S1310: Trametinib or Combination Chemotherapy in Treating Patients With Refractory or Advanced Biliary or Gallbladder Cancer or That Cannot Be Removed by Surgery

• Sponsor: National Cancer Institute (NCI) (NIH)
• Overall Status: Completed
• CT.gov ID: NCT02042443
• Collaborator: (none)
• Enrollment: 53
• Locations: 295
• Arms: 2
• Duration (Months): 38.9
• Patients Per Site: 0.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This randomized phase II trial studies how well trametinib or combination chemotherapy works in treating patients with refractory or advanced biliary or gallbladder cancer or that cannot be removed by surgery. Trametinib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as fluorouracil, leucovorin calcium, and capecitabine, 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. It is not yet known whether giving trametinib is more effective than combination chemotherapy in treating patients with biliary or gallbladder cancer.

Condition or Disease	Intervention/Treatment	Phase
Adult Cholangiocarcinoma; Advanced Adult Hepatocellular Carcinoma; BCLC Stage C Adult Hepatocellular Carcinoma; BCLC Stage D Adult Hepatocellular Carcinoma; Hilar Cholangiocarcinoma; Localized Non-Resectable Adult Liver Carcinoma; Recurrent Adult Liver Carcinoma; Recurrent Childhood Liver Cancer; Recurrent Extrahepatic Bile Duct Carcinoma; Recurrent Gallbladder Carcinoma; Stage II Gallbladder Cancer; Stage III Childhood Hepatocellular Carcinoma; Stage IIIA Gallbladder Cancer; Stage IIIB Gallbladder Cancer; Stage IV Childhood Hepatocellular Carcinoma; Stage IV Distal Bile Duct Cancer; Stage IVA Gallbladder Cancer; Stage IVB Gallbladder Cancer; Unresectable Extrahepatic Bile Duct Carcinoma	Drug: Capecitabine; Drug: Fluorouracil; Other: Laboratory Biomarker Analysis; Drug: Leucovorin Calcium; Drug: Trametinib	Phase 2

Detailed Description

PRIMARY OBJECTIVES:

1. To assess overall survival (OS) in patients with refractory advanced biliary cancer randomized to Arm 1: trametinib compared to those randomized to Arm 2: chemotherapy (either 5-fluorouracil [fluorouracil] and leucovorin [leucovorin calcium] or capecitabine).

SECONDARY OBJECTIVES:

1. To determine the frequency and severity of adverse events of trametinib in this patient population.

2. To assess response rate (RR) and progression-free survival (PFS) in patients randomized to Arm 1: trametinib and patients randomized to Arm 2: chemotherapy (fluorouracil [5-FU] or capecitabine in this patient population).

TERTIARY OBJECTIVES:

1. To determine if a 16-gene expression signature is predictive of mitogen-activated protein kinase kinase (MEK) efficacy as evidenced by improved RR, PFS, and OS.

2. To evaluate the effects of trametinib on the inflammatory cytokine and explore potential associations with response rate and survival.

3. To estimate lean soft tissue and fat mass weight gain as a result of treatment with trametinib vs. capecitabine in patients with advanced refractory biliary cancer.

4. To bank tissue samples for other future correlative studies including next generation sequencing and whole genome methylation assays. NOTE: These potential future correlative studies will not be performed until an amended protocol with relevant detailed information including specific arms and assays is approved by Cancer Therapy Evaluation Program (CTEP).

OUTLINE: Patients are randomized to 1 of 2 treatment arms.

ARM I: Patients receive trametinib orally (PO) once daily (QD) on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

ARM II: Patients receive 1 of 2 treatment regimens at the discretion of the investigator.

ARM IIA: Patients receive leucovorin calcium intravenously (IV) over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

ARM IIB: Patients receive capecitabine PO twice daily (BID) on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up every 3 months for 2 years.

Study Design

• Study Type: Interventional
• Actual Enrollment: 53 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: Randomized Phase II Trial of Single Agent MEK Inhibitor Trametinib (GSK1120212) Vs 5-Fluorouracil or Capecitabine in Refractory Advanced Biliary Cancer
• Study Start Date: Feb 1, 2014
• Actual Primary Completion Date: Jan 1, 2017
• Actual Study Completion Date: Apr 30, 2017

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Trametinib Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Trametinib; Given PO; Other Names: GSK1120212 JTP-74057 MEK Inhibitor GSK1120212 Mekinist
Experimental: Chemotherapy Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15 (courses repeat every 28 days); or B) capecitabine PO BID on days 1-14 (courses repeat every 21 days). Patients treated until disease progression or unacceptable toxicity.	Drug: Capecitabine; Given PO; Other Names: Ro 09-1978/000 Xeloda ; Drug: Fluorouracil; Given IV; Other Names: 5-Fluoro-2,4(1H, 3H)-pyrimidinedione 5-Fluorouracil 5-Fluracil 5-FU AccuSite Carac Fluoro Uracil Fluouracil Flurablastin Fluracedyl Fluracil Fluril Fluroblastin Ribofluor Ro 2-9757 Ro-2-9757 ; Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Leucovorin Calcium; Given IV; Other Names: Adinepar Calcifolin Calcium (6S)-Folinate Calcium Folinate Calcium Leucovorin Calfolex Calinat Cehafolin Citofolin Citrec Citrovorum Factor Cromatonbic Folinico Dalisol Disintox Divical Ecofol Emovis Factor, Citrovorum Flynoken A Folaren Folaxin FOLI-cell Foliben Folidan Folidar Folinac Folinate Calcium folinic acid Folinic Acid Calcium Salt Pentahydrate Folinoral Folinvit Foliplus Folix Imo Lederfolat Lederfolin Leucosar leucovorin Rescufolin Rescuvolin Tonofolin Wellcovorin

Outcome Measures

Primary Outcome Measures

1. Overall Survival [Up to 2 years from registration]

   From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.

Secondary Outcome Measures

1. Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug [Up to 2 years]

   Adverse event reporting followed the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.

2. Objective Response Rate [Up to 2 years from registration]

   Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.

3. Progression-free Survival [Up to 2 years from registration]

   From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.

Eligibility Criteria

Criteria

• Ages Eligible for Study: N/A and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• DISEASE RELATED CRITERIA

• Patients must have histologically or cytologically documented carcinoma primary to the intra- or extra-hepatic biliary system or gall bladder with clinical and/or radiologic evidence of unresectable, locally advanced or metastatic disease; patients with ampullary carcinoma are not eligible

• Patients must have measurable disease; computed tomography (CT) scans or magnetic resonance imaging (MRI)s used to assess measurable disease must have been completed within 28 days prior to registration; CT scans or MRIs used to assess non-measurable disease must have been completed within 42 days prior to registration; all disease must be assessed and documented on the Baseline Tumor Assessment Form (Response Evaluation Criteria in Solid Tumors [RECIST] 1.1)

• PRIOR/CONCURRENT THERAPY CRITERIA

• Patients must have completed any prior chemotherapy at least 21 days prior to registration and have recovered from any of the effects AND

• Patients must have experienced progression to no more than 1 prior regimen of systemic chemotherapy for advanced biliary cancer OR

• Patients who received adjuvant chemotherapy and had evidence of disease recurrence within 6 months of completion of the adjuvant treatment are also eligible; if patient received adjuvant treatment and had disease recurrence after 6 months, patients will only be eligible after failing one regimen of systemic chemotherapy used to treat the (unresectable or metastatic) disease recurrence

• Patients must not have been treated with prior MEK inhibitors; prior 5-FU or capecitabine treatment is allowed only if given as a radiosensitizer concurrently with radiation therapy at least 12 weeks prior to registration or if given as part of any adjuvant therapy regimen >= 12 months prior to study enrollment

• Patients must have no plans to receive concurrent chemotherapy, hormonal therapy, radiotherapy, immunotherapy or any other type of therapy (including herbal or natural supplements) for treatment of cancer while on this treatment protocol

• For patients who have received prior cryotherapy, radiation therapy, radiofrequency ablation, therasphere, ethanol injection, transarterial chemoembolization (TACE) or photodynamic therapy, the following criteria must be met:

• 28 days have elapsed since that therapy (lesions that have not been treated with local therapy must be present and measureable)

• CLINICAL/LABORATORY CRITERIA

• Patients must have a Zubrod performance status of 0-1

• Absolute neutrophil count (ANC) > 1000/mcL

• Platelets > 100000/mcL

• Total bilirubin =< 2.0 x the institutional upper limit of normal limits (IULN)

• Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) both =< 3 x IULN; if liver metastases are present, AST and ALT must be =< 5 x IULN

• If the patient has had decompression of the biliary tree within the last 14 days, stability of the bilirubin level needs to be confirmed with two measurements that are within 5 to 7 days of each other; (the second measurement must be obtained within 7 days prior to registration;) both the first and second measurement must be =< 2.0 x IULN; stability is defined as the second measurement being no more than one point higher than the first

• Patients must have adequate kidney function as evidenced by at least ONE of the following:

• Serum creatinine =< 1.5 x IULN within 28 days prior to registration

• Calculated creatinine clearance >= 50 ml/min for patients with creatinine level of 1.0-1.5 x IULN; the serum creatinine value used in the calculation must have been obtained within 28 days prior to registration

• Patients with known history or current evidence of retinal vein occlusion (RVO) or retinal pigment epithelial detachment (RPED) are not eligible:

• History of RVO or RPED, or predisposing factors to RVO or RPED (e.g. such as uncontrolled glaucoma or ocular hypertension, uncontrolled systemic disease such as hypertension, diabetes mellitus, or history of hyperviscosity or hypercoagulability syndromes)

• Visible retinal pathology as assessed by ophthalmic exam that is considered a risk factor for RVO or RPED such as:

• Evidence of new optic disc cupping

• Evidence of new visual field defects

• Intraocular pressure > 21 mmHg

• NOTE: ophthalmic exam is required for all patients; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration

• Patients must have echocardiogram and left ventricular ejection fraction (LVEF) >= institutional lower limit of normal (LLN) within 28 days prior to registration; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration

• Patients must not have uncontrolled or clinically significant cardiovascular disease including: myocardial infarction within past 6 months; uncontrolled angina within past 6 months; class II-IV New York Heart Association (NYHA) congestive heart failure; grade 3 cardiac valve dysfunction; cardiac arrhythmia not controlled by medication; history of stroke or transient ischemic attack within 6 months; history of arterial thrombotic event (ATE) of any type in the past 6 months; treatment-refractory hypertension defined as a blood pressure of systolic > 140 mmHg and/or diastolic > 90 mmHg which cannot be controlled with anti-hypertensive therapy; known intra-cardiac defibrillators; known cardiac metastases

• Patients must have an electrocardiogram (ECG) within 28 days prior to registration; patients must have corrected QT interval (QTc) =< 500 msec; this exam should not be performed until or unless it is very clear the patient is otherwise eligible for registration

• Must be able to swallow and retain orally-administered medication and does not have any clinically significant gastrointestinal abnormalities that may alter absorption such as malabsorption syndrome or major resection of the stomach or bowels

• Must not have a known immediate or delayed hypersensitivity reaction or idiosyncrasy to drugs chemically related to trametinib, or excipients or to dimethyl sulfoxide (DMSO) or other agents used in study

• Must not have active hepatitis B virus (HBV), or hepatitis C virus (HCV) infection (patients with chronic or cleared HBV and HCV infection are eligible)

• Human immunodeficiency virus (HIV)-positive patients on combination antiretroviral therapy are ineligible

• Patients must not be pregnant or nursing; women/men of reproductive potential must have agreed to use an effective contraceptive method while on study and for 4 months after discontinuation of study drug; a woman is considered to be of "reproductive potential" if she has had menses at any time in the preceding 12 consecutive months; in addition to routine contraceptive methods, "effective contraception" also includes heterosexual celibacy and surgery intended to prevent pregnancy (or with a side-effect of pregnancy prevention) defined as a hysterectomy, bilateral oophorectomy or bilateral tubal ligation; however, if at any point a previously celibate patient chooses to become heterosexually active during the time period for use of contraceptive measures outlined in the protocol, he/she is responsible for beginning contraceptive measures

• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated stage I or II cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease free for five years

• SPECIMEN SUBMISSION CRITERIA

• Patients must submit paraffin-embedded tissue and blood for banking within 28 days after registration; paraffin-embedded tissue from prior surgical resection or from a diagnostic biopsy is acceptable

• REGULATORY CRITERIA

• Patients or their legally authorized representative must be informed of the investigational nature of this study and must sign and give written informed consent in accordance with institutional and federal guidelines

• As a part of the Oncology Patient Enrollment Network (OPEN) registration process the treating institution's identity is provided in order to ensure that the current (within 365 days) date of institutional review board approval for this study has been entered in the system

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Alaska Breast Care and Surgery LLC	Anchorage	Alaska	United States	99508
2	Alaska Women's Cancer Care	Anchorage	Alaska	United States	99508
3	Anchorage Oncology Centre	Anchorage	Alaska	United States	99508
4	Katmai Oncology Group	Anchorage	Alaska	United States	99508
5	Providence Alaska Medical Center	Anchorage	Alaska	United States	99508
6	Kaiser Permanente-Anaheim	Anaheim	California	United States	92807
7	Sutter Auburn Faith Hospital	Auburn	California	United States	95602
8	Kaiser Permanente-Baldwin Park	Baldwin Park	California	United States	91706
9	Kaiser Permanente-Bellflower	Bellflower	California	United States	90706
10	Alta Bates Summit Medical Center-Herrick Campus	Berkeley	California	United States	94704
11	Mills - Peninsula Hospitals	Burlingame	California	United States	94010
12	Sutter Davis Hospital	Davis	California	United States	95616
13	City of Hope Comprehensive Cancer Center	Duarte	California	United States	91010
14	Kaiser Permanente Hospital	Fontana	California	United States	92335
15	Kaiser Permanente - Harbor City	Harbor City	California	United States	90710
16	Kaiser Permanente-Irvine	Irvine	California	United States	92618
17	Kaiser Permanente Los Angeles Medical Center	Los Angeles	California	United States	90027
18	Los Angeles County-USC Medical Center	Los Angeles	California	United States	90033
19	USC / Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
20	Kaiser Permanente-Cadillac	Los Angeles	California	United States	90034
21	Fremont - Rideout Cancer Center	Marysville	California	United States	95901
22	Memorial Medical Center	Modesto	California	United States	95355
23	Palo Alto Medical Foundation-Camino Division	Mountain View	California	United States	94040
24	Palo Alto Medical Foundation-Gynecologic Oncology	Mountain View	California	United States	94040
25	Sutter Cancer Research Consortium	Novato	California	United States	94945
26	UC Irvine Health/Chao Family Comprehensive Cancer Center	Orange	California	United States	92868
27	Palo Alto Medical Foundation Health Care	Palo Alto	California	United States	94301
28	Kaiser Permanente - Panorama City	Panorama City	California	United States	91402
29	Kaiser Permanente-Riverside	Riverside	California	United States	92505
30	Sutter Roseville Medical Center	Roseville	California	United States	95661
31	Sutter General Hospital	Sacramento	California	United States	95816
32	University of California Davis Comprehensive Cancer Center	Sacramento	California	United States	95817
33	Kaiser Permanente-San Diego Mission	San Diego	California	United States	92108
34	Kaiser Permanente-San Diego Zion	San Diego	California	United States	92120
35	California Pacific Medical Center-Pacific Campus	San Francisco	California	United States	94115
36	Kaiser Permanente-San Marcos	San Marcos	California	United States	92069
37	Palo Alto Medical Foundation-Santa Cruz	Santa Cruz	California	United States	95065
38	Sutter Pacific Medical Foundation	Santa Rosa	California	United States	95403
39	Palo Alto Medical Foundation-Sunnyvale	Sunnyvale	California	United States	94086
40	Sutter Solano Medical Center/Cancer Center	Vallejo	California	United States	94589
41	Kaiser Permanente	Woodland Hills	California	United States	91367
42	University of Colorado Cancer Center - Anschutz Cancer Pavilion	Aurora	Colorado	United States	80045
43	Memorial Hospital Colorado Springs	Colorado Springs	Colorado	United States	80909
44	Smilow Cancer Hospital-Derby Care Center	Derby	Connecticut	United States	06418
45	Medical Oncology and Hematology Group PC-Guilford	Guilford	Connecticut	United States	06437
46	Smilow Cancer Hospital Care Center at Saint Francis	Hartford	Connecticut	United States	06105
47	Yale University	New Haven	Connecticut	United States	06520
48	Yale-New Haven Hospital North Haven Medical Center	North Haven	Connecticut	United States	06473
49	Smilow Cancer Hospital-Orange Care Center	Orange	Connecticut	United States	06477
50	Charlotte Hungerford Hospital Center for Cancer Care	Torrington	Connecticut	United States	06790
51	Smilow Cancer Hospital-Waterbury Care Center	Waterbury	Connecticut	United States	06708
52	University of Florida	Gainesville	Florida	United States	32610
53	Moffitt Cancer Center	Tampa	Florida	United States	33612
54	Saint Alphonsus Cancer Care Center-Boise	Boise	Idaho	United States	83706
55	Kootenai Medical Center	Coeur d'Alene	Idaho	United States	83814
56	Kootenai Cancer Center	Post Falls	Idaho	United States	83854
57	Kootenai Cancer Clinic	Sandpoint	Idaho	United States	83864
58	Saint Joseph Medical Center	Bloomington	Illinois	United States	61701
59	Illinois CancerCare-Bloomington	Bloomington	Illinois	United States	61704
60	Illinois CancerCare-Canton	Canton	Illinois	United States	61520
61	Memorial Hospital of Carbondale	Carbondale	Illinois	United States	62902
62	Illinois CancerCare-Carthage	Carthage	Illinois	United States	62321
63	Centralia Oncology Clinic	Centralia	Illinois	United States	62801
64	Cancer Care Center of Decatur	Decatur	Illinois	United States	62526
65	Decatur Memorial Hospital	Decatur	Illinois	United States	62526
66	Crossroads Cancer Center	Effingham	Illinois	United States	62401
67	Illinois CancerCare-Eureka	Eureka	Illinois	United States	61530
68	Illinois CancerCare-Galesburg	Galesburg	Illinois	United States	61401
69	Western Illinois Cancer Treatment Center	Galesburg	Illinois	United States	61401
70	Illinois CancerCare-Kewanee Clinic	Kewanee	Illinois	United States	61443
71	Illinois CancerCare-Macomb	Macomb	Illinois	United States	61455
72	Loyola University Medical Center	Maywood	Illinois	United States	60153
73	Good Samaritan Regional Health Center	Mount Vernon	Illinois	United States	62864
74	Illinois CancerCare-Ottawa Clinic	Ottawa	Illinois	United States	61350
75	Radiation Oncology of Northern Illinois	Ottawa	Illinois	United States	61350
76	Illinois CancerCare-Pekin	Pekin	Illinois	United States	61554
77	OSF Saint Francis Radiation Oncology at Pekin Cancer Treatment Center	Pekin	Illinois	United States	61554
78	Methodist Medical Center of Illinois	Peoria	Illinois	United States	61603
79	Illinois CancerCare-Peoria	Peoria	Illinois	United States	61615
80	OSF Saint Francis Radiation Oncology at Peoria Cancer Center	Peoria	Illinois	United States	61615
81	OSF Saint Francis Medical Center	Peoria	Illinois	United States	61637
82	Illinois CancerCare-Peru	Peru	Illinois	United States	61354
83	Valley Radiation Oncology	Peru	Illinois	United States	61354
84	Illinois CancerCare-Princeton	Princeton	Illinois	United States	61356
85	Central Illinois Hematology Oncology Center	Springfield	Illinois	United States	62702
86	Southern Illinois University School of Medicine	Springfield	Illinois	United States	62702
87	Springfield Clinic	Springfield	Illinois	United States	62703
88	Memorial Medical Center	Springfield	Illinois	United States	62781
89	Reid Health	Richmond	Indiana	United States	47374
90	Cancer Center of Kansas - Chanute	Chanute	Kansas	United States	66720
91	Cancer Center of Kansas - Dodge City	Dodge City	Kansas	United States	67801
92	Cancer Center of Kansas - El Dorado	El Dorado	Kansas	United States	67042
93	Newman Regional Health	Emporia	Kansas	United States	66801
94	Cancer Center of Kansas - Fort Scott	Fort Scott	Kansas	United States	66701
95	Saint Catherine Hospital	Garden City	Kansas	United States	67846
96	Saint Rose Ambulatory and Surgery Center	Great Bend	Kansas	United States	67530
97	Hays Medical Center	Hays	Kansas	United States	67601
98	Cancer Center of Kansas-Independence	Independence	Kansas	United States	67301
99	University of Kansas Cancer Center-West	Kansas City	Kansas	United States	66112
100	University of Kansas Cancer Center	Kansas City	Kansas	United States	66160
101	Cancer Center of Kansas-Kingman	Kingman	Kansas	United States	67068
102	Lawrence Memorial Hospital	Lawrence	Kansas	United States	66044
103	Cancer Center of Kansas-Liberal	Liberal	Kansas	United States	67905
104	Cancer Center of Kansas-Manhattan	Manhattan	Kansas	United States	66502
105	Cancer Center of Kansas - McPherson	McPherson	Kansas	United States	67460
106	Cancer Center of Kansas - Newton	Newton	Kansas	United States	67114
107	Olathe Medical Center	Olathe	Kansas	United States	66061
108	University of Kansas Cancer Center-Overland Park	Overland Park	Kansas	United States	66210
109	Cancer Center of Kansas - Parsons	Parsons	Kansas	United States	67357
110	Via Christi Hospital-Pittsburg	Pittsburg	Kansas	United States	66762
111	Cancer Center of Kansas - Pratt	Pratt	Kansas	United States	67124
112	Cancer Center of Kansas - Salina	Salina	Kansas	United States	67401
113	Salina Regional Health Center	Salina	Kansas	United States	67401
114	Saint Francis Hospital and Medical Center - Topeka	Topeka	Kansas	United States	66606
115	Cancer Center of Kansas - Wellington	Wellington	Kansas	United States	67152
116	Associates In Womens Health	Wichita	Kansas	United States	67208
117	Cancer Center of Kansas-Wichita Medical Arts Tower	Wichita	Kansas	United States	67208
118	Cancer Center of Kansas - Wichita	Wichita	Kansas	United States	67214
119	Via Christi Regional Medical Center	Wichita	Kansas	United States	67214
120	Wichita NCI Community Oncology Research Program	Wichita	Kansas	United States	67214
121	Cancer Center of Kansas - Winfield	Winfield	Kansas	United States	67156
122	Oncology Hematology Care Inc-Crestview	Crestview Hills	Kentucky	United States	41017
123	Boston Medical Center	Boston	Massachusetts	United States	02118
124	Lahey Hospital and Medical Center	Burlington	Massachusetts	United States	01805
125	Saint Joseph Mercy Hospital	Ann Arbor	Michigan	United States	48106-0995
126	Michigan Cancer Research Consortium NCORP	Ann Arbor	Michigan	United States	48106
127	University of Michigan Comprehensive Cancer Center	Ann Arbor	Michigan	United States	48109
128	Bronson Battle Creek	Battle Creek	Michigan	United States	49017
129	Beaumont Hospital-Dearborn	Dearborn	Michigan	United States	48124
130	Wayne State University/Karmanos Cancer Institute	Detroit	Michigan	United States	48201
131	Saint John Hospital and Medical Center	Detroit	Michigan	United States	48236
132	Weisberg Cancer Treatment Center	Farmington Hills	Michigan	United States	48334
133	Hurley Medical Center	Flint	Michigan	United States	48502
134	Genesys Hurley Cancer Institute	Flint	Michigan	United States	48503
135	Mercy Health Saint Mary's	Grand Rapids	Michigan	United States	49503
136	Spectrum Health at Butterworth Campus	Grand Rapids	Michigan	United States	49503
137	Allegiance Health	Jackson	Michigan	United States	49201
138	Sparrow Hospital	Lansing	Michigan	United States	48912
139	Saint Mary Mercy Hospital	Livonia	Michigan	United States	48154
140	Mercy Health Mercy Campus	Muskegon	Michigan	United States	49444
141	Lakeland Community Hospital	Niles	Michigan	United States	49120
142	Saint Joseph Mercy Oakland	Pontiac	Michigan	United States	48341
143	Lake Huron Medical Center	Port Huron	Michigan	United States	48060
144	Spectrum Health Reed City Hospital	Reed City	Michigan	United States	49677
145	Saint Mary's of Michigan	Saginaw	Michigan	United States	48601
146	Lakeland Hospital	Saint Joseph	Michigan	United States	49085
147	Marie Yeager Cancer Center	Saint Joseph	Michigan	United States	49085
148	Munson Medical Center	Traverse City	Michigan	United States	49684
149	Saint John Macomb-Oakland Hospital	Warren	Michigan	United States	48093
150	Parkland Health Center-Bonne Terre	Bonne Terre	Missouri	United States	63628
151	Saint Francis Medical Center	Cape Girardeau	Missouri	United States	63703
152	Southeast Cancer Center	Cape Girardeau	Missouri	United States	63703
153	Capital Region Medical Center-Goldschmidt Cancer Center	Jefferson City	Missouri	United States	65109
154	Truman Medical Center	Kansas City	Missouri	United States	64108
155	The University of Kansas Cancer Center-South	Kansas City	Missouri	United States	64131
156	The University of Kansas Cancer Center-North	Kansas City	Missouri	United States	64154
157	The University of Kansas Cancer Center-Lee's Summit	Lee's Summit	Missouri	United States	64064
158	Phelps County Regional Medical Center	Rolla	Missouri	United States	65401
159	Saint John's Clinic-Rolla-Cancer and Hematology	Rolla	Missouri	United States	65401
160	Saint Louis Cancer and Breast Institute-South City	Saint Louis	Missouri	United States	63109
161	Missouri Baptist Medical Center	Saint Louis	Missouri	United States	63131
162	Mercy Hospital Saint Louis	Saint Louis	Missouri	United States	63141
163	Sainte Genevieve County Memorial Hospital	Sainte Genevieve	Missouri	United States	63670
164	Cancer Research for the Ozarks NCORP	Springfield	Missouri	United States	65804
165	Mercy Hospital Springfield	Springfield	Missouri	United States	65804
166	CoxHealth South Hospital	Springfield	Missouri	United States	65807
167	Missouri Baptist Sullivan Hospital	Sullivan	Missouri	United States	63080
168	Missouri Baptist Outpatient Center-Sunset Hills	Sunset Hills	Missouri	United States	63127
169	Billings Clinic Cancer Center	Billings	Montana	United States	59101
170	Montana Cancer Consortium NCORP	Billings	Montana	United States	59101
171	Saint Vincent Healthcare	Billings	Montana	United States	59101
172	Bozeman Deaconess Hospital	Bozeman	Montana	United States	59715
173	Saint James Community Hospital and Cancer Treatment Center	Butte	Montana	United States	59701
174	Benefis Healthcare- Sletten Cancer Institute	Great Falls	Montana	United States	59405
175	Saint Peter's Community Hospital	Helena	Montana	United States	59601
176	Kalispell Regional Medical Center	Kalispell	Montana	United States	59901
177	Saint Patrick Hospital - Community Hospital	Missoula	Montana	United States	59802
178	Community Medical Hospital	Missoula	Montana	United States	59804
179	Cancer and Blood Specialists-Henderson	Henderson	Nevada	United States	89052
180	Comprehensive Cancer Centers of Nevada - Henderson	Henderson	Nevada	United States	89052
181	Las Vegas Cancer Center-Henderson	Henderson	Nevada	United States	89052
182	21st Century Oncology - Henderson	Henderson	Nevada	United States	89074
183	Comprehensive Cancer Centers of Nevada-Southeast Henderson	Henderson	Nevada	United States	89074
184	University Medical Center of Southern Nevada	Las Vegas	Nevada	United States	89102
185	Cancer and Blood Specialists-Shadow	Las Vegas	Nevada	United States	89106
186	Nevada Cancer Research Foundation CCOP	Las Vegas	Nevada	United States	89106
187	Radiation Oncology Centers of Nevada Central	Las Vegas	Nevada	United States	89106
188	21st Century Oncology	Las Vegas	Nevada	United States	89109
189	HealthCare Partners Medical Group Oncology/Hematology-Maryland Parkway	Las Vegas	Nevada	United States	89109
190	HealthCare Partners Medical Group Oncology/Hematology-San Martin	Las Vegas	Nevada	United States	89113
191	Radiation Oncology Centers of Nevada Southeast	Las Vegas	Nevada	United States	89119
192	Cancer Therapy and Integrative Medicine	Las Vegas	Nevada	United States	89121
193	Cancer and Blood Specialists-Tenaya	Las Vegas	Nevada	United States	89128
194	Comprehensive Cancer Centers of Nevada - Northwest	Las Vegas	Nevada	United States	89128
195	HealthCare Partners Medical Group Oncology/Hematology-Tenaya	Las Vegas	Nevada	United States	89128
196	Comprehensive Cancer Centers of Nevada-Summerlin	Las Vegas	Nevada	United States	89144
197	Las Vegas Cancer Center-Medical Center	Las Vegas	Nevada	United States	89148-2405
198	21st Century Oncology - Fort Apache	Las Vegas	Nevada	United States	89148
199	Cancer and Blood Specialists-Fort Apache	Las Vegas	Nevada	United States	89148
200	Comprehensive Cancer Centers of Nevada	Las Vegas	Nevada	United States	89148
201	HealthCare Partners Medical Group Oncology/Hematology-Centennial Hills	Las Vegas	Nevada	United States	89149
202	Comprehensive Cancer Centers of Nevada - Central Valley	Las Vegas	Nevada	United States	89169
203	21st Century Oncology - Vegas Tenaya	Las Vegas	Nevada	United States	89182
204	University of New Mexico Cancer Center	Albuquerque	New Mexico	United States	87102
205	Christus Saint Vincent Regional Cancer Center	Santa Fe	New Mexico	United States	87505
206	Columbia University/Herbert Irving Cancer Center	New York	New York	United States	10032
207	University of Rochester	Rochester	New York	United States	14642
208	Cancer Care of Western North Carolina	Asheville	North Carolina	United States	28801
209	Mission Hospital-Memorial Campus	Asheville	North Carolina	United States	28801
210	Asheville Hematology-Oncology Associates	Asheville	North Carolina	United States	28803
211	Southeastern Medical Oncology Center-Clinton	Clinton	North Carolina	United States	28328
212	Southeastern Medical Oncology Center-Goldsboro	Goldsboro	North Carolina	United States	27534
213	Wayne Memorial Hospital	Goldsboro	North Carolina	United States	27534
214	Southeastern Medical Oncology Center-Jacksonville	Jacksonville	North Carolina	United States	28546
215	Iredell Memorial Hospital	Statesville	North Carolina	United States	28677
216	Southeastern Medical Oncology Center-Wilson	Wilson	North Carolina	United States	27893
217	Southeast Clinical Oncology Research (SCOR) Consortium NCORP	Winston-Salem	North Carolina	United States	27104
218	Strecker Cancer Center-Belpre	Belpre	Ohio	United States	45714
219	Adena Regional Medical Center	Chillicothe	Ohio	United States	45601
220	Oncology Hematology Care Inc-Eden Park	Cincinnati	Ohio	United States	45202
221	Oncology Hematology Care Inc-Mercy West	Cincinnati	Ohio	United States	45211
222	Oncology Hematology Care Inc - Anderson	Cincinnati	Ohio	United States	45230
223	Oncology Hematology Care Inc-Kenwood	Cincinnati	Ohio	United States	45236
224	Oncology Hematology Care Inc-Blue Ash	Cincinnati	Ohio	United States	45242
225	Ohio State University Comprehensive Cancer Center	Columbus	Ohio	United States	43210
226	Columbus Oncology and Hematology Associates Inc	Columbus	Ohio	United States	43214
227	Riverside Methodist Hospital	Columbus	Ohio	United States	43214
228	Columbus NCI Community Oncology Research Program	Columbus	Ohio	United States	43215
229	Grant Medical Center	Columbus	Ohio	United States	43215
230	The Mark H Zangmeister Center	Columbus	Ohio	United States	43219
231	Mount Carmel Health Center West	Columbus	Ohio	United States	43222
232	Doctors Hospital	Columbus	Ohio	United States	43228
233	Good Samaritan Hospital - Dayton	Dayton	Ohio	United States	45406
234	Miami Valley Hospital	Dayton	Ohio	United States	45409
235	Samaritan North Health Center	Dayton	Ohio	United States	45415
236	Dayton NCI Community Oncology Research Program	Dayton	Ohio	United States	45420
237	Delaware Health Center-Grady Cancer Center	Delaware	Ohio	United States	43015
238	Delaware Radiation Oncology	Delaware	Ohio	United States	43015
239	Grady Memorial Hospital	Delaware	Ohio	United States	43015
240	Oncology Hematology Care Inc-Healthplex	Fairfield	Ohio	United States	45014
241	Blanchard Valley Hospital	Findlay	Ohio	United States	45840
242	Atrium Medical Center-Middletown Regional Hospital	Franklin	Ohio	United States	45005-1066
243	Wayne Hospital	Greenville	Ohio	United States	45331
244	Kettering Medical Center	Kettering	Ohio	United States	45429
245	Fairfield Medical Center	Lancaster	Ohio	United States	43130
246	Marietta Memorial Hospital	Marietta	Ohio	United States	45750
247	Knox Community Hospital	Mount Vernon	Ohio	United States	43050
248	Licking Memorial Hospital	Newark	Ohio	United States	43055
249	Newark Radiation Oncology	Newark	Ohio	United States	43055
250	Southern Ohio Medical Center	Portsmouth	Ohio	United States	45662
251	Springfield Regional Medical Center	Springfield	Ohio	United States	45505
252	Upper Valley Medical Center	Troy	Ohio	United States	45373
253	Saint Ann's Hospital	Westerville	Ohio	United States	43081
254	Genesis Healthcare System Cancer Care Center	Zanesville	Ohio	United States	43701
255	University of Oklahoma Health Sciences Center	Oklahoma City	Oklahoma	United States	73104
256	Clackamas Radiation Oncology Center	Clackamas	Oregon	United States	97015
257	Providence Milwaukie Hospital	Milwaukie	Oregon	United States	97222
258	Providence Newberg Medical Center	Newberg	Oregon	United States	97132
259	Providence Willamette Falls Medical Center	Oregon City	Oregon	United States	97045
260	Providence Portland Medical Center	Portland	Oregon	United States	97213
261	Providence Saint Vincent Medical Center	Portland	Oregon	United States	97225
262	Oregon Health and Science University	Portland	Oregon	United States	97239
263	Roper Hospital	Charleston	South Carolina	United States	29401
264	Charleston Hematology Oncology Associates-Roper	Charleston	South Carolina	United States	29403
265	Lowcountry Hematology Oncology PA-North Charleston	Charleston	South Carolina	United States	29406
266	Charleston Hematology Oncology Associates PA-St. Francis	Charleston	South Carolina	United States	29414
267	Lowcountry Hematology Oncology PA-West Ashley	Charleston	South Carolina	United States	29414
268	Greenville Health System Cancer Institute-Easley	Easley	South Carolina	United States	29640
269	Saint Francis Hospital	Greenville	South Carolina	United States	29601
270	Greenville Health System Cancer Institute-Andrews	Greenville	South Carolina	United States	29605
271	Greenville Health System Cancer Institute-Butternut	Greenville	South Carolina	United States	29605
272	Greenville Health System Cancer Institute-Faris	Greenville	South Carolina	United States	29605
273	Greenville Memorial Hospital	Greenville	South Carolina	United States	29605
274	Greenville Health System Cancer Institute-Eastside	Greenville	South Carolina	United States	29615
275	Greenville Health System Cancer Institute-Greer	Greer	South Carolina	United States	29650
276	Gibbs Cancer Center-Pelham	Greer	South Carolina	United States	29651
277	Lowcountry Hematology Oncology PA-Mount Pleasant	Mount Pleasant	South Carolina	United States	29464
278	Greenville Health System Cancer Institute-Seneca	Seneca	South Carolina	United States	29672
279	Spartanburg Medical Center	Spartanburg	South Carolina	United States	29303
280	Greenville Health System Cancer Institute-Spartanburg	Spartanburg	South Carolina	United States	29307
281	Wellmont Bristol Regional Medical Center	Bristol	Tennessee	United States	37620
282	Wellmont Medical Associates Oncology and Hematology-Johnson City	Johnson City	Tennessee	United States	37604
283	Wellmont Holston Valley Hospital and Medical Center	Kingsport	Tennessee	United States	37660
284	Wellmont Medical Associates Oncology and Hematology-Kingsport	Kingsport	Tennessee	United States	37660
285	The Don and Sybil Harrington Cancer Center	Amarillo	Texas	United States	79106
286	The Methodist Hospital System	Houston	Texas	United States	77030
287	Huntsman Cancer Institute/University of Utah	Salt Lake City	Utah	United States	84112
288	Southwest VA Regional Cancer Center	Norton	Virginia	United States	24273
289	PeaceHealth Saint John Medical Center	Longview	Washington	United States	98632
290	Swedish Medical Center-First Hill	Seattle	Washington	United States	98122-4307
291	PeaceHealth Southwest Medical Center	Vancouver	Washington	United States	98664
292	Rocky Mountain Oncology	Casper	Wyoming	United States	82609
293	Big Horn Basin Cancer Center	Cody	Wyoming	United States	82414
294	Billings Clinic-Cody	Cody	Wyoming	United States	82414
295	Welch Cancer Center	Sheridan	Wyoming	United States	82801

Sponsors and Collaborators

• National Cancer Institute (NCI)

Investigators

• Principal Investigator: Richard Kim, Southwest Oncology Group

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: National Cancer Institute (NCI)
• ClinicalTrials.gov Identifier: NCT02042443
• Other Study ID Numbers: NCI-2013-02485; NCI-2013-02485; S1310; SWOG-S1310; S1310; S1310; U10CA180888; U10CA032102
• First Posted: Jan 22, 2014
• Last Update Posted: Sep 12, 2017
• Last Verified: Aug 1, 2017

• Additional relevant MeSH terms: Carcinoma; Carcinoma, Hepatocellular; Liver Neoplasms; Cholangiocarcinoma; Gallbladder Neoplasms; Bile Duct Neoplasms; Klatskin Tumor; Carcinoma, Ductal; Recurrence; Calcium, Dietary; Leucovorin; Folic Acid; Fluorouracil; Capecitabine; Trametinib; Calcium; Levoleucovorin

Study Results

Participant Flow

Arm/Group Title	Trametinib	Chemotherapy
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Period Title: Overall Study
STARTED	27	26
Eligible and Analyzable	24	20
COMPLETED	0	0
NOT COMPLETED	27	26

Baseline Characteristics

Arm/Group Title	Trametinib	Chemotherapy	Total
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Total of all reporting groups
Overall Participants	24	20	44
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	63	61	62
Sex: Female, Male (Count of Participants)
Female	18 75%	11 55%	29 65.9%
Male	6 25%	9 45%	15 34.1%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	3 12.5%	1 5%	4 9.1%
Not Hispanic or Latino	20 83.3%	19 95%	39 88.6%
Unknown or Not Reported	1 4.2%	0 0%	1 2.3%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	2 8.3%	3 15%	5 11.4%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	5 20.8%	2 10%	7 15.9%
White	16 66.7%	15 75%	31 70.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	1 4.2%	0 0%	1 2.3%
Planned Chemotherapy (Count of Participants)
5FU/LV	7 29.2%	6 30%	13 29.5%
Capecitabine	17 70.8%	14 70%	31 70.5%
Site of Disease (Count of Participants)
Cholangiocarcinoma	19 79.2%	15 75%	34 77.3%
Gall bladder	5 20.8%	5 25%	10 22.7%

Outcome Measures

1. Primary Outcome

Title	Overall Survival
Description	From date of registration to date of death due to any cause. Patients last known to be alive are censored at date of last contact.
Time Frame	Up to 2 years from registration

Outcome Measure Data

Analysis Population Description

Eligible and analyzable patients.

Arm/Group Title	Trametinib	Chemotherapy
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	24	20
Median (95% Confidence Interval) [months]	4.3	7.9

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Trametinib, Chemotherapy
	Comments
	Type of Statistical Test	Superiority
	Comments
Statistical Test of Hypothesis	p-Value	0.05
	Comments
	Method	Log Rank
	Comments
Method of Estimation	Estimation Parameter	Hazard Ratio (HR)
	Estimated Value	2.02
	Confidence Interval	(2-Sided) 95%; 1.01 to 4.03
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Secondary Outcome

Title	Number of Patients With Grade 3 Through Grade 5 Adverse Events That Are Related to Study Drug
Description	Adverse event reporting followed the CTCAE (NCI Common Terminology Criteria for Adverse Events) Version 4.0. Only adverse events that are possibly, probably or definitely related to study drug are reported.
Time Frame	Up to 2 years

Outcome Measure Data

Analysis Population Description

Eligible patients who received any treatment and were assessed for adverse events are included in this summary. One patient was hospitalized prior to receiving protocol treatment and was not assessed for adverse events.

Arm/Group Title	Trametinib	Chemotherapy
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity	Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	23	20
Alanine aminotransferase increased	1 4.2%	0 0%
Anemia	1 4.2%	0 0%
Ascites	1 4.2%	0 0%
Aspartate aminotransferase increased	1 4.2%	0 0%
Blood bilirubin increased	1 4.2%	0 0%
Colitis	0 0%	1 5%
Fatigue	0 0%	1 5%
Gastric ulcer	1 4.2%	0 0%
Gastritis	1 4.2%	0 0%
Gastrointestinal disorders - Other, specify	1 4.2%	0 0%
Generalized muscle weakness	0 0%	1 5%
Hepatobiliary disorders - Other, specify	1 4.2%	0 0%
Hyponatremia	1 4.2%	1 5%
Infections and infestations - Other, specify	0 0%	1 5%
Mucositis oral	0 0%	1 5%
Neutrophil count decreased	0 0%	1 5%
Pain in extremity	0 0%	1 5%
Palmar-plantar erythrodysesthesia syndrome	0 0%	1 5%
Sepsis	1 4.2%	0 0%
Thromboembolic event	1 4.2%	0 0%
Urinary tract infection	1 4.2%	0 0%
Vomiting	1 4.2%	0 0%

3. Secondary Outcome

Title	Objective Response Rate
Description	Confirmed response (CR) is two or more objective statuses of CR a minimum of four weeks apart documented before progression or symptomatic deterioration. Partial response (PR) is two or more objective statuses of PR or better a minimum of four weeks apart documented before progression or symptomatic deterioration. Unconfirmed CR is one objective status of CR documented before progression or symptomatic deterioration but not qualifying as CR or PR. Unconfirmed PR is one objective status of PR documented before progression or symptomatic deterioration but not qualifying as CR, PR or unconfirmed CR.
Time Frame	Up to 2 years from registration

Outcome Measure Data

Analysis Population Description

All eligible and analyzable patients with measurable disease.

Arm/Group Title	Trametinib	Chemotherapy
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	24	20
Partial Response	0 0%	2 10%
Unconfirmed Partial Response	2 8.3%	0 0%
Stable/No Response	2 8.3%	9 45%
Increasing Disease	19 79.2%	8 40%
Symptomatic Deterioration	1 4.2%	1 5%

4. Secondary Outcome

Title	Progression-free Survival
Description	From date of registration to date of first documentation of progression or symptomatic deterioration, or death due to any cause. Patients last known to be alive and progression free are censored at date of last contact.
Time Frame	Up to 2 years from registration

Outcome Measure Data

Analysis Population Description

Eligible and analyzable patients.

Arm/Group Title	Trametinib	Chemotherapy
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.	Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
Measure Participants	24	20
Median (95% Confidence Interval) [months]	1.3	2.8

Adverse Events

Time Frame	Up to 2 years
Adverse Event Reporting Description	Eligible patients who received any treatment and were assessed for adverse events are included in the adverse event summaries. One patient was hospitalized prior to receiving protocol treatment and was not assessed for adverse events.
Arm/Group Title	Trametinib		Chemotherapy
Arm/Group Description	Patients receive trametinib PO QD on days 1-21. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.		Patients receive either A) leucovorin calcium IV over 2 hours and fluorouracil IV continuously over 46-48 hours on days 1 and 15. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity or B) capecitabine PO BID on days 1-14. Courses repeat every 21 days in the absence of disease progression or unacceptable toxicity.
All Cause Mortality
	Trametinib		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Trametinib		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/23 (56.5%)		1/20 (5%)
Blood and lymphatic system disorders
Anemia	1/23 (4.3%)		0/20 (0%)
Cardiac disorders
Cardiac arrest	1/23 (4.3%)		0/20 (0%)
Gastrointestinal disorders
Esophageal varices hemorrhage	1/23 (4.3%)		0/20 (0%)
Gastric hemorrhage	1/23 (4.3%)		0/20 (0%)
Gastric ulcer	1/23 (4.3%)		0/20 (0%)
Gastritis	1/23 (4.3%)		0/20 (0%)
Gastrointestinal disorders-Other	1/23 (4.3%)		0/20 (0%)
Obstruction gastric	1/23 (4.3%)		0/20 (0%)
General disorders
Fever	2/23 (8.7%)		0/20 (0%)
Hepatobiliary disorders
Hepatobiliary disorders-Other	1/23 (4.3%)		0/20 (0%)
Infections and infestations
Infections and infestations-Other	1/23 (4.3%)		0/20 (0%)
Sepsis	3/23 (13%)		0/20 (0%)
Investigations
Alanine aminotransferase increased	1/23 (4.3%)		0/20 (0%)
Aspartate aminotransferase increased	1/23 (4.3%)		0/20 (0%)
Blood bilirubin increased	1/23 (4.3%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Generalized muscle weakness	1/23 (4.3%)		0/20 (0%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasms benign, malignant and unspecified - Other	2/23 (8.7%)		1/20 (5%)
Nervous system disorders
Intracranial hemorrhage	1/23 (4.3%)		0/20 (0%)
Presyncope	1/23 (4.3%)		0/20 (0%)
Psychiatric disorders
Confusion	1/23 (4.3%)		0/20 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	1/23 (4.3%)		0/20 (0%)
Respiratory failure	1/23 (4.3%)		0/20 (0%)
Vascular disorders
Thromboembolic event	2/23 (8.7%)		0/20 (0%)
Other (Not Including Serious) Adverse Events
	Trametinib		Chemotherapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	21/23 (91.3%)		19/20 (95%)
Blood and lymphatic system disorders
Anemia	8/23 (34.8%)		8/20 (40%)
Ear and labyrinth disorders
Ear and labyrinth disorders-Other	0/23 (0%)		1/20 (5%)
Hearing impaired	0/23 (0%)		1/20 (5%)
Eye disorders
Dry eye	3/23 (13%)		2/20 (10%)
Watering eyes	0/23 (0%)		2/20 (10%)
Gastrointestinal disorders
Abdominal distension	0/23 (0%)		1/20 (5%)
Abdominal pain	7/23 (30.4%)		4/20 (20%)
Ascites	1/23 (4.3%)		1/20 (5%)
Bloating	1/23 (4.3%)		1/20 (5%)
Colitis	0/23 (0%)		1/20 (5%)
Constipation	6/23 (26.1%)		6/20 (30%)
Diarrhea	4/23 (17.4%)		7/20 (35%)
Dry mouth	2/23 (8.7%)		3/20 (15%)
Dyspepsia	1/23 (4.3%)		1/20 (5%)
Flatulence	1/23 (4.3%)		1/20 (5%)
Gastroesophageal reflux disease	1/23 (4.3%)		1/20 (5%)
Mucositis oral	1/23 (4.3%)		3/20 (15%)
Nausea	7/23 (30.4%)		8/20 (40%)
Vomiting	7/23 (30.4%)		5/20 (25%)
General disorders
Chills	4/23 (17.4%)		1/20 (5%)
Edema limbs	4/23 (17.4%)		4/20 (20%)
Fatigue	11/23 (47.8%)		11/20 (55%)
Fever	4/23 (17.4%)		4/20 (20%)
Irritability	0/23 (0%)		1/20 (5%)
Malaise	0/23 (0%)		1/20 (5%)
Non-cardiac chest pain	0/23 (0%)		1/20 (5%)
Pain	6/23 (26.1%)		6/20 (30%)
Infections and infestations
Infections and infestations-Other	1/23 (4.3%)		2/20 (10%)
Papulopustular rash	2/23 (8.7%)		1/20 (5%)
Paronychia	0/23 (0%)		1/20 (5%)
Rhinitis infective	0/23 (0%)		1/20 (5%)
Sepsis	0/23 (0%)		1/20 (5%)
Urinary tract infection	1/23 (4.3%)		1/20 (5%)
Injury, poisoning and procedural complications
Bruising	1/23 (4.3%)		1/20 (5%)
Fall	0/23 (0%)		3/20 (15%)
Investigations
Alanine aminotransferase increased	6/23 (26.1%)		0/20 (0%)
Alkaline phosphatase increased	6/23 (26.1%)		3/20 (15%)
Aspartate aminotransferase increased	8/23 (34.8%)		5/20 (25%)
Blood bilirubin increased	3/23 (13%)		5/20 (25%)
Creatinine increased	1/23 (4.3%)		4/20 (20%)
Investigations-Other	0/23 (0%)		2/20 (10%)
Lymphocyte count decreased	0/23 (0%)		3/20 (15%)
Neutrophil count decreased	1/23 (4.3%)		2/20 (10%)
Platelet count decreased	6/23 (26.1%)		6/20 (30%)
Weight loss	0/23 (0%)		2/20 (10%)
White blood cell decreased	1/23 (4.3%)		3/20 (15%)
Metabolism and nutrition disorders
Anorexia	5/23 (21.7%)		4/20 (20%)
Dehydration	1/23 (4.3%)		2/20 (10%)
Hypercalcemia	0/23 (0%)		2/20 (10%)
Hyperglycemia	3/23 (13%)		7/20 (35%)
Hyperkalemia	0/23 (0%)		1/20 (5%)
Hypermagnesemia	1/23 (4.3%)		1/20 (5%)
Hypoalbuminemia	7/23 (30.4%)		2/20 (10%)
Hypocalcemia	5/23 (21.7%)		1/20 (5%)
Hypoglycemia	0/23 (0%)		1/20 (5%)
Hypokalemia	2/23 (8.7%)		2/20 (10%)
Hypomagnesemia	4/23 (17.4%)		3/20 (15%)
Hyponatremia	2/23 (8.7%)		3/20 (15%)
Hypophosphatemia	2/23 (8.7%)		0/20 (0%)
Musculoskeletal and connective tissue disorders
Back pain	0/23 (0%)		1/20 (5%)
Generalized muscle weakness	0/23 (0%)		2/20 (10%)
Muscle weakness lower limb	1/23 (4.3%)		1/20 (5%)
Musculoskeletal and connective tiss disorder - Other	0/23 (0%)		1/20 (5%)
Myalgia	0/23 (0%)		1/20 (5%)
Pain in extremity	0/23 (0%)		4/20 (20%)
Nervous system disorders
Dizziness	3/23 (13%)		1/20 (5%)
Headache	0/23 (0%)		1/20 (5%)
Paresthesia	3/23 (13%)		0/20 (0%)
Peripheral motor neuropathy	0/23 (0%)		1/20 (5%)
Peripheral sensory neuropathy	1/23 (4.3%)		3/20 (15%)
Presyncope	0/23 (0%)		2/20 (10%)
Tremor	0/23 (0%)		1/20 (5%)
Psychiatric disorders
Anxiety	1/23 (4.3%)		2/20 (10%)
Confusion	0/23 (0%)		2/20 (10%)
Depression	1/23 (4.3%)		2/20 (10%)
Insomnia	0/23 (0%)		1/20 (5%)
Restlessness	0/23 (0%)		1/20 (5%)
Renal and urinary disorders
Chronic kidney disease	0/23 (0%)		1/20 (5%)
Urinary frequency	1/23 (4.3%)		1/20 (5%)
Urine discoloration	2/23 (8.7%)		2/20 (10%)
Reproductive system and breast disorders
Breast pain	0/23 (0%)		1/20 (5%)
Respiratory, thoracic and mediastinal disorders
Cough	5/23 (21.7%)		2/20 (10%)
Dyspnea	3/23 (13%)		4/20 (20%)
Epistaxis	3/23 (13%)		1/20 (5%)
Resp, thoracic and mediastinal disorders - Other	0/23 (0%)		1/20 (5%)
Skin and subcutaneous tissue disorders
Alopecia	2/23 (8.7%)		0/20 (0%)
Dry skin	4/23 (17.4%)		5/20 (25%)
Nail ridging	0/23 (0%)		1/20 (5%)
Palmar-plantar erythrodysesthesia syndrome	2/23 (8.7%)		8/20 (40%)
Pruritus	3/23 (13%)		1/20 (5%)
Rash acneiform	14/23 (60.9%)		1/20 (5%)
Skin and subcutaneous tissue disorders - Other	0/23 (0%)		3/20 (15%)
Skin hyperpigmentation	0/23 (0%)		2/20 (10%)
Skin ulceration	0/23 (0%)		1/20 (5%)
Vascular disorders
Hypertension	6/23 (26.1%)		3/20 (15%)
Hypotension	1/23 (4.3%)		3/20 (15%)

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.