mg/kg) given intravenously every 21 days for 4 cycles. Maintenance therapy: 15 mg/kg given intravenously every 21 days until disease progression or treatment discontinuation.

Study Arms

• Experimental: Pemetrexed + Carboplatin + Pemetrexed
  Pemetrexed and Carboplatin followed by Pemetrexed
  Interventions:

  • Drug: Pemetrexed
  • Drug: Carboplatin
• Active Comparator: Paclitaxel + Carboplatin + Bevacizumab
  Paclitaxel, Carboplatin, and Bevacizumab followed by Bevacizumab
  Interventions:

  • Drug: Carboplatin
  • Drug: Paclitaxel
  • Biological: Bevacizumab

• Publications *: Zinner RG, Obasaju CK, Spigel DR, Weaver RW, Beck JT, Waterhouse DM, Modiano MR, Hrinczenko B, Nikolinakos PG, Liu J, Koustenis AG, Winfree KB, Melemed SA, Guba SC, Ortuzar WI, Desaiah D, Treat JA, Govindan R, Ross HJ. PRONOUNCE: randomized, open-label, phase III study of first-line pemetrexed + carboplatin followed by maintenance pemetrexed versus paclitaxel + carboplatin + bevacizumab followed by maintenance bevacizumab in patients ith advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2015 Jan;10(1):134-42. doi: 10.1097/JTO.0000000000000366.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: March 4, 2014): 361
• Original Estimated Enrollment (submitted: July 28, 2009): 360
• Actual Study Completion Date: November 6, 2020
• Actual Primary Completion Date: January 31, 2013 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• a histologic or cytologic diagnosis of advanced non-small cell lung cancer (NSCLC) [Stage IV from the American Joint Committee on Cancer Staging Criteria (AJCC) staging system, version 7.0, including both M1a and M1b], other than predominantly squamous cell histology, that is not amenable to curative therapy. Participants may not have received any prior systemic chemotherapy, immunotherapy, targeted therapy, or biological therapy, including adjuvant therapy, for any stage of NSCLC.
• prior radiation therapy is allowed to < 25% of the bone marrow; however, prior radiation to the whole pelvis not allowed.
• good performance status.
• adequate organ function.
• estimated life expectancy of at least 12 weeks.

Exclusion Criteria:

• known central nervous system (CNS) disease, other than treated brain metastasis.
• major surgical procedure, open biopsy, open pleurodesis, or significant traumatic injury within 28 days prior to study or have an anticipated need for major surgery during the study.
• core biopsy or other minor surgical procedure, excluding placement of vascular access device, closed pleurodesis, thoracentesis, and mediastinoscopy, within 7 days prior to study.
• history of gastrointestinal fistula, perforation, or abscess, inflammatory bowel disease, or diverticulitis.
• currently receiving ongoing treatment with full-dose warfarin or equivalent
• significant vascular disease within 6 months prior to Day 1 of Cycle 1.
• evidence of bleeding diathesis or coagulopathy.
• serious concomitant systemic disorder that, in the opinion of the investigator, would compromise the participant's ability to adhere to the protocol.
• serious cardiac condition, such as myocardial infarction, angina, or heart disease.
• inadequately controlled hypertension.
• any prior 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 last 5 years.
• previously received treatment with paclitaxel, carboplatin, pemetrexed, or bevacizumab (prior intravitreal administration of bevacizumab does not preclude study participation).
• pregnant or breast-feeding.
• history of stroke or transient ischemic attack within 6 months prior to study.
• known sensitivity to any component of paclitaxel, carboplatin, pemetrexed, or bevacizumab.
• history of hemoptysis within 3 months prior to randomization.
• unable to interrupt aspirin or other nonsteroidal anti-inflammatory drugs (NSAIDs).
• unwilling to take folic acid or vitamin B12 supplementation.
• clinically significant third-space fluid collections, for example, ascites or pleural effusions that cannot be controlled by drainage. Participants with M1a disease with pleural effusions are eligible if the effusions can be adequately controlled.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: United States
• Removed Location Countries: Puerto Rico

Administrative Information

• NCT Number: NCT00948675
• Other Study ID Numbers: 13258; H3E-US-S130 ( Other Identifier: Eli Lilly and Company )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided

IPD Sharing Statement

• Plan to Share IPD: Yes
• Plan Description: Anonymized individual patient level data will be provided in a secure access environment upon approval of a research proposal and a signed data sharing agreement.
• Supporting Materials: Study Protocol
• Supporting Materials: Statistical Analysis Plan (SAP)
• Supporting Materials: Clinical Study Report (CSR)
• Time Frame: Data are available 6 months after the primary publication and approval of the indication studied in the US and EU, whichever is later. Data will be indefinitely available for requesting.
• Access Criteria: A research proposal must be approved by an independent review panel and researchers must sign a data sharing agreement.
• URL: https://vivli.org/

• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Chief Medical Officer, Eli Lilly
• Current Study Sponsor: Eli Lilly and Company
• Original Study Sponsor: Same as current
• Collaborators: Not Provided

Investigators

• Study Director: Call 1-877-CTLILLY (1-877-285-4559) or 1-317-615-4559 Mon - Fri 9 AM - 5 PM Eastern time (UTC/GMT - 5 hours, EST); Eli Lilly and Company

• PRS Account: Eli Lilly and Company
• Verification Date: October 2021