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

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT00887159
• Collaborator: (none)
• Enrollment: 168
• Locations: 301
• Arms: 3
• Actual Duration (Months): 88
• Patients Per Site: 0.6
• Patients Per Site Per Month: 0

Study Details

Study Description

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.

Condition or Disease	Intervention/Treatment	Phase
Extensive Stage Small Cell Lung Carcinoma; Recurrent Small Cell Lung Carcinoma	Drug: Cisplatin; Biological: Cixutumumab; Drug: Etoposide; Other: Laboratory Biomarker Analysis; Drug: Vismodegib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. 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:

1. 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 Design

• Study Type: Interventional
• Actual Enrollment: 168 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: 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
• Actual Study Start Date: Jul 16, 2009
• Actual Primary Completion Date: Nov 15, 2016
• Actual Study Completion Date: Nov 15, 2016

Arms and Interventions

Arm	Intervention/Treatment
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.	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 ; 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
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.	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 ; 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
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.	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

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) [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.

Secondary Outcome Measures

1. Response Rate [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).

2. Overall Survival (OS) [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.

3. PFS [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).

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

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

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Mayo Clinic in Arizona	Scottsdale	Arizona	United States	85259
2	Stanford Cancer Institute Palo Alto	Palo Alto	California	United States	94304
3	The Medical Center of Aurora	Aurora	Colorado	United States	80012
4	Boulder Community Hospital	Boulder	Colorado	United States	80301
5	Penrose-Saint Francis Healthcare	Colorado Springs	Colorado	United States	80907
6	Porter Adventist Hospital	Denver	Colorado	United States	80210
7	Presbyterian - Saint Lukes Medical Center - Health One	Denver	Colorado	United States	80218
8	SCL Health Saint Joseph Hospital	Denver	Colorado	United States	80218
9	Rose Medical Center	Denver	Colorado	United States	80220
10	Colorado Cancer Research Program NCORP	Denver	Colorado	United States	80222
11	Swedish Medical Center	Englewood	Colorado	United States	80113
12	Saint Mary's Hospital and Regional Medical Center	Grand Junction	Colorado	United States	81501
13	North Colorado Medical Center	Greeley	Colorado	United States	80631
14	Saint Anthony Hospital	Lakewood	Colorado	United States	80228
15	Sky Ridge Medical Center	Lone Tree	Colorado	United States	80124
16	Longmont United Hospital	Longmont	Colorado	United States	80501
17	McKee Medical Center	Loveland	Colorado	United States	80539
18	Saint Mary Corwin Medical Center	Pueblo	Colorado	United States	81004
19	North Suburban Medical Center	Thornton	Colorado	United States	80229
20	SCL Health Lutheran Medical Center	Wheat Ridge	Colorado	United States	80033
21	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
22	The Hospital of Central Connecticut	New Britain	Connecticut	United States	06050
23	Smilow Cancer Hospital-Torrington Care Center	Torrington	Connecticut	United States	06790
24	Boca Raton Regional Hospital	Boca Raton	Florida	United States	33486
25	Mayo Clinic in Florida	Jacksonville	Florida	United States	32224-9980
26	Emory University Hospital/Winship Cancer Institute	Atlanta	Georgia	United States	30322
27	Atlanta VA Medical Center	Decatur	Georgia	United States	30033
28	Medical Center of Central Georgia	Macon	Georgia	United States	31201
29	Lewis Cancer and Research Pavilion at Saint Joseph's/Candler	Savannah	Georgia	United States	31405
30	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
31	Graham Hospital Association	Canton	Illinois	United States	61520
32	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
33	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
34	Memorial Hospital	Carthage	Illinois	United States	62321
35	Hematology and Oncology Associates	Chicago	Illinois	United States	60611
36	Northwestern University	Chicago	Illinois	United States	60611
37	John H Stroger Jr Hospital of Cook County	Chicago	Illinois	United States	60612
38	Rush University Medical Center	Chicago	Illinois	United States	60612
39	Presence Saint Joseph Hospital-Chicago	Chicago	Illinois	United States	60657
40	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
41	Heartland Cancer Research NCORP	Decatur	Illinois	United States	62526
42	Elmhurst Memorial Hospital	Elmhurst	Illinois	United States	60126
43	Eureka Hospital	Eureka	Illinois	United States	61530
44	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
45	NorthShore University HealthSystem-Evanston Hospital	Evanston	Illinois	United States	60201
46	Galesburg Cottage Hospital	Galesburg	Illinois	United States	61401
47	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
48	Ingalls Memorial Hospital	Harvey	Illinois	United States	60426
49	Illinois CancerCare-Havana	Havana	Illinois	United States	62644
50	Mason District Hospital	Havana	Illinois	United States	62644
51	Hematology Oncology Associates of Illinois-Highland Park	Highland Park	Illinois	United States	60035
52	Hinsdale Hematology Oncology Associates Incorporated	Hinsdale	Illinois	United States	60521
53	Joliet Oncology-Hematology Associates Limited	Joliet	Illinois	United States	60435
54	Presence Saint Mary's Hospital	Kankakee	Illinois	United States	60901
55	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
56	NorthShore Hematology Oncology-Libertyville	Libertyville	Illinois	United States	60048
57	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
58	Mcdonough District Hospital	Macomb	Illinois	United States	61455
59	Garneau, Stewart C MD (UIA Investigator)	Moline	Illinois	United States	61265
60	Porubcin, Michael MD (UIA Investigator)	Moline	Illinois	United States	61265
61	Sharis, Christine M MD (UIA Investigator)	Moline	Illinois	United States	61265
62	Spector, David MD (UIA Investigator)	Moline	Illinois	United States	61265
63	Stoffel, Thomas J MD (UIA Investigator)	Moline	Illinois	United States	61265
64	Trinity Medical Center	Moline	Illinois	United States	61265
65	Holy Family Medical Center	Monmouth	Illinois	United States	61462
66	Illinois CancerCare-Monmouth	Monmouth	Illinois	United States	61462
67	Illinois Cancer Specialists-Niles	Niles	Illinois	United States	60714
68	Bromenn Regional Medical Center	Normal	Illinois	United States	61761
69	Community Cancer Center Foundation	Normal	Illinois	United States	61761
70	Illinois CancerCare-Community Cancer Center	Normal	Illinois	United States	61761
71	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
72	Ottawa Regional Hospital and Healthcare Center	Ottawa	Illinois	United States	61350
73	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
74	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
75	Pekin Hospital	Pekin	Illinois	United States	61554
76	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61603
77	Proctor Hospital	Peoria	Illinois	United States	61614
78	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
79	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
80	Illinois Valley Hospital	Peru	Illinois	United States	61354
81	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
82	Perry Memorial Hospital	Princeton	Illinois	United States	61356
83	Swedish American Hospital	Rockford	Illinois	United States	61104
84	SwedishAmerican Regional Cancer Center/ACT	Rockford	Illinois	United States	61114
85	Hematology Oncology Associates of Illinois - Skokie	Skokie	Illinois	United States	60076
86	Illinois CancerCare-Spring Valley	Spring Valley	Illinois	United States	61362
87	Saint Margaret's Hospital	Spring Valley	Illinois	United States	61362
88	Memorial Medical Center	Springfield	Illinois	United States	62781
89	McFarland Clinic PC-William R Bliss Cancer Center	Ames	Iowa	United States	50010
90	Constantinou, Costas L MD (UIA Investigator)	Bettendorf	Iowa	United States	52722
91	Medical Oncology and Hematology Associates-West Des Moines	Clive	Iowa	United States	50325
92	Mercy Capitol	Des Moines	Iowa	United States	50307
93	Iowa Methodist Medical Center	Des Moines	Iowa	United States	50309
94	Iowa-Wide Oncology Research Coalition NCORP	Des Moines	Iowa	United States	50309
95	Medical Oncology and Hematology Associates-Des Moines	Des Moines	Iowa	United States	50309
96	Medical Oncology and Hematology Associates-Laurel	Des Moines	Iowa	United States	50314
97	Mercy Medical Center - Des Moines	Des Moines	Iowa	United States	50314
98	Iowa Lutheran Hospital	Des Moines	Iowa	United States	50316
99	Mercy Medical Center - North Iowa	Mason City	Iowa	United States	50401
100	Ottumwa Regional Health Center	Ottumwa	Iowa	United States	52501
101	Siouxland Regional Cancer Center	Sioux City	Iowa	United States	51101
102	Mercy Medical Center-Sioux City	Sioux City	Iowa	United States	51104
103	Saint Luke's Regional Medical Center	Sioux City	Iowa	United States	51104
104	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
105	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
106	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
107	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
108	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
109	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
110	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
111	Southwest Medical Center	Liberal	Kansas	United States	67901
112	Cancer Center of Kansas-Liberal	Liberal	Kansas	United States	67905
113	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
114	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
115	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
116	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
117	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
118	Associates In Womens Health	Wichita	Kansas	United States	67208
119	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
120	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
121	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
122	Wichita NCI Community Oncology Research Program	Wichita	Kansas	United States	67214
123	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
124	Doctors Carrol, Sheth, Raghavan	Louisville	Kentucky	United States	40215
125	Greater Baltimore Medical Center	Baltimore	Maryland	United States	21204
126	Johns Hopkins University/Sidney Kimmel Cancer Center	Baltimore	Maryland	United States	21287
127	The Memorial Hospital at Easton	Easton	Maryland	United States	21601
128	Frederick Memorial Hospital	Frederick	Maryland	United States	21701
129	Tufts Medical Center	Boston	Massachusetts	United States	02111
130	Bixby Medical Center	Adrian	Michigan	United States	49221
131	Hickman Cancer Center	Adrian	Michigan	United States	49221
132	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
133	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106
134	Beaumont Hospital-Dearborn	Dearborn	Michigan	United States	48124
135	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
136	Hurley Medical Center	Flint	Michigan	United States	48503
137	Genesys Regional Medical Center-West Flint Campus	Flint	Michigan	United States	48532
138	Allegiance Health	Jackson	Michigan	United States	49201
139	Borgess Medical Center	Kalamazoo	Michigan	United States	49001
140	Bronson Methodist Hospital	Kalamazoo	Michigan	United States	49007
141	West Michigan Cancer Center	Kalamazoo	Michigan	United States	49007
142	Sparrow Hospital	Lansing	Michigan	United States	48912
143	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
144	Mercy Memorial Hospital	Monroe	Michigan	United States	48162
145	Toledo Clinic Cancer Centers-Monroe	Monroe	Michigan	United States	48162
146	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
147	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
148	Saint Mary's of Michigan	Saginaw	Michigan	United States	48601
149	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
150	Sanford Clinic North-Bemidgi	Bemidji	Minnesota	United States	56601
151	Fairview Ridges Hospital	Burnsville	Minnesota	United States	55337
152	Mercy Hospital	Coon Rapids	Minnesota	United States	55433
153	Essentia Health Cancer Center	Duluth	Minnesota	United States	55805
154	Essentia Health Saint Mary's Medical Center	Duluth	Minnesota	United States	55805
155	Miller-Dwan Hospital	Duluth	Minnesota	United States	55805
156	Fairview-Southdale Hospital	Edina	Minnesota	United States	55435
157	Lake Region Healthcare Corporation-Cancer Care	Fergus Falls	Minnesota	United States	56537
158	Unity Hospital	Fridley	Minnesota	United States	55432
159	Hutchinson Area Health Care	Hutchinson	Minnesota	United States	55350
160	Minnesota Oncology Hematology PA-Maplewood	Maplewood	Minnesota	United States	55109
161	Saint John's Hospital - Healtheast	Maplewood	Minnesota	United States	55109
162	Abbott-Northwestern Hospital	Minneapolis	Minnesota	United States	55407
163	Hennepin County Medical Center	Minneapolis	Minnesota	United States	55415
164	North Memorial Medical Health Center	Robbinsdale	Minnesota	United States	55422
165	Metro Minnesota Community Oncology Research Consortium	Saint Louis Park	Minnesota	United States	55416
166	Park Nicollet Clinic - Saint Louis Park	Saint Louis Park	Minnesota	United States	55416
167	Regions Hospital	Saint Paul	Minnesota	United States	55101
168	United Hospital	Saint Paul	Minnesota	United States	55102
169	Saint Francis Regional Medical Center	Shakopee	Minnesota	United States	55379
170	Lakeview Hospital	Stillwater	Minnesota	United States	55082
171	Ridgeview Medical Center	Waconia	Minnesota	United States	55387
172	Rice Memorial Hospital	Willmar	Minnesota	United States	56201
173	Minnesota Oncology Hematology PA-Woodbury	Woodbury	Minnesota	United States	55125
174	Nebraska Cancer Research Center	Lincoln	Nebraska	United States	68510
175	Missouri Valley Cancer Consortium	Omaha	Nebraska	United States	68106
176	Alegent Health Immanuel Medical Center	Omaha	Nebraska	United States	68122
177	Alegent Health Bergan Mercy Medical Center	Omaha	Nebraska	United States	68124
178	Creighton University Medical Center	Omaha	Nebraska	United States	68131
179	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
180	Veterans Adminstration New Jersey Health Care System	East Orange	New Jersey	United States	07018-1095
181	Hunterdon Medical Center	Flemington	New Jersey	United States	08822
182	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
183	Sparta Cancer Treatment Center	Sparta	New Jersey	United States	07871
184	Lovelace Medical Center-Saint Joseph Square	Albuquerque	New Mexico	United States	87102
185	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
186	Presbyterian Kaseman Hospital	Albuquerque	New Mexico	United States	87110
187	New York Oncology Hematology PC - Albany	Albany	New York	United States	12206
188	New York Oncology Hematology PC -Albany Medical Center	Albany	New York	United States	12208
189	New York Oncology Hematology PC - Amsterdam	Amsterdam	New York	United States	12010
190	Montefiore Medical Center-Weiler Hospital	Bronx	New York	United States	10461
191	Montefiore Medical Center - Moses Campus	Bronx	New York	United States	10467
192	New York Oncology Hematology PC - Clifton Park	Clifton Park	New York	United States	12065
193	New York Oncology Hematology PC-Hudson	Hudson	New York	United States	12534
194	Laura and Isaac Perlmutter Cancer Center at NYU Langone	New York	New York	United States	10016
195	New York Oncology Hematology PC - Rexford	Rexford	New York	United States	12148
196	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
197	New York Oncology Hematology PC - Troy	Troy	New York	United States	12180
198	Dickstein Cancer Treatment Center	White Plains	New York	United States	10601
199	Sanford Broadway Medical Center	Fargo	North Dakota	United States	58122
200	Sanford Clinic North-Fargo	Fargo	North Dakota	United States	58122
201	Summa Akron City Hospital/Cooper Cancer Center	Akron	Ohio	United States	44304
202	Summa Barberton Hospital	Barberton	Ohio	United States	44203
203	Mary Rutan Hospital	Bellefontaine	Ohio	United States	43311
204	Toledo Clinic Cancer Centers-Bowling Green	Bowling Green	Ohio	United States	43402
205	Mercy Medical Center	Canton	Ohio	United States	44708
206	Aultman Health Foundation	Canton	Ohio	United States	44710
207	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
208	Case Western Reserve University	Cleveland	Ohio	United States	44106
209	North Coast Cancer Care-Clyde	Clyde	Ohio	United States	43410
210	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
211	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
212	Grant Medical Center	Columbus	Ohio	United States	43215
213	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
214	Doctors Hospital	Columbus	Ohio	United States	43228
215	Grady Memorial Hospital	Delaware	Ohio	United States	43015
216	Hematology Oncology Center Incorporated	Elyria	Ohio	United States	44035
217	Mercy Cancer Center-Elyria	Elyria	Ohio	United States	44035
218	Fairfield Medical Center	Lancaster	Ohio	United States	43130
219	Saint Rita's Medical Center	Lima	Ohio	United States	45801
220	Lima Memorial Hospital	Lima	Ohio	United States	45804
221	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
222	Saint Luke's Hospital	Maumee	Ohio	United States	43537
223	Toledo Clinic Cancer Centers-Maumee	Maumee	Ohio	United States	43537
224	Toledo Radiation Oncology at Northwest Ohio Onocolgy Center	Maumee	Ohio	United States	43537
225	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
226	Licking Memorial Hospital	Newark	Ohio	United States	43055
227	Fisher-Titus Medical Center	Norwalk	Ohio	United States	44857
228	Saint Charles Hospital	Oregon	Ohio	United States	43616
229	Toledo Clinic Cancer Centers-Oregon	Oregon	Ohio	United States	43616
230	North Coast Cancer Care	Sandusky	Ohio	United States	44870
231	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
232	Flower Hospital	Sylvania	Ohio	United States	43560
233	Mercy Hospital of Tiffin	Tiffin	Ohio	United States	44883
234	The Toledo Hospital/Toledo Children's Hospital	Toledo	Ohio	United States	43606
235	Saint Vincent Mercy Medical Center	Toledo	Ohio	United States	43608
236	University of Toledo	Toledo	Ohio	United States	43614
237	Toledo Community Hospital Oncology Program CCOP	Toledo	Ohio	United States	43617
238	Mercy Saint Anne Hospital	Toledo	Ohio	United States	43623
239	Toledo Clinic Cancer Centers-Toledo	Toledo	Ohio	United States	43623
240	Fulton County Health Center	Wauseon	Ohio	United States	43567
241	Saint Ann's Hospital	Westerville	Ohio	United States	43081
242	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
243	Natalie Warren Bryant Cancer Center at Saint Francis	Tulsa	Oklahoma	United States	74136
244	Abington Memorial Hospital	Abington	Pennsylvania	United States	19001
245	Lehigh Valley Hospital-Cedar Crest	Allentown	Pennsylvania	United States	18103
246	Bryn Mawr Hospital	Bryn Mawr	Pennsylvania	United States	19010
247	Butler Memorial Hospital	Butler	Pennsylvania	United States	16001
248	Geisinger Medical Center	Danville	Pennsylvania	United States	17822
249	Ephrata Cancer Center	Ephrata	Pennsylvania	United States	17522
250	Adams Cancer Center	Gettysburg	Pennsylvania	United States	17325
251	Cherry Tree Cancer Center	Hanover	Pennsylvania	United States	17331
252	Geisinger Medical Center-Cancer Center Hazleton	Hazleton	Pennsylvania	United States	18201
253	Penn State Milton S Hershey Medical Center	Hershey	Pennsylvania	United States	17033-0850
254	Lancaster General Hospital	Lancaster	Pennsylvania	United States	17604
255	Saint Mary Medical and Regional Cancer Center	Langhorne	Pennsylvania	United States	19047
256	Lewistown Hospital	Lewistown	Pennsylvania	United States	17044
257	Paoli Memorial Hospital	Paoli	Pennsylvania	United States	19301
258	University of Pennsylvania/Abramson Cancer Center	Philadelphia	Pennsylvania	United States	19104
259	Thomas Jefferson University Hospital	Philadelphia	Pennsylvania	United States	19107
260	Einstein Medical Center Philadelphia	Philadelphia	Pennsylvania	United States	19141
261	Guthrie Medical Group PC-Robert Packer Hospital	Sayre	Pennsylvania	United States	18840
262	Mercy Hospital	Scranton	Pennsylvania	United States	18501
263	Hematology and Oncology Associates of North East Pennsylvania	Scranton	Pennsylvania	United States	18508
264	Scranton Hematology Oncology	Scranton	Pennsylvania	United States	18510
265	Geisinger Medical Group	State College	Pennsylvania	United States	16801
266	Mount Nittany Medical Center	State College	Pennsylvania	United States	16803
267	Reading Hospital	West Reading	Pennsylvania	United States	19611
268	Geisinger Wyoming Valley/Henry Cancer Center	Wilkes-Barre	Pennsylvania	United States	18711
269	Lankenau Medical Center	Wynnewood	Pennsylvania	United States	19096
270	WellSpan Health-York Hospital	York	Pennsylvania	United States	17403
271	Sanford Cancer Center Oncology Clinic	Sioux Falls	South Dakota	United States	57104
272	Avera Cancer Institute	Sioux Falls	South Dakota	United States	57105
273	Avera McKennan Hospital and University Health Center	Sioux Falls	South Dakota	United States	57105
274	Medical X-Ray Center	Sioux Falls	South Dakota	United States	57105
275	Sanford USD Medical Center - Sioux Falls	Sioux Falls	South Dakota	United States	57117-5134
276	Wellmont Medical Associates Oncology and Hematology-Bristol	Bristol	Tennessee	United States	37620
277	Vanderbilt-Ingram Cancer Center Cool Springs	Franklin	Tennessee	United States	37067
278	Vanderbilt University/Ingram Cancer Center	Nashville	Tennessee	United States	37232
279	Dallas VA Medical Center	Dallas	Texas	United States	75216
280	Parkland Memorial Hospital	Dallas	Texas	United States	75235
281	UT Southwestern/Simmons Cancer Center-Dallas	Dallas	Texas	United States	75390
282	University of Virginia Cancer Center	Charlottesville	Virginia	United States	22908
283	Fredericksburg Oncology Inc	Fredericksburg	Virginia	United States	22401
284	West Virginia University Charleston	Charleston	West Virginia	United States	25304
285	West Virginia University Healthcare	Morgantown	West Virginia	United States	26506
286	Wheeling Hospital/Schiffler Cancer Center	Wheeling	West Virginia	United States	26003
287	Marshfield Clinic-Chippewa Center	Chippewa Falls	Wisconsin	United States	54729
288	Marshfield Clinic Cancer Center at Sacred Heart	Eau Claire	Wisconsin	United States	54701
289	Gundersen Lutheran Medical Center	La Crosse	Wisconsin	United States	54601
290	Dean Hematology and Oncology Clinic	Madison	Wisconsin	United States	53717
291	Marshfield Clinic	Marshfield	Wisconsin	United States	54449
292	Columbia Saint Mary's Water Tower Medical Commons	Milwaukee	Wisconsin	United States	53211
293	Aurora Saint Luke's Medical Center	Milwaukee	Wisconsin	United States	53215
294	Marshfield Clinic-Minocqua Center	Minocqua	Wisconsin	United States	54548
295	ProHealth Oconomowoc Memorial Hospital	Oconomowoc	Wisconsin	United States	53066
296	Ascension Saint Mary's Hospital	Rhinelander	Wisconsin	United States	54501
297	Marshfield Clinic-Rice Lake Center	Rice Lake	Wisconsin	United States	54868
298	Ascension Saint Michael's Hospital	Stevens Point	Wisconsin	United States	54481
299	ProHealth Waukesha Memorial Hospital	Waukesha	Wisconsin	United States	53188
300	Marshfield Clinic - Weston Center	Weston	Wisconsin	United States	54476
301	Marshfield Clinic - Wisconsin Rapids Center	Wisconsin Rapids	Wisconsin	United States	54494

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Chandra Belani, ECOG-ACRIN Cancer Research Group

Study Documents (Full-Text)

None provided.

More Information

Additional Information:

• Select individual patient-level data from this trial can be requested from the NCTN/NCORP Data Archive.

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT00887159
• Other Study ID Numbers: NCI-2011-01917; NCI-2011-01917; 09-0679; ECOG-E1508; CDR0000640898; E1508; E1508; U10CA180820; U10CA021115
• First Posted: Apr 23, 2009
• Last Update Posted: Jan 5, 2021
• Last Verified: Dec 1, 2020

• Additional relevant MeSH terms: Carcinoma; Lung Neoplasms; Small Cell Lung Carcinoma; Cisplatin; Etoposide; Etoposide phosphate; Podophyllotoxin; Antibodies, Monoclonal

Study Results

Participant Flow

Recruitment Details	Participants were recruited from ECOG member institutions between July, 16, 2009 and August 12, 2011.

Arm/Group Title	Arm A (CE)	Arm B (CE+GDC-0449)	Arm C (CE+IMC-A12)
Arm/Group Description	Patients receive cisplatin (75 mg/m2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m2) 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. cisplatin: Given IV etoposide: Given IV	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. vismodegib: Given PO cisplatin: Given IV etoposide: Given IV	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. cixutumumab: Given IV cisplatin: Given IV etoposide: Given IV
Period Title: Overall Study
STARTED	56	56	56
Patients Who Started Assigned Treatment	53	53	52
Eligible and Treated Patients	48	52	52
Eligible/Treated Pts With CTCs Results	40	42	38
COMPLETED	27	0	0
NOT COMPLETED	29	56	56

Baseline Characteristics

Arm/Group Title	Arm A (CE)	Arm B (CE+GDC-0449)	Arm C (CE+IMC-A12)	Total
Arm/Group Description	Patients receive cisplatin (75 mg/m2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m2) 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. cisplatin: Given IV etoposide: Given IV	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. vismodegib: Given PO cisplatin: Given IV etoposide: Given IV	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. cixutumumab: Given IV cisplatin: Given IV etoposide: Given IV	Total of all reporting groups
Overall Participants	48	52	52	152
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	61	64	64	63
Sex: Female, Male (Count of Participants)
Female	25 52.1%	26 50%	25 48.1%	76 50%
Male	23 47.9%	26 50%	27 51.9%	76 50%
Region of Enrollment (participants) [Number]
United States	48 100%	52 100%	52 100%	152 100%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS)
Description	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.
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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients.

Arm/Group Title	Arm A (CE)	Arm B (CE+GDC-0449)	Arm C (CE+IMC-A12)
Arm/Group Description	Patients receive cisplatin (75 mg/m2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m2) 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.	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.	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.
Measure Participants	48	52	52
Median (95% Confidence Interval) [months]	4.4	4.4	4.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (CE), Arm B (CE+GDC-0449)
	Comments	There are 2 primary comparisons and each involves comparing the experimental arms (B, C) to the control arm (A). Accrual goal was 54 patients per arm. With a 1-sided 0.1 level logrank test for each test, we have 90% power to detect a 42% reduction in the PFS hazard rate of 0.139 to 0.082 (corresponding to an improvement in median PFS of 5 months to 8.5 months) with 18-month accrual and 12-month follow-up; assuming exponential survival. For each test, 94 events are needed to achieve this power.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.45
	Comments	P-value is one-sided.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.98
	Confidence Interval	(2-Sided) 95%; 0.65 to 1.47
	Parameter Dispersion	Type: Value:
	Estimation Comments	The hazard ratio was derived comparing Arm B to Arm A.

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Arm A (CE), Arm C (CE+IMC-A12)
	Comments	There are 2 primary comparisons and each involves comparing the experimental arms (B, C) to the control arm (A). Accrual goal was 54 patients per arm. With a 1-sided 0.1 level logrank test for each test, we have 90% power to detect a 42% reduction in the PFS hazard rate of 0.139 to 0.082 (corresponding to an improvement in median PFS of 5 months to 8.5 months) with 18-month accrual and 12-month follow-up; assuming exponential survival. For each test, 94 events are needed to achieve this power.
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.48
	Comments	P-value is one-sided.
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	0.99
	Confidence Interval	(2-Sided) 95%; 0.66 to 1.48
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was derived comparing Arm C to Arm A.

2. Secondary Outcome

Title	Response Rate
Description	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).
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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients.

Arm/Group Title	Arm A (CE)	Arm B (CE+GDC-0449)	Arm C (CE+IMC-A12)
Arm/Group Description	Patients receive cisplatin (75 mg/m2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m2) 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.	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.	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.
Measure Participants	48	52	52
Number (95% Confidence Interval) [Proportion of patients]	0.48	0.56	0.50

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Overall survival is defined as the time from randomization to death or date of last known alive.
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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients.

Arm/Group Title	Arm A (CE)	Arm B (CE+GDC-0449)	Arm C (CE+IMC-A12)
Arm/Group Description	Patients receive cisplatin (75 mg/m2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m2) 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.	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.	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.
Measure Participants	48	52	52
Median (95% Confidence Interval) [months]	8.8	9.8	10.1

4. Secondary Outcome

Title	PFS
Description	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).
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

Outcome Measure Data

Analysis Population Description

Eligible and treated patients who had baseline CTC results available for analysis.

Arm/Group Title	High CTC Count	Low CTC Count
Arm/Group Description	High CTC count is defined as greater than 100 CTCs per 7.5 ml at baseline.	Low CTC count is defined as <= 100 CTCs per 7.5 ml at baseline.
Measure Participants	39	81
Median (95% Confidence Interval) [months]	4.1	4.5

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Arm A (CE), Arm B (CE+GDC-0449)
	Comments
	Type of Statistical Test	Superiority or Other (legacy)
	Comments
Statistical Test of Hypothesis	p-Value	0.01
	Comments
	Method	Regression, Cox
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	1.69
	Confidence Interval	(2-Sided) 95%; 1.13 to 2.52
	Parameter Dispersion	Type: Value:
	Estimation Comments	Hazard ratio was derived comparing the high CTCs group to the low CTCs group.

Adverse Events

Time Frame	Assessed every 3 weeks while on treatment and for 30 days after the end of treatment
Arm/Group Title	Arm A (CE)		Arm B (CE+GDC-0449)		Arm C (CE+IMC-A12)
Arm/Group Description	Patients receive cisplatin (75 mg/m2) intravenously (IV) over 1-2 hours on day 1 and etoposide (100 mg/m2) 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.		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.		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.
All Cause Mortality
	Arm A (CE)		Arm B (CE+GDC-0449)		Arm C (CE+IMC-A12)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Arm A (CE)		Arm B (CE+GDC-0449)		Arm C (CE+IMC-A12)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	45/53 (84.9%)		44/53 (83%)		47/52 (90.4%)
Blood and lymphatic system disorders
Anemia	13/53 (24.5%)		6/53 (11.3%)		7/52 (13.5%)
Febrile neutropenia	8/53 (15.1%)		6/53 (11.3%)		2/52 (3.8%)
Cardiac disorders
Myocardial infarction	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Ear and labyrinth disorders
Tinnitus	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Eye disorders
Eye disorders - Other, specify	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Gastrointestinal disorders
Abdominal pain	0/53 (0%)		1/53 (1.9%)		1/52 (1.9%)
Colonic perforation	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Diarrhea	0/53 (0%)		3/53 (5.7%)		6/52 (11.5%)
Dysphagia	0/53 (0%)		0/53 (0%)		2/52 (3.8%)
Esophagitis	0/53 (0%)		1/53 (1.9%)		2/52 (3.8%)
Mucositis oral	1/53 (1.9%)		0/53 (0%)		4/52 (7.7%)
Nausea	6/53 (11.3%)		6/53 (11.3%)		11/52 (21.2%)
Pancreatitis	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Upper gastrointestinal hemorrhage	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Vomiting	5/53 (9.4%)		3/53 (5.7%)		7/52 (13.5%)
Gastrointestinal disorders - Other	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
General disorders
Fatigue	13/53 (24.5%)		6/53 (11.3%)		12/52 (23.1%)
Fever	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Infections and infestations
Abdominal infection	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Bronchial infection	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Esophageal infection	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Lung infection	2/53 (3.8%)		3/53 (5.7%)		1/52 (1.9%)
Sepsis	0/53 (0%)		1/53 (1.9%)		2/52 (3.8%)
Upper respiratory infection	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Urinary tract infection	1/53 (1.9%)		1/53 (1.9%)		2/52 (3.8%)
Infections and infestations - Other	2/53 (3.8%)		0/53 (0%)		2/52 (3.8%)
Injury, poisoning and procedural complications
Fall	2/53 (3.8%)		0/53 (0%)		0/52 (0%)
Fracture	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Investigations
Alanine aminotransferase increased	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Creatinine increased	0/53 (0%)		1/53 (1.9%)		2/52 (3.8%)
INR increased	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Lipase increased	0/53 (0%)		1/53 (1.9%)		1/52 (1.9%)
Lymphocyte count decreased	4/53 (7.5%)		1/53 (1.9%)		3/52 (5.8%)
Neutrophil count decreased	26/53 (49.1%)		28/53 (52.8%)		31/52 (59.6%)
Platelet count decreased	12/53 (22.6%)		3/53 (5.7%)		13/52 (25%)
Weight loss	0/53 (0%)		3/53 (5.7%)		3/52 (5.8%)
White blood cell decreased	25/53 (47.2%)		23/53 (43.4%)		27/52 (51.9%)
Metabolism and nutrition disorders
Acidosis	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Anorexia	4/53 (7.5%)		2/53 (3.8%)		6/52 (11.5%)
Dehydration	7/53 (13.2%)		2/53 (3.8%)		7/52 (13.5%)
Glucose intolerance	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Hyperglycemia	1/53 (1.9%)		0/53 (0%)		4/52 (7.7%)
Hyperkalemia	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Hyperuricemia	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Hypocalcemia	1/53 (1.9%)		1/53 (1.9%)		1/52 (1.9%)
Hypokalemia	5/53 (9.4%)		1/53 (1.9%)		3/52 (5.8%)
Hypomagnesemia	0/53 (0%)		0/53 (0%)		2/52 (3.8%)
Hyponatremia	7/53 (13.2%)		7/53 (13.2%)		8/52 (15.4%)
Hypophosphatemia	0/53 (0%)		2/53 (3.8%)		2/52 (3.8%)
Tumor lysis syndrome	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Chest wall pain	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Generalized muscle weakness	2/53 (3.8%)		1/53 (1.9%)		2/52 (3.8%)
Myalgia	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Musculoskeletal and connective - Other	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Nervous system disorders
Acoustic nerve disorder NOS	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Cognitive disturbance	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Dizziness	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Headache	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Peripheral sensory neuropathy	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Syncope	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Psychiatric disorders
Confusion	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Delirium	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Insomnia	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Suicide attempt	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Renal and urinary disorders
Acute kidney injury	3/53 (5.7%)		0/53 (0%)		3/52 (5.8%)
Respiratory, thoracic and mediastinal disorders
Dyspnea	2/53 (3.8%)		1/53 (1.9%)		1/52 (1.9%)
Hypoxia	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Pleural effusion	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Respiratory failure	1/53 (1.9%)		0/53 (0%)		0/52 (0%)
Sore throat	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Wheezing	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Skin and subcutaneous tissue disorders
Rash acneiform	0/53 (0%)		1/53 (1.9%)		0/52 (0%)
Rash maculo-papular	0/53 (0%)		0/53 (0%)		1/52 (1.9%)
Vascular disorders
Hypertension	0/53 (0%)		2/53 (3.8%)		0/52 (0%)
Hypotension	3/53 (5.7%)		0/53 (0%)		1/52 (1.9%)
Thromboembolic event	2/53 (3.8%)		1/53 (1.9%)		1/52 (1.9%)
Other (Not Including Serious) Adverse Events
	Arm A (CE)		Arm B (CE+GDC-0449)		Arm C (CE+IMC-A12)
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	52/53 (98.1%)		52/53 (98.1%)		51/52 (98.1%)
Blood and lymphatic system disorders
Anemia	39/53 (73.6%)		43/53 (81.1%)		46/52 (88.5%)
Cardiac disorders
Atrial fibrillation	1/53 (1.9%)		3/53 (5.7%)		0/52 (0%)
Ear and labyrinth disorders
Hearing impaired	0/53 (0%)		4/53 (7.5%)		2/52 (3.8%)
Tinnitus	4/53 (7.5%)		5/53 (9.4%)		6/52 (11.5%)
Eye disorders
Blurred vision	2/53 (3.8%)		2/53 (3.8%)		5/52 (9.6%)
Gastrointestinal disorders
Abdominal pain	1/53 (1.9%)		6/53 (11.3%)		5/52 (9.6%)
Constipation	18/53 (34%)		20/53 (37.7%)		18/52 (34.6%)
Diarrhea	12/53 (22.6%)		15/53 (28.3%)		21/52 (40.4%)
Dyspepsia	2/53 (3.8%)		5/53 (9.4%)		3/52 (5.8%)
Mucositis oral	10/53 (18.9%)		8/53 (15.1%)		23/52 (44.2%)
Nausea	33/53 (62.3%)		31/53 (58.5%)		35/52 (67.3%)
Vomiting	19/53 (35.8%)		16/53 (30.2%)		19/52 (36.5%)
General disorders
Chills	4/53 (7.5%)		2/53 (3.8%)		2/52 (3.8%)
Edema limbs	3/53 (5.7%)		4/53 (7.5%)		3/52 (5.8%)
Fatigue	38/53 (71.7%)		46/53 (86.8%)		42/52 (80.8%)
Fever	4/53 (7.5%)		1/53 (1.9%)		1/52 (1.9%)
Infections and infestations
Mucosal infection	0/53 (0%)		3/53 (5.7%)		2/52 (3.8%)
Urinary tract infection	2/53 (3.8%)		2/53 (3.8%)		3/52 (5.8%)
Investigations
Alanine aminotransferase increased	2/53 (3.8%)		8/53 (15.1%)		12/52 (23.1%)
Alkaline phosphatase increased	7/53 (13.2%)		10/53 (18.9%)		11/52 (21.2%)
Aspartate aminotransferase increased	1/53 (1.9%)		5/53 (9.4%)		11/52 (21.2%)
Blood bilirubin increased	1/53 (1.9%)		1/53 (1.9%)		3/52 (5.8%)
Creatinine increased	7/53 (13.2%)		10/53 (18.9%)		18/52 (34.6%)
Lymphocyte count decreased	5/53 (9.4%)		6/53 (11.3%)		5/52 (9.6%)
Neutrophil count decreased	12/53 (22.6%)		14/53 (26.4%)		11/52 (21.2%)
Platelet count decreased	28/53 (52.8%)		23/53 (43.4%)		34/52 (65.4%)
Weight loss	20/53 (37.7%)		26/53 (49.1%)		35/52 (67.3%)
White blood cell decreased	30/53 (56.6%)		19/53 (35.8%)		31/52 (59.6%)
Investigations - Other, specify	1/53 (1.9%)		2/53 (3.8%)		5/52 (9.6%)
Metabolism and nutrition disorders
Anorexia	26/53 (49.1%)		31/53 (58.5%)		32/52 (61.5%)
Dehydration	8/53 (15.1%)		4/53 (7.5%)		13/52 (25%)
Hypercalcemia	1/53 (1.9%)		3/53 (5.7%)		3/52 (5.8%)
Hyperglycemia	6/53 (11.3%)		12/53 (22.6%)		30/52 (57.7%)
Hyperkalemia	2/53 (3.8%)		3/53 (5.7%)		7/52 (13.5%)
Hypoalbuminemia	7/53 (13.2%)		11/53 (20.8%)		16/52 (30.8%)
Hypocalcemia	9/53 (17%)		6/53 (11.3%)		19/52 (36.5%)
Hypokalemia	9/53 (17%)		10/53 (18.9%)		9/52 (17.3%)
Hypomagnesemia	19/53 (35.8%)		21/53 (39.6%)		21/52 (40.4%)
Hyponatremia	17/53 (32.1%)		14/53 (26.4%)		17/52 (32.7%)
Hypophosphatemia	7/53 (13.2%)		5/53 (9.4%)		4/52 (7.7%)
Metabolism and nutrition - Other	2/53 (3.8%)		2/53 (3.8%)		3/52 (5.8%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	3/53 (5.7%)		6/53 (11.3%)		8/52 (15.4%)
Myalgia	2/53 (3.8%)		4/53 (7.5%)		4/52 (7.7%)
Pain in extremity	2/53 (3.8%)		4/53 (7.5%)		3/52 (5.8%)
Musculoskeletal and connective - Other	0/53 (0%)		5/53 (9.4%)		0/52 (0%)
Nervous system disorders
Dizziness	8/53 (15.1%)		9/53 (17%)		13/52 (25%)
Dysgeusia	10/53 (18.9%)		18/53 (34%)		13/52 (25%)
Headache	9/53 (17%)		6/53 (11.3%)		7/52 (13.5%)
Peripheral sensory neuropathy	7/53 (13.2%)		10/53 (18.9%)		8/52 (15.4%)
Psychiatric disorders
Insomnia	7/53 (13.2%)		3/53 (5.7%)		3/52 (5.8%)
Renal and urinary disorders
Chronic kidney disease	1/53 (1.9%)		3/53 (5.7%)		1/52 (1.9%)
Respiratory, thoracic and mediastinal disorders
Allergic rhinitis	2/53 (3.8%)		2/53 (3.8%)		4/52 (7.7%)
Cough	3/53 (5.7%)		4/53 (7.5%)		2/52 (3.8%)
Dyspnea	6/53 (11.3%)		6/53 (11.3%)		7/52 (13.5%)
Epistaxis	3/53 (5.7%)		0/53 (0%)		4/52 (7.7%)
Skin and subcutaneous tissue disorders
Alopecia	37/53 (69.8%)		34/53 (64.2%)		40/52 (76.9%)
Dry skin	0/53 (0%)		1/53 (1.9%)		4/52 (7.7%)
Pruritus	4/53 (7.5%)		1/53 (1.9%)		3/52 (5.8%)
Rash acneiform	1/53 (1.9%)		5/53 (9.4%)		4/52 (7.7%)
Rash maculo-papular	3/53 (5.7%)		5/53 (9.4%)		6/52 (11.5%)
Vascular disorders
Hypertension	1/53 (1.9%)		2/53 (3.8%)		3/52 (5.8%)
Hypotension	7/53 (13.2%)		5/53 (9.4%)		6/52 (11.5%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

The only disclosure restriction on the PI is that the sponsor can review results communications prior to public release and can embargo communications regarding trial results for a period that is less than or equal to 60 days. The sponsor cannot require changes to the communication and cannot extend the embargo.