A Study of Onartuzumab in Combination With mFOLFOX6 in Participants With Metastatic HER2-Negative and MET-Positive Gastroesophageal Cancer

Sponsor

Hoffmann-La Roche (Industry)

Overall Status

Completed

CT.gov ID

NCT01662869

Collaborator

Genentech, Inc. (Industry)

564

Enrollment

125

Locations

Arms

Duration (Months)

4.5

Patients Per Site

0.1

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

This randomized, multicenter, double-blind, placebo-controlled study will evaluate the efficacy and safety of onartuzumab (MetMAb) in combination with 5-fluorouracil, folinic Acid, and oxaliplatin (mFOLFOX6) in participants with metastatic human epidermal growth receptor (HER) 2-negative and MET-positive adenocarcinoma of the stomach or gastroesophageal junction. Participants will be randomized in a 1:1 ratio to receive either onartuzumab or placebo in combination with mFOLFOX6. Participants may continue to receive onartuzumab or placebo until disease progression, unacceptable toxicity, participant or physician decision to discontinue treatment.

Condition or Disease	Intervention/Treatment	Phase
Gastric Cancer	Drug: 5-Fluoruracil Drug: Folinic acid Drug: Onartuzumab Drug: Oxaliplatin Drug: Placebo	Phase 3

Study Design

Study Type:

Interventional

Actual Enrollment :

564 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

A Randomized, Phase III, Multicenter, Double-Blind, Placebo-Controlled Study Evaluating the Efficacy and Safety of Onartuzumab (MetMAb) in Combination With 5-Fluorouracil, Folinic Acid, and Oxaliplatin (mFOLFOX6) in Patients With Metastatic HER2-Negative, MET-Positive Gastroesophageal Cancer

Study Start Date :

Nov 1, 2012

Actual Primary Completion Date :

Dec 1, 2015

Actual Study Completion Date :

Dec 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Onartuzumab+mFOLFOX6 Participants will receive onartuzumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion + mFOLFOX6 (oxaliplatin, folinic acid, and 5-fluoruracil) regimen. Participants will receive a maximum of 12 cycles (each cycle is 14 days) of mFOLFOX6 with onartuzumab. Participants whose disease has not progressed after 12 cycles of mFOLFOX6 with onartuzumab will continue treatment with onartuzumab until disease progression, unacceptable toxicity, or death.	Drug: 5-Fluoruracil Participants will receive 5-fluorouracil 400 milligrams per square meter (mg/m^2) IV bolus and then 2400 mg/m^2 as a continuous IV infusion over 46-48 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first. Drug: Folinic acid Participants will receive folinic acid 400 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first. Drug: Onartuzumab Participants will receive onartuzumab 10 mg/kg IV infusion on Day 1 of every cycle (each cycle = 14 days) until disease progression, unacceptable toxicity, or participant or physician decision to discontinue treatment. Other Names: MetMAb, RO5490258, PRO143966 Drug: Oxaliplatin Participants will receive oxaliplatin 85 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first.
Placebo Comparator: Placebo+mFOLFOX6 Participants will receive onartuzumab matching placebo + mFOLFOX6. Participants will receive a maximum of 12 cycles (each cycle is 14 days) of mFOLFOX6 with placebo. Participants whose disease has not progressed after 12 cycles of mFOLFOX6 with placebo will continue treatment with placebo until disease progression, unacceptable toxicity, or death.	Drug: 5-Fluoruracil Participants will receive 5-fluorouracil 400 milligrams per square meter (mg/m^2) IV bolus and then 2400 mg/m^2 as a continuous IV infusion over 46-48 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first. Drug: Folinic acid Participants will receive folinic acid 400 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first. Drug: Oxaliplatin Participants will receive oxaliplatin 85 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first. Drug: Placebo Participants will receive onartuzumab matching placebo on Day 1 of every cycle (each cycle = 14 days) until disease progression, unacceptable toxicity, or participant or physician decision to discontinue treatment.

Arm

Intervention/Treatment

Experimental: Onartuzumab+mFOLFOX6

Participants will receive onartuzumab 10 milligrams per kilogram (mg/kg) intravenous (IV) infusion + mFOLFOX6 (oxaliplatin, folinic acid, and 5-fluoruracil) regimen. Participants will receive a maximum of 12 cycles (each cycle is 14 days) of mFOLFOX6 with onartuzumab. Participants whose disease has not progressed after 12 cycles of mFOLFOX6 with onartuzumab will continue treatment with onartuzumab until disease progression, unacceptable toxicity, or death.

Drug: 5-Fluoruracil

Participants will receive 5-fluorouracil 400 milligrams per square meter (mg/m^2) IV bolus and then 2400 mg/m^2 as a continuous IV infusion over 46-48 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first.

Drug: Folinic acid

Participants will receive folinic acid 400 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first.

Drug: Onartuzumab

Participants will receive onartuzumab 10 mg/kg IV infusion on Day 1 of every cycle (each cycle = 14 days) until disease progression, unacceptable toxicity, or participant or physician decision to discontinue treatment.

Other Names:

MetMAb, RO5490258, PRO143966

Drug: Oxaliplatin

Participants will receive oxaliplatin 85 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first.

Placebo Comparator: Placebo+mFOLFOX6

Participants will receive onartuzumab matching placebo + mFOLFOX6. Participants will receive a maximum of 12 cycles (each cycle is 14 days) of mFOLFOX6 with placebo. Participants whose disease has not progressed after 12 cycles of mFOLFOX6 with placebo will continue treatment with placebo until disease progression, unacceptable toxicity, or death.

Drug: 5-Fluoruracil

Drug: Folinic acid

Participants will receive folinic acid 400 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first.

Drug: Oxaliplatin

Participants will receive oxaliplatin 85 mg/m^2 IV infusion over 2 hours on Day 1 of every cycle until disease progression or at the maximum of 12 cycles, whichever occurs first.

Drug: Placebo

Participants will receive onartuzumab matching placebo on Day 1 of every cycle (each cycle = 14 days) until disease progression, unacceptable toxicity, or participant or physician decision to discontinue treatment.

Outcome Measures

Primary Outcome Measures

Overall survival (OS) in the MET Immunohistochemistry (IHC) 2+/3+ Participant Subgroup [Baseline until death (up to approximately 38 months overall)]
OS in the Intent-To-Treat (ITT) Population [Baseline until death (up to approximately 38 months overall)]

Secondary Outcome Measures

Duration of Response, as Assessed by Investigator Using RECIST v1.1 [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 6 weeks for 12 months and thereafter every 12 weeks up to approximately 38 months overall)]
Percentage of Participants with a Tumor Response of CR or PR or Stable Disease (SD, Maintained for At Least 6 Months) as Determined by the Investigator Using RECIST v1.1 [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 6 weeks for 12 months and thereafter every 12 weeks up to approximately 38 months overall)]
Percentage of Participants with Adverse Events [Baseline up to approximately 38 months]
Percentage of Participants with Anti-Therapeutic Antibodies (ATAs) of Onartuzumab [Pre-dose (within 1 hour before infusion start) on Day 1 of Cycles 1 and 4, (cycle length = 14 days), at study drug discontinuation visit (up to 38 months)]
Change from Baseline in ATAs Level of Onartuzumab [Baseline (pre-dose [within 1 hour before infusion start] on Cycle 1 Day 1), pre-dose on Cycle 4 Day 1 (cycle length = 14 days), at study drug discontinuation visit (up to 38 months)]
Minimum Serum Concentration of Onartuzumab (Cmin) [Pre-dose (within 1 hour before infusion start) on Day 1 of Cycles 1, 2 and 4, 30 minutes after end of infusion (duration of infusion = 60 minutes) on Cycle 1 Day 1 (cycle length = 14 days), at study drug discontinuation visit (up to 38 months)]
Maximum Serum Concentration (Cmax) of Onartuzumab [Pre-dose (within 1 hour before infusion start) on Day 1 of Cycles 1, 2 and 4, 30 minutes after end of infusion (duration of infusion = 60 minutes) on Cycle 1 Day 1 (cycle length = 14 days), at study drug discontinuation visit (up to 38 months)]
Progression-Free Survival (PFS), as Assessed by Investigator Using Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1) in MET IHC 2+/3+ Participant Subgroup [Baseline up to disease progression or death due to any cause, whichever occurs first (up to approximately 38 months overall)]
PFS, as Assessed by Investigator Using RECIST v1.1 in ITT Population [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 6 weeks for 12 months and thereafter every 12 weeks up to approximately 38 months overall)]
Percentage of Participants with a Tumor Response of Complete Response (CR) or Partial Response (PR) as Determined by the Investigator Using RECIST v1.1 in MET IHC 2+/3+ Participant Subgroup [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 6 weeks for 12 months and thereafter every 12 weeks up to approximately 38 months overall)]
Percentage of Participants with a Tumor Response of CR or PR as Determined by the Investigator Using RECIST v1.1 in ITT Population [Baseline up to disease progression or death due to any cause, whichever occurs first (assessed every 6 weeks for 12 months and thereafter every 12 weeks up to approximately 38 months overall)]
European Organization for Research and Treatment Cancer Quality of Life Questionnaire (EORTC QLQ) Core 30 (EORTC QLQ-C30) Score [Day 1 of each treatment cycle (cycle length = 14 days) up to approximately 38 months]
EORTC QLQ-Gastric cancer Specific Quality of Life Questionnaire (EORTC QLQ-STOC22) Score [Day 1 of each treatment cycle (cycle length = 14 days) up to approximately 38 months]
European Quality of Life-5 Dimensions (EQ-5D) Questionnaire Score [Day 1 of each treatment cycle (cycle length = 14 days) up to approximately 38 months]

Eligibility Criteria

Criteria

Ages Eligible for Study:

18 Years and Older

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

Inclusion Criteria:

Adenocarcinoma of the stomach or gastroesophageal junction with inoperable, metastatic disease, not amenable to curative therapy
Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
Life expectancy greater than (>) 3 months
Presence of tissue sample for IHC assay of MET receptor and HER2 status
Tumor (primary or metastatic lesion) defined as MET-positive by IHC
Measurable disease or non-measurable but evaluable disease, according to the RECIST v1.1; Participants with peritoneal disease would generally be regarded as having evaluable disease and allowed to enter the trial
For women who are not postmenopausal or surgically sterile; agreement to use an adequate method of contraception (hormonal implant) during the treatment period and for at least 90 days after the last dose of onartuzumab/placebo and 6 months after the last dose of oxaliplatin
For men: agreement to use a barrier method of contraception during the treatment period and for 90 days after the last dose of onartuzumab/placebo and 6 months after the last dose of oxaliplatin

Exclusion Criteria:

HER2-positive tumor (primary tumor or metastasis)
Previous chemotherapy for locally advanced or metastatic gastric carcinoma (adjuvant or neoadjuvant chemotherapy must be completed at least 6 months prior to randomization)
Prior treatment with investigational drugs that target the human growth factor (HGF) or MET pathway
History of another malignancy within the previous 5 years, except for appropriately treated and presumed cured carcinoma in situ of the cervix, non-melanoma skin carcinoma, Stage 1 uterine cancer, and localized prostate cancer
Pregnancy or lactation
Receipt of an investigational drug within 28 days prior to study start
Clinically significant gastrointestinal abnormalities, apart from gastric cancer, including uncontrolled inflammatory gastrointestinal diseases
Significant history of cardiac disease
Significant vascular disease
Serious active infection at the time of randomization, or other serious underlying medical conditions that would impair the ability of the participant to receive protocol treatment
Infection with human immunodeficiency virus, hepatitis B, or hepatitis C
Radiotherapy within 4 weeks before start of study treatment
Major surgery within 4 weeks before start of study treatment, without complete recovery
Any condition (psychological, geographical) that does not permit compliance with study and follow-up procedures
Peripheral neuropathy
Prior unanticipated severe reaction to fluoropyrimidine therapy
Known sensitivity or contraindication to any component of study treatment
Active gastrointestinal bleeding

Contacts and Locations

Locations

	City	State	Country	Postal Code
1	Los Angeles	California	United States	90095
2	Denver	Colorado	United States	80218
3	Fort Myers	Florida	United States	33908
4	St Petersburg	Florida	United States	33705
5	Chicago	Illinois	United States	60637
6	Albany	New York	United States	12206
7	New York	New York	United States	10065
8	Durham	North Carolina	United States	27710
9	Cincinnati	Ohio	United States	45219
10	Providence	Rhode Island	United States	02903
11	Providence	Rhode Island	United States	02906
12	Nashville	Tennessee	United States	37203
13	Austin	Texas	United States	78731
14	Tyler	Texas	United States	75702
15	Vancouver	Washington	United States	98684
16	Port Macquarie	New South Wales	Australia	2444
17	Sydney	New South Wales	Australia	2139
18	Herston	Queensland	Australia	4029
19	Box Hill	Victoria	Australia	3128
20	East Bentleigh	Victoria	Australia	VIC 3165
21	Nedlands	Western Australia	Australia	6009
22	Brugge		Belgium	8000
23	Leuven		Belgium	3000
24	Sint-Niklaas		Belgium	9100
25	Hamilton	Ontario	Canada	L8L 2X2
26	Toronto	Ontario	Canada	M4N 3M5
27	Toronto	Ontario	Canada	M5B 1N9
28	Toronto	Ontario	Canada	M5G 1X5
29	Toronto	Ontario	Canada	M5G 2M9
30	Montreal	Quebec	Canada	H3T 1E2
31	Brno		Czech Republic	656 53
32	Olomouc		Czech Republic	775 20
33	Angers		France	49055
34	Avignon		France	84918
35	Besancon		France	25030
36	Brest		France	29200
37	Clichy		France	92118
38	Marseille		France	13273
39	Paris		France	75475
40	Paris		France	75571
41	Paris		France	75674
42	St Herblain		France	44805
43	Toulouse		France	31059
44	Bochum		Germany	44892
45	Essen		Germany	45122
46	Hamburg		Germany	22767
47	Leipzig		Germany	04103
48	Ludwigsburg		Germany	71640
49	Mannheim		Germany	68167
50	Marburg		Germany	35043
51	München		Germany	81675
52	Guatemala		Guatemala	01010
53	Hong Kong		Hong Kong	852
54	Hong Kong		Hong Kong
55	Jerusalem		Israel	91120-01
56	Ramat Gan		Israel	5262100
57	Tel Aviv		Israel	64239-06
58	Catanzaro	Calabria	Italy	88100
59	Udine	Friuli-Venezia Giulia	Italy	33100
60	Roma	Lazio	Italy	00168
61	Milano	Lombardia	Italy	20132
62	Milano	Lombardia	Italy	20133
63	Torino	Piemonte	Italy	10126
64	Firenze	Toscana	Italy	50139
65	Prato	Toscana	Italy	59100
66	Seoul		Korea, Republic of	02841
67	Seoul		Korea, Republic of	03080
68	Seoul		Korea, Republic of	05505
69	Seoul		Korea, Republic of	06351
70	Seoul		Korea, Republic of	06591
71	Seoul		Korea, Republic of	120-749
72	Seoul		Korea, Republic of	135-720
73	Kuala Lumpur		Malaysia	59100
74	Sabah		Malaysia	88996
75	Aguascalientes		Mexico	20230
76	Monterrey		Mexico	64020
77	Oaxaca		Mexico	68000
78	Panama		Panama	0834-02723
79	Bydgoszcz		Poland	85-796
80	Gdansk		Poland	80-952
81	Krakow		Poland	31-501
82	Lublin		Poland	20-081
83	Rybnik		Poland	44-200
84	Warszawa		Poland	02-781
85	Ivanovo		Russian Federation	153040
86	Omsk		Russian Federation	644013
87	Ryazan		Russian Federation	390011
88	Samara		Russian Federation	443031
89	Tula		Russian Federation	300053
90	Singapore		Singapore	169610
91	Elche	Alicante	Spain	03203
92	Santander	Cantabria	Spain	39008
93	Barcelona		Spain	08003
94	Barcelona		Spain	08035
95	Barcelona		Spain	08036
96	Madrid		Spain	28007
97	Madrid		Spain	28046
98	Zaragoza		Spain	50009
99	Luzern		Switzerland	6004
100	Zürich		Switzerland	8063
101	Changhua		Taiwan	500
102	Kaohisung		Taiwan
103	Taichung		Taiwan	404
104	Taichung		Taiwan	407
105	Taipei		Taiwan	00112
106	Taipei		Taiwan	100
107	Taipei		Taiwan	112
108	Bangkok		Thailand	10330
109	Bangkok		Thailand	10400
110	Bangkok		Thailand	10700
111	Chiang Rai		Thailand	57000
112	Hat Yai		Thailand	90110
113	Lopburi		Thailand	15000
114	Antalya		Turkey	07070
115	Edirne		Turkey	22770
116	Erzurum		Turkey	25240
117	Malatya		Turkey	44280
118	Samsun		Turkey	55139
119	Sıhhiye, ANKARA		Turkey	06100
120	Bristol		United Kingdom	BS2 8ED
121	Cardiff		United Kingdom	CF14 2TL
122	London		United Kingdom	SW3 6JJ
123	Manchester		United Kingdom	M2O 4BX
124	Southampton		United Kingdom	SO16 6YD
125	Sutton		United Kingdom	SM2 5PT