A Study of Induction and Maintenance Treatment of Advanced Non-squamous Non-Small Cell Lung Cancer

• ClinicalTrials.gov Identifier: NCT00789373
• Recruitment Status: Completed
• First Posted: November 11, 2008
• Results First Posted: July 18, 2011
• Last Update Posted: December 14, 2018
• Sponsor: Eli Lilly and Company
• Information provided by (Responsible Party): Eli Lilly and Company

Tracking Information

• First Submitted Date: November 10, 2008
• First Posted Date: November 11, 2008
• Results First Submitted Date: June 20, 2011
• Results First Posted Date: July 18, 2011
• Last Update Posted Date: December 14, 2018
• Study Start Date: November 2008
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: June 20, 2011)

Investigator-assessed Objective Progression-free Survival (PFS) [ Time Frame: Date of randomization to the date of measured PD or date of death from any cause (up to 19.3 months) ]

Investigator-assessed objective PFS was measured from the date of randomization to the first date of objectively determined progressive disease (PD) or death from any cause. For patients not known to have died as of the data cutoff date and who did not have objective PD, PFS was censored at the date of last objective tumor assessment. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD = 20% increase in sum of longest diameter of target lesions.

• Original Primary Outcome Measures (submitted: November 10, 2008): Progression-free survival time (PFS) [ Time Frame: Date of randomization to the first date of measured progressive disease or date of death from any cause. ]

Current Secondary Outcome Measures (submitted: March 4, 2013)

• Independently-assessed Objective Progression-free Survival (PFS) [ Time Frame: Date of randomization to first date of measured PD or date of death from any cause (up to 19.3 months) ]
  To further evaluate the robustness of the PFS analysis, Lilly established an independent review of PFS to assess the potential for investigator bias in the determination of objective PD. PFS was measured from the date of randomization to the first date of objectively determined PD or death. For patients alive as of the data cutoff date and who did not have PD, PFS was censored at the date of the last objective tumor assessment. PD was determined using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. PD = 20% increase in sum of longest diameter of target lesions.
• Overall Survival (OS) [ Time Frame: Date of randomization to the date of death from any cause up to 39.5 months ]
  OS is the duration from enrollment to death. For patients who are alive, OS is censored at the last contact.
• Change From Baseline in the EuroQol Instrument (EQ-5D) Index Score [ Time Frame: Baseline randomization through 30-day post-discontinuation visit (up to 19.3 months) ]
  The EQ-5D is a generic instrument that describes health status in 5 attributes (mobility, self-care, pain/discomfort, anxiety/depression, usual activities) using a three level scale (no problem, some problems, and major problems). These combinations of attributes are converted into a weighted health-state Index Score according to the United Kingdom (UK) population-based algorithm. The possible values for the Index Score range from -0.59 (severe problems in all 5 dimensions) to 1.0 (no problem in any dimension).
• Change From Baseline in EuroQol Instrument (EQ-5D) Visual Analog Scale (VAS) [ Time Frame: Baseline randomization through 30-day post-discontinuation visit (up to 19.3 months) ]
  Patients indicate their present health state through completion of the VAS. Possible scores range from 0 (worst imaginable health state) to 100 (best imaginable health state).
• Percentage of Participants With Hospitalizations Due to Adverse Events or Requiring Transfusion (Resource Utilization) [ Time Frame: Baseline randomization through 30-day post-discontinuation visit (up to 19.3 months) ]
• Percentage of Participants With a Non-Serious Adverse Event (AE) During Maintenance Phase [ Time Frame: Baseline randomization through 30-day post-discontinuation visit (up to 49.7 months) ]
  A summary of non-serious AEs is located in the Reported Adverse Event Module.
• Percentage of Participants With Serious Adverse Events During Maintenance Phase [ Time Frame: Baseline randomization through 30-day post-discontinuation visit (up to 49.7 months) ]
  A summary of serious adverse events is located in the Reported Adverse Event Module.
• Percentage of Participants With Objective Tumor Response (Response Rate) During Maintenance Phase of Study up to Primary Data Cut-Off [ Time Frame: Baseline to date of measured progressive disease (up to 19.3 months) ]
  Analysis for combined phases was not performed since response was calculated separately for each phase of study. Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR)=disappearance of all target lesions; Partial Response(PR)is at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease(PD) is at least a 20% increase in sum of longest diameter of target lesions; Stable Disease(SD)=no change or small changes that do not meet the above criteria for CR, PR, or PD.
• Percentage of Participants With Independently-Assessed Objective Tumor Response (Response Rate) During Maintenance Phase Up to Primary Data Cut-Off [ Time Frame: Date of randomization to date of measured PD (up to 19.3 months) ]
  Response using Response Evaluation Criteria In Solid Tumors (RECIST) criteria. Complete Response (CR)=disappearance of all target lesions; Partial Response (PR) is at least a 30% decrease in sum of longest diameter of target lesions; Progressive Disease (PD) is at least a 20% increase in sum of longest diameter of target lesions; Stable Disease (SD)=no change or small changes that do not meet the above criteria for CR, PR, or PD. Response Rate = (CR+PR)/Participants in Arm*100. Disease Control Rate=(CR+PR+SD)/Number of Participants in Arm*100.

Original Secondary Outcome Measures (submitted: November 10, 2008)

• Overall survival [ Time Frame: Date of randomization to the date of death from any cause ]
• Patient Reported Outcomes (EQ-5D) [ Time Frame: Baseline, every cycle, through the 30-day postdiscontinuation period. ]
• Resource Utilization [ Time Frame: Baseline, throughout study, until the 30-day postdiscontinuation visit ]
• Adverse Events [ Time Frame: Every cycle ]
• Serious Adverse Events [ Time Frame: Every cycle ]
• Objective tumor response rate: induction phase plus maintenance phase = whole treatment [ Time Frame: Baseline to date of measured progressive disease ]
• Objective tumor response rate: maintenance phase [ Time Frame: Date of randomization to date of measured progressive disease ]

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

Descriptive Information

• Brief Title: A Study of Induction and Maintenance Treatment of Advanced Non-squamous Non-Small Cell Lung Cancer
• Official Title: A Phase 3, Double-Blind, Placebo-Controlled Study of Maintenance Pemetrexed Plus Best Supportive Care Versus Best Supportive Care Immediately Following Induction Treatment With Pemetrexed + Cisplatin for Advanced Non-squamous Non-Small Cell Lung Cancer.
• Brief Summary: This study will compare progression-free survival in patients with advanced non-squamous non-small cell lung cancer. Patients who do not progress following 4 cycles of induction treatment with pemetrexed and cisplatin will be randomized 2:1 to receive either maintenance pemetrexed or placebo.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 3
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor); Primary Purpose: Treatment
• Condition: Non-Small Cell Lung Cancer

Intervention

• Drug: Pemetrexed
  Induction therapy: 500 mg/m^2, intravenous (IV), on Day 1 of each 21-day cycle for 4 cycles
  Other Names:

  • Alimta
  • LY231514
• Drug: Cisplatin
  Induction therapy: Cisplatin: 75 mg/m^2, IV, on Day 1 of each 21-day cycle for 4 cycles
• Drug: Placebo
  Maintenance therapy: Normal saline (0.9% sodium chloride) administered IV on Day 1 every 21-day cycle until progressive disease or treatment discontinuation
• Drug: Pemetrexed
  Maintenance therapy: 500 mg/m^2, IV, on Day 1 of each 21-day cycle until progressive disease or treatment discontinuation.
  Other Names:

  • Alimta
  • LY231514
• Other: Best Supportive Care
  Best Supportive Care is treatment given with the intent to maximize quality of life. Best Supportive Care excludes any treatment in which the goal is to cure or slow the progression of the study disease. Patients will receive Best Supportive Care as judged by their treating physician. Those therapies considered acceptable include, but are not limited to, palliative radiation to extrathoracic structures, antibiotics, analgesics, antiemetics, thoracentesis, pleurodesis, blood transfusions, and/or nutritional support (enteral or parenteral).

Study Arms

• Experimental: pemetrexed + cisplatin followed by pemetrexed
  pemetrexed plus cisplatin followed by pemetrexed plus best supportive care
  Interventions:

  • Drug: Pemetrexed
  • Drug: Cisplatin
  • Drug: Pemetrexed
  • Other: Best Supportive Care
• Placebo Comparator: pemetrexed + cisplatin followed by placebo
  pemetrexed plus cisplatin followed by placebo plus best supportive care
  Interventions:

  • Drug: Pemetrexed
  • Drug: Cisplatin
  • Drug: Placebo
  • Other: Best Supportive Care

Publications *

• Middleton G, Gridelli C, De Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Visseren-Grul CM, San Antonio B, John WJ, Zimmermann AH, Chouaki N, Paz-Ares L. Evaluation of changes in renal function in PARAMOUNT: a phase III study of maintenance pemetrexed plus best supportive care versus placebo plus best supportive care after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. Curr Med Res Opin. 2018 May;34(5):865-871. doi: 10.1080/03007995.2018.1439462. Epub 2018 Mar 27.
• Pujol JL, Paz-Ares L, de Marinis F, Dediu M, Thomas M, Bidoli P, Corral J, San Antonio B, Chouaki N, John W, Zimmermann A, Visseren-Grul C, Gridelli C. Long-term and low-grade safety results of a phase III study (PARAMOUNT): maintenance pemetrexed plus best supportive care versus placebo plus best supportive care immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. Clin Lung Cancer. 2014 Nov;15(6):418-25. doi: 10.1016/j.cllc.2014.06.007. Epub 2014 Jun 21.
• Reck M, Paz-Ares LG, de Marinis F, Molinier O, Sahoo TP, Laack E, John W, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Descriptive subgroup analyses of final overall survival for the phase III study of maintenance pemetrexed versus placebo following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2014 Feb;9(2):205-13. doi: 10.1097/JTO.0000000000000076.
• Paz-Ares LG, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. PARAMOUNT: Final overall survival results of the phase III study of maintenance pemetrexed versus placebo immediately after induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Clin Oncol. 2013 Aug 10;31(23):2895-902. doi: 10.1200/JCO.2012.47.1102. Epub 2013 Jul 8.
• Zeng X, Peng L, Li J, Chen G, Tan C, Wang S, Wan X, Ouyang L, Zhao Z. Cost-effectiveness of continuation maintenance pemetrexed after cisplatin and pemetrexed chemotherapy for advanced nonsquamous non-small-cell lung cancer: estimates from the perspective of the Chinese health care system. Clin Ther. 2013 Jan;35(1):54-65. doi: 10.1016/j.clinthera.2012.12.013.
• Gridelli C, de Marinis F, Pujol JL, Reck M, Ramlau R, Parente B, Pieters T, Middleton G, Corral J, Winfree K, Melemed S, Zimmermann A, John W, Beyrer J, Chouaki N, Visseren-Grul C, Paz-Ares LG. Safety, resource use, and quality of life in paramount: a phase III study of maintenance pemetrexed versus placebo after induction pemetrexed plus cisplatin for advanced nonsquamous non-small-cell lung cancer. J Thorac Oncol. 2012 Nov;7(11):1713-21. doi: 10.1097/JTO.0b013e318267cf84.
• Paz-Ares L, de Marinis F, Dediu M, Thomas M, Pujol JL, Bidoli P, Molinier O, Sahoo TP, Laack E, Reck M, Corral J, Melemed S, John W, Chouaki N, Zimmermann AH, Visseren-Grul C, Gridelli C. Maintenance therapy with pemetrexed plus best supportive care versus placebo plus best supportive care after induction therapy with pemetrexed plus cisplatin for advanced non-squamous non-small-cell lung cancer (PARAMOUNT): a double-blind, phase 3, randomised controlled trial. Lancet Oncol. 2012 Mar;13(3):247-55. doi: 10.1016/S1470-2045(12)70063-3. Epub 2012 Feb 16.
• Paz-Ares LG, Altug S, Vaury AT, Jaime JC, Russo F, Visseren-Grul C. Treatment rationale and study design for a phase III, double-blind, placebo-controlled study of maintenance pemetrexed plus best supportive care versus best supportive care immediately following induction treatment with pemetrexed plus cisplatin for advanced nonsquamous non-small cell lung cancer. BMC Cancer. 2010 Mar 8;10:85. doi: 10.1186/1471-2407-10-85.

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: June 20, 2011): 939
• Original Estimated Enrollment (submitted: November 10, 2008): 600
• Actual Study Completion Date: November 2017
• Actual Primary Completion Date: June 2010 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria for the Induction Phase:

• You must sign an informed consent document for clinical research.
• You must have Stage IIIB or IV nonsquamous Non-Small Cell Lung Cancer.
• You must at least be able to be physically mobile, take care of yourself, and must be up and about and able to perform light activities such as light housework or office work.
• You are allowed to have had prior radiation therapy as long as it was not to more than 25% of the bone marrow and did not include the whole pelvis. Thoracic radiation must be completed more than 30 days before the study. You must be recovered from the toxic effects (except hair loss).
• You must have at least 1 measurable tumor lesion according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines or disease that can be evaluated by computed tomography (CT) Scan.
• Your test results assessing the function of your blood forming tissue, kidneys, and liver must be satisfactory.
• You must be 18 years of age or older.
• Women must be sterile, postmenopausal or on contraception and men must be on contraception or sterile (e.g. post-vasectomy).

Exclusion Criteria for the Induction Phase:

• You cannot have squamous cell and/or mixed small cell, non-small cell lung cancer
• You cannot have received other investigational drugs within the last 30 days of entering the trial.
• You cannot have previously completed or withdrawn from this study or any other study investigating pemetrexed.
• You cannot have other serious on-going illnesses including active infections.
• You cannot have a serious cardiac condition, such as a heart attack, angina, or heart disease within 6 months of entering the trial.
• You cannot have had another form of cancer other than superficial basal cell and superficial squamous (skin) cell cancer, or carcinoma in situ of the cervix within the last 5 years. Patients with a history of low-grade (Gleason score less than or equal to 6) localized prostate cancer will be eligible even if diagnosed less than 5 years ago.
• You cannot have known central nervous system (CNS) metastases, other than treated, stable brain metastasis.
• You cannot be receiving nor have received any prior systemic anticancer therapy for lung cancer (including chemotherapy given after surgery in early-stage treatment).
• You cannot have clinically significant third-space fluid collections (e.g. ascites or pleural effusions that cannot be controlled by drainage or other procedures).
• You cannot have received a recent (within 30 days) or are receiving a yellow fever vaccination.
• You are unable to stop taking more than 1.3 grams of aspirin on a daily basis or other non-steroidal anti-inflammatory drugs (NSAIDs).
• You are unable or unwilling to take folic acid, injections of vitamin B12, or corticosteroids.
• You cannot be pregnant or breastfeeding.

Inclusion criteria at Randomization for the Maintenance Phase:

• You must at least be able to be physically mobile, take care of yourself, and must be up and about and able to perform light activities such as light housework or office work.
• You must have documented radiographic evidence of a tumor response of complete response (CR), partial response (PR), or stable disease (SD) according to the Response Evaluation Criteria in Solid Tumors (RECIST) guidelines. Tumor assessment must occur between Cycle 4 (Day 1) of induction therapy and the date of randomization. This response does not have to be confirmed in order for the patient to be randomized to the maintenance phase.

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: Australia, Belgium, Finland, France, Germany, Greece, India, Italy, Netherlands, Poland, Portugal, Romania, Spain, Turkey, United Kingdom
• Removed Location Countries: Canada

Administrative Information

• NCT Number: NCT00789373
• Other Study ID Numbers: 12560; H3E-EW-S124 ( Other Identifier: Eli Lilly and Company ); CTRI/2009/091/000113 ( Registry Identifier: India )
• Has Data Monitoring Committee: No
• U.S. FDA-regulated Product: Not Provided
• IPD Sharing Statement: Not Provided
• Current Responsible Party: Eli Lilly and Company
• Original Responsible Party: Chief Medical Officer, Eli Lilly and Company
• 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: February 2018