Sym004 in Patients With Advanced Solid Tumors

• Sponsor: Symphogen A/S (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01117428
• Collaborator: (none)
• Enrollment: 111
• Locations: 7
• Arm: 1
• Actual Duration (Months): 62
• Patients Per Site: 15.9
• Patients Per Site Per Month: 0.3

Study Details

Study Description

Brief Summary

This trial is designed as a multi-centre, open label, dose-escalation, phase I trial and consists of five parts.

Condition or Disease	Intervention/Treatment	Phase
Metastatic Colorectal Cancer	Drug: Sym004	Phase 1/Phase 2

Detailed Description

Part A investigates the safety and pharmacokinetics (PK) of escalating weekly dosing of Sym004 in patients with recurrent advanced solid tumors.

Part B and C validates the safety, PK and efficacy of weekly dosing of Sym004 at the maximum tolerated dose (MTD) in a homogenous patient population with advanced metastatic colorectal cancer (mCRC) and wild-type Kirsten rat sarcoma (KRAS). Part B will be initiated when a safe dose has been established in Part A.

If MTD equals 12 mg/kg, then part C will explore the 9 mg/kg level.

Part D and E is to validate the safety, PK and efficacy when administered every 2 weeks at doses of 12 mg/kg and 18 mg/kg, respectively.

Part F is to validate safety, PK and efficacy when administered with a single loading dose of 9 mg/kg followed by weekly doses of 6 mg/kg.

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: An Open-label, Multi-center Phase I Dose Escalation Study to Investigate the Safety and Tolerability of Multiple Doses of Sym004 in Patients With Advanced Solid Tumors
• Actual Study Start Date: Mar 1, 2010
• Actual Primary Completion Date: Feb 1, 2015
• Actual Study Completion Date: May 1, 2015

Arms and Interventions

Arm

Intervention/Treatment

Experimental: Sym004

Drug: Sym004; In part A, patients in all dose cohorts will continue weekly treatment with the assigned dose of Sym004 until disease progression. In Part B, patients will continue weekly treatment with the tolerated dose of Sym004 until disease progression. In Part C, patients will receive weekly doses of Sym004 at the dose level below 12 mg/kg i.e. 9 mg/kg until disease progression. In Part D and E, patients will receive doses of Sym004 administered every 2 weeks at dose level 12 mg/kg and 18 mg/kg, respectively until disease progression. In Part F, patients will receive a single loading dose of 9 mg/kg followed by weekly doses of 6 mg/kg.

Outcome Measures

Primary Outcome Measures

1. Number of Participants With Adverse Events (AEs) [Visit 2 until first follow-up visit (up to 66 weeks)]

   The AEs were used as a primary endpoint. AEs were summarized using descriptive statistics and presented overall by system organ class and preferred term. The frequencies of AEs were presented including number and percentages of participants with events and the total number of events.

Secondary Outcome Measures

1. Antitumor Activity [Up to 62 weeks]

   Best Overall Response (OR) on the Full Analysis Set (FAS) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, based on central evaluation with confirmatory CT scan or MRI [Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Overall Response (OR): CR + PR]. Baseline was defined as Visit 2 (pre-infusion). The outcome measure was measured from screening until PD.

2. Antitumor Activity Endpoints - Time-to-event Endpoints [Up to 62 weeks]

   Median Progression Free Survival (PFS) was defined as the time interval without PD from start of first infusion until death or documented PD (i.e. at least a 20% increase in the sum of diameters of target lesions) according to RECIST v1.1. Patients who died without confirmed PD were considered as progressed. Patients who died or showed PD more than 21 days after last treatment were censored (i.e. were considered alive without progression on Day 21 after last treatment). Patients without events were censored at date of last scan or 22 days after last treatment, whichever occurred first. Median Overall Survival (OS) was defined as the time from start of first infusion until date of death from any cause. Patients alive at the time of the analysis or prematurely withdrawn from the trial (e.g. lost to follow-up or consent withdrawn) were censored for the OS analysis. In any case of censoring, the date of censoring was the last time point documenting survival status.

3. Terminal Half-Life (T½) [See Time Frame in the Outcome Measure Description]

   For Part A, the endpoint was not calculated. For Parts B, C and F, the endpoint was calculated for each patient following the first and fourth Sym004 infusions. For Parts D and E, the endpoint was calculated for each patient following the first and third Sym004 infusions. T½ was estimated using non-compartmental methods and actual time points. Outcome Measure Time Frame: Parts B, C and F (Weekly dosing): Sample collection at Visit 2 (1st dose from end of infusion, 1-, 2-, 4-, 8-, 24-, 48-hours) until 1 week post-infusion (168-hours) and at Visit 5 (4th dose from end of infusion, 1-, 2-, 4-, 8-, 24-hours) until 1 week post-infusion (168-hours). Parts D, E (Dosing every second week): Sample collection at Visit 2 (1st dose from end of infusion, 1-, 2-, 4-, 8-, 24-, 48-hours) to end of 3rd dose (from end of infusion, 1-, 2-, 4-, 8-, 24-hours) until 2 weeks post-infusion (336 hours).

Eligibility Criteria

Criteria

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

Inclusion Criteria:

Part A:

1. Patients with refractory or recurrent advanced late stage solid tumors without available therapeutic options .

Part B, C, D, E and F:

1. Patients with refractory or recurrent advanced mCRC and wild-type KRAS who have progressed on epidermal growth factor receptor (EGFR) Ab treatment.

2. Patients wit confirmed response while on treatment anti-EGFR Ab treatment.

3. Documented disease progression during or within 6 months after cessation of anti-EGFR Ab treatment.

4. Patients must be willing to have a biopsy performed from a tumor lesion at screening and at Visit 6.

Part A, B, C, D, E and F:

1. Histologically or cytologically confirmed diagnosis of cancer

2. Failure and/or intolerance to standard chemotherapy

3. Life expectancy of at least 3 months

4. Eastern Cooperative Oncology Group (ECOG) performance status ≤2

Exclusion Criteria:

1. Patients with clinically symptomatic brain metastases.

2. Received the following treatments prior to Visit 2:

• Cytotoxic or cytostatic anti-cancer chemotherapy within 4 weeks

• Total resection or irradiation of the target lesion

• Antibody therapy within 4 weeks and vaccines within 12 weeks

• Tyrosin kinase inhibitors within 4 weeks

• Any investigational agent within 4 weeks

1. Diarrhea CTCAE >1

2. Skin rash CTCAE >1

3. Abnormal organ or bone marrow function.

4. Use of immunosuppressive agents for the past 4 weeks prior to trial start, including systemic corticosteroids used at doses above 20mg/day of prednisolone or equivalent.

5. History of other malignancy within 5 years prior to trial start, with the exception of basal cell carcinoma of the skin and carcinoma in situ of the cervix (not in Part A).

6. Active severe infection, any other concurrent disease or medical conditions that are deemed to interfere with the conduct of the trial as judged by the investigator.

7. Known HIV positive

8. Known active hepatitis B or C

9. Patients with known uncontrolled allergic conditions or allergy to the study drug and/or their components.

10. Clinically significant cardiac disease including unstable angina, acute myocardial infarction within six months from Visit 1, congestive heart failure, and arrhythmia requiring therapy, with the exception of extra systoles or minor conduction abnormalities and controlled and well treated chronic atrial fibrillation.

11. Significant concurrent, uncontrolled medical condition evaluated by the investigator to interfere with effect of the trial drug.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	South Texas Accelerated Research Therapeutics (START)	San Antonio	Texas	United States	78229
2	UZ Brussel, Medische Oncologie	Brussel		Belgium	1090
3	UZ Gasthuisberg, Digestive Oncology Unit	Brussel		Belgium	3000
4	UZ Antwerp, Oncologie	Edegem		Belgium	2650
5	Medical Oncology Department, Vall d´Hebron University Hospital	Barcelona		Spain	08035
6	Servicio de Oncología Médica, Hospital Universitario Virgen del Rocío	Sevilla		Spain	41013
7	Hospital Clínico Universitario de Valencia	Valencia		Spain	46010

Sponsors and Collaborators

• Symphogen A/S

Investigators

• Principal Investigator: Josep Tabernero, MD, PhD, Vall d´Hebron University Hospital

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Symphogen A/S
• ClinicalTrials.gov Identifier: NCT01117428
• Other Study ID Numbers: Sym004-01; 2009-017119-13
• First Posted: May 5, 2010
• Last Update Posted: Oct 15, 2018
• Last Verified: Sep 1, 2018

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Keywords provided by Symphogen A/S: Advanced solid tumors; Metastatic colorectal Cancer
• Additional relevant MeSH terms: Colorectal Neoplasms

Study Results

Participant Flow

Arm/Group Title	Part A: Dose Escalation	Part B: Dose Expansion Cohort	Part C: Dose Expansion Cohort	Part D: Dose Expansion Cohort	Part E: Dose Expansion Cohort	Part F: Dose Expansion Cohort
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004: 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-epidermal growth factor receptor (anti-EGFR) antibody refractory metastatic colorectal cancer (mCRC). Sym004: 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 18 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusions
Period Title: Overall Study
STARTED	20	29	13	12	17	20
COMPLETED	0	0	0	0	0	0
NOT COMPLETED	20	29	13	12	17	20

Baseline Characteristics

Arm/Group Title	Part A: Dose Escalation	Part B: Dose Expansion Cohort	Part C: Dose Expansion Cohort	Part D: Dose Expansion Cohort	Part E: Dose Expansion Cohort	Part F: Dose Expansion Cohort	Total
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004: 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 18 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusions	Total of all reporting groups
Overall Participants	20	29	13	12	17	20	111
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	11 55%	16 55.2%	4 30.8%	5 41.7%	10 58.8%	11 55%	57 51.4%
>=65 years	9 45%	13 44.8%	9 69.2%	7 58.3%	7 41.2%	9 45%	54 48.6%
Sex: Female, Male (Count of Participants)
Female	13 65%	14 48.3%	6 46.2%	6 50%	4 23.5%	6 30%	49 44.1%
Male	7 35%	15 51.7%	7 53.8%	6 50%	13 76.5%	14 70%	62 55.9%
Ethnicity (NIH/OMB) (Count of Participants)
Hispanic or Latino	5 25%	1 3.4%	0 0%	0 0%	1 5.9%	0 0%	7 6.3%
Not Hispanic or Latino	15 75%	28 96.6%	13 100%	12 100%	16 94.1%	20 100%	104 93.7%
Unknown or Not Reported	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
Belgium	0 0%	5 17.2%	1 7.7%	0 0%	0 0%	3 15%	9 8.1%
United States	11 55%	0 0%	0 0%	0 0%	0 0%	0 0%	11 9.9%
Spain	9 45%	24 82.8%	12 92.3%	12 100%	17 100%	17 85%	91 82%
Disease duration (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	4.2 (2.7)	3.6 (1.6)	4.1 (2.7)	2.8 (1.0)	4.0 (2.9)	3.8 (2.3)	NA (NA)

Outcome Measures

1. Primary Outcome

Title	Number of Participants With Adverse Events (AEs)
Description	The AEs were used as a primary endpoint. AEs were summarized using descriptive statistics and presented overall by system organ class and preferred term. The frequencies of AEs were presented including number and percentages of participants with events and the total number of events.
Time Frame	Visit 2 until first follow-up visit (up to 66 weeks)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part A: Dose Escalation	Part B: Dose Expansion Cohort	Part C: Dose Expansion Cohort	Part D: Dose Expansion Cohort	Part E: Dose Expansion Cohort	Part F: Dose Expansion Cohort
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004: 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 18 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusions
Measure Participants	20	29	13	12	17	20
Count of Participants [Participants]	20 100%	29 100%	13 100%	12 100%	17 100%	20 100%

2. Secondary Outcome

Title	Antitumor Activity
Description	Best Overall Response (OR) on the Full Analysis Set (FAS) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, based on central evaluation with confirmatory CT scan or MRI [Complete Response (CR): disappearance of all target lesions; Partial Response (PR): at least a 30% decrease in the sum of diameters of target lesions; Progressive Disease (PD): at least a 20% increase in the sum of diameters of target lesions; Stable Disease (SD): neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD; Overall Response (OR): CR + PR]. Baseline was defined as Visit 2 (pre-infusion). The outcome measure was measured from screening until PD.
Time Frame	Up to 62 weeks

Outcome Measure Data

Analysis Population Description

Data for Part A were presented only for the FAS. For Parts B to F, analyses and summaries were performed both for the FAS and for the per protocol population. The FAS was considered the primary analysis population.

Arm/Group Title	Part A: Dose Escalation	Part B: Dose Expansion Cohort	Part C: Dose Expansion Cohort	Part D: Dose Expansion Cohort	Part E: Dose Expansion Cohort	Part F: Dose Expansion Cohort
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004: 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 18 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusions
Measure Participants	20	29	13	12	17	20
Stable Disease	45 225%	58.6 202.1%	46.2 355.4%	16.7 139.2%	70.6 415.3%	65 325%
Progressive Disease	40 200%	24.1 83.1%	30.8 236.9%	75 625%	17.6 103.5%	30 150%
Partial Response	0 0%	6.9 23.8%	7.7 59.2%	0 0%	0 0%	0 0%
Missing	15 75%	6.9 23.8%	7.7 59.2%	0 0%	11.8 69.4%	5 25%
Not Evaluable	0 0%	3.4 11.7%	7.7 59.2%	8.3 69.2%	0 0%	0 0%

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Part E: Dose Expansion Cohort, Part F: Dose Expansion Cohort
	Comments
	Type of Statistical Test	Equivalence
	Comments	Differences between Parts E and F in terms of Best Overall Response evaluated from screening until disease progression.
Statistical Test of Hypothesis	p-Value	0.6645
	Comments	No adjustment, 5% significance level
	Method	Fisher Exact
	Comments

3. Secondary Outcome

Title	Antitumor Activity Endpoints - Time-to-event Endpoints
Description	Median Progression Free Survival (PFS) was defined as the time interval without PD from start of first infusion until death or documented PD (i.e. at least a 20% increase in the sum of diameters of target lesions) according to RECIST v1.1. Patients who died without confirmed PD were considered as progressed. Patients who died or showed PD more than 21 days after last treatment were censored (i.e. were considered alive without progression on Day 21 after last treatment). Patients without events were censored at date of last scan or 22 days after last treatment, whichever occurred first. Median Overall Survival (OS) was defined as the time from start of first infusion until date of death from any cause. Patients alive at the time of the analysis or prematurely withdrawn from the trial (e.g. lost to follow-up or consent withdrawn) were censored for the OS analysis. In any case of censoring, the date of censoring was the last time point documenting survival status.
Time Frame	Up to 62 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Part A: Dose Escalation	Part B: Dose Expansion Cohort	Part C: Dose Expansion Cohort	Part D: Dose Expansion Cohort	Part E: Dose Expansion Cohort	Part F: Dose Expansion Cohort
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004: 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 18 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusions
Measure Participants	20	29	13	12	17	20
Progression Free Survival	3	3.6	3.3	1.4	3.3	3.1
Overall Survival	7.9	6.9	6.2	2.9	6.3	9.6

4. Secondary Outcome

Title	Terminal Half-Life (T½)
Description	For Part A, the endpoint was not calculated. For Parts B, C and F, the endpoint was calculated for each patient following the first and fourth Sym004 infusions. For Parts D and E, the endpoint was calculated for each patient following the first and third Sym004 infusions. T½ was estimated using non-compartmental methods and actual time points. Outcome Measure Time Frame: Parts B, C and F (Weekly dosing): Sample collection at Visit 2 (1st dose from end of infusion, 1-, 2-, 4-, 8-, 24-, 48-hours) until 1 week post-infusion (168-hours) and at Visit 5 (4th dose from end of infusion, 1-, 2-, 4-, 8-, 24-hours) until 1 week post-infusion (168-hours). Parts D, E (Dosing every second week): Sample collection at Visit 2 (1st dose from end of infusion, 1-, 2-, 4-, 8-, 24-, 48-hours) to end of 3rd dose (from end of infusion, 1-, 2-, 4-, 8-, 24-hours) until 2 weeks post-infusion (336 hours).
Time Frame	See Time Frame in the Outcome Measure Description

Outcome Measure Data

Analysis Population Description

For Part A, data could not be reported as the endpoint was not calculated and no pharmacokinetics (PK) analysis set was defined. For Parts B to F, a PK analysis set was used.

Arm/Group Title	Part A: Dose Escalation	Part B: Dose Expansion Cohort	Part C: Dose Expansion Cohort	Part D: Dose Expansion Cohort	Part E: Dose Expansion Cohort	Part F: Dose Expansion Cohort
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004: 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg, weekly - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 12 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 18 mg/kg, once every 2 weeks - i.v. infusions	Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004: 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusion
Measure Participants	0	17	6	12	16	20
1st Dose	74.8 (20.9)	61.8 (20)	65.6 (33.6)	108 (18.9)	66.6 (21.2)
3rd Dose	0 (0)	0 (0)	88.7 (41.8)	120.7 (25.5)	0 (0)
4th Dose	123.6 (38.9)	120.7 (23.5)	0 (0)	0 (0)	91.7 (24)

Adverse Events

Time Frame	The Adverse Event (AE) reporting period for non-serious AEs started at Visit 2 (first dosing visit) and lasted until the first Follow-up Visit (4 weeks following last dose) or end of trial if the patient was withdrawn from the trial without the Follow-up Visits being performed. The AE reporting period for Serious Adverse Events (SAEs) started when the patient signed the informed consent and lasted until termination of the trial.
Adverse Event Reporting Description	Any non-serious signs or symptoms occurring between Visit 1 and start of treatment at Visit 2 were recorded as medical history. In the survival period after end of trial, only SAEs with fatal outcome and SAEs considered related to Sym004 by the Investigator were collected.
Arm/Group Title	Part A: Dose Escalation		Part B: Dose Expansion Cohort		Part C: Dose Expansion Cohort		Part D: Dose Expansion Cohort		Part E: Dose Expansion Cohort		Part F: Dose Expansion Cohort
Arm/Group Description	Dose escalation in patients with refractory or recurrent advanced solid tumors. Sym004 - 0.4 mg/kg, 0.75 mg/kg, 1.5 mg/kg, 3 mg/kg, 6 mg/kg, 9 mg/kg, 12 mg/kg, weekly - i.v. infusions		Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004 - 12 mg/kg, weekly - i.v. infusions		Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004 - 9 mg/kg, weekly - i.v. infusions		Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004 - 12 mg/kg, once every 2 weeks - i.v. infusions		Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004 - 18 mg/kg, once every 2 weeks - i.v. infusions		Dose expansion cohort in patients with advanced anti-EGFR antibody refractory mCRC. Sym004 - 9 mg/kg loading dose followed by 6 mg/kg, weekly - i.v. infusions
All Cause Mortality
	Part A: Dose Escalation		Part B: Dose Expansion Cohort		Part C: Dose Expansion Cohort		Part D: Dose Expansion Cohort		Part E: Dose Expansion Cohort		Part F: Dose Expansion Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	14/20 (70%)		29/29 (100%)		13/13 (100%)		9/12 (75%)		15/17 (88.2%)		14/20 (70%)
Serious Adverse Events
	Part A: Dose Escalation		Part B: Dose Expansion Cohort		Part C: Dose Expansion Cohort		Part D: Dose Expansion Cohort		Part E: Dose Expansion Cohort		Part F: Dose Expansion Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	10/20 (50%)		16/29 (55.2%)		10/13 (76.9%)		7/12 (58.3%)		6/17 (35.3%)		7/20 (35%)
Cardiac disorders
Myocardial infarction	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Gastrointestinal disorders
Ascites	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Constipation	1/20 (5%)	1	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Pancreatic cyst	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Intestinal obstruction	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Subileus	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Gastric hemorrhage	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
General disorders
Asthenia	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
General physical health deterioration	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Performance status decreased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Hepatobiliary disorders
Hyperbilirubinemia	0/20 (0%)	0	1/29 (3.4%)	1	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Cholangitis	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Jaundice	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Jaundice cholestatic	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	2/12 (16.7%)	2	0/17 (0%)	0	0/20 (0%)	0
Immune system disorders
Hypersensitivity	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Infections and infestations
Abdominal abscess	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Esophageal candidiasis	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Peritonitis	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Pneumonia	1/20 (5%)	1	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Sepsis	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Urinary tract infection	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Catheter site infection	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Endocarditis	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Injury, poisoning and procedural complications
Fracture	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Infusion related reaction	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Spinal fracture	1/20 (5%)	2	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Investigations
Blood bilirubin increased	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Metabolism and nutrition disorders
Hypocalcemia	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Hypomagnesemia	1/20 (5%)	1	4/29 (13.8%)	4	0/13 (0%)	0	1/12 (8.3%)	1	2/17 (11.8%)	2	4/20 (20%)	4
Hypophosphatemia	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Arthralgia	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Neck pain	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Neoplasm malignant	7/20 (35%)	7	9/29 (31%)	9	6/13 (46.2%)	6	4/12 (33.3%)	4	1/17 (5.9%)	1	2/20 (10%)	2
Metastases to central nervous system	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Tumor pain	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Nervous system disorders
Spinal cord compression	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Renal and urinary disorders
Obstructive uropathy	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Renal failure acute	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Respiratory, thoracic and mediastinal disorders
Bronchospasm	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Pulmonary embolism	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Dermatitis acneiform	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Dermatosis	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Rash	1/20 (5%)	1	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Vascular disorders
Shock	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Hypovolemic shock	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Other (Not Including Serious) Adverse Events
	Part A: Dose Escalation		Part B: Dose Expansion Cohort		Part C: Dose Expansion Cohort		Part D: Dose Expansion Cohort		Part E: Dose Expansion Cohort		Part F: Dose Expansion Cohort
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	18/20 (90%)		29/29 (100%)		13/13 (100%)		12/12 (100%)		16/17 (94.1%)		20/20 (100%)
Blood and lymphatic system disorders
Anemia	1/20 (5%)	1	4/29 (13.8%)	4	0/13 (0%)	0	1/12 (8.3%)	1	3/17 (17.6%)	3	2/20 (10%)	2
Thrombocytopenia	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Leukocytosis	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Congenital, familial and genetic disorders
Trichomegaly	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Eye disorders
Conjunctivitis	1/20 (5%)	1	10/29 (34.5%)	14	2/13 (15.4%)	4	1/12 (8.3%)	1	4/17 (23.5%)	4	1/20 (5%)	2
Dry eye	1/20 (5%)	1	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	2/20 (10%)	2
Blepharitis	0/20 (0%)	0	1/29 (3.4%)	1	2/13 (15.4%)	2	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Lacrimation increased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Ocular icterus	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Gastrointestinal disorders
Diarrhea	6/20 (30%)	9	10/29 (34.5%)	14	7/13 (53.8%)	13	4/12 (33.3%)	7	10/17 (58.8%)	20	7/20 (35%)	12
Nausea	3/20 (15%)	5	8/29 (27.6%)	13	3/13 (23.1%)	3	4/12 (33.3%)	4	2/17 (11.8%)	2	2/20 (10%)	4
Vomiting	0/20 (0%)	0	5/29 (17.2%)	9	4/13 (30.8%)	8	3/12 (25%)	5	1/17 (5.9%)	1	2/20 (10%)	5
Constipation	0/20 (0%)	0	4/29 (13.8%)	4	2/13 (15.4%)	4	0/12 (0%)	0	3/17 (17.6%)	4	4/20 (20%)	6
Abdominal pain	0/20 (0%)	0	3/29 (10.3%)	3	0/13 (0%)	0	3/12 (25%)	3	2/17 (11.8%)	2	2/20 (10%)	4
Dyspepsia	1/20 (5%)	1	2/29 (6.9%)	2	1/13 (7.7%)	1	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Stomatitis	0/20 (0%)	0	2/29 (6.9%)	2	1/13 (7.7%)	1	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Abdominal pain upper	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	2/20 (10%)	2
Ascites	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Hemorrhoids	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Flatulence	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	3/20 (15%)	3
Dry mouth	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
General disorders
Asthenia	1/20 (5%)	1	7/29 (24.1%)	11	7/13 (53.8%)	10	7/12 (58.3%)	11	7/17 (41.2%)	10	8/20 (40%)	14
Mucosal inflammation	6/20 (30%)	8	10/29 (34.5%)	16	4/13 (30.8%)	7	1/12 (8.3%)	6	4/17 (23.5%)	6	5/20 (25%)	8
Xerosis	0/20 (0%)	0	8/29 (27.6%)	8	2/13 (15.4%)	2	1/12 (8.3%)	1	5/17 (29.4%)	5	3/20 (15%)	4
Edema peripheral	2/20 (10%)	2	4/29 (13.8%)	4	3/13 (23.1%)	3	2/12 (16.7%)	2	0/17 (0%)	0	1/20 (5%)	1
Fatigue	3/20 (15%)	3	4/29 (13.8%)	4	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Edema	2/20 (10%)	2	1/29 (3.4%)	1	1/13 (7.7%)	1	1/12 (8.3%)	2	0/17 (0%)	0	0/20 (0%)	0
Chills	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1
Device occlusion	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Pyrexia	1/20 (5%)	2	3/29 (10.3%)	3	0/13 (0%)	0	1/12 (8.3%)	1	2/17 (11.8%)	5	7/20 (35%)	10
Hepatobiliary disorders
Hyperbilirubinemia	0/20 (0%)	0	1/29 (3.4%)	1	1/13 (7.7%)	1	1/12 (8.3%)	1	2/17 (11.8%)	2	1/20 (5%)	1
Hepatic pain	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	2/20 (10%)	2
Immune system disorders
Hypersensitivity	1/20 (5%)	11	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1
Infections and infestations
Paronychia	3/20 (15%)	4	9/29 (31%)	15	2/13 (15.4%)	4	2/12 (16.7%)	4	4/17 (23.5%)	5	3/20 (15%)	3
Superinfection	2/20 (10%)	4	6/29 (20.7%)	8	1/13 (7.7%)	2	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Urinary tract infection	1/20 (5%)	1	1/29 (3.4%)	2	1/13 (7.7%)	1	1/12 (8.3%)	1	2/17 (11.8%)	2	2/20 (10%)	3
Nasopharyngitis	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	3/20 (15%)	4
Respiratory tract infection	2/20 (10%)	2	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	2/20 (10%)	2
Gastroenteritis	1/20 (5%)	1	1/29 (3.4%)	1	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Skin infection	1/20 (5%)	1	1/29 (3.4%)	1	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Upper respiratory tract infection	2/20 (10%)	4	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Fungal infection	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Nail infection	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Injury, poisoning and procedural complications
Infusion related reaction	3/20 (15%)	3	1/29 (3.4%)	2	0/13 (0%)	0	1/12 (8.3%)	1	2/17 (11.8%)	4	2/20 (10%)	3
Procedural pain	0/20 (0%)	0	2/29 (6.9%)	2	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Ligament sprain	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Toxicity to various agents	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Investigations
Aspartate aminotransferase increased	1/20 (5%)	1	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	3/17 (17.6%)	3	3/20 (15%)	4
Alanine aminotransferase increased	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	2/17 (11.8%)	2	3/20 (15%)	4
Blood alkaline phosphatase increase	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	2/20 (10%)	2
Blood magnesium decreased	1/20 (5%)	1	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Hemoglobin decreased	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Body temperature decreased	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Amylase increased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1
Blood albumin decreased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1
Lipase increased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1
Blood creatinine increased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Platelet count decreased	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Metabolism and nutrition disorders
Hypomagnesemia	5/20 (25%)	5	17/29 (58.6%)	19	6/13 (46.2%)	8	7/12 (58.3%)	9	12/17 (70.6%)	15	9/20 (45%)	14
Decreased appetite	0/20 (0%)	0	9/29 (31%)	9	5/13 (38.5%)	6	4/12 (33.3%)	4	2/17 (11.8%)	2	4/20 (20%)	6
Hypocalcemia	0/20 (0%)	0	10/29 (34.5%)	11	1/13 (7.7%)	1	1/12 (8.3%)	1	1/17 (5.9%)	1	4/20 (20%)	4
Hypokalemia	1/20 (5%)	1	2/29 (6.9%)	4	3/13 (23.1%)	3	2/12 (16.7%)	2	0/17 (0%)	0	2/20 (10%)	2
Hyperglycemia	1/20 (5%)	1	2/29 (6.9%)	2	1/13 (7.7%)	1	1/12 (8.3%)	1	2/17 (11.8%)	2	1/20 (5%)	1
Hypophosphatemia	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Hyperkalemia	1/20 (5%)	1	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Hypoalbuminemia	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Iron deficiency	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Hypertriglyceridemia	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Musculoskeletal and connective tissue disorders
Back pain	2/20 (10%)	3	1/29 (3.4%)	1	1/13 (7.7%)	1	1/12 (8.3%)	1	1/17 (5.9%)	1	3/20 (15%)	4
Musculoskeletal pain	2/20 (10%)	2	1/29 (3.4%)	2	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Muscle spasms	1/20 (5%)	1	1/29 (3.4%)	1	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Arthralgia	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Bone pain	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Groin pain	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Musculoskeletal stiffness	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Tumor pain	1/20 (5%)	2	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Tumor associated fever	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Nervous system disorders
Headache	2/20 (10%)	2	0/29 (0%)	0	1/13 (7.7%)	1	1/12 (8.3%)	1	2/17 (11.8%)	5	0/20 (0%)	0
Dysgeusia	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	3/17 (17.6%)	3	1/20 (5%)	1
Neuropathy peripheral	1/20 (5%)	1	1/29 (3.4%)	1	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Psychiatric disorders
Insomnia	0/20 (0%)	0	3/29 (10.3%)	3	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	2/20 (10%)	2
Depression	0/20 (0%)	0	1/29 (3.4%)	1	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Anxiety	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Renal and urinary disorders
Dysuria	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Leukocyturia	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Urinary incontinence	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Reproductive system and breast disorders
Metrorrhagia	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	2/20 (10%)	2
Atrophic vulvovaginitis	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Pruritus genital	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Respiratory, thoracic and mediastinal disorders
Dyspnea	3/20 (15%)	3	5/29 (17.2%)	5	3/13 (23.1%)	3	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Cough	2/20 (10%)	2	3/29 (10.3%)	3	1/13 (7.7%)	1	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Productive cough	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	2/20 (10%)	2
Wheezing	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Skin and subcutaneous tissue disorders
Rash	8/20 (40%)	9	23/29 (79.3%)	26	10/13 (76.9%)	13	11/12 (91.7%)	12	16/17 (94.1%)	17	18/20 (90%)	26
Dry skin	9/20 (45%)	9	14/29 (48.3%)	14	5/13 (38.5%)	6	2/12 (16.7%)	2	5/17 (29.4%)	5	3/20 (15%)	3
Pruritus	6/20 (30%)	6	13/29 (44.8%)	14	5/13 (38.5%)	7	1/12 (8.3%)	1	7/17 (41.2%)	8	5/20 (25%)	6
Skin fissures	4/20 (20%)	6	10/29 (34.5%)	14	4/13 (30.8%)	4	2/12 (16.7%)	4	2/17 (11.8%)	4	10/20 (50%)	14
Erythema	1/20 (5%)	2	7/29 (24.1%)	8	3/13 (23.1%)	4	0/12 (0%)	0	2/17 (11.8%)	2	1/20 (5%)	1
Dermatitis acneiform	6/20 (30%)	6	5/29 (17.2%)	5	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	2
Alopecia	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	2/20 (10%)	2
Eczema	0/20 (0%)	0	2/29 (6.9%)	2	1/13 (7.7%)	1	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Hypertrichosis	1/20 (5%)	1	3/29 (10.3%)	3	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Nail toxicity	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	1/20 (5%)	1
Onycholysis	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	1/17 (5.9%)	1	1/20 (5%)	1
Pain of skin	2/20 (10%)	2	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Rash maculo-papular	3/20 (15%)	3	0/29 (0%)	0	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Palmar-plantar erythrodysaesthesia syndrome	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0
Scab	0/20 (0%)	0	2/29 (6.9%)	2	0/13 (0%)	0	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Skin hyperpigmentation	0/20 (0%)	0	1/29 (3.4%)	1	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Acne	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Skin exfoliation	0/20 (0%)	0	0/29 (0%)	0	1/13 (7.7%)	1	0/12 (0%)	0	0/17 (0%)	0	0/20 (0%)	0
Rash erythematous	0/20 (0%)	0	0/29 (0%)	0	0/13 (0%)	0	1/12 (8.3%)	1	0/17 (0%)	0	0/20 (0%)	0
Vascular disorders
Hypertension	0/20 (0%)	0	1/29 (3.4%)	1	0/13 (0%)	0	0/12 (0%)	0	1/17 (5.9%)	1	0/20 (0%)	0

Limitations/Caveats

None reported

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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.