Pemetrexed Plus Gemcitabine or Carboplatin for Patients With Advanced Malignant Pleural Mesothelioma

Pemetrexed Plus Gemcitabine Or Carboplatin In Patients With Advanced Malignant Mesothelioma: A Randomized Phase II Trial

RATIONALE: Drugs used in chemotherapy, such as pemetrexed disodium, gemcitabine, and carboplatin, work in different ways to stop the growth of tumor cells, either by killing the cells or by stopping them from dividing. Giving more than one drug (combination chemotherapy) may kill more tumor cells. It is not yet known whether giving pemetrexed disodium with gemcitabine is more effective than giving pemetrexed disodium with carboplatin in treating malignant pleural mesothelioma.

PURPOSE: This randomized phase II trial is studying pemetrexed disodium with gemcitabine and pemetrexed disodium with carboplatin to see how well the combinations work compared to historical controls in treating patients with advanced malignant pleural mesothelioma.

Study Overview

• Status: Completed
• Conditions: Mesothelioma
• Intervention / Treatment: Drug: pemetrexed disodium; Drug: carboplatin; Drug: gemcitabine hydrochloride

Detailed Description

OBJECTIVES:

Primary

• Estimate the response rates in patients with advanced malignant mesothelioma of the pleura treated with pemetrexed disodium combined with either gemcitabine or carboplatin.

Secondary

• Assess the toxic effects of these regimens in these patients.
• Estimate survival time in patients treated with these regimens.
• Correlate smoking status with outcome in patients treated with these regimens.

OUTLINE: This is a randomized, multicenter study. Patients are randomized to 1 of 2 treatment arms. While randomized, the study is not a comparative study. Rather, outcomes on each arm will be compared to a historical control rate from previous studies. Randomization allows simultaneous testing of two experimental arms.

• Arm I: Patients receive intravenous (IV) pemetrexed disodium over 10 minutes and carboplatin IV over 30 minutes on day 1.
• Arm II: Patients receive pemetrexed disodium as in arm I and gemcitabine IV over 30 minutes on days 1 and 8.

In both arms, treatment repeats every 21 days for up to 6 courses in the absence of disease progression or unacceptable toxicity.

Beginning approximately 5-10 days before the start of chemotherapy and continuing until approximately 3 weeks after completion of chemotherapy, all patients receive oral folic acid once daily and cyanocobalamin (vitamin B12) intramuscularly every 9 weeks.

Patients are followed every 3 months for 2 years and then every 6 months for 1 year.

PROJECTED ACCRUAL: A total of 32-60 patients (16-30 per treatment arm) will be accrued for this study within 12.8-27.0 months.

• Study Type: Interventional
• Enrollment (Actual): 32
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • Connecticut
    • Norwich, Connecticut, United States, 06360
      • Eastern Connecticut Hematology and Oncology Associates
  • Delaware
    • Lewes, Delaware, United States, 19958
      • Tunnell Cancer Center at Beebe Medical Center
    • Newark, Delaware, United States, 19713
      • CCOP - Christiana Care Health Services
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Mayo Clinic - Jacksonville
  • Georgia
    • Atlanta, Georgia, United States, 30322
      • Winship Cancer Institute of Emory University
  • Illinois
    • Aurora, Illinois, United States, 60504
      • Rush-Copley Cancer Care Center
    • Bloomington, Illinois, United States, 61701
      • St. Joseph Medical Center
    • Canton, Illinois, United States, 61520
      • Graham Hospital
    • Carthage, Illinois, United States, 62321
      • Memorial Hospital
    • Decatur, Illinois, United States, 62526
      • Decatur Memorial Hospital Cancer Care Institute
    • Eureka, Illinois, United States, 61530
      • Eureka Community Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Cottage Hospital
    • Galesburg, Illinois, United States, 61401
      • Galesburg Clinic, PC
    • Havana, Illinois, United States, 62644
      • Mason District Hospital
    • Hopedale, Illinois, United States, 61747
      • Hopedale Medical Complex
    • Joliet, Illinois, United States, 60435
      • Joliet Oncology-Hematology Associates, Limited - West
    • Kewanee, Illinois, United States, 61443
      • Kewanee Hospital
    • Macomb, Illinois, United States, 61455
      • Mcdonough District Hospital
    • Moline, Illinois, United States, 61265
      • Trinity Cancer Center at Trinity Medical Center - 7th Street Campus
    • Normal, Illinois, United States, 61761
      • Bromenn Regional Medical Center
    • Normal, Illinois, United States, 61761
      • Community Cancer Center
    • Ottawa, Illinois, United States, 61350
      • Community Hospital of Ottawa
    • Ottawa, Illinois, United States, 61350
      • Oncology Hematology Associates of Central Illinois, PC - Ottawa
    • Pekin, Illinois, United States, 61554
      • Cancer Treatment Center at Pekin Hospital
    • Peoria, Illinois, United States, 61636
      • Methodist Medical Center of Illinois
    • Peoria, Illinois, United States, 61614
      • Proctor Hospital
    • Peoria, Illinois, United States, 61637
      • OSF St. Francis Medical Center
    • Peoria, Illinois, United States, 61615
      • CCOP - Illinois Oncology Research Association
    • Peoria, Illinois, United States, 61615
      • Oncology Hematology Associates of Central Illinois, PC - Peoria
    • Peru, Illinois, United States, 61354
      • Illinois Valley Community Hospital
    • Princeton, Illinois, United States, 61356
      • Perry Memorial Hospital
    • Spring Valley, Illinois, United States, 61362
      • St. Margaret's Hospital
    • Springfield, Illinois, United States, 62781-0001
      • Regional Cancer Center at Memorial Medical Center
    • Urbana, Illinois, United States, 61801
      • Carle Cancer Center at Carle Foundation Hospital
    • Urbana, Illinois, United States, 61801
      • CCOP - Carle Cancer Center
  • Indiana
    • Elkhart, Indiana, United States, 46515
      • Elkhart General Hospital
    • Indianapolis, Indiana, United States, 46202-5289
      • Indiana University Melvin and Bren Simon Cancer Center
    • Indianapolis, Indiana, United States, 46202
      • William N. Wishard Memorial Hospital
    • Indianapolis, Indiana, United States, 46202
      • Veterans Affairs Medical Center - Indianapolis
    • Kokomo, Indiana, United States, 46904
      • Howard Community Hospital
    • La Porte, Indiana, United States, 46350
      • Center for Cancer Therapy at LaPorte Hospital and Health Services
    • Michigan City, Indiana, United States, 46360
      • Saint Anthony Memorial Health Centers
    • South Bend, Indiana, United States, 46601
      • Memorial Hospital of South Bend
    • South Bend, Indiana, United States, 46601
      • CCOP - Northern Indiana CR Consortium
    • South Bend, Indiana, United States, 46617
      • Saint Joseph Regional Medical Center
  • Iowa
    • Ames, Iowa, United States, 50010
      • McFarland Clinic, PC
    • Cedar Rapids, Iowa, United States, 52403
      • Cedar Rapids Oncology Associates
    • Sioux City, Iowa, United States, 51101
      • Siouxland Hematology-Oncology Associates, LLP
    • Sioux City, Iowa, United States, 51104
      • St. Luke's Regional Medical Center
    • Sioux City, Iowa, United States, 51104
      • Mercy Medical Center - Sioux City
  • Maryland
    • Baltimore, Maryland, United States, 21231-2410
      • Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins
    • Elkton, Maryland, United States, 21921
      • Union Hospital Cancer Program at Union Hospital
  • Michigan
    • Ann Arbor, Michigan, United States, 48106-0995
      • Saint Joseph Mercy Cancer Center
    • Ann Arbor, Michigan, United States, 48106
      • CCOP - Michigan Cancer Research Consortium
    • Dearborn, Michigan, United States, 48123-2500
      • Oakwood Cancer Center at Oakwood Hospital and Medical Center
    • Flint, Michigan, United States, 48503
      • Hurley Medical Center
    • Flint, Michigan, United States, 48503
      • Genesys Hurley Cancer Institute
    • Grosse Pointe Woods, Michigan, United States, 48236
      • Van Elslander Cancer Center at St. John Hospital and Medical Center
    • Jackson, Michigan, United States, 49201
      • Foote Memorial Hospital
    • Kalamazoo, Michigan, United States, 49007
      • Bronson Methodist Hospital
    • Kalamazoo, Michigan, United States, 49001
      • Borgess Medical Center
    • Kalamazoo, Michigan, United States, 49007-3731
      • West Michigan Cancer Center
    • Lansing, Michigan, United States, 48912-1811
      • Sparrow Regional Cancer Center
    • Saginaw, Michigan, United States, 48601
      • Seton Cancer Institute at Saint Mary's - Saginaw
    • Saint Joseph, Michigan, United States, 49085
      • Lakeland Regional Cancer Care Center - St. Joseph
    • Warren, Michigan, United States, 48093
      • St. John Macomb Hospital
  • Minnesota
    • Burnsville, Minnesota, United States, 55337
      • Fairview Ridges Hospital
    • Coon Rapids, Minnesota, United States, 55433
      • Mercy and Unity Cancer Center at Mercy Hospital
    • Duluth, Minnesota, United States, 55805
      • CCOP - Duluth
    • Duluth, Minnesota, United States, 55805-1983
      • Duluth Clinic Cancer Center - Duluth
    • Duluth, Minnesota, United States, 55805
      • Miller - Dwan Medical Center
    • Edina, Minnesota, United States, 55435
      • Fairview Southdale Hospital
    • Fridley, Minnesota, United States, 55432
      • Mercy and Unity Cancer Center at Unity Hospital
    • Hutchinson, Minnesota, United States, 55350
      • Hutchinson Area Health Care
    • Litchfield, Minnesota, United States, 55355
      • Meeker County Memorial Hospital
    • Maplewood, Minnesota, United States, 55109
      • Minnesota Oncology Hematology, PA - Maplewood
    • Maplewood, Minnesota, United States, 55109
      • HealthEast Cancer Care at St. John's Hospital
    • Minneapolis, Minnesota, United States, 55407
      • Virginia Piper Cancer Institute at Abbott - Northwestern Hospital
    • Minneapolis, Minnesota, United States, 55415
      • Hennepin County Medical Center - Minneapolis
    • Robbinsdale, Minnesota, United States, 55422-2900
      • Hubert H. Humphrey Cancer Center at North Memorial Outpatient Center
    • Rochester, Minnesota, United States, 55905
      • Mayo Clinic Cancer Center
    • Saint Louis Park, Minnesota, United States, 55416
      • CCOP - Metro-Minnesota
    • Saint Louis Park, Minnesota, United States, 55416
      • Park Nicollet Cancer Center
    • Saint Paul, Minnesota, United States, 55102
      • United Hospital
    • Saint Paul, Minnesota, United States, 55101
      • Regions Hospital Cancer Care Center
    • Saint Paul, Minnesota, United States, 55102
      • HealthEast Cancer Care at St. Joseph's Hospital
    • Shakopee, Minnesota, United States, 55379
      • St. Francis Cancer Center at St. Francis Medical Center
    • Waconia, Minnesota, United States, 55387
      • Ridgeview Medical Center
    • Woodbury, Minnesota, United States, 55125
      • Minnesota Oncology Hematology, PA - Woodbury
    • Woodbury, Minnesota, United States, 55125
      • HealthEast Cancer Care at Woodwinds Health Campus
  • New Jersey
    • East Orange, New Jersey, United States, 07018-1095
      • Veterans Affairs Medical Center - East Orange
    • Hackensack, New Jersey, United States, 07601
      • CCOP - Northern New Jersey
    • Marlton, New Jersey, United States, 08053
      • Fox Chase Virtua Health Cancer Program at Virtua Memorial Hospital Marlton
    • New Brunswick, New Jersey, United States, 08903
      • Cancer Institute of New Jersey at UMDNJ - Robert Wood Johnson Medical School
    • Voorhees, New Jersey, United States, 08043
      • Cancer Institute of New Jersey at Cooper - Voorhees
    • Voorhees, New Jersey, United States, 08043
      • Fox Chase Virtua Health Cancer Program at Virtua West Jersey
  • North Dakota
    • Bismarck, North Dakota, United States, 58501
      • Bismarck Cancer Center
    • Bismarck, North Dakota, United States, 58501
      • Medcenter One Hospital Cancer Care Center
    • Bismarck, North Dakota, United States, 58501
      • Mid Dakota Clinic, PC
    • Bismarck, North Dakota, United States, 58502
      • St. Alexius Medical Center Cancer Center
  • Ohio
    • Akron, Ohio, United States, 44309-2090
      • Summa Center for Cancer Care at Akron City Hospital
    • Canton, Ohio, United States, 44710-1799
      • Aultman Cancer Center at Aultman Hospital
    • Cleveland, Ohio, United States, 44106-5065
      • Case Comprehensive Cancer Center
    • Lima, Ohio, United States, 45801
      • St. Rita's Medical Center
  • Pennsylvania
    • Allentown, Pennsylvania, United States, 18105
      • Morgan Cancer Center at Lehigh Valley Hospital - Cedar Crest
    • Hershey, Pennsylvania, United States, 17033-0850
      • Penn State Cancer Institute at Milton S. Hershey Medical Center
    • Lewistown, Pennsylvania, United States, 17044
      • Lewistown Hospital
    • Philadelphia, Pennsylvania, United States, 19111-2497
      • Fox Chase Cancer Center - Philadelphia
    • Philadelphia, Pennsylvania, United States, 19141
      • Albert Einstein Cancer Center
    • State College, Pennsylvania, United States, 16803
      • Mount Nittany Medical Center
  • South Dakota
    • Sioux Falls, South Dakota, United States, 57105
      • Avera Cancer Institute
    • Sioux Falls, South Dakota, United States, 57105
      • Medical X-Ray Center, PC
    • Sioux Falls, South Dakota, United States, 57117-5039
      • Sanford Cancer Center at Sanford USD Medical Center
  • Wisconsin
    • La Crosse, Wisconsin, United States, 54601
      • Gundersen Lutheran Cancer Center at Gundersen Lutheran Medical Center
    • Madison, Wisconsin, United States, 53792-6164
      • University of Wisconsin Paul P. Carbone Comprehensive Cancer Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 14 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Histologically or cytologically confirmed advanced mesothelioma of the pleura
• Measurable disease, as defined by RECIST criteria, within 4 weeks of randomization. Patients with pleural rinds not measurable by RECIST were eligible if disease was evaluable within 4 weeks of randomization using mesothelioma response criteria
• May have undergone pleurodesis. If pleurodesis was performed, there must have been at least a 2-week delay before Pemetrexed administration. A CT must have been performed after 2 weeks after pleurodesis to serve as the baseline scan.
• ECOG Performance Status of 0 or 1

• Normal organ and marrow function, as defined by:

  • Absolute neutrophil count ≥ 1,500/ul
  • Platelet count ≥ 100,000/ul
  • Bilirubin ≤ 1.5 times upper limit of normal (ULN)
  • AST and ALT ≤ 3 times ULN (5 times ULN if liver has tumor involvement)
  • Albumin ≥ 2.5 g/dL
  • Creatinine clearance ≥ 45 mL/min or Creatinine ≤ 2.0 g/dL
• Age 18 years and over
• Able to take folic acid and cyanocobalamin (vitamin B12)
• Willing and able to take dexamethasone
• Women of childbearing potential and sexually active men were required to use contraception during and for the first 3 months after the study

Exclusion Criteria

• A candidate for curative surgery
• Prior radiation therapy to the target lesion, unless the lesion was clearly progressing per RECIST criteria after prior radiation and the interval between the most recent radiation therapy and enrollment was at least 4 weeks
• Prior systemic chemotherapy for mesothelioma. Prior intracavitary cytotoxic drugs or immunomodulators were not permitted, unless given for the purpose of pleurodesis.
• Active infection or serious concomitant systemic disorder
• Second primary malignancy, other than in situ malignancies or adequately treated basal cell carcinoma of the skin or other malignancy treated at least 3 years previously with no evidence of recurrence.
• Treatment with an investigational agent within 4 weeks before enrollment
• Known or suspected brain metastases
• Women must not be pregnant or breastfeeding
• Obviously malnourished or with a weight loss of greater than 10% in the preceding 6 weeks
• Aspirin or other nonsteroidal anti-inflammatory drugs for 2 days before, during, and for 2 days after each administration of pemetrexed disodium (5 days before, during, and 2 days after each administration of pemetrexed disodium for piroxicam, naproxen, diflunisal, or nabumetone)

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Pemetrexed/Carboplatin; Pemetrexed disodium 500 mg/m2 IV over 10 minutes and carboplatin to area under the curve (AUC) 5 IV over 30 minutes on day 1 of a 21-day cycle.	Drug: pemetrexed disodium; 500 mg/m2 IV over 10 minutes on day 1 of a 21-day cycle; Other Names: Alimta; LY231514; MTA; Drug: carboplatin; Given by IV over 30 minutes at an area under the curve (AUC) of 5 on day 1 of a 21-day cycle; Other Names: CBDCA; JM-8; Paraplatin; NSC-241240
Experimental: Pemetrexed/Gemcitabine; Pemetrexed disodium 500 mg/m2 IV over 10 minutes on day 1 and gemcitabine 1000 mg/m2 IV over 30 minutes on days 1 and 8 of a 21-day cycle.	Drug: pemetrexed disodium; 500 mg/m2 IV over 10 minutes on day 1 of a 21-day cycle; Other Names: Alimta; LY231514; MTA; Drug: gemcitabine hydrochloride; 1000 mg/m2 IV over 30 minutes on days 1 and 8 of a 21-day cycle; Other Names: Gemzar

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Best Overall Response by RECIST Criteria (Version 1.0)	Number of eligible, treated participants in each response category by RECIST criteria. Response categories represent best response for each patient prior to progression.	Assessed every 2 cycles (6 weeks) while on treatment, then every 3 months for 2 years, then every 6 months for 1 year until disease progression

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Overall Survival	Time from randomization to death. Patients alive at last follow-up were censored.	Assessed every 3 months for 2 years, then every 6 months for 1 year
Progression-Free Survival	Time from randomization to the earlier of disease progression or death. Patients alive and progression-free at last follow-up were censored.	Assessed every 3 months for 2 years, then every 6 months for 1 year

Collaborators and Investigators

• Sponsor: Eastern Cooperative Oncology Group
• Collaborators: National Cancer Institute (NCI); North Central Cancer Treatment Group
• Investigators: Study Chair: Nasser H. Hanna, MD, Indiana University Melvin and Bren Simon Cancer Center; Study Chair: Scott Okuno, MD, Mayo Clinic

Study record dates

Study Major Dates

• Study Start (Actual): February 23, 2006
• Primary Completion (Actual): September 1, 2009
• Study Completion (Actual): May 1, 2011

Study Registration Dates

• First Submitted: January 7, 2005
• First Submitted That Met QC Criteria: January 7, 2005
• First Posted (Estimated): January 10, 2005

Study Record Updates

• Last Update Posted (Actual): July 3, 2023
• Last Update Submitted That Met QC Criteria: June 14, 2023
• Last Verified: June 1, 2023

More Information

Terms related to this study

• Keywords: advanced malignant mesothelioma; recurrent malignant mesothelioma
• Additional Relevant MeSH Terms: Respiratory Tract Diseases; Neoplasms by Histologic Type; Neoplasms; Lung Diseases; Neoplasms by Site; Neoplasms, Glandular and Epithelial; Respiratory Tract Neoplasms; Thoracic Neoplasms; Lung Neoplasms; Adenoma; Neoplasms, Mesothelial; Pleural Neoplasms; Mesothelioma; Mesothelioma, Malignant; Molecular Mechanisms of Pharmacological Action; Nucleic Acid Synthesis Inhibitors; Enzyme Inhibitors; Antimetabolites, Antineoplastic; Antimetabolites; Antineoplastic Agents; Folic Acid Antagonists; Carboplatin; Pemetrexed; Gemcitabine
• Other Study ID Numbers: CDR0000401795; U10CA021115 (U.S. NIH Grant/Contract); E1B03 (Other Identifier: NCCTG)