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A Study of Carboplatin and Paclitaxel With or Without MEDI-575 in Untreated, Advanced Non-Small Cell Lung Cancer

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ClinicalTrials.gov Identifier: NCT01268059
Recruitment Status : Terminated (In conjunction with the overall risk-benefit assessment, study was terminated prematurely due to safety concerns.)
First Posted : December 29, 2010
Results First Posted : December 23, 2020
Last Update Posted : December 23, 2020
Sponsor:
Information provided by (Responsible Party):
MedImmune LLC

Brief Summary:
The purpose of this study is to evaluate the dose, antitumor activity, safety and pharmacology of MEDI-575 in combination with carboplatin/paclitaxel in subjects with previously untreated, advanced non-small cell lung cancer (NSCLC).

Condition or disease Intervention/treatment Phase
Non-small Cell Lung Cancer Drug: Carboplatin Drug: Paclitaxel Drug: MEDI-575 Phase 1 Phase 2

Detailed Description:
This is a Phase 1b/2, multicenter, open-label study of MEDI-575 to evaluate the dose, anti-tumor activity, safety, and pharmacology (pharmacokinetics, immunogenicity, and biomarkers) of MEDI-575 in combination with carboplatin/paclitaxel in subjects with previously untreated, advanced non-small cell lung cancer. This study has two phases: dose determination (Phase 1b) and randomization (Phase 2).

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 99 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1b/2 Randomized Study of MEDI-575 in Combination With Carboplatin Plus Paclitaxel Versus Carboplatin Plus Paclitaxel Alone in Adult Subjects With Previously Untreated, Advanced Non-Small Cell Lung Cancer
Actual Study Start Date : December 16, 2010
Actual Primary Completion Date : September 11, 2013
Actual Study Completion Date : September 11, 2013

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Active Comparator: Carboplatin/Paclitaxel
Carboplatin/paclitaxel regimen (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min], and paclitaxel 200 milligram per square meter [mg/m^2]) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal. Subjects were enrolled from North America/European Union (EU) and Japan regions.
Drug: Carboplatin
Carboplatin (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min] administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

Drug: Paclitaxel
Paclitaxel 200 milligram per square meter (mg/m^2) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

Experimental: Carboplatin/Paclitaxel + MEDI-575
Carboplatin/paclitaxel regimen (carboplatin AUC = 6 mg/mL*min, and paclitaxel 200 mg/m^2) followed by MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal. MEDI-575 alone continued in those participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575. Subjects were enrolled from North America/European Union (EU) and Japan regions.
Drug: Carboplatin
Carboplatin (carboplatin area under the plasma concentration-time curve [AUC] of 6 milligram per milliliter into minute [mg/mL*min] administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

Drug: Paclitaxel
Paclitaxel 200 milligram per square meter (mg/m^2) administered as an intravenous (IV) infusion once every 21 days on Day 1, for a total of 6 doses (cycles) until unacceptable toxicity, disease progression, or other reasons for participant withdrawal.

Drug: MEDI-575
MEDI-575 at a dose of 25 milligram per kilogram (mg/kg) administered as an IV infusion once every 21 days on Day 1 for a total of 6 cycles until unacceptable toxicity, disease progression, initiation of alternative anticancer therapy, or other reasons for participant withdrawal. MEDI-575 alone continued in those participants who achieved stable disease or better at the completion of carboplatin/paclitaxel therapy and did not demonstrate toxicity to MEDI-575.




Primary Outcome Measures :
  1. Number of Participants With Dose Limiting Toxicities (DLT): Phase 1b [ Time Frame: From Day 1 to Day 21 of first cycle ]

    A DLT was defined as:

    1. Any treatment-related Grade 3 or higher non-hematologic toxicity that occurred during the DLT assessment period with the following exceptions:

      1. Grade 3 fever (in the absence of neutropenia) defined as more than (>) 40.0 degree Celcius (> 104.0 degree Fahrenheit) that resolved to normal or baseline within 24 hours of treatment and was not considered a serious adverse event (SAE); or
      2. Grade 3 rigors/chills that responded to optimal therapy.
    2. Any treatment-related Grade 3 or higher hematologic toxicity.

  2. Progression Free-Survival (PFS) [ Time Frame: From randomization until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    Progression-free survival defined as the time from randomization (randomization referred to the date of treatment assignment) to disease progression (defined according to Response Evaluation Criteria for Solid Tumors [RECIST] version 1.1 guidelines) or death due to any cause, whichever occurs first. Participants without progression or death at the time of analysis were censored at their last date of tumor evaluation. PFS was assessed only in North America/European Union (EU) participants. Progression-free survival was evaluated using Kaplan-Meier method.


Secondary Outcome Measures :
  1. Best Overall Response [ Time Frame: From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    Best overall response of a participant was defined as the best tumor response [Complete Response (CR), Partial Response (PR), Stable Disease (SD), or Progressive Disease (PD)] observed during the trial period assessed according to the Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1 criteria. The participant's best overall response assignment depended on the findings of both target and non-target disease and also on the appearance of new lesions. CR was defined as disappearance of tumor lesions, PR was defined as a decrease of at least 30 percent (%) in the sum of diameters of target lesion, SD was defined as steady state of disease, and PD was defined as an increase of at least 20% in the sum of diameters of target lesions.

  2. Objective Response Rate (ORR) [ Time Frame: From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    The ORR defined as the percentage of participants with confirmed CR or confirmed PR according to RECIST version 1.1 guidelines. Confirmed responses were those that persist on repeat imaging or assessment greater than or equal to (>=) 4 weeks after the initial documentation of response. The ORR was evaluated using Kaplan-Meier method.

  3. Time to Response (TTR) [ Time Frame: From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    The TTR was measured from initiation of study treatment to the first documentation of objective response (OR). The OR defined as the participants with confirmed CR or confirmed PR according to RECIST version 1.1 guidelines. Confirmed responses were those that persist on repeat imaging or assessment >=4 weeks after the initial documentation of response. The TTR was evaluated using Kaplan-Meier method.

  4. Duration of Response (DR) [ Time Frame: From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    The DR defined as the duration from the first documentation of OR to the first documented disease progression. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. The DR was evaluated using Kaplan-Meier method.

  5. Time to Progression (TTP) [ Time Frame: From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    The TTP was measured from randomization until the documentation of disease progression. Disease progression defined according to RECIST version 1.1 guidelines. Participants without progression at the time of analysis were censored at their last date of tumor evaluation. The TTP was evaluated using Kaplan-Meier method.

  6. Overall Survival (OS) [ Time Frame: From initiation of treatment until the end of study (14 months from last participant enrolled or sponsor stopped the study), assessed at every 6 weeks until disease progression and every 3 months until the end of the study (approximately 3 years) ]
    Overall survival defined as the time from initiation of study treatment until death due to any cause. Participants who were still alive at the time of analysis were censored at their last date of last contact. The OS was evaluated using Kaplan-Meier method.

  7. Number of Participants With Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years) ]
    An adverse event (AE) was any untoward medical occurrence in a participant who received study drug without regard to possibility of causal relationship. A serious adverse event (SAE) was an AE resulting in any of the following outcomes or deemed significant for any other reason: death; initial or prolonged inpatient hospitalization; life-threatening experience (immediate risk of dying); persistent or significant disability/incapacity; congenital anomaly.

  8. Number of Participants With Abnormalities in Laboratory Investigations Reported as AEs or SAEs [ Time Frame: From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years) ]
    Laboratory investigations included hematology, coagulation, serum chemistry and urinalysis parameters. Participants with abnormalities in these laboratory investigations recorded as AEs or SAEs were reported.

  9. Number of Participants With Electrocardiogram (ECG) Abnormalities Reported as AEs [ Time Frame: From signing of informed consent form until 90 days post the last dose treatment (approximately 3 years) ]
    The 12-lead ECG data were performed and obtained in triplicate that is 3 ECGs obtained within a 5 minute time period. Number of participants with ECG abnormalities were reported and recorded as AEs.

  10. Maximum Observed Serum Concentration (Cmax) of MEDI-575 After First Dose [ Time Frame: Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15 ]
    The Cmax of MEDI-575 after first dose is reported.

  11. Time of Maximal Observed Concentration (Tmax) of MEDI-575 After First Dose [ Time Frame: Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15 ]
    The tmax refers to the time after dosing when a drug attains its highest measurable concentration (Cmax). The Tmax of MEDI-575 after first dose is reported.

  12. Area Under the Concentration-Time Curve Over the Dosing Interval (AUCtau) of MEDI-575 After First Dose [ Time Frame: Day 1 (pre-infusion and end of infusion), Day 2 (24 hours post Day 1 infusion), Day 8, and Day 15 ]
    The AUCtau defined as area under the plasma concentration time profile from time zero to the end of the dosing interval (tau). The AUCtau of MEDI-575 after first dose is reported.

  13. Maximum Serum Concentration at Steady State (Cmax,ss) of MEDI-575 [ Time Frame: Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion) ]
    The Cmax,ss of MEDI-575 is reported.

  14. Time to Maximum Serum Concentration at Steady State (Tmax,ss) of MEDI-575 [ Time Frame: Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion) ]
    The Tmax,ss of MEDI-575 is reported.

  15. Trough Serum Concentration at Steady State (Ctrough,ss) of MEDI-575 [ Time Frame: Cycle 1 (pre-infusion and end of infusion on Day 1, Day 2, Day 8, and Day 15); Day 1 of Cycles 2 to 4 (pre-infusion and end of infusion) ]
    The Ctrough,ss of MEDI-575 is reported.

  16. Percentage of Participants With Positive Anti-MEDI-575 Antibodies [ Time Frame: Day 1 (prior to infusion) of Cycles 1 to 7 (21-day cycle), end of treatment, 30 and 60 days after the last dose (approximately 3 years) ]
    Immunogenicity assessment included determination of anti-drug (MEDI-575) antibodies in serum samples.

  17. Number of Participants With Platelet-derived Growth Factor Receptor Alpha (PDGFRα) Expression in Tumor Cells of Archived Tumor Samples [ Time Frame: Baseline (Screening [Days -28 to -1]) ]
    The immunohistochemical expression of PDGFRα in tumor cells in archived formalin-fixed paraffin-embedded tissue samples collected at baseline are reported. The transmembrane receptor tyrosine kinase PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and also as a mediator of stromal support for cancer cell growth. The data of positive-staining tumor cells are reported in 3 categories: intensity (1+ [weak expression, staining in <5 % of tumor cells]; 2+ [moderate expression, staining in >= 5 % of tumor cells]; and 3+ [strong expression, staining in >5 % of the tumor cells]), localization (membranous, cytoplasmic, or nuclear), and frequency (rare, occasional, or frequent).

  18. Number of Participants With PDGFRα Expression in Stromal Cells of Archived Tumor Samples [ Time Frame: Baseline (Screening [Days -28 to -1]) ]
    The immunohistochemical expression of PDGFRα in stromal cells in archived formalin-fixed paraffin-embedded tissue samples collected at baseline are reported. The transmembrane receptor tyrosine kinase PDGFRα plays an important role in human carcinogenesis, both as a direct target on tumor cells and also as a mediator of stromal support for cancer cell growth. The data of positive-staining stromal cells are reported in 3 categories: intensity (1+ [weak expression, staining in <5 % of tumor cells]; 2+ [moderate expression, staining in >= 5 % of tumor cells]; and 3+ [strong expression, staining in >5 % of the tumor cells]), localization (membranous, cytoplasmic, or nuclear), and frequency (rare, occasional, or frequent).



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years to 99 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Histologically confirmed inoperable Stage IIIB or Stage IV non-small cell lung cancer according to the Seventh Edition of the American Joint Committee on Cancer (AJCC) Tumor Node Metastases (TNM) staging system (only participants with squamous cell carcinoma will be enrolled)
  • Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
  • Life expectancy of greater than or equal to (>=) 3 months
  • Prothrombin time elevation less than or equal to (<=) Grade 2 by National Cancer Institute Common Toxicity Criteria for Adverse Events (NCI CTCAE) criteria (Version 4.0) is acceptable for participants on anticoagulant therapy
  • Adequate hematologic function
  • Adequate organ function
  • Suitable candidates for therapy with carboplatin/paclitaxel
  • Participants must have at least 1 lesion that is measurable using Response Evaluation Criteria for Solid Tumors
  • Participants must be willing to consent to allow collection of archived NSCLC tumor samples
  • Negative serum beta-human chorionic gonadotropin (beta-hCG) test (women of childbearing potential only)
  • Females of childbearing potential, unless surgically sterile has a sterile male partner, is premenarchal or at least 2 years postmenopausal, or practices abstinence, must use 2 effective methods of avoiding pregnancy (including oral, transdermal, or implanted contraceptives, intrauterine device, female condom with spermicide, diaphragm with spermicide, cervical cap, or use of a condom with spermicide by the sexual partner) from screening, and must agree to continue using such precautions for 90 days after the final dose of treatment; cessation of birth control after this point should be discussed with a responsible physician
  • Males, unless surgically sterile, must use 2 effective methods of birth control with a female partner and must agree to continue using such contraceptive precautions from screening through 90 days after the final dose of treatment

Exclusion Criteria:

  • At discretion of the investigator regarding safety of the participants
  • Concurrent enrollment in another clinical study
  • Any concurrent chemotherapy, radiotherapy, immunotherapy, biologic, or hormonal therapy for treatment of cancer
  • Previous monoclonal antibody (mAb) treatment specifically directed against platelet-derived growth factor (PDGF) or PDGF receptors
  • History of serious allergy or reaction to any component of the MEDI-575 formulation
  • Receipt of any previous systemic anticancer therapies for advanced or metastatic disease
  • Previous adjuvant/neoadjuvant radiotherapy or chemotherapy for treatment of previous nonmetastatic disease is allowed provided that 6 months have elapsed from the end of such therapies to the time of enrollment
  • New York Heart Association >= Class II congestive heart failure
  • History of myocardial infarction, unstable angina, transient ischemic attack or stroke within the previous 6 months prior to enrollment
  • History of other invasive malignancy within 5 years except for cervical carcinoma in situ (CIS), non-melanomatous carcinoma of the skin or ductal carcinoma in situ (DCIS) of the breast that have been surgically cured
  • Evidence of active infection requiring the use of systemic antimicrobial treatment within 72 hours prior to initial treatment with MEDI-575
  • Use of immunosuppressive medication (inhaled and topical corticosteroids are permitted) within 7 days prior to enrollment
  • Systemic immunosuppressive steroid therapy
  • Participants may take replacement doses of steroids if on a stable dose for at least 2 weeks prior to enrollment
  • History of active human immunodeficiency virus (HIV) or active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection
  • Pregnancy or lactation
  • Previous medical history or evidence of an inter-current illness
  • Any physical, social, or psychiatric condition which would prevent effective cooperation or participation in the study

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT01268059


Locations
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United States, California
Research Site
Fountain Valley, California, United States, 92708
Research Site
Oxnard, California, United States, 93030
United States, Illinois
Research Site
Chicago, Illinois, United States, 60637
United States, Indiana
Research Site
Lafayette, Indiana, United States, 47905
United States, Louisiana
Research Site
Baton Rouge, Louisiana, United States, 70809
United States, Maryland
Research Site
Annapolis, Maryland, United States, 21401
Research Site
Baltimore, Maryland, United States, 21204
Research Site
Baltimore, Maryland, United States, 21231
United States, Massachusetts
Research Site
Boston, Massachusetts, United States, 02114
Research Site
Danvers, Massachusetts, United States, 01923
United States, Michigan
Research Site
Detroit, Michigan, United States, 48201
United States, Nebraska
Research Site
Omaha, Nebraska, United States, 68144
United States, New York
Research Site
Lake Success, New York, United States, 11042
United States, Ohio
Research Site
Canton, Ohio, United States, 44718
United States, Pennsylvania
Research Site
Hershey, Pennsylvania, United States, 17033-0850
United States, South Carolina
Research Site
Hilton Head Island, South Carolina, United States, 29926
United States, Tennessee
Research Site
Chattanooga, Tennessee, United States, 37404
United States, Texas
Research Site
Corpus Christi, Texas, United States, 78404
Research Site
Houston, Texas, United States, 77030
Canada, Ontario
Research Site
Ottawa, Ontario, Canada, K1H 8L6
France
Research Site
Marseille cedex, France, 13915
Germany
Research Site
Berlin, Germany, 12351
Hungary
Research Site
Szombathely, Hungary, 9700
Japan
Research Site
Fukuoka-shi, Japan, 811-1347
Research Site
Sunto-gun, Japan, 411-8777
Poland
Research Site
Gdansk, Poland, 80-952
Research Site
Lodz, Poland, 90-242
Research Site
Mrozy, Poland, 05-320
Research Site
Szczecin, Poland, 70-891
Sponsors and Collaborators
MedImmune LLC
Investigators
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Study Director: MedImmune LLC MedImmune LLC
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Responsible Party: MedImmune LLC
ClinicalTrials.gov Identifier: NCT01268059    
Other Study ID Numbers: CD-ON-MEDI-575-1031
First Posted: December 29, 2010    Key Record Dates
Results First Posted: December 23, 2020
Last Update Posted: December 23, 2020
Last Verified: November 2020
Keywords provided by MedImmune LLC:
Non-small cell lung cancer
NSCLC
MEDI-575
Platelet-derived growth factor receptor alpha
Additional relevant MeSH terms:
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Lung Neoplasms
Carcinoma, Non-Small-Cell Lung
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Neoplasms
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
Paclitaxel
Carboplatin
Antineoplastic Agents, Phytogenic
Antineoplastic Agents
Tubulin Modulators
Antimitotic Agents
Mitosis Modulators
Molecular Mechanisms of Pharmacological Action