A Phase 1B Dose-escalation and Phase 2a Study of Carotuximab (TRC105) in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma

• Sponsor: Tracon Pharmaceuticals Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01975519
• Collaborator: (none)
• Enrollment: 111
• Locations: 9
• Arm: 1
• Actual Duration (Months): 63
• Patients Per Site: 12.3
• Patients Per Site Per Month: 0.2

Study Details

Study Description

Brief Summary

The purpose of the phase 1b portion is to evaluate safety and tolerability and determine a recommended phase 2 dose for TRC105 when added to standard dose pazopanib in patients with advanced soft tissue sarcoma. Up to 30 patients will be treated.

The purpose of the phase 2 portion is to estimate the PFS of patients with advanced soft tissue sarcoma by RECIST 1.1 and estimate ORR in a separate cohort of patients with angiosarcoma by RECIST 1.1. Up to 89 patients will be treated in phase 2, including two cohorts of up to 13 patients with angiosarcoma.

Condition or Disease	Intervention/Treatment	Phase
Advanced Soft Tissue Sarcoma	Drug: TRC105 and Pazopanib	Phase 1/Phase 2

Detailed Description

Pazopanib is an oral inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptor VEGFR-1, VEGFR-2, and VEGFR-3 at therapeutic plasma concentrations. These receptors are implicated in pathologic angiogenesis, tumor growth, and cancer progression. Pazopanib is approved for the treatment of advanced soft tissue sarcoma, following progression on one prior systemic therapy, based on improved progression free survival. TRC105 is an antibody to CD105, an important angiogenic target on vascular endothelial cells that is distinct from VEGFR. TRC105 inhibits angiogenesis, tumor growth and metastases in preclinical models and complements the activity of bevacizumab and multi-kinase inhibitors that target the VEGFR. In a phase 1 study of advanced solid tumors, TRC105 therapy caused a global reduction in angiogenic biomarkers and reduced tumor burden at doses that were well-tolerated. In a phase 1b study, the combination of TRC105 and bevacizumab produced radiographic reductions in tumor volume in bevacizumab-refractory patients, and was well tolerated. TRC105 potentiates bevacizumab and VEGFR tyrosine kinases (VEGFR TKI) in preclinical models. By targeting a non-VEGF pathway that is upregulated following VEGF inhibition, TRC105 has the potential to complement VEGFR TKIs and could represent a major advance in cancer therapy. Together, the use of TRC105 with pazopanib may result in more effective angiogenesis inhibition and improved clinical efficacy over that seen with pazopanib alone.

Study Design

• Study Type: Interventional
• Actual Enrollment: 111 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Phase 1B Dose-escalation and Phase 2a Study of Carotuximab (TRC105) in Combination With Pazopanib in Patients With Advanced Soft Tissue Sarcoma
• Actual Study Start Date: Dec 10, 2013
• Actual Primary Completion Date: Mar 11, 2019
• Actual Study Completion Date: Mar 11, 2019

Arms and Interventions

Arm	Intervention/Treatment
Experimental: TRC105 and Pazopanib Weekly TRC105 in combination with standard dose pazopanib or every two week administration during cycle 1, and starting on cycle 2 day 1 and beyond, TRC105 may be administered every two weeks. This is also in combination with standard dose pazopanib.	Drug: TRC105 and Pazopanib; Weekly TRC105 in combination with standard dose Pazopanib.; Other Names: Chimeric Antibody (TRC105) to CD105 Votrient

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Dose Limiting Toxicity (DLT) [56 days]

   For DLT evaluation, severity (grade) was classified according to common terminology criteria for adverse events version 4.0 (CTCAE v4.0). DLTs were defined as grade 4 neutropenia persisting for ≥ 5 days, febrile neutropenia (grade 4 neutropenia with fever > 38.5 ºC both sustained over a 24 hour period), neutropenic infection (grade ≥ 3 neutropenia with grade ≥ 3 infection), anemia ≥ grade 4, grade > 4 thrombocytopenia or grade ≥ 3 thrombocytopenia and grade ≥ 3 hemorrhage, or grade 3 or 4 nonhematologic toxicity with the following exceptions: nausea, vomiting, or diarrhea for <48 hours, asymptomatic electrolyte abnormalities that are corrected to grade 1 or better in < 72 hours, or headache lasting less than 48 hours.

2. Progression Free Survival of Patients With Advanced Soft Tissue Sarcoma (Phase 1 and 2) [from screening to either disease progression or death]

   Number of patients with progression free survival, as defined as time from screening to either first disease progression or death from any cause per RECIST version 1.1

3. Objective Response Rate in a Cohort of Patients With Angiosarcoma [1.5 years]

   The best response according to RECIST 1.1 for each patient in the phase 2 angiosarcoma cohort with measurable disease and who received at least one dose of study drug will be listed by cohort and tumor type

Secondary Outcome Measures

1. Trough Concentrations of TRC105 (Phase 2) [4, 6, 8, and 10 weeks]

   Trough serum TRC105 concentrations will be measured using validated ELISA methods.

2. Number of Patients With and Without Development of Immunogenicity Antibodies (Phase 1 and 2) [32 months]

   Anti-product antibody concentrations will be measured using validated ELISA methods. Anti-product antibody concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles.

3. Number of Patients With and Without Expression of Endoglin on Sarcoma Tissue (Phase 1 and 2) [12 months]

   Expression will be determined by immunohistochemistry for each patient who received at least one dose of TRC105

4. Objective Response Rate in Patients With Advanced Soft Tissue Sarcoma by RECIST 1.1 [12 months]

   The best response (CR, PR, SD or PD according to RECIST 1.1) for each patient (phase 1 and phase 2) with measurable disease who received at least one dose of TRC105 study drug

5. Progression Free Survival in a Cohort of Patients With Angiosarcoma (Phase 2) [26 months]

   Time from screening to either first disease progression or death from any cause per RECIST version 1.1

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years to 120 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

1. Histologically confirmed unresectable soft tissue sarcoma that has progressed following treatment with chemotherapy. Prior pazopanib is allowed if the drug was not discontinued for toxicity ( Phase 1b only)

2. Histologically confirmed metastatic soft tissue sarcoma that has progressed by RECIST following treatment with anthracycline chemotherapy. Patients may have received up to four lines of systemic therapy for metastatic disease and no more than two lines of combination treatment ( Phase 2 only)

3. Histologically confirmed locally advanced (e.g. unresectable) or metastatic angiosarcoma that has progressed following treatment with prior systemic therapy. Progression must be documented on or following the most recent systemic therapy. Prior pazopanib is allowed if the drug was not discontinued for toxicity (Phase 2 angiosarcoma cohorts only)

4. Measurable disease by RECIST

5. Age of 12 years or older (patient must weigh ≥ 40 kg)

6. ECOG performance status ≤ 1

7. Resolution of all acute adverse events resulting from prior cancer therapies to NCI CTCAE grade ≤ 1 or baseline (except alopecia or neuropathy)

8. Adequate organ function.

9. Willingness and ability to consent for self to participate in study

10. Willingness and ability to comply with scheduled visits, treatment plan, laboratory tests, and other study procedures

11. Available archival tumor specimen of the soft tissue sarcoma that meets inclusion criterion #1, #2 or #3

Exclusion Criteria:

1. Prior treatment with TRC105

2. Prior treatment with a VEGFR TKI (including pazopanib) (Phase 2 only)

3. Current treatment on another therapeutic clinical trial

4. Receipt of systemic anticancer therapy, including investigational agents, within 28 days of starting study treatment.

5. No major surgical procedure or significant traumatic injury within 6 weeks prior to study registration, and must have fully recovered from any such procedure; date of surgery (if applicable) or the anticipated need for a major surgical procedure within the next six months.

6. Patients who have received wide field radiotherapy ≤ 28 days or limited field radiation for palliation < 14 days prior to cycle 1 day 1 or those patients who have not recovered adequately from side effects of such therapy

7. Uncontrolled chronic hypertension

8. Significant ascites or pericardial or pleural effusion

9. History of brain involvement with cancer, spinal cord compression, or carcinomatous meningitis, or new evidence of brain or leptomeningeal disease.

10. Angina, MI, symptomatic congestive heart failure, cerebrovascular accident, transient ischemic attack, arterial embolism, pulmonary embolism, PTCA or CABG within the past 6 months. Deep venous thrombosis within 6 months, unless the patient is anti-coagulated without the use of warfarin for at least 2 weeks. In this situation, low molecular weight heparin is preferred.

11. Active bleeding or pathologic condition that carries a high risk of bleeding. Patients who have been uneventfully anti-coagulated with low molecular weight heparin are eligible.

12. Thrombolytic use (except to maintain i.v. catheters) within 10 days prior to first day of study therapy

13. Known active viral or nonviral hepatitis or cirrhosis

14. History of hemorrhage or hemoptysis within 3 months of starting study treatment

15. History of peptic ulcer within the past 3 months of treatment

16. History of gastrointestinal perforation or fistula in the past 6 months, or while previously on antiangiogenic therapy, unless underlying risk has been resolved

17. Known human immunodeficiency virus (HIV) or acquired immunodeficiency syndrome (AIDS) related illness

18. Receipt of a strong CYP3A4 inducer within 12 days prior to cycle 1 day 1 or a strong CYP3A4 inhibitor within 7 days prior to cycle 1 day 1.

19. Pregnancy or breastfeeding. Female patients must be surgically sterile (i.e.: hysterectomy) or be postmenopausal, or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. All female patients of reproductive potential must have a negative pregnancy test (serum or urine) within 7 days prior to first dose. Male patients must be surgically sterile or must agree to use effective contraception during the study and for 3 months following last dose of TRC105. The definition of effective contraception will be based on the judgment of the Principal Investigator or a designated associate.

20. Other severe acute or chronic medical or psychiatric condition or laboratory abnormality that may increase the risk associated with study participation or may interfere with the interpretation of study results and, in the judgment of the Investigator, would make the patient inappropriate for this study.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	University of Alabama at Birmingham	Birmingham	Alabama	United States	35243
2	Sarcoma Oncology Center	Santa Monica	California	United States	90403
3	Mayo Clinic Jacksonville	Jacksonville	Florida	United States	32224
4	Mayo Clinic Rochester	Rochester	Minnesota	United States	55905
5	Roswell Park Cancer Institute	Buffalo	New York	United States	92122
6	Mount Sinai School of Medicine-Tisch Cancer Institute	New York	New York	United States	10029
7	Duke University	Durham	North Carolina	United States	27710
8	Mary Crowley Cancer Research Center	Dallas	Texas	United States	75230
9	University of Utah	Salt Lake City	Utah	United States	84112

Sponsors and Collaborators

• Tracon Pharmaceuticals Inc.

Investigators

• Study Director: Charles Theuer, MD, Tracon Pharmaceuticals Inc.

Study Documents (Full-Text)

• Study Protocol and Statistical Analysis Plan - Jul 22, 2016

More Information

Publications

None provided.

• Responsible Party: Tracon Pharmaceuticals Inc.
• ClinicalTrials.gov Identifier: NCT01975519
• Other Study ID Numbers: 105SAR101
• First Posted: Nov 3, 2013
• Last Update Posted: May 20, 2020
• Last Verified: May 1, 2020

• Keywords provided by Tracon Pharmaceuticals Inc.: TRC105; CD105; Endoglin; Angiogenesis Inhibitor; STS; Soft Tissue Sarcoma; TKI; Tyrosine Kinase Inhibitor; Pazopanib; Votrient; Advanced Soft Tissue Sarcoma; Angiosarcoma
• Additional relevant MeSH terms: Sarcoma; Antibodies, Monoclonal

Study Results

Participant Flow

Arm/Group Title	8 mg/kg TRC105 + Pazopanib	10 mg/kg TRC105 + Pazopanib
Arm/Group Description	8 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.	10 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.
Period Title: Overall Study
STARTED	3	108
Phase 1b	3	23
Phase 2a Soft Tissue Sarcoma	0	63
Phase 2a Angiosarcoma Cohort	0	22
COMPLETED	3	108
NOT COMPLETED	0	0

Baseline Characteristics

Arm/Group Title	8 mg/kg TRC105 + Pazopanib	10 mg/kg TRC105 + Pazopanib	Total
Arm/Group Description	8 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.	10 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.	Total of all reporting groups
Overall Participants	3	108	111
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	55	58	58
Sex: Female, Male (Count of Participants)
Female	1 33.3%	59 54.6%	60 54.1%
Male	2 66.7%	49 45.4%	51 45.9%
Race/Ethnicity, Customized (Count of Participants)
Asian	0 0%	6 5.6%	6 5.4%
Black or African American	1 33.3%	8 7.4%	9 8.1%
Caucasian	2 66.7%	89 82.4%	91 82%
Hispanic or Latino	0 0%	5 4.6%	5 4.5%
Region of Enrollment (participants) [Number]
United States	3 100%	108 100%	111 100%
ECOG Performance Status (Count of Participants)
ECOG Grade 0	2 66.7%	31 28.7%	33 29.7%
ECOG Grade 1	1 33.3%	77 71.3%	78 70.3%
ECOG Grade 2	0 0%	0 0%	0 0%
ECOG Grade 3	0 0%	0 0%	0 0%
ECOG Grade 4	0 0%	0 0%	0 0%
ECOG Grade 5	0 0%	0 0%	0 0%

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Dose Limiting Toxicity (DLT)
Description	For DLT evaluation, severity (grade) was classified according to common terminology criteria for adverse events version 4.0 (CTCAE v4.0). DLTs were defined as grade 4 neutropenia persisting for ≥ 5 days, febrile neutropenia (grade 4 neutropenia with fever > 38.5 ºC both sustained over a 24 hour period), neutropenic infection (grade ≥ 3 neutropenia with grade ≥ 3 infection), anemia ≥ grade 4, grade > 4 thrombocytopenia or grade ≥ 3 thrombocytopenia and grade ≥ 3 hemorrhage, or grade 3 or 4 nonhematologic toxicity with the following exceptions: nausea, vomiting, or diarrhea for <48 hours, asymptomatic electrolyte abnormalities that are corrected to grade 1 or better in < 72 hours, or headache lasting less than 48 hours.
Time Frame	56 days

Outcome Measure Data

Analysis Population Description

All phase 1b patients who received at least a portion of a dose of TRC105

Arm/Group Title	TRC105 Plus Pazopanib
Arm/Group Description	All patients in Phase 1b portion of study who received TRC105 + Pazopanib TRC105: IV (8 mg/kg or 10 mg/kg). Pazopanib: oral (800 mg)
Measure Participants	26
Patients with DLT at 8 mg/kg	0 0%
Patients without DLT at 8 mg/kg	3 100%
Patients with DLT at 10 mg/kg	1 33.3%
Patients without DLT at 10 mg/kg	22 733.3%

2. Primary Outcome

Title	Progression Free Survival of Patients With Advanced Soft Tissue Sarcoma (Phase 1 and 2)
Description	Number of patients with progression free survival, as defined as time from screening to either first disease progression or death from any cause per RECIST version 1.1
Time Frame	from screening to either disease progression or death

Outcome Measure Data

Analysis Population Description

All patients with scans completed at baseline and at least 1 time point on study.

Arm/Group Title	8 mg/kg TRC105 + Pazopanib	10 mg/kg TRC105 + Pazopanib
Arm/Group Description	All patients who received 8 mg/kg TRC105 + Pazopanib	All patients who received 10 mg/kg TRC105 + Pazopanib
Measure Participants	3	90
Mean (95% Confidence Interval) [months]	5.06	3.45

3. Primary Outcome

Title	Objective Response Rate in a Cohort of Patients With Angiosarcoma
Description	The best response according to RECIST 1.1 for each patient in the phase 2 angiosarcoma cohort with measurable disease and who received at least one dose of study drug will be listed by cohort and tumor type
Time Frame	1.5 years

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	10 mg/kg TRC105 + Pazopanib With Angiosarcoma
Arm/Group Description	10 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.
Measure Participants	5
Complete Response (CR)	2 66.7%
Partial Response (PR)	0 0%
Stable Disease (SD)	3 100%
Progressive Disease (PD)	0 0%
Not Evaluable	0 0%

4. Secondary Outcome

Title	Trough Concentrations of TRC105 (Phase 2)
Description	Trough serum TRC105 concentrations will be measured using validated ELISA methods.
Time Frame	4, 6, 8, and 10 weeks

Outcome Measure Data

Analysis Population Description

All patients who received at least a portion of a dose of TRC105 with PK samples collected at baseline and at least 1 time point on study

Arm/Group Title	10 mg/kg TRC105 + Pazopanib
Arm/Group Description	All patients who received hybrid dose of 10 mg/kg TRC105 weekly followed by 15 mg/kg every other week in combination with 800 mg pazopanib daily
Measure Participants	6
Cycle 2 Day 1 (4 weeks) trough PK concentrations	124
Cycle 2 Day 15 (6 weeks) trough PK concentrations	86
Cycle 3 Day 1 (8 weeks) trough PK concentrations	91
Cycle 3 Day 15 (10 weeks) trough PK concentrations	80

5. Secondary Outcome

Title	Number of Patients With and Without Development of Immunogenicity Antibodies (Phase 1 and 2)
Description	Anti-product antibody concentrations will be measured using validated ELISA methods. Anti-product antibody concentrations will be evaluated in the context of pharmacokinetic parameters and AE profiles.
Time Frame	32 months

Outcome Measure Data

Analysis Population Description

All patients who received at least a portion of a dose of TRC105 with immunogenicity samples collected at baseline and at least 1 time point on study

Arm/Group Title	8 mg/kg TRC105 + Pazopanib	10 mg/kg TRC105 + Pazopanib
Arm/Group Description	All patients who received TRC105 + Pazopanib TRC105: IV 8 mg/kg and Pazopanib: oral (800 mg)	All patients who received TRC105 + Pazopanib TRC105: IV 10 mg/kg and Pazopanib: oral (800 mg)
Measure Participants	3	79
Pt with treatment emergent ADA	1 33.3%	12 11.1%
Pt without treatment emergent ADA	2 66.7%	67 62%

6. Secondary Outcome

Title	Number of Patients With and Without Expression of Endoglin on Sarcoma Tissue (Phase 1 and 2)
Description	Expression will be determined by immunohistochemistry for each patient who received at least one dose of TRC105
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

All patients who received TRC105. Endoglin expression levels determined through archival tumor samples, which were drawn before dosing. Therefore dose levels combined.

Arm/Group Title	TRC105 Plus Pazopanib
Arm/Group Description	All patients in Phase 1b and Phase 2 portion of study who received TRC105 + Pazopanib TRC105: IV (8 mg/kg or 10 mg/kg). Pazopanib: oral (800 mg)
Measure Participants	66
Tumor endoglin expression positive	15 500%
Tumor endoglin expression negative	51 1700%

7. Secondary Outcome

Title	Objective Response Rate in Patients With Advanced Soft Tissue Sarcoma by RECIST 1.1
Description	The best response (CR, PR, SD or PD according to RECIST 1.1) for each patient (phase 1 and phase 2) with measurable disease who received at least one dose of TRC105 study drug
Time Frame	12 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	8 mg/kg TRC105 + Pazopanib	10 mg/kg TRC105 + Pazopanib
Arm/Group Description	8 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.	10 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.
Measure Participants	3	78
Complete Response (CR)	0 0%	3 2.8%
Partial Response (PR)	0 0%	1 0.9%
Stable Disease (SD)	3 100%	43 39.8%
Progressive Disease (PD)	0 0%	27 25%
Not Evaluable	0 0%	4 3.7%

8. Secondary Outcome

Title	Progression Free Survival in a Cohort of Patients With Angiosarcoma (Phase 2)
Description	Time from screening to either first disease progression or death from any cause per RECIST version 1.1
Time Frame	26 months

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	10 mg/kg TRC105 + Pazopanib With Angiosarcoma
Arm/Group Description	10 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.
Measure Participants	9
Mean (95% Confidence Interval) [months]	5.59

Adverse Events

Time Frame	Adverse events are collected for each patient from the time of informed consent through 28 days following the last dose of study drug. Patients were eligible for participation in the trial until they progressed. The longest duration of AE collection for a given patient was 34 months.
Arm/Group Title	8 mg/kg TRC105 + Pazopanib		10 mg/kg TRC105 + Pazopanib
Arm/Group Description	8 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.		10 mg/kg of TRC105 in combination with standard dose pazopanib in patients with advanced soft tissue sarcoma.
All Cause Mortality
	8 mg/kg TRC105 + Pazopanib		10 mg/kg TRC105 + Pazopanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		9/106 (8.5%)
Serious Adverse Events
	8 mg/kg TRC105 + Pazopanib		10 mg/kg TRC105 + Pazopanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/3 (0%)		9/106 (8.5%)
Gastrointestinal disorders
Colitis	0/3 (0%)		1/106 (0.9%)
Metabolism and nutrition disorders
Dehydration	0/3 (0%)		1/106 (0.9%)
Decreased Appetite	0/3 (0%)		1/106 (0.9%)
Nervous system disorders
Transient Ischemic Attack	0/3 (0%)		1/106 (0.9%)
Respiratory, thoracic and mediastinal disorders
Pneumothorax	0/3 (0%)		3/106 (2.8%)
Pulmonary Venous Thrombosis	0/3 (0%)		1/106 (0.9%)
Pulmonary Hemorrhage	0/3 (0%)		1/106 (0.9%)
Pulmonary Embolism	0/3 (0%)		1/106 (0.9%)
Acute Respiratory Distress Syndrome	0/3 (0%)		1/106 (0.9%)
Other (Not Including Serious) Adverse Events
	8 mg/kg TRC105 + Pazopanib		10 mg/kg TRC105 + Pazopanib
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/3 (100%)		106/106 (100%)
Blood and lymphatic system disorders
Anemia	1/3 (33.3%)		45/106 (42.5%)
Thrombocytopenia	0/3 (0%)		10/106 (9.4%)
Neutropenia	0/3 (0%)		8/106 (7.5%)
Cardiac disorders
Bradycardia	0/3 (0%)		6/106 (5.7%)
Palpitations	1/3 (33.3%)		2/106 (1.9%)
Endocrine disorders
Hypothyroidism	0/3 (0%)		10/106 (9.4%)
Eye disorders
Vitreous Floaters	0/3 (0%)		6/106 (5.7%)
Visual Impairment	1/3 (33.3%)		3/106 (2.8%)
Gastrointestinal disorders
Nausea	2/3 (66.7%)		66/106 (62.3%)
Diarrhea	3/3 (100%)		64/106 (60.4%)
Vomiting	1/3 (33.3%)		52/106 (49.1%)
Gingival Bleeding	2/3 (66.7%)		40/106 (37.7%)
Stomatitis	1/3 (33.3%)		25/106 (23.6%)
Constipation	0/3 (0%)		22/106 (20.8%)
Abdominal Pain	0/3 (0%)		19/106 (17.9%)
Oral Pain	1/3 (33.3%)		16/106 (15.1%)
Gingival Pain	1/3 (33.3%)		13/106 (12.3%)
Abdominal Discomfort	1/3 (33.3%)		13/106 (12.3%)
Dyspepsia	0/3 (0%)		12/106 (11.3%)
Dry Mouth	1/3 (33.3%)		10/106 (9.4%)
Oral Mucosal Exfoliation	1/3 (33.3%)		9/106 (8.5%)
Mouth Hemorrhage	0/3 (0%)		9/106 (8.5%)
Flatulence	0/3 (0%)		9/106 (8.5%)
Toothache	0/3 (0%)		7/106 (6.6%)
Gastroesophageal Reflux	0/3 (0%)		7/106 (6.6%)
Dysphagia	1/3 (33.3%)		6/106 (5.7%)
Abdominal Upper Pain	0/3 (0%)		7/106 (6.6%)
Oral Dysaesthesia	0/3 (0%)		6/106 (5.7%)
Loose Tooth	1/3 (33.3%)		1/106 (0.9%)
General disorders
Fatigue	2/3 (66.7%)		80/106 (75.5%)
Pyrexia	1/3 (33.3%)		31/106 (29.2%)
Edema Peripheral	0/3 (0%)		25/106 (23.6%)
Asthenia	0/3 (0%)		15/106 (14.2%)
Chills	0/3 (0%)		14/106 (13.2%)
Influenza-like Illness	0/3 (0%)		11/106 (10.4%)
Glossodynia	0/3 (0%)		11/106 (10.4%)
Mucosal Inflammation	0/3 (0%)		8/106 (7.5%)
Malaise	0/3 (0%)		8/106 (7.5%)
Chest Pain	1/3 (33.3%)		7/106 (6.6%)
Disease Progression	0/3 (0%)		6/106 (5.7%)
Infections and infestations
Urinary Tract Infection	0/3 (0%)		21/106 (19.8%)
Palmar-Plantar Erythrodysaesthesia Syndrome	0/3 (0%)		20/106 (18.9%)
Upper Respiratory Infection	2/3 (66.7%)		4/106 (3.8%)
Bronchitis	0/3 (0%)		6/106 (5.7%)
Sinusitis	1/3 (33.3%)		4/106 (3.8%)
Injury, poisoning and procedural complications
Back Pain	0/3 (0%)		23/106 (21.7%)
Infusion Related Reaction	0/3 (0%)		23/106 (21.7%)
Tooth Fracture	1/3 (33.3%)		1/106 (0.9%)
Investigations
Weight Decreased	0/3 (0%)		21/106 (19.8%)
Blood Thyroid Stimulating Hormone Increased	1/3 (33.3%)		14/106 (13.2%)
Aspartate Aminotransferase	0/3 (0%)		11/106 (10.4%)
Alanine Aminotransferase	0/3 (0%)		10/106 (9.4%)
Blood Bilirubin Increased	1/3 (33.3%)		8/106 (7.5%)
Lipase Increased	0/3 (0%)		7/106 (6.6%)
Blood Calcium Decreased	1/3 (33.3%)		3/106 (2.8%)
Metabolism and nutrition disorders
Decreased Appetite	2/3 (66.7%)		47/106 (44.3%)
Dehydration	0/3 (0%)		15/106 (14.2%)
Hypokalemia	0/3 (0%)		11/106 (10.4%)
Hyponatremia	0/3 (0%)		9/106 (8.5%)
Hypomagnesemia	1/3 (33.3%)		8/106 (7.5%)
Hypocalcemia	1/3 (33.3%)		7/106 (6.6%)
Hyperglycemia	2/3 (66.7%)		4/106 (3.8%)
Musculoskeletal and connective tissue disorders
Pain in Extremity	0/3 (0%)		18/106 (17%)
Arthralgia	2/3 (66.7%)		14/106 (13.2%)
Myalgia	1/3 (33.3%)		10/106 (9.4%)
Musculoskeletal Chest Pain	0/3 (0%)		8/106 (7.5%)
Muscle Spasms	0/3 (0%)		7/106 (6.6%)
Nervous system disorders
Headache	2/3 (66.7%)		75/106 (70.8%)
Dysgeusia	2/3 (66.7%)		31/106 (29.2%)
Dizziness	1/3 (33.3%)		19/106 (17.9%)
Migraine	0/3 (0%)		13/106 (12.3%)
Neuropathy Peripheral	0/3 (0%)		7/106 (6.6%)
Hypoaesthesia	1/3 (33.3%)		3/106 (2.8%)
Psychiatric disorders
Insomnia	1/3 (33.3%)		22/106 (20.8%)
Anxiety	0/3 (0%)		17/106 (16%)
Depression	0/3 (0%)		8/106 (7.5%)
Renal and urinary disorders
Acute Kidney Injury	0/3 (0%)		9/106 (8.5%)
Urinary Hesitation	1/3 (33.3%)		0/106 (0%)
Respiratory, thoracic and mediastinal disorders
Epistaxis	3/3 (100%)		73/106 (68.9%)
Dyspnea	1/3 (33.3%)		37/106 (34.9%)
Cough	2/3 (66.7%)		22/106 (20.8%)
Pleural Effusion	0/3 (0%)		16/106 (15.1%)
Oropharyngeal Pain	1/3 (33.3%)		13/106 (12.3%)
Nasal Congestion	0/3 (0%)		12/106 (11.3%)
Dysphonia	1/3 (33.3%)		11/106 (10.4%)
Hypoxia	0/3 (0%)		11/106 (10.4%)
Pneumothorax	0/3 (0%)		7/106 (6.6%)
Hemoptysis	1/3 (33.3%)		4/106 (3.8%)
Respiratory Tract Congestion	2/3 (66.7%)		0/106 (0%)
Dyspnea Exertional	1/3 (33.3%)		3/106 (2.8%)
Skin and subcutaneous tissue disorders
Rash	0/3 (0%)		17/106 (16%)
Skin Hypopigmentation	1/3 (33.3%)		14/106 (13.2%)
Hair Color Changes	0/3 (0%)		15/106 (14.2%)
Telangiectasia	0/3 (0%)		14/106 (13.2%)
Erythema	0/3 (0%)		13/106 (12.3%)
Pruritus	0/3 (0%)		10/106 (9.4%)
Dry Skin	0/3 (0%)		8/106 (7.5%)
Alopecia	0/3 (0%)		7/106 (6.6%)
Rash Maculo-Papular	0/3 (0%)		6/106 (5.7%)
Dermatitis Acneiform	0/3 (0%)		6/106 (5.7%)
Vitiligo	1/3 (33.3%)		1/106 (0.9%)
Skin Ulcer	1/3 (33.3%)		1/106 (0.9%)
Skin Atrophy	1/3 (33.3%)		1/106 (0.9%)
Vascular disorders
Hypertension	2/3 (66.7%)		46/106 (43.4%)
Flushing	0/3 (0%)		22/106 (20.8%)
Hypotension	0/3 (0%)		14/106 (13.2%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

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

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