HER2CLIMB: A Study of Tucatinib vs. Placebo in Combination With Capecitabine & Trastuzumab in Patients With Advanced HER2+ Breast Cancer

• Sponsor: Seagen Inc. (Industry)
• Overall Status: Active, not recruiting
• CT.gov ID: NCT02614794
• Collaborator: (none)
• Enrollment: 612
• Locations: 176
• Arms: 2
• Anticipated Duration (Months): 77.1
• Patients Per Site: 3.5
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

This study is being done to see if tucatinib works better than placebo to help patients who have a specific type of breast cancer called HER2 positive breast carcinoma. The breast cancer in this study is either metastatic (spread into other parts of the body) or cannot be removed completely with surgery. All patients in the study will get capecitabine and trastuzumab, two drugs that are often used to treat this cancer.

There are two parts to this study. The first part of the study is already complete. Patients were randomly assigned to get either tucatinib or placebo (a pill with no medicine). Since this part was "blinded," neither patients nor their doctors knew whether a patient got tucatinib or placebo.

The second part of the study is called the Unblinded Phase. In this part of the study, participants and their doctors know which drugs are being given. Participants who used to get or are currently getting placebo may be able to start taking tucatinib instead.

Each treatment cycle lasts 21 days. Patients will swallow tucatinib pills two times every day. They will swallow capecitabine pills two times a day during the first two weeks of each cycle. Patients will get trastuzumab injections from the study site staff on the first day of every cycle.

Condition or Disease	Intervention/Treatment	Phase
HER2 Positive Breast Cancer	Drug: tucatinib; Drug: capecitabine; Drug: trastuzumab; Drug: placebo	Phase 2

Detailed Description

This is a randomized, international, multi-center study in patients with progressive unresectable locally advanced or metastatic HER2+ breast cancer who have had prior treatment with trastuzumab, pertuzumab and T-DM1. There are two phases to this trial: the Double-blind Phase and the Unblinded Phase. In the Double-blind phase, participants were randomized in a 2:1 ratio to receive tucatinib or placebo in combination with capecitabine and trastuzumab. In the Unblinded Phase, patients on placebo may be offered tucatinib.

Stratification factors include presence or history of treated or untreated brain metastases or brain lesions of equivocal significance (yes/no), Eastern Cooperative Oncology Group (ECOG) Performance Status (0 vs. 1), and region of world (US vs. Canada vs. Rest of World).

Safety assessments will be performed at a minimum of once every three weeks throughout study treatment and 30 days after the last dose of study drugs. Laboratory assessments will be performed locally at sites. Left ventricular ejection fraction will be assessed by MUGA or ECHO at screening and once every 12 weeks thereafter.

For the blinded phase, contrast brain MRI was performed at baseline. Efficacy assessments (CT of chest, abdomen and pelvis at a minimum) utilized RECIST 1.1 and included patients with evaluable tumors defined as measurable target lesions and non-measurable non-target lesions. RECIST assessment was performed at baseline, every 6 weeks for the first 24 weeks, and then every 9 weeks thereafter. Repeat MRI of the brain was required on this same schedule only in those patients with brain metastases identified at baseline. All treatment decisions were made based upon investigator assessment. All patients underwent a repeat MRI of the brain within 30 days of the end of treatment unless previously performed at time of disease progression.

For the unblinded phase, RECIST assessments will be performed per standard clinical practice as determined by investigator with a maximum interval of 12 weeks.

Study Design

• Study Type: Interventional
• Actual Enrollment: 612 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Masking Description: Masking applied only during the Double-blind phase of the trial. The Unblinded Phase is open-label.
• Primary Purpose: Treatment
• Official Title: Phase 2 Randomized, Double-Blinded, Controlled Study of Tucatinib vs Placebo in Combination With Capecitabine and Trastuzumab in Patients With Pretreated Unresectable Locally Advanced or Metastatic HER2+ Breast Carcinoma
• Actual Study Start Date: Jan 28, 2016
• Actual Primary Completion Date: Sep 4, 2019
• Anticipated Study Completion Date: Jul 1, 2022

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Tucatinib in combination with capecitabine & trastuzumab Tucatinib + capecitabine + trastuzumab	Drug: tucatinib; 300 mg orally twice daily; Other Names: ONT-380, ARRY-380 ; Drug: capecitabine; 1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle; Other Names: Xeloda ; Drug: trastuzumab; 8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day1 of each 21-day cycle. In regions where approved, trastuzumab may be given at 600mg subcutaneously once every 3-weeks at either study initiation or crossing over from previous IV trastuzumab.; Other Names: Herceptin, Herceptin Hycleta
Active Comparator: Placebo in combination with capecitabine & trastuzumab Placebo + capecitabine + trastuzumab	Drug: capecitabine; 1000 mg/m2 orally twice daily on Days 1-14 of each 21-day cycle; Other Names: Xeloda ; Drug: trastuzumab; 8 mg/kg intravenously (IV) on Day 1 of Cycle 1, followed by 6 mg/kg on Day1 of each 21-day cycle. In regions where approved, trastuzumab may be given at 600mg subcutaneously once every 3-weeks at either study initiation or crossing over from previous IV trastuzumab.; Other Names: Herceptin, Herceptin Hycleta ; Drug: placebo; Oral dose twice daily

Outcome Measures

Primary Outcome Measures

1. Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR) [34.6 months]

   Defined as the time from the date of randomization to the date of documented disease progression.

Secondary Outcome Measures

1. PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR [34.6 months]

   Defined as the time from the date of randomization to the date of documented disease progression.

2. Overall Survival (OS) [35.9 months]

   Defined as time from randomization to death from any cause

3. Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR [34.6 months]

   Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR).

4. ORR Per RECIST 1.1 as Determined by Investigator Assessment [34.6 months]

   Defined as achieving a best overall response of confirmed CR or confirmed PR.

5. PFS Per RECIST 1.1 as Determined by Investigator Assessment [34.6 months]

   Defined as the time from the date of randomization to the date of documented disease progression

6. Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR [24.6 months]

   Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.

7. DOR Per RECIST 1.1 as Determined by Investigator Assessment [33.2 months]

   Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.

8. Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1 [34.6 months]

   Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR).

9. CBR Per RECIST 1.1 as Determined by Investigator Assessment [34.6 months]

   Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR.

10. Incidence of Adverse Events (AEs) [36.1 months]

    As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.

11. Frequency of Dose Modifications [35.1 months]

12. Incidence of Health Resources Utilization [36.1 months]

    Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire.

13. Pharmacokinetic Measure: Ctrough of Tucatinib [3.5 months]

    Individual plasma tucatinib concentrations at each sampling time

14. Pharmacokinetic Measure: ONT-993 [3.5 months]

    Individual plasma primary metabolite concentrations at each sampling time

Eligibility Criteria

Criteria

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

Double-blind Phase Inclusion Criteria

• Histologically confirmed HER2+ breast carcinoma, with HER2+ defined by in situ hybridization (ISH), immunohistochemistry (IHC), or fluorescence in situ hybridization (FISH) methodology

• Received previous treatment with trastuzumab, pertuzumab, and T-DM1

• Progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy

• Have measurable or non-measurable disease assessable by RECIST 1.1

• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 or 1

• Adequate hepatic and renal function and hematologic parameters

• Left ventricular ejection fraction (LVEF) ≥ 50%

• CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:

1. No evidence of brain metastases

2. Untreated brain metastases not needing immediate local therapy

3. Previously treated brain metastases not needing immediate local therapy

4. Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy

5. Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met:

1. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment, or time since surgical resection is ≥ 28 days.

1. Other sites of disease assessable by RECIST 1.1 are present

1. Relevant records of any CNS treatment must be available to allow for classification of target and non-target lesions

Double-blind Phase Exclusion Criteria

• Previously been treated with:

1. lapatinib within 12 months of starting study treatment (except in cases where lapatinib was given for ≤ 21 days and was discontinued for reasons other than disease progression or toxicity)

2. neratinib, afatinib, or other investigational HER2/epidermal growth factor receptor (EGFR) or HER2 tyrosine kinase inhibitor (TKI) at any time previously

3. capecitabine (or other fluoropyrimidine) for metastatic disease except in cases where capecitabine was given for < 21 days and was discontinued for reasons other than disease progression or toxicity. Patients who have received capecitabine for adjuvant or neoadjuvant treatment at least 12 months prior to starting study treatment are eligible.

• Clinically significant cardiopulmonary disease

• Carriers of Hepatitis B or Hepatitis C or have other known chronic liver disease

• Positive for human immunodeficiency virus (HIV)

• Unable for any reason to undergo MRI of the brain

• Have used a strong CYP3A4 or CYP2C8 inhibitor within 5 half-lives of the inhibitor, or a strong CYP3A4 or CYP2C8 inducer within 5 days prior to first dose of study treatment

• Have known dihydropyrimidine dehydrogenase deficiency (DPD)

• CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

1. Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor

2. Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)

3. Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria

4. Known or suspected leptomeningeal disease (LMD)

5. Poorly controlled seizures Unblinded Phase Crossover Inclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) must meet the following criteria to be eligible to crossover to the experimental arm.

• Have measurable or non-measurable disease assessable by RECIST 1.1

• For patients who were randomized to the control arm and on the long-term follow-up period at the time of crossover screening: have progression of unresectable locally advanced or metastatic breast cancer after last systemic therapy (as confirmed by investigator), or be intolerant of last systemic therapy.

• Have an ECOG Performance Status of 0 or 1

• Have a life expectancy of at least 6 months

• Have adequate hepatic and renal function and hematologic parameters

• Left ventricular ejection fraction (LVEF) ≥ 50%

• CNS Inclusion - Based on screening brain magnetic resonance imaging (MRI), patients must have one of the following:

1. No evidence of brain metastases ii. Untreated brain metastases not needing immediate local therapy iii. Previously treated brain metastases not needing immediate local therapy

• Brain metastases previously treated with local therapy may either be stable since treatment or may have progressed since prior local CNS therapy

• Patients treated with CNS local therapy for newly identified lesions found on contrast brain MRI performed during screening for this study may be eligible to enroll if the following criteria are met:

1. Time since whole brain radiation therapy (WBRT) is ≥ 21 days prior to first dose of study treatment, time since stereotactic radiosurgery (SRS) is ≥ 7 days prior to first dose of study treatment, or time since surgical resection is ≥ 28 days.

2. Other sites of disease assessable by RECIST 1.1 are present Unblinded Phase Crossover Exclusion Criteria - Participants who were randomized to the control arm (placebo + trastuzumab + capecitabine) will be excluded from the crossover to the experimental arm for any of the following reasons.

• Discontinuation of study treatment due to an adverse event while on the double-blind phase of the study. If the adverse event leading to discontinuation of study treatment has resolved, the patient may be allowed to crossover with approval from the medical monitor.

• History of exposure to the following cumulative doses of anthracyclines:

• Doxorubicin > 360 mg/m^2

• Epirubicin > 720 mg/m^2

• Mitoxantrone > 120 mg/m^2

• Idarubicin > 90 mg/m^2

• Liposomal doxorubicin > 550 mg/m^2

• History of allergic reactions to trastuzumab, capecitabine, or compounds chemically or biologically similar to tucatinib

o Exceptions for Grade 1 or 2 infusion related reactions to trastuzumab that were successfully managed, or known allergy to one of the excipients in the study drugs

• Have received treatment with any systemic anti-cancer therapy, non-CNS radiation, or experimental agent within 3 weeks prior to start of crossover therapy

• Any toxicity related to prior cancer therapies that has not resolved to ≤ Grade 1, with the following exceptions:

• Alopecia and neuropathy (must have resolved to ≤ Grade 2)

• CHF (must have been ≤ Grade 1 in severity at the time of occurrence and must have resolved completely)

• Anemia (must have resolved to ≤ Grade 2)

• Have clinically significant cardiopulmonary disease

• Have known myocardial infarction or unstable angina within 6 months prior to start of crossover therapy

• Require therapy with warfarin or other coumarin derivatives

• Inability to swallow pills or significant gastrointestinal disease which would preclude the adequate oral absorption of medications

• Have used a strong CYP2C8 inhibitor within 5 half-lives of the inhibitor or have used a strong CYP2C8 or CYP34A inducer within 5 days prior to start of the crossover (tucatinib) treatment.

• Known dihydropyrimidine dehydrogenase deficiency

• Unable to undergo contract MRI of the brain

• Have evidence within 2 years prior to start of crossover therapy of another malignancy that required systemic treatment

• CNS Exclusion:

• CNS Exclusion - Based on screening brain MRI, patients must not have any of the following:

• Any untreated brain lesions > 2.0 cm in size, unless approved by medical monitor

• Ongoing use of systemic corticosteroids for control of symptoms of brain metastases at a total daily dose of > 2 mg of dexamethasone (or equivalent)

• Any brain lesion thought to require immediate local therapy. Patients who undergo local treatment for such lesions identified by screening contrast brain MRI may still be eligible for the study based on criteria described under CNS inclusion criteria

• Known or suspected leptomeningeal disease (LMD)

• Poorly controlled seizures

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35249
2	University of South Alabama - Mitchell Cancer Institute	Mobile	Alabama	United States	36604
3	Cancer Treatment Centers of America - Phoenix	Goodyear	Arizona	United States	85338
4	Arizona Oncology Associates, PC - HAL	Phoenix	Arizona	United States	85016
5	City of Hope National Medical Center	Duarte	California	United States	91010-3000
6	TRIO - Central Regulatory Office	Los Angeles	California	United States	90095
7	UCLA Medical Center / David Geffen School of Medicine	Los Angeles	California	United States	90095
8	Torrance Memorial Physician Network - TRIO	Redondo Beach	California	United States	90277
9	University of California at San Francisco	San Francisco	California	United States	94134
10	Kaiser Permanente San Marcos Medical Offices	San Marcos	California	United States	92078
11	Central Coast Medical Oncology Corporation TRIO	Santa Maria	California	United States	93454
12	Kaiser Permanente Medical Center Northern California	Vallejo	California	United States	94589
13	University of Colorado Hospital / University of Colorado	Aurora	Colorado	United States	80045-0510
14	Yale Cancer Center	New Haven	Connecticut	United States	06520
15	Lombardi Cancer Center / Georgetown University Medical Center	Washington	District of Columbia	United States	20007
16	Florida Cancer Specialists - South Region	Fort Myers	Florida	United States	33901
17	Memorial Regional Hospital TRIO	Hollywood	Florida	United States	33021
18	Baptist MD Anderson Cancer Center	Jacksonville	Florida	United States	32207
19	Mount Sinai Medical Center / Florida	Miami Beach	Florida	United States	33140
20	University of Miami	Miami	Florida	United States	33136
21	Orlando Health, Inc. TRIO	Orlando	Florida	United States	32806
22	Florida Cancer Specialists - North Region	Saint Petersburg	Florida	United States	33705
23	H. Lee Moffitt Cancer Center and Research Institute	Tampa	Florida	United States	33612
24	Florida Cancer Specialists - East West Palm Beach, FL (SCRI)	West Palm Beach	Florida	United States	33401
25	Winship Cancer Institute / Emory University School of Medicine	Atlanta	Georgia	United States	30322
26	Northside Hospital	Atlanta	Georgia	United States	30342
27	Augusta University	Augusta	Georgia	United States	30912
28	Cancer Treatment Centers of America	Newnan	Georgia	United States	30265
29	Rush University Medical Center	Chicago	Illinois	United States	60612
30	University of Chicago	Chicago	Illinois	United States	60637-1470
31	Illinois Cancer Specialists / Advocate Lutheran General Hospital	Niles	Illinois	United States	60714
32	Carle Cancer Center	Urbana	Illinois	United States	61801
33	University of Kansas Cancer Center	Westwood	Kansas	United States	66205
34	University of Maryland	Baltimore	Maryland	United States	21201
35	Maryland Oncology Hematology, P.A.	Rockville	Maryland	United States	20850
36	Dana Farber Cancer Institute	Boston	Massachusetts	United States	02215
37	Henry Ford Health System	Detroit	Michigan	United States	48202
38	William Beaumont Hospital	Royal Oak	Michigan	United States	48073
39	Virginia Piper Cancer Institute	Minneapolis	Minnesota	United States	55407
40	Saint Luke's Cancer Institute LLC	Kansas City	Missouri	United States	64113
41	Nebraska Cancer Specialists	Omaha	Nebraska	United States	68130
42	Dartmouth-Hitchcock Medical Center/ Norris Cotton Cancer Center	Lebanon	New Hampshire	United States	03756
43	Hackensack University Medical Center	Hackensack	New Jersey	United States	07601
44	Montefiore Medical Center	Bronx	New York	United States	10467
45	Mount Sinai Beth Israel	New York	New York	United States	10003
46	New York University (NYU) Cancer Institute	New York	New York	United States	10016
47	Stony Brook University Cancer Center	Stony Brook	New York	United States	11794
48	UNC Lineberger Comprehensive Cancer Center / University of North Carolina	Chapel Hill	North Carolina	United States	27599
49	Duke University Medical Center	Durham	North Carolina	United States	27710
50	Leo W. Jenkins Cancer Services / Brody School of Medicine East Carolina University	Greenville	North Carolina	United States	27834
51	James Cancer Hospital / Ohio State University	Columbus	Ohio	United States	43210
52	Providence Portland Medical Center	Portland	Oregon	United States	97213
53	Oregon Health and Science University	Portland	Oregon	United States	97239-3098
54	Northwest Cancer Specialists, P.C.	Tualatin	Oregon	United States	97062
55	University of Pennsylvania / Perelman Center for Advanced Medicine	Philadelphia	Pennsylvania	United States	19104
56	Cancer Treatment Centers of America / Eastern Regional Medical Center	Philadelphia	Pennsylvania	United States	19124
57	Roper St. Francis Healthcare	Charleston	South Carolina	United States	29414
58	Medical University of South Carolina/Hollings Cancer Center	Charleston	South Carolina	United States	29425
59	Wellmont Cancer Institute	Kingsport	Tennessee	United States	37660
60	Tennessee Oncology - Nashville	Nashville	Tennessee	United States	37203
61	Vanderbilt University Medical Center	Nashville	Tennessee	United States	37204
62	Texas Oncology - Austin Midtown	Austin	Texas	United States	78705
63	Texas Oncology Methodist	Dallas	Texas	United States	75203
64	Texas Oncology - Denton South	Denton	Texas	United States	76210
65	The Center for Cancer and Blood Disorders: Fortworth	Fort Worth	Texas	United States	76104
66	Texas Oncology - Houston Memorial City	Houston	Texas	United States	77024
67	MD Anderson Cancer Center / University of Texas	Houston	Texas	United States	77030-4095
68	Baylor Clinic	Houston	Texas	United States	77030
69	Joe Arrington Cancer Research and Treatment Center	Lubbock	Texas	United States	79410
70	Paris Regional Medical Center / US Oncology	Paris	Texas	United States	75460
71	Texas Oncology - Plano East	Plano	Texas	United States	75075
72	Texas Oncology - San Antonio Medical Center Northeast	San Antonio	Texas	United States	78212
73	University of Texas Health Science Center at San Antonio	San Antonio	Texas	United States	78229
74	US Oncology Central Regulatory	The Woodlands	Texas	United States	77380
75	Texas Oncology - Deke Slayton Cancer Center	Webster	Texas	United States	77598
76	University of Utah	Salt Lake City	Utah	United States	84112
77	Virginia Cancer Specialists, PC	Fairfax	Virginia	United States	22031
78	Shenandoah Oncology P.C.	Winchester	Virginia	United States	22601
79	Swedish Cancer Institute	Seattle	Washington	United States	98104
80	Seattle Cancer Care Alliance / University of Washington	Seattle	Washington	United States	98109-1023
81	Carbone Cancer Center / University of Wisconsin	Madison	Wisconsin	United States	53792
82	Austin Hospital	Heidelberg		Australia	3084
83	Cabrini Education and Research Precinct	Malvern		Australia	3144
84	Peter MacCallum Cancer Centre	Melbourne		Australia	3000
85	Breast Cancer Research Centre	Nedlands		Australia	6009
86	Mater Hospital	North Sydney		Australia	2060
87	Icon Cancer Care South Brisbane	South Brisbane		Australia	4101
88	Mater Health Services	South Brisbane		Australia	4101
89	Sunshine Hospital	St Albans		Australia	3021
90	Westmead Hospital	Westmead		Australia	2145
91	LKH- Universitat Klinikum Graz	Graz		Austria	8036
92	Medizinische Universitat Innsbruck	Innsbruck		Austria	6020
93	KH d. Barmherzigen Schwestern Linz	Linz		Austria	4010
94	LKH Salzburg, Universitatsklinikum der PMU	Salzburg		Austria	5020
95	AZ Klina	Brasschaat		Belgium	2930
96	Cliniques Universitaires Saint Luc	Brussels		Belgium	1200
97	Grand Hopital de Charleroi	Charleroi		Belgium	6000
98	Centre Hospitalier de l'Ardenne	Libramont		Belgium	6800
99	CHU UCL Namur-Site de Saint Elisabeth	Namur		Belgium	5000
100	Tom Baker Cancer Centre	Calgary		Canada	T2N 4N2
101	University of Alberta / Cross Cancer Institute	Edmonton		Canada	T6G 1Z2
102	Queen Elizabeth II Health Sciences Centre	Halifax		Canada	B3H 2Y9
103	Jewish General Hospital	Montreal		Canada	H3T 1E2
104	Hopital du Saint-Sacrement, CHU de Quebec-Universite Laval	Quebec		Canada	G1S 4L8
105	Allan Blair Cancer Centre	Regina		Canada	S4T7T1
106	Saskatoon Cancer Centre	Saskatoon		Canada	S7N 4H4
107	H. Bliss Murphy Cancer Centre	St John's		Canada	A1B 3V6
108	Sunnybrook Health Sciences Centre	Toronto		Canada	M4N 3M5
109	University Health Network, Princess Margaret Hospital	Toronto		Canada	M5G 2M9
110	British Columbia Cancer Agency - Vancouver Centre	Vancouver		Canada	V5Z 4E6
111	Fakultni nemocnice Hradec Kralove-oddeleni klinicke hematologie	Hradec Kralove		Czechia	500 05
112	Fakultni Nemocnice Olomouc (Fnol) - Onkologicka Klinika	Olomouc		Czechia	77520
113	Aalborg Universitetshospital	Aalborg		Denmark	9100
114	Rigs Hospiltalet	Copenhagen		Denmark	DK 2100
115	Herlev Hospital	Herlev		Denmark	2730
116	Odense University Hospital	Odense C		Denmark	5000
117	Sygehus Lillebaelt - Vejle Sygehus	Vejle		Denmark	7100
118	University Hospital of Besancon	Besancon cedex		France	25030
119	Clinique Victor Hugo	Le Mans		France	72000
120	Centre Leon Berard - Centre regional de lutte contre le cancer Rhone-Alpes	Lyon		France	69373
121	Institut Paoli Calmettes	Marseille		France	13273
122	Institute Curie - Centre de Lutte Contre Le Cancer CLCC de Paris	Paris		France	75005
123	Centre Hospitalier Lyon Sud	Pierre Bénite Cedex		France	69495
124	Institut Jean Godinot	REIMS Cedex		France	51056
125	Centre Eugene Marquis	Rennes Cedex		France	35042
126	Hopitaux Universitaires de Strasbourg	Strasbourg		France	67200
127	Institut Claudius Regaud	Toulouse Cedex 9		France	31059
128	CHU Tours - Hopital Bretonneau	TOURS Cedex 09		France	37044
129	Charite Universitatsmedizin Berlin	Berlin		Germany	10117
130	Kliniken Essen-Mitte - Evang. Huyssens-Stiftung	Essen		Germany	45136
131	Universitaetsklinikum Hamburg-Eppendorf (UKE) - Onkologisches Zentrum - Interdisziplinaere Klinik und Poliklinik fuer Stammzelltransplantation	Hamburg		Germany	20246
132	Medizinische Hochschule Hannover	Hannover		Germany	30625
133	Universitatsklinikum Schleswig-Holstein	Kiel		Germany	24105
134	InVO- Institut fUr Versorgungsforschung in der onkologie GbR	Koblenz		Germany	56068
135	Universitatsklinikum Koln	Köln		Germany	50937
136	HOPE- Onkologisches Zentrum Rotkreuzklinikum	Munchen		Germany	80639
137	Sana Klinikum Offenbach GmbH	Offenbach am Main		Germany	63069
138	Rambam Health Corp.	Haifa		Israel	31096
139	Hadassah Medical Center	Jerusalem		Israel	91120
140	Meir Medical Center	Kfar Saba		Israel	44281
141	Rabin Medical Center	Petach Tikva		Israel	49414
142	Kaplan Medical Center	Rehovot		Israel	76100
143	Tel Aviv Sourasky Medical Center	Tel Aviv		Israel	64239
144	Sheba Medical Center	Tel Hashomer		Israel	52621
145	Azienda Ospedaliero-Universitaria di Bologna Policlinico S. Orsola-Malpighi	Bologna		Italy	40138
146	Ospedale di Bolzano	Bolzano		Italy	39100
147	Presido Ospedaliero- Senatore Antonio Perrino	Brindisi		Italy	72100
148	Ospedale Ramazzini di Carpi	Carpi		Italy	41012
149	Ospedale Policlinico San Martino	Genova		Italy	16132
150	Istituto Europeo di Oncologia	Milano		Italy	20141
151	IRCSS Policlinico San Matteo	Pavia		Italy	27100
152	Azienda Ospedaliera S. Maria di Terni	Terni		Italy	05100
153	A.O.U. - Ospedali Riuniti di Ancona	Torrette		Italy	60126
154	Hospital Cuf Descobertas R. Mario Botas Parque das Nacoes	Lisboa		Portugal	1998-018
155	Centro Hospitalar do Porto - Hospital Santo Antonio	Porto		Portugal	4099-001
156	Hospital Universitario Vall d'Hebron	Barcelona		Spain	08035
157	Hospital Clinic i Provincial de Barcelona	Barcelona		Spain	08036
158	Hospital San Pedro de Alcantara	Caceres		Spain	10002
159	Complejo Asistencial Universitario de Leon	Leon		Spain	24008
160	Hospital General Universitario Gregorio Marañon	Madrid		Spain	28007
161	Hospital Universitario 12 de Octubre	Madrid		Spain	28041
162	Hospital Son Espases	Palma de Mallorca		Spain	07010
163	Hospital Clinico Univ De Santiago De Compostela	Santiago de Compostela		Spain	15706
164	Hospital Arnau De Vilanova	Valencia		Spain	46015
165	Hospital Clinico Universitario Lozano Blesa de Zaragoza	Zaragoza		Spain	50009
166	Institute of Oncology of Southern Switzerland	Bellinzona		Switzerland	6500
167	Colchester Hospital University NHS Foundation Trust	Colchester		United Kingdom	C04 5JL
168	The Royal Marsden Hospital	London		United Kingdom	SW3 6JJ
169	Sarah Cannon Research Institute UK	London		United Kingdom	W1G 6AD
170	The Christie NHS Foundation Trust	Manchester		United Kingdom	M20 4BX
171	Mount Vernon Hospital, UK	Northwood		United Kingdom	HA6 2RN
172	Nottingham University Hospitals NHS Trust	Nottingham		United Kingdom	NG5 1PD
173	Peterborough City Hospital	Peterborough		United Kingdom	PE3 9GZ
174	Weston Park Hospital- UK	Sheffield		United Kingdom	S10 2SJ
175	The Royal Marsden Hospital (Surrey)	Sutton		United Kingdom	SM2 5PT
176	Royal Cornwall Hospitals NHS Trust	Truro		United Kingdom	TR1 3LQ

Sponsors and Collaborators

• Seagen Inc.

Investigators

• Study Director: Jorge Ramos, DO, Seagen Inc.
• Study Director: Corinna Palanca-Wessels, MD, PhD, Seagen Inc.

Study Documents (Full-Text)

• Study Protocol - Mar 25, 2019
• Statistical Analysis Plan - Aug 7, 2019

More Information

Publications

None provided.

• Responsible Party: Seagen Inc.
• ClinicalTrials.gov Identifier: NCT02614794
• Other Study ID Numbers: ONT-380-206; 2015-002801-12
• First Posted: Nov 25, 2015
• Last Update Posted: Jun 22, 2022
• Last Verified: May 1, 2022

• Keywords provided by Seagen Inc.: Tucatinib; Capecitabine; Trastuzumab; Xeloda; Herceptin; Breast Cancer; ARRY-380; ONT-380; HER2 Positive Breast Carcinoma; HER2 Positive Locally Advanced Breast Cancer; HER-2 Positive Breast Cancer; HER-2 Positive Breast Carcinoma; HER-2 Positive Locally Advanced Breast Cancer; Recurrent Breast Carcinoma; Stage IV Breast Cancer; Metastatic Breast Cancer; Breast Carcinoma; Metastatic Malignant Neoplasm in the Brain; Brain Metastases in Breast Cancer; Asymptomatic Brain Metastases in Breast Cancer; Low Symptomatic Brain Metastases in Breast Cancer; Seattle Genetics
• Additional relevant MeSH terms: Breast Neoplasms; Capecitabine; Trastuzumab; Tucatinib

Study Results

Participant Flow

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Period Title: Overall Study
STARTED	410	202
COMPLETED	0	0
NOT COMPLETED	410	202

Baseline Characteristics

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra	Total
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab	Total of all reporting groups
Overall Participants	410	202	612
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%
Between 18 and 65 years	328 80%	168 83.2%	496 81%
>=65 years	82 20%	34 16.8%	116 19%
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	54	54
Sex: Female, Male (Count of Participants)
Female	407 99.3%	200 99%	607 99.2%
Male	3 0.7%	2 1%	5 0.8%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	37 9%	14 6.9%	51 8.3%
Not Hispanic or Latino	362 88.3%	184 91.1%	546 89.2%
Unknown or Not Reported	11 2.7%	4 2%	15 2.5%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	18 4.4%	5 2.5%	23 3.8%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	41 10%	14 6.9%	55 9%
White	287 70%	157 77.7%	444 72.5%
More than one race	0 0%	0 0%	0 0%
Unknown or Not Reported	64 15.6%	26 12.9%	90 14.7%
Region of Enrollment (Count of Participants)
United States	220 53.7%	111 55%	331 54.1%
France	29 7.1%	17 8.4%	46 7.5%
United Kingdom	33 8%	12 5.9%	45 7.4%
Australia	27 6.6%	12 5.9%	39 6.4%
Canada	26 6.3%	12 5.9%	38 6.2%
Spain	19 4.6%	7 3.5%	26 4.2%
Denmark	13 3.2%	7 3.5%	20 3.3%
Germany	9 2.2%	8 4%	17 2.8%
Israel	13 3.2%	3 1.5%	16 2.6%
Belgium	4 1%	6 3%	10 1.6%
Italy	6 1.5%	3 1.5%	9 1.5%
Austria	6 1.5%	1 0.5%	7 1.1%
Portugal	3 0.7%	1 0.5%	4 0.7%
Czech Republic	2 0.5%	1 0.5%	3 0.5%
Switzerland	0 0%	1 0.5%	1 0.2%
Eastern Cooperative Oncology Group (ECOG) Performance Status (Count of Participants)
0: Normal activity	204 49.8%	94 46.5%	298 48.7%
1: Symptoms, but ambulatory	206 50.2%	108 53.5%	314 51.3%

Outcome Measures

1. Primary Outcome

Title	Progression-free Survival (PFS) Per RECIST 1.1 as Determined by Blinded Independent Central Review (BICR)
Description	Defined as the time from the date of randomization to the date of documented disease progression.
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

Intent-to-treat Progression Free Survival (ITT-PFS) Population: Includes the first 480 randomized participants in the ITT analysis population (evaluated by their random treatment assignment).

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	320	160
Median (Inter-Quartile Range) [months]	7.8	5.6

2. Secondary Outcome

Title	PFS in Patients With Brain Metastases at Baseline Using RECIST 1.1 as Determined by BICR
Description	Defined as the time from the date of randomization to the date of documented disease progression.
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

ITT-PFSBrainMets population: included all randomized subjects with brain metastases (evaluated by their random treatment assignment).

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	198	93
Median (Inter-Quartile Range) [months]	7.6	5.4

3. Secondary Outcome

Title	Overall Survival (OS)
Description	Defined as time from randomization to death from any cause
Time Frame	35.9 months

Outcome Measure Data

Analysis Population Description

ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	410	202
Median (95% Confidence Interval) [months]	21.9	17.4

4. Secondary Outcome

Title	Confirmed Objective Response Rate (ORR) Per RECIST 1.1 as Determined by BICR
Description	Defined as achieving a best overall response of confirmed complete response (CR) or confirmed partial response (PR).
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

ITT - PFS population, subset of participants with measurable disease by BICR at baseline. The ITT-PFS Population includes the first 480 randomized participants in the ITT analysis population (evaluated by their randomized treatment assignment).

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	273	137
Number (95% Confidence Interval) [percentage of participants]	40.7 9.9%	23.4 11.6%

5. Secondary Outcome

Title	ORR Per RECIST 1.1 as Determined by Investigator Assessment
Description	Defined as achieving a best overall response of confirmed CR or confirmed PR.
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

ITT - PFS population, subset of participants with measurable disease by investigator at baseline. The ITT-PFS Population includes the first 480 randomized participants in the ITT analysis population (evaluated by their randomized treatment assignment).

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	280	139
Number (95% Confidence Interval) [percentage of participants]	41.4 10.1%	23.0 11.4%

6. Secondary Outcome

Title	PFS Per RECIST 1.1 as Determined by Investigator Assessment
Description	Defined as the time from the date of randomization to the date of documented disease progression
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

ITT-PFS Population: Includes the first 480 randomized participants in the ITT analysis population (evaluated by their randomized treatment assignment).

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	320	160
Median (Inter-Quartile Range) [months]	7.5	4.3

7. Secondary Outcome

Title	Duration of Response (DOR) Per RECIST 1.1 as Determined by BICR
Description	Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.
Time Frame	24.6 months

Outcome Measure Data

Analysis Population Description

ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	410	202
Median (Inter-Quartile Range) [months]	8.3	6.3

8. Secondary Outcome

Title	DOR Per RECIST 1.1 as Determined by Investigator Assessment
Description	Defined as the time from the first objective response to documented disease progression or death from any cause, whichever occurred first.
Time Frame	33.2 months

Outcome Measure Data

Analysis Population Description

ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	410	202
Median (Inter-Quartile Range) [months]	7.0	6.9

9. Secondary Outcome

Title	Clinical Benefit Rate (CBR) as Determined by BICR Per RECIST 1.1
Description	Clinical benefit was defined as achieving stable disease (SD) or non-complete response (CR)/non-progressive disease (PD) for at least 6 months or a best overall response of confirmed CR or confirmed partial response (PR).
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	410	202
Number (95% Confidence Interval) [percentage of participants]	59.8 14.6%	38.1 18.9%

10. Secondary Outcome

Title	CBR Per RECIST 1.1 as Determined by Investigator Assessment
Description	Clinical benefit was defined as achieving stable disease (SD) or non-CR/non-PD for at least 6 months or a best overall response of confirmed CR or confirmed PR.
Time Frame	34.6 months

Outcome Measure Data

Analysis Population Description

ITT-OS Population: Includes all randomized participants evaluated by their randomized treatment assignment.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	410	202
Number (95% Confidence Interval) [percentage of participants]	58.0 14.1%	37.6 18.6%

11. Secondary Outcome

Title	Incidence of Adverse Events (AEs)
Description	As determined by assessment of AEs, clinical laboratory tests, and vital signs measurements. AEs were classified by system organ class (SOC) and preferred term using the Medical Dictionary for Regulatory Activities (MedDRA) Version 22.0 or higher; AE severities were classified using Version 4.03 of the (Common Terminology Criteria for Adverse Events) CTCAE criteria.
Time Frame	36.1 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	404	197
Any treatment-emergent AE (TEAE)	401 97.8%	191 94.6%
Any Grade 3 or higher TEAE	223 54.4%	96 47.5%
Any treatment-emergent serious AE	104 25.4%	53 26.2%
TEAE leading to death	8 2%	6 3%

12. Secondary Outcome

Title	Frequency of Dose Modifications
Time Frame	35.1 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	404	197
TEAEs resulting in tuc/pbo dose modification	220 53.7%	81 40.1%
TEAEs resulting in tucatinib/placebo dose hold	216 52.7%	80 39.6%
TEAEs resulting in tuc/pbo dose reduction	84 20.5%	21 10.4%
TEAEs resulting capecitabine dose modification	313 76.3%	122 60.4%
TEAEs resulting in capecitabine dose hold	276 67.3%	113 55.9%
TEAEs resulting in capecitabine dose reduction	243 59.3%	77 38.1%
TEAEs resulting trastuzumab dose modification	104 25.4%	38 18.8%
TEAEs resulting in trastuzumab dose hold	104 25.4%	38 18.8%

13. Secondary Outcome

Title	Incidence of Health Resources Utilization
Description	Cumulative incidence of health resource utilization, including length of stay, hospitalizations, and ER visits using the EQ-5D-5L questionnaire.
Time Frame	36.1 months

Outcome Measure Data

Analysis Population Description

Safety Analysis Population: Includes all randomized participants who received at least one dose of study treatment (tucatinib/placebo, trastuzumab, or capecitabine), with participants allocated to the treatment group associated with the regimen actually received.

Arm/Group Title	Tuc+Cap+Tra	Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab	Placebo in combination with capecitabine & trastuzumab
Measure Participants	404	197
Total number of hospitalizations	143	75
Hospitalization for AE	124	64
Planned hospitalization (other than AE)	10	6
Ambulatory Surgery	3	0
Other	6	5

14. Secondary Outcome

Title	Pharmacokinetic Measure: Ctrough of Tucatinib
Description	Individual plasma tucatinib concentrations at each sampling time
Time Frame	3.5 months

Outcome Measure Data

Analysis Population Description

Pharmacokinetics (PK) Analysis Set: Includes all randomized participants who received at least one dose of tucatinib and who had at least one evaluable PK assessment. Participants were evaluated by the treatment actually received.

Arm/Group Title	Tuc+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab
Measure Participants	373
Cycle 2, Day 1 (Pre-dose)	246.1 (260.9)
Cycle 3, Day 1 (Pre-dose)	227.6 (210.8)
Cycle 3, Day 1 (Post-dose)	507.1 (357.1)
Cycle 4, Day 1 (Pre-dose)	253.2 (236.1)
Cycle 5, Day 1 (Pre-dose)	257.6 (286.9)
Cycle 6, Day 1 (Pre-dose)	247.8 (225.1)

15. Secondary Outcome

Title	Pharmacokinetic Measure: ONT-993
Description	Individual plasma primary metabolite concentrations at each sampling time
Time Frame	3.5 months

Outcome Measure Data

Analysis Population Description

PK Analysis Set: Includes all randomized participants who received at least one dose of tucatinib and who had at least one evaluable PK assessment. Participants were evaluated by the treatment actually received.

Arm/Group Title	Tuc+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab
Measure Participants	373
Cycle 2, Day 1 (Pre-dose)	25.5 (24.4)
Cycle 3, Day 1 (Pre-dose)	22.6 (20.6)
Cycle 3, Day 1 (Post-dose)	47.7 (47.2)
Cycle 4, Day 1 (Pre-dose)	25.2 (24.3)
Cycle 5, Day 1 (Pre-dose)	24.5 (30.6)
Cycle 6, Day 1 (Pre-dose)	20.9 (18.0)

Adverse Events

Time Frame	36.1 months
Arm/Group Title	Tuc+Cap+Tra		Pbo+Cap+Tra
Arm/Group Description	Tucatinib in combination with capecitabine & trastuzumab		Placebo in combination with capecitabine & trastuzumab
All Cause Mortality
	Tuc+Cap+Tra		Pbo+Cap+Tra
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	130/410 (31.7%)		85/202 (42.1%)
Serious Adverse Events
	Tuc+Cap+Tra		Pbo+Cap+Tra
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	104/404 (25.7%)		53/197 (26.9%)
Blood and lymphatic system disorders
Neutropenia	2/404 (0.5%)		0/197 (0%)
Anaemia	1/404 (0.2%)		0/197 (0%)
Febrile neutropenia	1/404 (0.2%)		0/197 (0%)
Thrombocytopenia	1/404 (0.2%)		0/197 (0%)
Cardiac disorders
Cardiac failure	2/404 (0.5%)		1/197 (0.5%)
Atrial fibrillation	1/404 (0.2%)		0/197 (0%)
Cardiac arrest	1/404 (0.2%)		1/197 (0.5%)
Cardiovascular disorder	1/404 (0.2%)		0/197 (0%)
Pericardial effusion	1/404 (0.2%)		2/197 (1%)
Acute coronary syndrome	0/404 (0%)		1/197 (0.5%)
Myocardial infarction	0/404 (0%)		1/197 (0.5%)
Eye disorders
Diplopia	1/404 (0.2%)		0/197 (0%)
Optic neuropathy	1/404 (0.2%)		0/197 (0%)
Gastrointestinal disorders
Diarrhoea	16/404 (4%)		7/197 (3.6%)
Vomiting	10/404 (2.5%)		5/197 (2.5%)
Nausea	8/404 (2%)		3/197 (1.5%)
Abdominal pain	4/404 (1%)		0/197 (0%)
Abdominal pain upper	3/404 (0.7%)		0/197 (0%)
Constipation	2/404 (0.5%)		2/197 (1%)
Abdominal distension	1/404 (0.2%)		0/197 (0%)
Abdominal pain lower	1/404 (0.2%)		0/197 (0%)
Gastrointestinal haemorrhage	1/404 (0.2%)		0/197 (0%)
Intestinal perforation	1/404 (0.2%)		0/197 (0%)
Pancreatitis	1/404 (0.2%)		0/197 (0%)
Small intestinal obstruction	1/404 (0.2%)		2/197 (1%)
Stomatitis	1/404 (0.2%)		0/197 (0%)
Ascites	0/404 (0%)		1/197 (0.5%)
Enteritis	0/404 (0%)		1/197 (0.5%)
Enterocolitis	0/404 (0%)		2/197 (1%)
Oesophageal varices haemorrhage	0/404 (0%)		2/197 (1%)
General disorders
Fatigue	3/404 (0.7%)		2/197 (1%)
Sudden death	2/404 (0.5%)		0/197 (0%)
General physical health deterioration	1/404 (0.2%)		0/197 (0%)
Multiple organ dysfunction syndrome	1/404 (0.2%)		1/197 (0.5%)
Non-cardiac chest pain	1/404 (0.2%)		0/197 (0%)
Pyrexia	1/404 (0.2%)		1/197 (0.5%)
Oedema peripheral	0/404 (0%)		1/197 (0.5%)
Pain	0/404 (0%)		1/197 (0.5%)
Systemic inflammatory response syndrome	0/404 (0%)		1/197 (0.5%)
Hepatobiliary disorders
Cholecystitis	2/404 (0.5%)		0/197 (0%)
Hyperbilirubinaemia	1/404 (0.2%)		0/197 (0%)
Infections and infestations
Pneumonia	4/404 (1%)		2/197 (1%)
Sepsis	4/404 (1%)		1/197 (0.5%)
Gastroenteritis	3/404 (0.7%)		1/197 (0.5%)
Upper respiratory tract infection	2/404 (0.5%)		1/197 (0.5%)
Anal abscess	1/404 (0.2%)		0/197 (0%)
Cellulitis	1/404 (0.2%)		1/197 (0.5%)
Clostridium difficile colitis	1/404 (0.2%)		2/197 (1%)
Infected skin ulcer	1/404 (0.2%)		0/197 (0%)
Influenza	1/404 (0.2%)		1/197 (0.5%)
Lung infection	1/404 (0.2%)		0/197 (0%)
Oesophageal candidiasis	1/404 (0.2%)		0/197 (0%)
Oral candidiasis	1/404 (0.2%)		0/197 (0%)
Peritonitis	1/404 (0.2%)		0/197 (0%)
Septic shock	1/404 (0.2%)		0/197 (0%)
Soft tissue infection	1/404 (0.2%)		0/197 (0%)
Urinary tract infection	1/404 (0.2%)		0/197 (0%)
Gastroenteritis viral	0/404 (0%)		1/197 (0.5%)
Klebsiella sepsis	0/404 (0%)		1/197 (0.5%)
Large intestine infection	0/404 (0%)		1/197 (0.5%)
Respiratory tract infection viral	0/404 (0%)		1/197 (0.5%)
Urosepsis	0/404 (0%)		1/197 (0.5%)
Injury, poisoning and procedural complications
Fall	2/404 (0.5%)		0/197 (0%)
Spinal fracture	2/404 (0.5%)		0/197 (0%)
Ankle fracture	1/404 (0.2%)		0/197 (0%)
Foot fracture	1/404 (0.2%)		0/197 (0%)
Patella fracture	1/404 (0.2%)		0/197 (0%)
Radius fracture	1/404 (0.2%)		0/197 (0%)
Spinal compression fracture	1/404 (0.2%)		0/197 (0%)
Sternal fracture	1/404 (0.2%)		0/197 (0%)
Investigations
Ejection fraction decreased	5/404 (1.2%)		2/197 (1%)
Blood bilirubin increased	1/404 (0.2%)		1/197 (0.5%)
White blood cell count decreased	1/404 (0.2%)		0/197 (0%)
Electrocardiogram QT prolonged	0/404 (0%)		1/197 (0.5%)
Metabolism and nutrition disorders
Dehydration	4/404 (1%)		0/197 (0%)
Decreased appetite	1/404 (0.2%)		0/197 (0%)
Hypercalcaemia	1/404 (0.2%)		0/197 (0%)
Hypernatraemia	1/404 (0.2%)		0/197 (0%)
Hypoglycaemia	1/404 (0.2%)		0/197 (0%)
Hypokalaemia	1/404 (0.2%)		4/197 (2%)
Hyponatraemia	1/404 (0.2%)		0/197 (0%)
Hypophosphataemia	1/404 (0.2%)		0/197 (0%)
Lactic acidosis	1/404 (0.2%)		0/197 (0%)
Hypovolaemia	0/404 (0%)		1/197 (0.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	3/404 (0.7%)		0/197 (0%)
Muscular weakness	3/404 (0.7%)		1/197 (0.5%)
Fracture nonunion	1/404 (0.2%)		0/197 (0%)
Musculoskeletal chest pain	1/404 (0.2%)		0/197 (0%)
Pain in extremity	1/404 (0.2%)		0/197 (0%)
Back pain	0/404 (0%)		1/197 (0.5%)
Bone pain	0/404 (0%)		1/197 (0.5%)
Rheumatoid arthritis	0/404 (0%)		1/197 (0.5%)
Spinal disorder	0/404 (0%)		1/197 (0.5%)
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Cancer pain	2/404 (0.5%)		1/197 (0.5%)
Acral lentiginous melanoma	1/404 (0.2%)		0/197 (0%)
Malignant pleural effusion	1/404 (0.2%)		0/197 (0%)
Pyogenic granuloma	1/404 (0.2%)		0/197 (0%)
Nervous system disorders
Seizure	7/404 (1.7%)		2/197 (1%)
Depressed level of consciousness	2/404 (0.5%)		0/197 (0%)
Headache	2/404 (0.5%)		3/197 (1.5%)
Hemiparesis	2/404 (0.5%)		0/197 (0%)
Syncope	2/404 (0.5%)		1/197 (0.5%)
Aphasia	1/404 (0.2%)		1/197 (0.5%)
Cauda equina syndrome	1/404 (0.2%)		0/197 (0%)
Central nervous system necrosis	1/404 (0.2%)		0/197 (0%)
Encephalopathy	1/404 (0.2%)		0/197 (0%)
Epilepsy	1/404 (0.2%)		0/197 (0%)
Haemorrhagic stroke	1/404 (0.2%)		0/197 (0%)
Spinal cord compression	1/404 (0.2%)		0/197 (0%)
Brain oedema	0/404 (0%)		1/197 (0.5%)
Cerebral infarction	0/404 (0%)		1/197 (0.5%)
Facial paralysis	0/404 (0%)		1/197 (0.5%)
Generalised tonic-clonic seizure	0/404 (0%)		1/197 (0.5%)
Psychiatric disorders
Confusional state	1/404 (0.2%)		1/197 (0.5%)
Mental status changes	1/404 (0.2%)		2/197 (1%)
Renal and urinary disorders
Acute kidney injury	1/404 (0.2%)		1/197 (0.5%)
Ureterolithiasis	1/404 (0.2%)		0/197 (0%)
Urinary retention	1/404 (0.2%)		0/197 (0%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	5/404 (1.2%)		6/197 (3%)
Pulmonary embolism	4/404 (1%)		3/197 (1.5%)
Pleural effusion	3/404 (0.7%)		6/197 (3%)
Pneumothorax	2/404 (0.5%)		0/197 (0%)
Respiratory failure	2/404 (0.5%)		1/197 (0.5%)
Acute respiratory failure	1/404 (0.2%)		1/197 (0.5%)
Choking	1/404 (0.2%)		0/197 (0%)
Hypoxia	1/404 (0.2%)		1/197 (0.5%)
Pneumothorax spontaneous	1/404 (0.2%)		0/197 (0%)
Skin and subcutaneous tissue disorders
Dermatomyositis	1/404 (0.2%)		0/197 (0%)
Vascular disorders
Hypotension	2/404 (0.5%)		0/197 (0%)
Lymphoedema	1/404 (0.2%)		0/197 (0%)
Orthostatic hypotension	1/404 (0.2%)		1/197 (0.5%)
Vena cava thrombosis	0/404 (0%)		1/197 (0.5%)
Other (Not Including Serious) Adverse Events
	Tuc+Cap+Tra		Pbo+Cap+Tra
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	400/404 (99%)		190/197 (96.4%)
Blood and lymphatic system disorders
Anaemia	80/404 (19.8%)		23/197 (11.7%)
Neutropenia	32/404 (7.9%)		17/197 (8.6%)
Thrombocytopenia	25/404 (6.2%)		11/197 (5.6%)
Eye disorders
Dry eye	22/404 (5.4%)		9/197 (4.6%)
Gastrointestinal disorders
Diarrhoea	325/404 (80.4%)		105/197 (53.3%)
Nausea	236/404 (58.4%)		85/197 (43.1%)
Vomiting	144/404 (35.6%)		48/197 (24.4%)
Stomatitis	103/404 (25.5%)		28/197 (14.2%)
Abdominal pain	59/404 (14.6%)		31/197 (15.7%)
Constipation	59/404 (14.6%)		37/197 (18.8%)
Dyspepsia	43/404 (10.6%)		19/197 (9.6%)
Abdominal pain upper	27/404 (6.7%)		18/197 (9.1%)
Gastrooesophageal reflux disease	23/404 (5.7%)		6/197 (3%)
Abdominal distension	21/404 (5.2%)		9/197 (4.6%)
Dry mouth	21/404 (5.2%)		5/197 (2.5%)
General disorders
Fatigue	181/404 (44.8%)		85/197 (43.1%)
Oedema peripheral	42/404 (10.4%)		19/197 (9.6%)
Asthenia	29/404 (7.2%)		15/197 (7.6%)
Pyrexia	20/404 (5%)		7/197 (3.6%)
Hepatobiliary disorders
Hyperbilirubinaemia	26/404 (6.4%)		8/197 (4.1%)
Infections and infestations
Urinary tract infection	42/404 (10.4%)		15/197 (7.6%)
Upper respiratory tract infection	37/404 (9.2%)		14/197 (7.1%)
Nasopharyngitis	20/404 (5%)		12/197 (6.1%)
Paronychia	20/404 (5%)		3/197 (1.5%)
Injury, poisoning and procedural complications
Fall	22/404 (5.4%)		8/197 (4.1%)
Investigations
Aspartate aminotransferase increased	86/404 (21.3%)		22/197 (11.2%)
Alanine aminotransferase increased	81/404 (20%)		13/197 (6.6%)
Blood bilirubin increased	75/404 (18.6%)		20/197 (10.2%)
Blood creatinine increased	56/404 (13.9%)		3/197 (1.5%)
Weight decreased	54/404 (13.4%)		11/197 (5.6%)
Blood alkaline phosphatase increased	25/404 (6.2%)		6/197 (3%)
White blood cell count decreased	18/404 (4.5%)		10/197 (5.1%)
Metabolism and nutrition disorders
Decreased appetite	100/404 (24.8%)		39/197 (19.8%)
Hypokalaemia	64/404 (15.8%)		23/197 (11.7%)
Hypomagnesaemia	35/404 (8.7%)		9/197 (4.6%)
Dehydration	29/404 (7.2%)		10/197 (5.1%)
Hypophosphataemia	24/404 (5.9%)		10/197 (5.1%)
Hyperglycaemia	23/404 (5.7%)		3/197 (1.5%)
Musculoskeletal and connective tissue disorders
Arthralgia	57/404 (14.1%)		9/197 (4.6%)
Back pain	45/404 (11.1%)		23/197 (11.7%)
Pain in extremity	41/404 (10.1%)		17/197 (8.6%)
Muscle spasms	38/404 (9.4%)		5/197 (2.5%)
Myalgia	26/404 (6.4%)		9/197 (4.6%)
Nervous system disorders
Headache	86/404 (21.3%)		38/197 (19.3%)
Peripheral sensory neuropathy	47/404 (11.6%)		12/197 (6.1%)
Dizziness	45/404 (11.1%)		27/197 (13.7%)
Dysgeusia	30/404 (7.4%)		5/197 (2.5%)
Paraesthesia	20/404 (5%)		8/197 (4.1%)
Psychiatric disorders
Insomnia	33/404 (8.2%)		17/197 (8.6%)
Respiratory, thoracic and mediastinal disorders
Cough	57/404 (14.1%)		23/197 (11.7%)
Epistaxis	47/404 (11.6%)		10/197 (5.1%)
Dyspnoea	46/404 (11.4%)		21/197 (10.7%)
Oropharyngeal pain	25/404 (6.2%)		8/197 (4.1%)
Rhinorrhoea	21/404 (5.2%)		5/197 (2.5%)
Skin and subcutaneous tissue disorders
Palmar-plantar erythrodysaesthesia syndrome	256/404 (63.4%)		104/197 (52.8%)
Dry skin	38/404 (9.4%)		18/197 (9.1%)
Skin hyperpigmentation	34/404 (8.4%)		11/197 (5.6%)
Rash maculo-papular	27/404 (6.7%)		10/197 (5.1%)
Pruritus	23/404 (5.7%)		12/197 (6.1%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

There IS 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.