A Phase 1/2 Study Of HKI-272 (Neratinib) in Combination With Trastuzumab (Herceptin) In Subjects With Advanced Breast Cancer

• Sponsor: Puma Biotechnology, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT00398567
• Collaborator: (none)
• Enrollment: 45
• Locations: 14
• Arms: 3
• Actual Duration (Months): 130.9
• Patients Per Site: 3.2
• Patients Per Site Per Month: 0

Study Details

Study Description

Brief Summary

The purpose of this study is to determine the safety and efficacy of HKI-272 (neratinib) in combination with trastuzumab in patients with advanced breast cancer.

Condition or Disease	Intervention/Treatment	Phase
Advanced Breast Cancer	Drug: HKI-272; Drug: trastuzumab	Phase 1/Phase 2

Detailed Description

Open label phase 1/2 study of ascending multiple oral doses of HKI-272 in combination with IV trastuzumab in subjects with advanced human epidermal growth factor receptor 2 positive (HER2+) breast cancer. Three to six subjects will be enrolled in each dose group. Adverse events and dose limiting toxicities will be assessed from the first dose of study drug though day 21. When the maximum tolerated dose (MTD) of HKI-272 plus trastuzumab is determined, an additional 30 subjects will be enrolled at that dose level, and followed for progression free survival for approximately 1 year.

Study Design

• Study Type: Interventional
• Actual Enrollment: 45 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase I/II Study of HKI-272 in Combination With Trastuzumab (Herceptin) in Subjects With Advanced Breast Cancer
• Actual Study Start Date: Apr 4, 2007
• Actual Primary Completion Date: Jul 31, 2009
• Actual Study Completion Date: Mar 2, 2018

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Part 1 - dose level 1 (160 mg) All subjects receiving HKI-272 dose level 1 in combination with trastuzumab	Drug: HKI-272; HKI-272 by mouth; Other Names: neratinib ; Drug: trastuzumab; trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter; Other Names: Herceptin
Experimental: Part 1 - dose level 2 (240 mg) All subjects receiving HKI-272 dose level 2 in combination with trastuzumab	Drug: HKI-272; HKI-272 by mouth; Other Names: neratinib ; Drug: trastuzumab; trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter; Other Names: Herceptin
Experimental: Part 2 - expanded MTD cohort All subjects receiving HKI-272 in combination with trastuzumab	Drug: HKI-272; HKI-272 by mouth; Other Names: neratinib ; Drug: trastuzumab; trastuzumab 4 mg/kg IV as a loading dose followed by trastuzumab 2 mg/kg weekly thereafter; Other Names: Herceptin

Outcome Measures

Primary Outcome Measures

1. 16-week Progression-free Survival (PFS) Rate [From first dose date to progression status (PD or death) at 16-week]

   16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.

Secondary Outcome Measures

1. Objective Response Rate (ORR) [From first dose date to progression or last tumor assessment, up to five and a half years.]

   Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.

2. Duration of Response (DOR) [From start date of response to first PD, assessed up to five and half years after the first subject was randomized]

   Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started.

3. Progression Free Survival (PFS) [From first dose date to progression or death, assessed up to five and half years.]

   Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment.

4. Clinical Benefit Rate (CBR) [From first dose date to progression or last tumor assessment, assessed up to five and half years.]

   The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) >=24 weeks.

5. Area Under the Curve of Neratinib Concentration [Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22.]

   Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer.

6. Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab. [Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6]

   Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer.

Eligibility Criteria

Criteria

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

Inclusion Criteria:

• Pathologic diagnosis of breast cancer with current stage IIIB, IIIC or IV not curable by available therapy

• Progression following at least one Herceptin-containing cytotoxic chemotherapy regimen (neoadjuvant, adjuvant, or metastatic setting)

• HER2 positive breast cancer

• At least one measurable target lesion

• Adequate performance status

• Adequate cardiac, kidney, and liver function

• Adequate blood counts

• Willingness of all subjects who are not surgically sterile or post menopausal to use acceptable methods of birth control

Exclusion Criteria:

• More than 3 prior cytotoxic chemotherapy regimens for locally advanced or metastatic disease

• Major surgery, chemotherapy, radiotherapy, investigational agents, Herceptin or other cancer therapy within 2 weeks of treatment day 1

• Prior treatment with anthracyclines with cumulative dose of >400 mg/m^2

• Extensive visceral disease

• Active central nervous system metastases

• Pregnant or breast feeding women

• Significant chronic or recent acute gastrointestinal disorder with diarrhea as a major symptom

• Prior exposure to HKI-272 or other HER2 targeted agents (except Herceptin and Tykerb)

• Significant cardiac disease or dysfunction

• History of life-threatening hypersensitivity to Herceptin

• Inability or unwillingness to swallow HKI-272 capsules

• Any other cancer within 5 years with the exception of contralateral breast cancer, adequately treated cervical carcinoma in situ, or adequately treated basal or squamous cell carcinoma of the skin

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	City of Hope National Medical Center	Duarte	California	United States	91010-3000
2	LAC/USC Medical Center, USC/Norris Comprehensive Cancer Center	Los Angeles	California	United States	90033
3	City of Hope National Medical Center	Pasadena	California	United States	91105
4	University of Maryland, University of Maryland Medical Center	Baltimore	Maryland	United States	21201
5	Duke University, Duke University Medical Center	Durham	North Carolina	United States	27710
6	Fox Chase Cancer Center	Philadelphia	Pennsylvania	United States	19111
7	Chinese Nanjing Bayi Hospital	Nanjing	Jiangsu	China	210002
8	Tianjin Union Medicine Center	Tianjin	Tianjin	China	300121
9	Cancer Hospital, Academy of Med Science and Peking Union Med	Beijing		China	100021
10	307 Hospital of Chinese People's Liberation Army	Beijing		China	100071
11	Chinese PLA General Hospital	Beijing		China	100853
12	Institut Curie	Paris		France	75005
13	Centre Rene Gauducheau	Saint-Herblain		France	44805
14	Centre Hospitalier Universitaire Vaudois	Lausanne		Switzerland	CH-1011

Sponsors and Collaborators

• Puma Biotechnology, Inc.

Investigators

• Study Director: Puma, Biotechnology

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Puma Biotechnology, Inc.
• ClinicalTrials.gov Identifier: NCT00398567
• Other Study ID Numbers: 3144A1-202 / B1891013
• First Posted: Nov 10, 2006
• Last Update Posted: Jul 24, 2018
• Last Verified: Jun 1, 2018

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Puma Biotechnology, Inc.: HKI-272; neratinib; trastuzumab; breast cancer; Nerlynx; PB-272; HER2
• Additional relevant MeSH terms: Breast Neoplasms; Trastuzumab

Study Results

Participant Flow

Arm/Group Title	Neratinib 160mg + Trastuzumab	Neratinib 240mg + Trastuzumab	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Period Title: Overall Study
STARTED	4	4	37
COMPLETED	0	0	3
NOT COMPLETED	4	4	34

Baseline Characteristics

Arm/Group Title	Neratinib 160 mg + Trastuzumab	Neratinib 240 mg + Trastuzumab	Part 2 - Expanded MTD Cohort	Total
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter	Total of all reporting groups
Overall Participants	4	4	37	45
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	52.5 (10.1)	61.0 (12.8)	50.5 (13.0)	51.6 (12.9)
Sex: Female, Male (Count of Participants)
Female	4 100%	4 100%	37 100%	45 100%
Male	0 0%	0 0%	0 0%	0 0%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	21 56.8%	21 46.7%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%	0 0%
Black or African American	0 0%	1 25%	1 2.7%	2 4.4%
White	3 75%	3 75%	15 40.5%	21 46.7%
More than one race	0 0%	0 0%	0 0%	0 0%
Unknown or Not Reported	1 25%	0 0%	0 0%	1 2.2%

Outcome Measures

1. Primary Outcome

Title	16-week Progression-free Survival (PFS) Rate
Description	16-week progression-free survival (PFS) rate for subjects with advanced breast cancer who receive neratinib at the maximum tolerated dose (MTD) in combination with trastuzumab, evaluable population.
Time Frame	From first dose date to progression status (PD or death) at 16-week

Outcome Measure Data

Analysis Population Description

The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	28
Number (95% Confidence Interval) [percentage of population]	44.8

2. Secondary Outcome

Title	Objective Response Rate (ORR)
Description	Percentage of participants with partial response (PR) or complete response (CR) per Response Evaluation Criteria In Solid Tumors Criteria (RECIST) v.1.0: Complete Response (CR), disappearance of all target lesions; Partial Response (PR), >=30% decrease in the sum of the longest diameter of target lesions; and Non-PD for non-target lesions, and no new lesions.
Time Frame	From first dose date to progression or last tumor assessment, up to five and a half years.

Outcome Measure Data

Analysis Population Description

The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	28.6 715%

3. Secondary Outcome

Title	Duration of Response (DOR)
Description	Duration of response was measured from the time at which response criteria were met for complete response (CR) or partial response (PR) (whichever status was recorded first) until the first date on which recurrence or PD was objectively documented, taking as the reference for PD the smallest measurements recorded since the test article administration started.
Time Frame	From start date of response to first PD, assessed up to five and half years after the first subject was randomized

Outcome Measure Data

Analysis Population Description

The subjects who had a complete response or partial response.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	8
Median (95% Confidence Interval) [weeks]	44.2

4. Secondary Outcome

Title	Progression Free Survival (PFS)
Description	Progression Free Survival was measured from the date of the first dose of test article until the first date on which recurrence or progression, or death due to any cause, was documented, censored at the last evaluation, investigator assessment.
Time Frame	From first dose date to progression or death, assessed up to five and half years.

Outcome Measure Data

Analysis Population Description

The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	28
Median (95% Confidence Interval) [weeks]	15.9

5. Secondary Outcome

Title	Clinical Benefit Rate (CBR)
Description	The percentage of participants with a best overall response of a complete response (CR) or partial response (PR) or stable disease (SD) >=24 weeks.
Time Frame	From first dose date to progression or last tumor assessment, assessed up to five and half years.

Outcome Measure Data

Analysis Population Description

The evaluable population was defined as the subjects who met the eligibility criteria for study enrollment, received at least 1 week of neratinib and at least 2 doses of trastuzumab, and had a baseline tumor assessment and at least 1 follow-up tumor assessment approximately 8 weeks after starting test article administration.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	28
Number (95% Confidence Interval) [percentage of participants]	35.7 892.5%

6. Secondary Outcome

Title	Area Under the Curve of Neratinib Concentration
Description	Area Under the Curve of Neratinib concentration at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg in Subjects with Cancer.
Time Frame	Prior to the first dose, and at hours 1, 2, 4, 6, 8 and 24 on days 22.

Outcome Measure Data

Analysis Population Description

Subjects for whom complete blood samples at day 22 were available.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	33
Mean (Standard Deviation) [ng*hr/mL]	1110 (430)

7. Secondary Outcome

Title	Terminal-phase Elimination Half-life of Neratinib in Combination With Trastuzumab.
Description	Terminal-phase elimination half-life of Neratinib at day 22 following Administration of Neratinib 240 mg in combination with Trastuzumab 2 mg/kg to Subjects with Cancer.
Time Frame	Prior to the first dose, on days 22 through 23 of month 1, and on day 1 in months 2 through 6

Outcome Measure Data

Analysis Population Description

Subjects for whom complete blood samples at day 22 were available.

Arm/Group Title	Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
Measure Participants	27
Mean (Standard Deviation) [hr]	21.22 (10.16)

Adverse Events

Time Frame	From first dose date through last dose date + 28 days.
Arm/Group Title	Neratinib 160 mg + Trastuzumab		Neratinib 240 mg + Trastuzumab		Part 2 - Expanded MTD Cohort
Arm/Group Description	All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 160 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter		All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter		All subjects receiving HKI-272 (neratinib) in combination with trastuzumab (Herceptin) HKI-272: neratinib 240 mg daily by mouth Herceptin: Herceptin 4 mg/kg IV as a loading dose followed by Herceptin 2 mg/kg weekly thereafter
All Cause Mortality
	Neratinib 160 mg + Trastuzumab		Neratinib 240 mg + Trastuzumab		Part 2 - Expanded MTD Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)		/ (NaN)
Serious Adverse Events
	Neratinib 160 mg + Trastuzumab		Neratinib 240 mg + Trastuzumab		Part 2 - Expanded MTD Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/4 (25%)		0/4 (0%)		9/37 (24.3%)
Ear and labyrinth disorders
Vertigo	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Gastrointestinal disorders
Abdominal adhesions	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Abdominal distension	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Abdominal pain	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Diarrhoea	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Nausea	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Vomiting	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
General disorders
Disease progression	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Infections and infestations
Influenza	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Nasopharyngitis	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Injury, poisoning and procedural complications
Lumbar vertebral fracture	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Metabolism and nutrition disorders
Hyponatraemia	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Nervous system disorders
Ataxia	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Respiratory, thoracic and mediastinal disorders
Dyspnoea	1/4 (25%)		0/4 (0%)		1/37 (2.7%)
Skin and subcutaneous tissue disorders
Angioedema	0/4 (0%)		0/4 (0%)		1/37 (2.7%)
Other (Not Including Serious) Adverse Events
	Neratinib 160 mg + Trastuzumab		Neratinib 240 mg + Trastuzumab		Part 2 - Expanded MTD Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	4/4 (100%)		4/4 (100%)		37/37 (100%)
Blood and lymphatic system disorders
Anaemia	1/4 (25%)		1/4 (25%)		2/37 (5.4%)
Leukopenia	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Neutropenia	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Neutrophilia	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Thrombocytopenia	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Cardiac disorders
Palpitations	0/4 (0%)		1/4 (25%)		0/37 (0%)
Ear and labyrinth disorders
Vertigo	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Eye disorders
Dry eye	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Gastrointestinal disorders
Abdominal discomfort	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Abdominal pain	1/4 (25%)		1/4 (25%)		6/37 (16.2%)
Abdominal pain upper	2/4 (50%)		0/4 (0%)		2/37 (5.4%)
Constipation	0/4 (0%)		1/4 (25%)		1/37 (2.7%)
Diarrhoea	4/4 (100%)		4/4 (100%)		34/37 (91.9%)
Dyspepsia	0/4 (0%)		0/4 (0%)		4/37 (10.8%)
Dysphagia	1/4 (25%)		0/4 (0%)		1/37 (2.7%)
Haemorrhoids	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Nausea	3/4 (75%)		3/4 (75%)		17/37 (45.9%)
Stomatitis	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Vomiting	2/4 (50%)		2/4 (50%)		14/37 (37.8%)
General disorders
Asthenia	0/4 (0%)		0/4 (0%)		13/37 (35.1%)
Catheter site pain	0/4 (0%)		1/4 (25%)		0/37 (0%)
Chills	0/4 (0%)		1/4 (25%)		1/37 (2.7%)
Crying	0/4 (0%)		1/4 (25%)		0/37 (0%)
Fatigue	1/4 (25%)		2/4 (50%)		6/37 (16.2%)
Non-cardiac chest pain	1/4 (25%)		0/4 (0%)		0/37 (0%)
Oedema peripheral	0/4 (0%)		1/4 (25%)		2/37 (5.4%)
Pyrexia	1/4 (25%)		0/4 (0%)		4/37 (10.8%)
Infections and infestations
Conjunctivitis	1/4 (25%)		0/4 (0%)		1/37 (2.7%)
Gastroenteritis	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Lymphangitis	1/4 (25%)		0/4 (0%)		0/37 (0%)
Paronychia	1/4 (25%)		0/4 (0%)		1/37 (2.7%)
Pharyngitis	1/4 (25%)		0/4 (0%)		1/37 (2.7%)
Rhinitis	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Upper respiratory tract infection	0/4 (0%)		1/4 (25%)		2/37 (5.4%)
Urinary tract infection	0/4 (0%)		2/4 (50%)		3/37 (8.1%)
Investigations
Alanine aminotransferase increased	0/4 (0%)		0/4 (0%)		4/37 (10.8%)
Aspartate aminotransferase increased	0/4 (0%)		0/4 (0%)		5/37 (13.5%)
Blood alkaline phosphatase increased	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Blood lactate dehydrogenase increased	1/4 (25%)		0/4 (0%)		0/37 (0%)
Ejection fraction decreased	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Haemoglobin decreased	0/4 (0%)		1/4 (25%)		4/37 (10.8%)
Hepatic enzyme increased	1/4 (25%)		0/4 (0%)		0/37 (0%)
Weight decreased	0/4 (0%)		2/4 (50%)		7/37 (18.9%)
Weight increased	0/4 (0%)		1/4 (25%)		0/37 (0%)
White blood cell count decreased	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Metabolism and nutrition disorders
Decreased appetite	1/4 (25%)		2/4 (50%)		19/37 (51.4%)
Dehydration	0/4 (0%)		1/4 (25%)		2/37 (5.4%)
Hypocalcaemia	1/4 (25%)		0/4 (0%)		1/37 (2.7%)
Hypokalaemia	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Musculoskeletal and connective tissue disorders
Arthralgia	0/4 (0%)		1/4 (25%)		2/37 (5.4%)
Back pain	0/4 (0%)		1/4 (25%)		2/37 (5.4%)
Bone pain	1/4 (25%)		0/4 (0%)		0/37 (0%)
Muscle spasms	0/4 (0%)		0/4 (0%)		4/37 (10.8%)
Muscular weakness	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Pain in extremity	0/4 (0%)		1/4 (25%)		1/37 (2.7%)
Nervous system disorders
Balance disorder	0/4 (0%)		1/4 (25%)		0/37 (0%)
Dizziness	0/4 (0%)		0/4 (0%)		5/37 (13.5%)
Dysgeusia	0/4 (0%)		1/4 (25%)		2/37 (5.4%)
Headache	2/4 (50%)		1/4 (25%)		5/37 (13.5%)
Psychiatric disorders
Anxiety	0/4 (0%)		1/4 (25%)		0/37 (0%)
Insomnia	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Irritability	0/4 (0%)		1/4 (25%)		0/37 (0%)
Renal and urinary disorders
Dysuria	0/4 (0%)		1/4 (25%)		4/37 (10.8%)
Reproductive system and breast disorders
Vulvovaginal pruritus	1/4 (25%)		0/4 (0%)		0/37 (0%)
Respiratory, thoracic and mediastinal disorders
Cough	0/4 (0%)		1/4 (25%)		3/37 (8.1%)
Dry throat	0/4 (0%)		1/4 (25%)		0/37 (0%)
Dysphonia	0/4 (0%)		1/4 (25%)		1/37 (2.7%)
Dyspnoea	0/4 (0%)		0/4 (0%)		4/37 (10.8%)
Epistaxis	0/4 (0%)		1/4 (25%)		1/37 (2.7%)
Nasal congestion	0/4 (0%)		1/4 (25%)		0/37 (0%)
Oropharyngeal pain	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Rhinorrhoea	0/4 (0%)		0/4 (0%)		3/37 (8.1%)
Upper-airway cough syndrome	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Skin and subcutaneous tissue disorders
Acne	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Alopecia	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Dermatitis acneiform	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Dry skin	1/4 (25%)		0/4 (0%)		4/37 (10.8%)
Erythema	2/4 (50%)		1/4 (25%)		2/37 (5.4%)
Exfoliative rash	1/4 (25%)		1/4 (25%)		0/37 (0%)
Nail disorder	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Pruritus	0/4 (0%)		2/4 (50%)		2/37 (5.4%)
Rash	1/4 (25%)		1/4 (25%)		8/37 (21.6%)
Skin exfoliation	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Skin lesion	0/4 (0%)		0/4 (0%)		2/37 (5.4%)
Vascular disorders
Hot flush	0/4 (0%)		1/4 (25%)		1/37 (2.7%)
Hypotension	0/4 (0%)		1/4 (25%)		0/37 (0%)
Lymphoedema	0/4 (0%)		1/4 (25%)		2/37 (5.4%)

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.