METRIC: Study of Glembatumumab Vedotin (CDX-011) in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer

• Sponsor: Celldex Therapeutics (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01997333
• Collaborator: (none)
• Enrollment: 327
• Locations: 140
• Arms: 2
• Duration (Months): 57.2
• Patients Per Site: 2.3
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The main purpose of this study is to see whether CDX-011 (glembatumumab vedotin, an antibody-drug conjugate) is effective in treating patients who have advanced Triple-Negative Breast Cancer (TNBC), and whose tumor cells make a protein called glycoprotein NMB (gpNMB), which CDX-011 binds to. The study will also further characterize the safety of CDX-011 treatment in this patient population.

Condition or Disease	Intervention/Treatment	Phase
Metastatic gpNMB Over-expressing Triple Negative Breast Cancer	Drug: CDX-011; Drug: Capecitabine	Phase 2

Detailed Description

CDX-011 consists of an antibody attached to a drug, monomethyl auristatin E (MMAE), that can kill cancer cells. The antibody delivers the drug to cancer cells by attaching to a protein called glycoprotein NMB (gpNMB) that is expressed on the cancer cell. The MMAE is then released inside of the cell, where it interferes with cell growth and may lead to cell death.

This study will examine the efficacy and safety of CDX-011 in patients with advanced TNBC that makes the gpNMB protein. The effect of CDX-011 will be compared to treatment with capecitabine.

Eligible patients who enroll in the study will be randomly assigned (by chance) to receive treatment with CDX-011 or with capecitabine. For every three patients enrolled, two will receive CDX-011 and one will receive treatment with capecitabine. All patients enrolled in the study will be closely monitored to determine if their cancer is responding to treatment and for any side effects that may occur.

Study Design

• Study Type: Interventional
• Actual Enrollment: 327 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Randomized Multicenter Pivotal Study of CDX-011 (CR011-vcMMAE)in Patients With Metastatic, gpNMB Over-Expressing, Triple Negative Breast Cancer (The METRIC Study)
• Study Start Date: Nov 1, 2013
• Actual Primary Completion Date: Nov 30, 2017
• Actual Study Completion Date: Aug 7, 2018

Arms and Interventions

Arm	Intervention/Treatment
Active Comparator: Capecitabine Capecitabine will be administered on Days 1 through 14 of each 21 day cycle.	Drug: Capecitabine
Experimental: Drug: CDX-011 CDX-011 administered as an intravenous infusion on Day 1 of each 21 day cycle.	Drug: CDX-011

Outcome Measures

Primary Outcome Measures

1. Progression Free Survival (PFS) [Evaluated every 6 - 9 weeks following treatment initiation]

   PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or progression in a non-target lesion, or the appearance of new lesions. The primary analysis of PFS was based on PFS events determined retrospectively by the central independent review committee, blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria.

Secondary Outcome Measures

1. Objective Response Rate (ORR) [Evaluated every 6 - 9 weeks following treatment initiation]

   ORR is defined as the percentage of patients who achieve best overall response of complete or partial response. The analysis of ORR was based on ORR events determined retrospectively by the central independent review committee, blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Complete Response (CR) = Disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions.

2. Duration of Response [Evaluated every 6 - 9 weeks following treatment initiation]

   Duration of response (DOR) is the number of months from the time criteria are first met for either CR or PR, until the first date that PD is objectively documented. The analysis of DOR was determined retrospectively by the central independent review committee,blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Complete Response (CR) = Disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions.

3. Overall Survival [During treatment and 3 months from end of treatment through end of study or approximately up to 5 years.]

   Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause.

4. Adverse Events (AE) [Usually following at least 1 cycle of study treatment (1 dose of CDX-011 or capecitabine and until discontinuation of follow-up)]

   The percentage of patients experiencing one or more adverse events will be summarized by treatment arm, relationship to study drug, and severity.

5. Pharmacokinetics (PK) [Following 1 dose of CDX-011.]

   Concentration of the antibody drug conjugate (ADC), total antibody (TA) and free MMAE will be determined.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Among other criteria, patients must meet all of the following conditions to be eligible for the study:

1. Diagnosed with metastatic (i.e., cancer that has spread) TNBC

• minimal or no expression of estrogen and progesterone receptors (ER/PR) <10% of cells positive by immunohistochemistry

• HER 2 staining 0 or 1+ by IHC or copy number <4.0 signals/cell

1. Documented progression of disease based on radiographic, clinical or pathologic assessment during or subsequent to the last anticancer regimen received.

2. Breast cancer tumor confirmed to express gpNMB. This will be determined by submitting a tissue sample from the advanced (locally advanced/recurrent or metastatic) disease setting to a central laboratory for analysis.

3. Received no more than two prior chemotherapy treatments for advanced (locally advanced/recurrent or metastatic) breast cancer.

4. Prior chemotherapy treatment must have contained an anthracycline (e.g. doxorubicin or Doxil) if clinically indicated and a taxane (eg: Taxol).

5. ECOG performance status of 0 - 1.

6. Adequate bone marrow, liver and renal function.

Exclusion:

Among other criteria, patients who meet any of the following conditions are NOT eligible for the study:

1. Progression/recurrence of breast cancer during or within 3 months of completion of neoadjuvant or adjuvant chemotherapy.

2. Ongoing neuropathy or other chemotherapy or radiation-related toxicities that are moderate (Grade 2) or worse in severity.

3. Known brain metastases, unless previously treated and asymptomatic for 2 months and not progressive in size or number for 2 months.

4. Significant cardiovascular disease.

5. Previously received capecitabine and discontinued due to progression or intolerance; previously received CDX-011 or other MMAE containing agents.

6. Active systemic infection requiring treatment. Infection controlled by oral therapy will not be exclusionary.

7. Chronic use of systemic corticosteroids.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alabama Oncology	Birmingham	Alabama	United States	35211
2	University of Alabama at Birmingham	Birmingham	Alabama	United States	35294
3	University of South Alabama Cancer Research Insititute	Mobile	Alabama	United States	36604
4	Arizona Cancer Research Alliance	Glendale	Arizona	United States	85304
5	Arizona Cancer Center	Tucson	Arizona	United States	85724
6	University of Arkansas for Medical Sciences	Little Rock	Arkansas	United States	72205
7	Compassionate Care Research Group	Fountain Valley	California	United States	92708
8	St. Jude Heritage Medical Group	Fullerton	California	United States	92835
9	USC Norris Comprehensive Cancer Center and Hospital	Los Angeles	California	United States	90033
10	University of California Davis Medical Center	Sacramento	California	United States	95817
11	Pacific Cancer Care	Salinas	California	United States	93901
12	University of California San Francisco	San Francisco	California	United States	94115
13	Kaiser Permaente	Vallejo	California	United States	94589
14	Wellness Hematology Oncology	West Hills	California	United States	91307
15	University of Miami Miller School of Medicine	Deerfield Beach	Florida	United States	33442
16	Florida Cancer Specialists South	Fort Myers	Florida	United States	33916
17	Memorial Regional Hospital	Hollywood	Florida	United States	33021
18	Baptist Cancer Institute	Jacksonville	Florida	United States	32207
19	Florida Cancer Specialists	New Port Richey	Florida	United States	34655
20	Tallahassee Memorial HealthCare	Tallahassee	Florida	United States	32308
21	Peachtree Hematology Oncology Consultants, PC	Atlanta	Georgia	United States	30318
22	Winship Cancer Institute, Emory University	Atlanta	Georgia	United States	30322
23	Georgia Cancer Specialists Clinic	Atlanta	Georgia	United States	30341
24	Northwest Georgia Oncology Centers P.C.	Marietta	Georgia	United States	30060
25	Summit Cancer Care, PC-Savannah	Savannah	Georgia	United States	31405
26	University of Chicago	Chicago	Illinois	United States	60637
27	Ingalis Memorial Hospital	Harvey	Illinois	United States	60426
28	Illinois CancerCare	Peoria	Illinois	United States	60615
29	Orchard Healthcare Research Inc.	Skokie	Illinois	United States	60077
30	Carle Cancer Center	Urbana	Illinois	United States	61801
31	Lafayette General Medical Center	Lafayette	Louisiana	United States	70503
32	Hematology and Oncology Specialists	Marrero	Louisiana	United States	70072
33	Louisiana State University Health New Orleans	New Orleans	Louisiana	United States	70112
34	Oschner Medical Center	New Orleans	Louisiana	United States	70121
35	Anne Arundel Medical Center	Annapolis	Maryland	United States	21401
36	University of Maryland	Baltimore	Maryland	United States	21201
37	Sidney Kimmel Comprehensive Cancer Center at Johns Hopkins	Baltimore	Maryland	United States	21287-0013
38	Frederick Memorial Hospital	Frederick	Maryland	United States	21701
39	Holy Cross Hospital	Silver Spring	Maryland	United States	20902
40	Virginia Piper Cancer Center	Minneapolis	Minnesota	United States	55407
41	HCA Midwest Health	Kansas City	Missouri	United States	64132
42	Washington University Dept of Oncology	Saint Louis	Missouri	United States	63110
43	St John's Mercy Medical Center	Saint Louis	Missouri	United States	63141
44	Hunterdon Regional Cancer Center	Flemington	New Jersey	United States	08822
45	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
46	Clinical Research Alliance, Inc.	Lake Success	New York	United States	11042
47	ProHEALTH Care Associates	Lake Success	New York	United States	11042
48	Beth Isreal Medical Center	New York	New York	United States	10011
49	Weill Cornell Medical Center	New York	New York	United States	10021
50	Stony Brook University Medical Center	Stony Brook	New York	United States	11794
51	Novant Health	Charlotte	North Carolina	United States	28204
52	Duke University Medical Center	Durham	North Carolina	United States	27710
53	Oncology Hematology Care	Cincinnati	Ohio	United States	45242
54	Cleveland Clinic-Taussig Cancer Institute-R35	Cleveland	Ohio	United States	44195
55	Signal Point Clinical Research Center, LLC	Middletown	Ohio	United States	45042
56	Mercy Clinic of Oklahoma	Oklahoma City	Oklahoma	United States	73120
57	Oregon Health and Science University	Beaverton	Oregon	United States	97006
58	St Mary Medical Center	Langhorne	Pennsylvania	United States	19047
59	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
60	Guthrie Clinical Research	Sayre	Pennsylvania	United States	18840
61	Charleston Hematology Oncology Associates (CHOA)	Charleston	South Carolina	United States	29414
62	Chattanooga Oncology Hematology Associates	Chattanooga	Tennessee	United States	37404
63	Center for Biomedical Research, LLC	Knoxville	Tennessee	United States	37909
64	Sarah Cannon Cancer Center	Nashville	Tennessee	United States	37203
65	Oncology Hematology Consultants PA	Fort Worth	Texas	United States	76104
66	Baylor College of Medicine	Houston	Texas	United States	77030
67	Houston Methodist Cancer Center	Houston	Texas	United States	77030
68	University of Texas Health Science Center at Houston	Houston	Texas	United States	77030
69	Texas Tech University Health Sciences Center	Lubbock	Texas	United States	79430
70	Swedish Cancer Institute	Seattle	Washington	United States	98104
71	Seattle Cancer Care Alliance	Seattle	Washington	United States	98109
72	St. Vincents Hospital Sydney	Darlinghurst	New South Wales	Australia	2010
73	Macquarie University	Macquarie Park	New South Wales	Australia	2109
74	The Tweed Hospital	Tweed Heads	New South Wales	Australia	2485
75	Sydney Adventist Hospital	Wahroonga	New South Wales	Australia	2076
76	Townsville Hospital	Douglas	Queensland	Australia	4814
77	Box Hill Hospital	Box Hill	Victoria	Australia	3128
78	Western Hospital	Footscray	Victoria	Australia	3011
79	Joint Ludwig-Austin Dept of Medical Oncology	Heidelberg	Victoria	Australia	3084
80	Epworth Health Care	Richmond	Victoria	Australia	3121
81	GasthuisZusters Antwerpen	Wilrijk	Antwerpen	Belgium	2610
82	Grand Hopital de Charleroi asbl	Charleroi	Hainaut	Belgium	6000
83	UZ Leuven	Leuven	Vlaams Brabant	Belgium	3000
84	Clinique Edith Cavell	Brussels Capital Region		Belgium	1180
85	Institute Jules Bordet	Bruxelles		Belgium	1000
86	Algoma District Cancer Program Sault Area Hospital	Sault Ste Marie	Ontario	Canada	P6B-0A8
87	Sunnybrook Health Sciences Centre Odette Cancer Center	Toronto	Ontario	Canada	M4N 3M5
88	St. MIchael's Hospital	Toronto	Ontario	Canada	M5B 1W8
89	Sir Mortimer B Davis Jewish General Hospital	Montreal	Quebec	Canada	H3T 1E2
90	Universite de Montreal-Hopital Du Sacre-Coeur De Montreal	Montreal	Quebec	Canada	H4J 1C5
91	Centre Antoine Lacassagne Centre Régional de Lutte Contre Le Cancer	Nice	Alpes-Maritimes	France	06189
92	Centre Léon Bérard Centre Régional de Lutte Contre Le Cancer Rhône Alpes	Lyon	Rhône	France	69373
93	Centre Jean Bernard Clinique Victor Hugo	Le Mans	Sarthe	France	72000
94	Institut Sainte Catherine	Avignon		France	84000
95	Centre Oscar Lambret	Lille		France	59000
96	Hôpital de La Croix Rousse	Lyon		France	69317
97	Centre Hospitalier de Mont de Marson - Hôpital Layné	Mont de Marsan		France	40000
98	Institut Curie	Paris		France	75005
99	Hospices Civils de Lyon	Pierre Benite		France	69495
100	Centre Hospitalier Prive Saint-Gregoire	St Gregoire		France	35768
101	Klinikum Essingen GmbH	Esslingen Am Neckar	Baden-Wurttemberg	Germany	73730
102	Helios Klinikum Berlin Buch	Berlin		Germany	13125
103	Kliniken der Stadt Koeln gGmbH - Krankenhaus Holweide	Cologne		Germany	51067
104	Universitätsklinikum Düsseldorf	Düsseldorf		Germany	40225
105	Universitätsklinikum Erlangen	Erlangen		Germany	91054
106	Klinikum Frankfurt Höchst GmbH	Frankfurt am Main		Germany	65929
107	Martin-Luther-Universität Halle-Wittenberg	Halle		Germany	06120
108	Universität Des Saarlandes	Homberg		Germany	66421
109	Rotkreuzklinikum München	Munich		Germany	80637
110	Universitätsklinikum Münster	Münster		Germany	48149
111	Hämatologisch-Onkologische Schwerpunktpraxis	Troisdorf		Germany	53840
112	Istituto Scientifico romagnolo Per Lo Studio E La Cura Del Tumori IRST	Meldola	Emilia-Romagna	Italy	47014
113	Fondazione Policlinico Universitario A Gemelli	Roma	Lazio	Italy	00168
114	Azienda Ospedaliera Fatebenefratelli e Oftaimico	Milano	Lombardia	Italy	20121
115	Istituto Nazionale Dei Tumori	Milano	Lombardia	Italy	20133
116	Istituto Europeo Di Oncologia	Milano	Lombardia	Italy	20141
117	Istituto Clinico Humanitas	Rozzano	Lombardia	Italy	20089
118	Centro Di Riferimento Oncologico	Aviano	Pordenone	Italy	33081
119	Azienda Ospedaliera Universitaria Pisana	Pisa	Toscana	Italy	56126
120	Azienda Ospedaliero Universitaria Di Bologna - Policlinico S Orsola Malpighi	Bologna		Italy	40138
121	Azienda Ospedaliera Citta della Salute e della Scienza de Torino	Torino		Italy	10126
122	Hospital Universitario Central de Asturias	Oviedo	Asturias	Spain	33011
123	Hospital Universitari Germans Trias i Pujol	Badalona	Barcelona	Spain	08916
124	Corporacio Sanitaria Parc Tauli	Sabadell	Barcelona	Spain	08208
125	Consorcio Hospitalario Provincial de Castellon	Castellon de La Plana	Castellón	Spain	12002
126	Hospital Universitario Ramon y Cajal	Madrid	Communidad Delaware	Spain	28034
127	Hospital Regional Universitario de Malaga - Hospital General	Malaga	Málaga	Spain	29011
128	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
129	Hospital Clinic de Barcelona	Barcelona		Spain	08036
130	MD Anderson Cancer Center Madrid-Espana	Madrid		Spain	28033
131	Hospital Clinico San Carlos	Madrid		Spain
132	Hospital Clinico Universitario de Valencia	Valencia		Spain	46010
133	Barts Health NHS Trust	London	City Of London	United Kingdom	EC1A 7BE
134	Derriford Hospital	Plymouth	Devon	United Kingdom	PL6 8DH
135	Royal Sussex County Hospital	Brighton	East Sussex	United Kingdom	BN2 5BE
136	Beatson West of Scotland Cancer Centre	Glasgow	Glasgow City	United Kingdom	G12 0YN
137	Blackpool Victoria Hospital	Blackpool	Lancashire	United Kingdom	FY3 8NR
138	University College London	London	London, City Of	United Kingdom	NW1 2PG
139	Nottingham University Hospitals NHS Trust	Nottingham	Nottinghamshire	United Kingdom	NG5 1PB
140	Sarah Cannon Research Institute UK	City of London		United Kingdom	W1G 6AD

Sponsors and Collaborators

• Celldex Therapeutics

Investigators

None specified.

Study Documents (Full-Text)

• Study Protocol - Jul 28, 2015
• Statistical Analysis Plan - Aug 31, 2017

More Information

Publications

None provided.

• Responsible Party: Celldex Therapeutics
• ClinicalTrials.gov Identifier: NCT01997333
• Other Study ID Numbers: CDX011-04
• First Posted: Nov 28, 2013
• Last Update Posted: Mar 8, 2019
• Last Verified: Mar 1, 2019

• Keywords provided by Celldex Therapeutics: Metastatic Breast Cancer; Locally advanced breast cancer; Breast cancer; Triple negative; Estrogen; Progesterone; HER2 receptors; Targeted treatment for breast cancer; Antibody-drug-conjugate; Breast Neoplasms; CDX-011; gpNMB; METRIC; Glembatumumab vedotin; Triple Negative Breast Cancer; TNBC
• Additional relevant MeSH terms: Breast Neoplasms; Triple Negative Breast Neoplasms; Capecitabine

Study Results

Participant Flow

Pre-assignment Detail	1531 patients screened to randomize 327 patients. Most common reasons for screen failure were tumor tissue inadequate/gpNMB negative (697), failure to meet other eligibility (256) and refused to participate (77).

Arm/Group Title	Capecitabine	CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Period Title: Randomization and Treatment
STARTED	109	218
COMPLETED	6	15
NOT COMPLETED	103	203
Period Title: Randomization and Treatment
STARTED	92	213
COMPLETED	76	199
NOT COMPLETED	16	14

Baseline Characteristics

Arm/Group Title	Capecitabine	CDX-011	Total
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	Total of all reporting groups
Overall Participants	109	218	327
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	55	55
Sex: Female, Male (Count of Participants)
Female	109 100%	218 100%	327 100%
Male	0 0%	0 0%	0 0%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 4.6%	11 5%	16 4.9%
Not Hispanic or Latino	99 90.8%	191 87.6%	290 88.7%
Unknown or Not Reported	5 4.6%	16 7.3%	21 6.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	1 0.5%	1 0.3%
Asian	2 1.8%	3 1.4%	5 1.5%
Native Hawaiian or Other Pacific Islander	0 0%	2 0.9%	2 0.6%
Black or African American	9 8.3%	20 9.2%	29 8.9%
White	91 83.5%	176 80.7%	267 81.7%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	7 6.4%	16 7.3%	23 7%
Region of Enrollment (participants) [Number]
Canada	7 6.4%	5 2.3%	12 3.7%
Belgium	2 1.8%	6 2.8%	8 2.4%
United States	72 66.1%	143 65.6%	215 65.7%
Italy	6 5.5%	7 3.2%	13 4%
United Kingdom	5 4.6%	6 2.8%	11 3.4%
Australia	3 2.8%	15 6.9%	18 5.5%
France	4 3.7%	14 6.4%	18 5.5%
Germany	5 4.6%	9 4.1%	14 4.3%
Spain	5 4.6%	13 6%	18 5.5%
Number of prior relapses in advanced stage (participants) [Number]
0	21 19.3%	45 20.6%	66 20.2%
1	58 53.2%	122 56%	180 55%
2	24 22%	42 19.3%	66 20.2%
3	6 5.5%	9 4.1%	15 4.6%
Number of cytotoxic regimens in advanced stage (cytotoxic regimen) [Median (Full Range) ]
Median (Full Range) [cytotoxic regimen]	1	1	1
Prior Taxane Use (Count of Participants)
Count of Participants [Participants]	108 99.1%	218 100%	326 99.7%
Prior Anthracycline Use (Count of Participants)
Count of Participants [Participants]	95 87.2%	185 84.9%	280 85.6%
Progression Free Interval post last Taxane (Count of Participants)
less than or equal to 6 months	51 46.8%	112 51.4%	163 49.8%
greater than 6 months	58 53.2%	106 48.6%	164 50.2%

Outcome Measures

1. Primary Outcome

Title	Progression Free Survival (PFS)
Description	PFS is defined as the time from randomization to the earlier of disease progression or death due to any cause. Disease progression is defined using Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), as a 20% increase in the sum of the longest diameter of target lesions, or progression in a non-target lesion, or the appearance of new lesions. The primary analysis of PFS was based on PFS events determined retrospectively by the central independent review committee, blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria.
Time Frame	Evaluated every 6 - 9 weeks following treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Capecitabine	CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Measure Participants	109	218
Median (95% Confidence Interval) [months]	2.8	2.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Capecitabine, CDX-011
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.761
	Comments
	Method	Log Rank
	Comments	Stratified log rank test.

2. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	ORR is defined as the percentage of patients who achieve best overall response of complete or partial response. The analysis of ORR was based on ORR events determined retrospectively by the central independent review committee, blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Complete Response (CR) = Disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions.
Time Frame	Evaluated every 6 - 9 weeks following treatment initiation

Outcome Measure Data

Analysis Population Description

Patients with measurable disease.

Arm/Group Title	Capecitabine	CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Measure Participants	100	179
Median (95% Confidence Interval) [percentage of participants]	21 19.3%	26 11.9%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Capecitabine, CDX-011
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.264
	Comments
	Method	Cochran-Mantel-Haenszel
	Comments	Adjusted for stratification factors.

3. Secondary Outcome

Title	Duration of Response
Description	Duration of response (DOR) is the number of months from the time criteria are first met for either CR or PR, until the first date that PD is objectively documented. The analysis of DOR was determined retrospectively by the central independent review committee,blinded to treatment assignment and investigator assessments according to RECIST 1.1 criteria. Per Response Evaluation Criteria In Solid Tumors Criteria (RECIST v1.1), Complete Response (CR) = Disappearance of all target lesions and non-target lesions, Partial Response (PR), >= 30% decrease in the sum of the longest diameter of target lesions with no progression in non-target lesions and no new lesions.
Time Frame	Evaluated every 6 - 9 weeks following treatment initiation

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Capecitabine	CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Measure Participants	21	46
Median (95% Confidence Interval) [months]	4.2	2.8

4. Secondary Outcome

Title	Overall Survival
Description	Overall Survival (OS) is defined as the number of months from randomization to the date of death due to any cause.
Time Frame	During treatment and 3 months from end of treatment through end of study or approximately up to 5 years.

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Capecitabine	CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered as on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Measure Participants	109	218
Median (95% Confidence Interval) [months]	8.7	8.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Capecitabine, CDX-011
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.726
	Comments
	Method	Log Rank
	Comments	Stratified log rank.

5. Secondary Outcome

Title	Adverse Events (AE)
Description	The percentage of patients experiencing one or more adverse events will be summarized by treatment arm, relationship to study drug, and severity.
Time Frame	Usually following at least 1 cycle of study treatment (1 dose of CDX-011 or capecitabine and until discontinuation of follow-up)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Capecitabine	CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Measure Participants	92	213
Patients with at least 1 AE	92 84.4%	211 96.8%
Patients with at least 1 treatment related AE	84 77.1%	204 93.6%
Patients with Grade 1 treatment related AE	7 6.4%	7 3.2%
Patients with Grade 2 treatment related AE	33 30.3%	54 24.8%
Patients with Grade 3 treatment related AE	44 40.4%	114 52.3%
Patients with Grade 4 treatment related AE	8 7.3%	32 14.7%
Patients with Grade 5 treatment related AE	0 0%	4 1.8%

6. Secondary Outcome

Title	Pharmacokinetics (PK)
Description	Concentration of the antibody drug conjugate (ADC), total antibody (TA) and free MMAE will be determined.
Time Frame	Following 1 dose of CDX-011.

Outcome Measure Data

Analysis Population Description

Samples were obtained from 201 of 213 patients treated with CDX-011. A partial analysis provided below results. Additional analyses were not completed. Results should be interpreted with caution.

Arm/Group Title	CDX-011
Arm/Group Description	CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
Measure Participants	201
Cycle 1 post infusion ADC levels	58.6
Cycle 1 post infusion TA levels	49.4
Cycle 1 post infusion MMAE levels	0.0015

Adverse Events

Time Frame	Adverse event data were collected from the time a subject took their first dose of study treatment (CDX-011 or Capecitabine) through (whichever occurs first) either a) 28 calendar days after the last administration of study treatment, or b) initiation of alternate anticancer therapy.
Arm/Group Title	Capecitabine		CDX-011
Arm/Group Description	Capecitabine administered on Days 1 through 14 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.		CDX-011 administered on Day 1 of each 21 day cycle until disease progression, discontinuation due to toxicity, withdrawal of consent, or end of study.
All Cause Mortality
	Capecitabine		CDX-011
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	65/92 (70.7%)		134/213 (62.9%)
Serious Adverse Events
	Capecitabine		CDX-011
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	19/92 (20.7%)		71/213 (33.3%)
Blood and lymphatic system disorders
Anemia	0/92 (0%)		2/213 (0.9%)
Febrile neutropenia	0/92 (0%)		3/213 (1.4%)
Leukopenia	0/92 (0%)		1/213 (0.5%)
Neutropenia	1/92 (1.1%)		2/213 (0.9%)
Cardiac disorders
Pericardial effusion	0/92 (0%)		2/213 (0.9%)
Sinus tachycardia	0/92 (0%)		1/213 (0.5%)
Eye disorders
Cataract nuclear	0/92 (0%)		1/213 (0.5%)
Gastrointestinal disorders
Abdominal pain	2/92 (2.2%)		6/213 (2.8%)
Colitis	0/92 (0%)		1/213 (0.5%)
Constipation	0/92 (0%)		4/213 (1.9%)
Diarrhoea	5/92 (5.4%)		6/213 (2.8%)
Enterocolitis	2/92 (2.2%)		0/213 (0%)
Faecaloma	0/92 (0%)		1/213 (0.5%)
Ileus	0/92 (0%)		2/213 (0.9%)
Intestinal obstruction	1/92 (1.1%)		1/213 (0.5%)
Large intestinal obstruction	0/92 (0%)		1/213 (0.5%)
Megacolon	0/92 (0%)		1/213 (0.5%)
Nausea	3/92 (3.3%)		8/213 (3.8%)
Pancreatitis	1/92 (1.1%)		1/213 (0.5%)
Small intestinal obstruction	1/92 (1.1%)		1/213 (0.5%)
Stomatitis	0/92 (0%)		3/213 (1.4%)
Vomiting	4/92 (4.3%)		7/213 (3.3%)
General disorders
Asthenia	0/92 (0%)		1/213 (0.5%)
Axillary pain	0/92 (0%)		1/213 (0.5%)
Fatigue	3/92 (3.3%)		2/213 (0.9%)
General physical health deterioration	0/92 (0%)		2/213 (0.9%)
Influenza like illness	0/92 (0%)		1/213 (0.5%)
Multiple organ dysfunction syndrome	0/92 (0%)		1/213 (0.5%)
Pain	0/92 (0%)		3/213 (1.4%)
Polyserositis	0/92 (0%)		1/213 (0.5%)
Pyrexia	1/92 (1.1%)		7/213 (3.3%)
Hepatobiliary disorders
Bile duct obstruction	1/92 (1.1%)		0/213 (0%)
Bile duct stone	0/92 (0%)		1/213 (0.5%)
Cholecystitis acute	0/92 (0%)		1/213 (0.5%)
Cholelithiasis	0/92 (0%)		2/213 (0.9%)
Infections and infestations
Bacterascites	0/92 (0%)		1/213 (0.5%)
Breast cellulitis	0/92 (0%)		1/213 (0.5%)
Chest wall abcess	0/92 (0%)		1/213 (0.5%)
Clostridium difficile infection	1/92 (1.1%)		0/213 (0%)
Device related infection	0/92 (0%)		1/213 (0.5%)
Empyema	1/92 (1.1%)		0/213 (0%)
Mastitis	0/92 (0%)		1/213 (0.5%)
Oral candidiasis	0/92 (0%)		1/213 (0.5%)
Osteomyelitis	0/92 (0%)		1/213 (0.5%)
Pneumonia	0/92 (0%)		5/213 (2.3%)
Pyelonephritis	0/92 (0%)		1/213 (0.5%)
Sepsis	1/92 (1.1%)		5/213 (2.3%)
Sepsis syndrome	0/92 (0%)		1/213 (0.5%)
Septic shock	0/92 (0%)		1/213 (0.5%)
Urinary tract infection	0/92 (0%)		4/213 (1.9%)
Urosepsis	0/92 (0%)		1/213 (0.5%)
Viral infection	1/92 (1.1%)		0/213 (0%)
Injury, poisoning and procedural complications
Accidental overdose	1/92 (1.1%)		0/213 (0%)
Gastrointestinal stoma compliaction	0/92 (0%)		1/213 (0.5%)
Hip fracture	0/92 (0%)		1/213 (0.5%)
Stoma site haemorrhage	0/92 (0%)		1/213 (0.5%)
Investigations
Blood bilirubin increased	0/92 (0%)		1/213 (0.5%)
Blood creatinine increased	0/92 (0%)		1/213 (0.5%)
Weight decreased	0/92 (0%)		1/213 (0.5%)
White blood cell count decreased	0/92 (0%)		1/213 (0.5%)
Metabolism and nutrition disorders
Decreased appetite	1/92 (1.1%)		1/213 (0.5%)
Dehydration	2/92 (2.2%)		3/213 (1.4%)
Electrolyte imbalance	0/92 (0%)		1/213 (0.5%)
Hyperglycaemia	0/92 (0%)		1/213 (0.5%)
Hypocalcaemia	0/92 (0%)		1/213 (0.5%)
Hypokalaemia	0/92 (0%)		2/213 (0.9%)
Hyponatraemia	1/92 (1.1%)		0/213 (0%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/92 (0%)		2/213 (0.9%)
Back pain	1/92 (1.1%)		2/213 (0.9%)
Bone pain	1/92 (1.1%)		1/213 (0.5%)
Chest wall mass	0/92 (0%)		1/213 (0.5%)
Muscular weakness	1/92 (1.1%)		0/213 (0%)
Musculoskeletal pain	1/92 (1.1%)		0/213 (0%)
Pain in extremity	1/92 (1.1%)		2/213 (0.9%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Metastases to central nervous system	0/92 (0%)		1/213 (0.5%)
Metastases to meninges	0/92 (0%)		1/213 (0.5%)
Nervous system disorders
Brain oedema	1/92 (1.1%)		0/213 (0%)
Dysarthria	0/92 (0%)		2/213 (0.9%)
Headache	0/92 (0%)		2/213 (0.9%)
Hepatic encephalopathy	0/92 (0%)		1/213 (0.5%)
Peripheral motor neuropathy	1/92 (1.1%)		0/213 (0%)
Psychiatric disorders
Anxiety	0/92 (0%)		2/213 (0.9%)
Hallucination	1/92 (1.1%)		1/213 (0.5%)
Mental status changes	1/92 (1.1%)		0/213 (0%)
Renal and urinary disorders
Proteinuria	0/92 (0%)		1/213 (0.5%)
Reproductive system and breast disorders
Breast pain	1/92 (1.1%)		0/213 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	0/92 (0%)		6/213 (2.8%)
Hypoxia	0/92 (0%)		1/213 (0.5%)
Interstitial lung disease	0/92 (0%)		1/213 (0.5%)
Pharyngeal oedema	0/92 (0%)		1/213 (0.5%)
Pleural effusion	2/92 (2.2%)		3/213 (1.4%)
Pneumonia aspiration	0/92 (0%)		1/213 (0.5%)
Pulmonary embolism	2/92 (2.2%)		2/213 (0.9%)
Respiratory failure	0/92 (0%)		1/213 (0.5%)
Pneumonitis	0/92 (0%)		1/213 (0.5%)
Skin and subcutaneous tissue disorders
Drug eruption	0/92 (0%)		1/213 (0.5%)
Erthyema	0/92 (0%)		1/213 (0.5%)
Pain of skin	0/92 (0%)		1/213 (0.5%)
Palmar-plantar erythrodysaesthesia syndrome	0/92 (0%)		1/213 (0.5%)
Pruritis	0/92 (0%)		1/213 (0.5%)
Rash Erythematous	0/92 (0%)		1/213 (0.5%)
Rash generalised	0/92 (0%)		1/213 (0.5%)
Rash maculo-papular	0/92 (0%)		3/213 (1.4%)
Toxic epidermal necrolysis	0/92 (0%)		1/213 (0.5%)
Vascular disorders
Embolism	0/92 (0%)		1/213 (0.5%)
Hypertension	0/92 (0%)		1/213 (0.5%)
Hypotension	0/92 (0%)		1/213 (0.5%)
Other (Not Including Serious) Adverse Events
	Capecitabine		CDX-011
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	91/92 (98.9%)		211/213 (99.1%)
Blood and lymphatic system disorders
Anaemia	9/92 (9.8%)		33/213 (15.5%)
Neutropenia	5/92 (5.4%)		49/213 (23%)
Gastrointestinal disorders
Abdominal distension	3/92 (3.3%)		12/213 (5.6%)
Abdominal pain	16/92 (17.4%)		22/213 (10.3%)
Abdominal pain upper	6/92 (6.5%)		17/213 (8%)
Constipation	13/92 (14.1%)		61/213 (28.6%)
Diarrhoea	44/92 (47.8%)		55/213 (25.8%)
Dyspepsia	4/92 (4.3%)		22/213 (10.3%)
Dysphagia	0/92 (0%)		12/213 (5.6%)
Gastrooesophageal reflux disease	4/92 (4.3%)		16/213 (7.5%)
Nausea	39/92 (42.4%)		91/213 (42.7%)
Oral pain	2/92 (2.2%)		11/213 (5.2%)
Stomatitis	24/92 (26.1%)		37/213 (17.4%)
Vomiting	17/92 (18.5%)		46/213 (21.6%)
Dry mouth	5/92 (5.4%)		10/213 (4.7%)
General disorders
Asthenia	5/92 (5.4%)		14/213 (6.6%)
Chills	4/92 (4.3%)		14/213 (6.6%)
Fatigue	37/92 (40.2%)		101/213 (47.4%)
Non-cardiac chest pain	5/92 (5.4%)		4/213 (1.9%)
Oedema peripheral	10/92 (10.9%)		13/213 (6.1%)
Pain	4/92 (4.3%)		21/213 (9.9%)
Pyrexia	12/92 (13%)		37/213 (17.4%)
Infections and infestations
Oral candidiasis	1/92 (1.1%)		18/213 (8.5%)
Urinary tract infection	3/92 (3.3%)		18/213 (8.5%)
Investigations
Alanine aminotransferase increased	3/92 (3.3%)		23/213 (10.8%)
Asparate aminotransferase increased	6/92 (6.5%)		25/213 (11.7%)
Blood alkaline phosphotase increased	2/92 (2.2%)		18/213 (8.5%)
Lymphocyte count decreased	3/92 (3.3%)		12/213 (5.6%)
Neutrophil count decreased	1/92 (1.1%)		38/213 (17.8%)
Weight decreased	5/92 (5.4%)		37/213 (17.4%)
White blood cell count decreased	2/92 (2.2%)		24/213 (11.3%)
Metabolism and nutrition disorders
Decreased appetite	17/92 (18.5%)		63/213 (29.6%)
Dehydration	6/92 (6.5%)		15/213 (7%)
Hyperglycaemia	0/92 (0%)		15/213 (7%)
Hypoalbuminaemia	5/92 (5.4%)		11/213 (5.2%)
Hypokalaemia	8/92 (8.7%)		24/213 (11.3%)
Hypophosphataemia	5/92 (5.4%)		14/213 (6.6%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/92 (3.3%)		38/213 (17.8%)
Back pain	12/92 (13%)		21/213 (9.9%)
Bone pain	3/92 (3.3%)		24/213 (11.3%)
Muscle spasms	1/92 (1.1%)		12/213 (5.6%)
Muscular weakness	3/92 (3.3%)		12/213 (5.6%)
Musculoskeletal chest pain	11/92 (12%)		9/213 (4.2%)
Musculoskeletal pain	8/92 (8.7%)		10/213 (4.7%)
Myalgia	4/92 (4.3%)		27/213 (12.7%)
Pain in extremity	9/92 (9.8%)		25/213 (11.7%)
Nervous system disorders
Dizziness	4/92 (4.3%)		19/213 (8.9%)
Dysgeusia	2/92 (2.2%)		23/213 (10.8%)
Headache	5/92 (5.4%)		39/213 (18.3%)
Neuropathy peripheral	4/92 (4.3%)		28/213 (13.1%)
Paraesthesia	5/92 (5.4%)		12/213 (5.6%)
Peripheral sensory neuropathy	4/92 (4.3%)		47/213 (22.1%)
Psychiatric disorders
Anxiety	5/92 (5.4%)		15/213 (7%)
Insomnia	6/92 (6.5%)		24/213 (11.3%)
Respiratory, thoracic and mediastinal disorders
Cough	10/92 (10.9%)		24/213 (11.3%)
Dyspnoea	11/92 (12%)		32/213 (15%)
Oropharyngeal pain	2/92 (2.2%)		15/213 (7%)
Pleural effusion	5/92 (5.4%)		5/213 (2.3%)
Skin and subcutaneous tissue disorders
Alopecia	1/92 (1.1%)		88/213 (41.3%)
Dry skin	5/92 (5.4%)		8/213 (3.8%)
Palmar-plantar erythrodysaethesia syndrome	40/92 (43.5%)		10/213 (4.7%)
Pruritis	4/92 (4.3%)		69/213 (32.4%)
Pruritis generalised	0/92 (0%)		12/213 (5.6%)
Rash	3/92 (3.3%)		29/213 (13.6%)
Rash erythematous	1/92 (1.1%)		15/213 (7%)
Rash macular	0/92 (0%)		11/213 (5.2%)
Rash macular-papular	5/92 (5.4%)		40/213 (18.8%)
Rash pruritic	0/92 (0%)		18/213 (8.5%)
Skin hyerppigmentation	3/92 (3.3%)		19/213 (8.9%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.