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
Condition: Extensive Stage Small Cell Lung Carcinoma; Recurrent Small Cell Lung Carcinoma
MeSH terms: Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma
Intervention: Cisplatin; Cixutumumab; Etoposide; Laboratory Biomarker Analysis; Vismodegib
Intervention description: Given IV; Given IV; Given IV; Correlative studies; Given PO
Intervention MeSH terms: Cisplatin; Etoposide; Etoposide phosphate; Podophyllotoxin; Antibodies, Monoclonal
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Enrollment: 168.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No

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.
    

Eligibility criteria:

        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