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A Randomized Phase II Study of Cisplatin and Etoposide in Combination With Either Hedgehog Inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for Patients With Extensive Stage

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT00887159
Recruitment Status : Completed
First Posted : April 23, 2009
Results First Posted : July 29, 2015
Last Update Posted : April 20, 2018
Sponsor:
Information provided by (Responsible Party):
National Cancer Institute (NCI)

Tracking Information
First Submitted Date  ICMJE April 22, 2009
First Posted Date  ICMJE April 23, 2009
Results First Submitted Date  ICMJE July 1, 2015
Results First Posted Date  ICMJE July 29, 2015
Last Update Posted Date April 20, 2018
Actual Study Start Date  ICMJE July 16, 2009
Actual Primary Completion Date November 15, 2016   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: July 1, 2015)
Progression-free Survival (PFS) [ Time Frame: Assessed every 6 weeks while on treatment or observation; follow-up after discontinuation of treatment or observation: every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry ]
Progression-free survival (PFS) is defined as the time from randomization to death or disease progression, whichever occurred first. Patients who were alive at the time of analysis are censored at the date at which they are last known to be alive and progression-free.
Original Primary Outcome Measures  ICMJE
 (submitted: April 22, 2009)
Progression-free survival
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: July 1, 2015)
  • Response Rate [ Time Frame: Assessed every 6 weeks while on treatment or observation; follow-up after discontinuation of treatment or observation: every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry ]
    Response rate is defined as number of patients with complete response (CR) or partial response (PR) divided by all eligible and treated patients. Responses are evaluated using the Response Evaluation Criteria in Solid Tumors (RECIST) guideline. CR is defined as disappearance of all target and non-target lesions. PR is defined as at least a 30% decrease in the sum of the diameters of target lesions (taking as reference the baseline sum diameters), and persistence of one or more non-target lesion(s).
  • Overall Survival (OS) [ Time Frame: Assessed every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry ]
    Overall survival is defined as the time from randomization to death or date of last known alive.
  • PFS [ Time Frame: Assessed every 6 weeks while on treatment or observation; follow-up after discontinuation of treatment or observation: every 3 months if patient is < 2 years from study entry, every 6 months if patient is 2-3 years from study entry ]
    Progression-free survival (PFS) is defined as the time from randomization to death or disease progression, whichever occurred first. Patients who were alive at the time of analysis are censored at the date at which they are last known to be alive and progression-free. This analysis is to evaluate the association between PFS and circulating tumor cells (CTCs).
Original Secondary Outcome Measures  ICMJE
 (submitted: April 22, 2009)
  • Overall survival
  • Overall response
  • Toxicity
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE A Randomized Phase II Study of Cisplatin and Etoposide in Combination With Either Hedgehog Inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for Patients With Extensive Stage
Official Title  ICMJE A Randomized Phase II Study of Cisplatin and Etoposide in Combination With Either Hedgehog Inhibitor GDC-0449 or IGF-1R MOAB IMC-A12 for Patients With Extensive Stage Small Cell Lung Cancer
Brief Summary This randomized phase II trial studies cisplatin and etoposide to see how well they work when given with or without Hedgehog inhibitor GDC-0449 (vismodegib) or IGF-1R MOAB IMC-A12 (cixutumumab) in treating patients with extensive-stage small cell lung cancer. Drugs used in chemotherapy, such as cisplatin, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Etoposide may slow the growth of tumor cells by blocking some of the enzymes needed for cell growth. Vismodegib may slow the growth of tumor cells. Monoclonal antibodies, such as cixutumumab, may interfere with the ability of tumor cells to grow and spread. It is not yet known whether giving cisplatin and etoposide are more effective when given together with vismodegib or cixutumumab in treating small cell lung cancer.
Detailed Description

PRIMARY OBJECTIVES:

I. To evaluate the progression-free survival (PFS) of patients with extensive stage small cell lung cancer (SCLC-ED) treated with cisplatin and etoposide (CE), CE with hedgehog (HH) inhibitor GDC-0449 (vismodegib), and CE with insulin-like growth factor-1 receptor (IGF-1R) monoclonal antibody (IMC-A12) (cixutumumab).

SECONDARY OBJECTIVES:

I. To evaluate response rate, overall survival, and toxicity for each arm. II. To explore putative correlates of clinical benefit from combination therapy in tumor and circulating tumor cells in patients treated on this protocol.

OUTLINE: Patients are randomized to 1 of 3 treatment arms.

ARM A (CE): Patients receive cisplatin (75 mg/m^2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m^2) IV over 1-2 hours on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.

ARM B (CE +GDC-0449): Patients receive cisplatin and etoposide as in Arm A and vismodegib (GDC-0449; 150 mg tablet) orally (PO) once daily (QD) on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive vismodegib alone QD in the absence of disease progression or unacceptable toxicity.

ARM C (CE + IMC-A12): Patients receive cisplatin and etoposide as in Arm A and cixutumumab (IMC-A12; 6 mg/kg) IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cixutumumab alone once weekly in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years and then every 6 months for 1 year.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Extensive Stage Small Cell Lung Carcinoma
  • Recurrent Small Cell Lung Carcinoma
Intervention  ICMJE
  • Drug: Cisplatin
    Given IV
    Other Names:
    • Abiplatin
    • Blastolem
    • Briplatin
    • CDDP
    • Cis-diammine-dichloroplatinum
    • Cis-diamminedichloridoplatinum
    • Cis-diamminedichloro Platinum (II)
    • Cis-diamminedichloroplatinum
    • Cis-dichloroammine Platinum (II)
    • Cis-platinous Diamine Dichloride
    • Cis-platinum
    • Cis-platinum II
    • Cis-platinum II Diamine Dichloride
    • Cismaplat
    • Cisplatina
    • Cisplatinum
    • Cisplatyl
    • Citoplatino
    • Citosin
    • Cysplatyna
    • DDP
    • Lederplatin
    • Metaplatin
    • Neoplatin
    • Peyrone's Chloride
    • Peyrone's Salt
    • Placis
    • Plastistil
    • Platamine
    • Platiblastin
    • Platiblastin-S
    • Platinex
    • Platinol
    • Platinol- AQ
    • Platinol-AQ
    • Platinol-AQ VHA Plus
    • Platinoxan
    • Platinum
    • Platinum Diamminodichloride
    • Platiran
    • Platistin
    • Platosin
  • Biological: Cixutumumab
    Given IV
    Other Names:
    • Anti-IGF-1R Recombinant Monoclonal Antibody IMC-A12
    • IMC-A12
  • Drug: Etoposide
    Given IV
    Other Names:
    • Demethyl Epipodophyllotoxin Ethylidine Glucoside
    • EPEG
    • Lastet
    • Toposar
    • Vepesid
    • VP 16-213
    • VP-16
    • VP-16-213
  • Other: Laboratory Biomarker Analysis
    Correlative studies
  • Drug: Vismodegib
    Given PO
    Other Names:
    • Erivedge
    • GDC-0449
    • Hedgehog Antagonist GDC-0449
Study Arms  ICMJE
  • Active Comparator: Arm A (CE)
    Patients receive cisplatin IV over 1-2 hours on day 1 and etoposide IV over 1-2 hours on days 1-3. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
  • Experimental: Arm B (CE + GDC-0449)
    Patients receive cisplatin and etoposide as in Arm A and vismodegib PO QD on days 1-21. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive vismodegib alone QD in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
    • Drug: Vismodegib
  • Experimental: Arm C (CE + IMC-A12)
    Patients receive cisplatin and etoposide as in Arm A and cixutumumab IV over 1 hour on days 1, 8, and 15. Treatment repeats every 21 days for 4 courses in the absence of disease progression or unacceptable toxicity. Patients then receive cixutumumab alone once weekly in the absence of disease progression or unacceptable toxicity.
    Interventions:
    • Drug: Cisplatin
    • Biological: Cixutumumab
    • Drug: Etoposide
    • Other: Laboratory Biomarker Analysis
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Completed
Actual Enrollment  ICMJE
 (submitted: July 1, 2015)
168
Original Estimated Enrollment  ICMJE
 (submitted: April 22, 2009)
170
Actual Study Completion Date  ICMJE November 15, 2016
Actual Primary Completion Date November 15, 2016   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Histologically or cytologically confirmed small cell lung cancer (SCLC)
  • Extensive stage SCLC

    • Extensive stage disease: the extensive disease classification for this protocol includes all patients with disease sites not defined as limited stage; limited stage disease category includes patients with disease restricted to one hemithorax with regional lymph node metastases, including hilar, ipsilateral and contralateral mediastinal, and/or ipsilateral supraclavicular nodes; extensive disease patients are defined as those patients with extrathoracic metastatic disease, malignant pleural effusion, bilateral or contralateral supraclavicular adenopathy
  • Measurable disease based on Response Evaluation Criteria in Solid Tumors (RECIST); baseline measurements and evaluations of all sites of disease must be obtained =< 4 weeks prior to randomization
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
  • Absolute neutrophil count (ANC) >= 1,500/mm^3
  • Platelets >= 100,000/mm^3
  • Total bilirubin =< 1.5 x institutional upper limit of normal (ULN)
  • Aspartate aminotransferase (AST) (serum glutamic oxaloacetic transaminase)/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase) =< 3 x institutional ULN (=< 5 x ULN if liver function test [LFT] elevations are due to liver metastases)
  • Creatinine =< 1.5 x institutional ULN OR creatinine clearance >= 60 mL/min/1.73 m^2 for patients with creatinine levels > 1.5 x institutional ULN
  • Leukocytes >= 3,000/mm^3
  • Hemoglobin >= 9 g/dL
  • Fasting serum glucose < 120 mg/dL or below institutional ULN =< 7 days prior to protocol randomization
  • Patients with central nervous system (CNS) metastases will be eligible if they have completed a course of CNS radiotherapy and have stable neurologic function for a minimum of 28 days prior to study randomization; radiotherapy must have been completed a minimum of 28 days prior to randomization, and patients must have recovered from any adverse events related to the radiotherapy (except alopecia and grade 1 neuropathy) and have stable neurologic function for a minimum of 28 days prior to study randomization

    • NOTE: the use of prophylactic cranial irradiation (recommended dose 25 Gy) in those who completed protocol chemotherapy and have a response (in the absence of progressive disease [PD]) is allowed; for patients on Arms B and C, GDC-0449 and IMC-A12 will be held while patient is receiving prophylactic cranial irradiation (PCI); these agents can be reinstituted after PCI is completed
  • Women of child-bearing potential (WCBP) and men must agree to use adequate contraception (hormonal or barrier method of birth control; abstinence) prior to study entry and for the duration of study participation

    • WCBP must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse; the two methods of reliable contraception must include one highly effective method (i.e., intrauterine device [IUD], hormonal [birth control pills, injections, or implants], tubal ligation, partner?s vasectomy) and one additional effective (barrier) method (i.e., latex condom, diaphragm, cervical cap); WCBP must be referred to a qualified provider of contraceptive methods if needed

      • NOTE: the WCBP randomized to Arm B must agree to use two reliable forms of contraception simultaneously or to practice complete abstinence from heterosexual intercourse during the following two additional time periods related to this study: 1) while participating in the study; and 2) for at least 12 months after discontinuation from the study
    • Before starting the study drugs, all WCBP must have a negative pregnancy test (sensitivity of at least 50 mIU/mL); the pregnancy test must be performed within 10-14 days prior to randomization

      • NOTE: the WCBP randomized to Arm B must have a second pregnancy test performed within the 24 hours prior to the start of the GDC-0449; the subject may not receive GDC-0449 until the investigator has verified that the results of these pregnancy tests are negative
    • The WCBP randomized to Arm B will be warned that sharing the study drug is prohibited and will be counseled about pregnancy precautions and potential risks or fetal exposure; she must also agree to abstain from donating blood during study participation and at least 12 months after discontinuation from the study drug

      • NOTE: male subjects randomized to Arm B must agree to use a latex condom during sexual contact with WCBP while participating in the study and for at least 12 months following discontinuation from the study even if he has undergone a successful vasectomy
    • Male subjects randomized to Arm B will be warned that sharing study drug is prohibited and will be counseled about pregnancy precautions and potential risks of fetal exposure; male subjects must agree to abstain from donating blood, semen, or sperm during study participation and for at least 3 months after discontinuation from the study drug

Exclusion Criteria:

  • Pregnant or breastfeeding; all WCBP must have a blood test within 10-14 days prior to randomization to rule out pregnancy
  • Prior chemotherapy or biologic therapy for SCLC; patients with prior radiation may be eligible or after palliative radiotherapy for other sites of disease; patients receiving prior radiation cannot start therapy within 14 days after completion of radiation, and must have recovered from adverse events attributed to radiation; no previous irradiation to the only site of measurable or evaluable disease, unless that site had subsequent evidence of progression
  • Receiving any other investigational agents
  • History of allergic reactions attributed to compounds of similar chemical or biological composition to GDC-0449 and IMC-A12 or other agents used in the study
  • Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, uncontrolled cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
  • Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy
  • Poorly controlled diabetes mellitus; patients with a history of diabetes mellitus are allowed to participate, provided that their blood glucose is within normal range (fasting < 120 mg/dL or below institutional upper limit of normal) and that they are on a stable dietary or therapeutic regimen for this condition
  • Patients with major surgery, hormonal therapy (other than replacement), within 4 weeks prior to entering the study or those who have not recovered from adverse events
  • Prior treatment with other agents targeting the IGFR or the Hedgehog signaling pathway
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT00887159
Other Study ID Numbers  ICMJE NCI-2011-01917
NCI-2011-01917 ( Registry Identifier: CTRP (Clinical Trial Reporting Program) )
09-0679
ECOG-E1508
CDR0000640898
E1508 ( Other Identifier: ECOG-ACRIN Cancer Research Group )
E1508 ( Other Identifier: CTEP )
U10CA180820 ( U.S. NIH Grant/Contract )
U10CA021115 ( U.S. NIH Grant/Contract )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE Not Provided
Responsible Party National Cancer Institute (NCI)
Study Sponsor  ICMJE National Cancer Institute (NCI)
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Chandra Belani ECOG-ACRIN Cancer Research Group
PRS Account National Cancer Institute (NCI)
Verification Date March 2018

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP