Back to resultsSym004 in Patients With Advanced Solid Tumors
Primary Purpose
Metastatic Colorectal Cancer
Status
Completed
Phase
Phase 1
Locations
International
Study Type
Interventional
Intervention
Sym004
Sponsored by
About this trial
This is an interventional treatment trial for Metastatic Colorectal Cancer focused on measuring Advanced solid tumors, Metastatic colorectal Cancer
Eligibility Criteria
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:
- Patients with refractory or recurrent advanced mCRC and wild-type KRAS who have progressed on epidermal growth factor receptor (EGFR) Ab treatment.
- Patients wit confirmed response while on treatment anti-EGFR Ab treatment.
- Documented disease progression during or within 6 months after cessation of anti-EGFR Ab treatment.
- 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:
- Histologically or cytologically confirmed diagnosis of cancer
- Failure and/or intolerance to standard chemotherapy
- Life expectancy of at least 3 months
- Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Exclusion Criteria:
- Patients with clinically symptomatic brain metastases.
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
- Diarrhea CTCAE >1
- Skin rash CTCAE >1
- Abnormal organ or bone marrow function.
- 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.
- 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).
- 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.
- Known HIV positive
- Known active hepatitis B or C
- Patients with known uncontrolled allergic conditions or allergy to the study drug and/or their components.
- 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.
- Significant concurrent, uncontrolled medical condition evaluated by the investigator to interfere with effect of the trial drug.
Sites / Locations
- South Texas Accelerated Research Therapeutics (START)
- UZ Brussel, Medische Oncologie
- UZ Gasthuisberg, Digestive Oncology Unit
- UZ Antwerp, Oncologie
- Medical Oncology Department, Vall d´Hebron University Hospital
- Servicio de Oncología Médica, Hospital Universitario Virgen del Rocío
- Hospital Clínico Universitario de Valencia
Arms of the Study
Arm 1
Arm Type
Experimental
Arm Label
Sym004
Arm Description
Outcomes
Primary Outcome Measures
Number of Participants With Adverse Events (AEs)
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
Antitumor Activity
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.
Antitumor Activity Endpoints - Time-to-event Endpoints
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.
Terminal Half-Life (T½)
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).
Full Information
1. Study Identification
Unique Protocol Identification Number
NCT01117428
Brief Title
Sym004 in Patients With Advanced Solid Tumors
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
Study Type
Interventional
2. Study Status
Record Verification Date
September 2018
Overall Recruitment Status
Completed
Study Start Date
March 2010 (Actual)
Primary Completion Date
February 2015 (Actual)
Study Completion Date
May 2015 (Actual)
3. Sponsor/Collaborators
Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Symphogen A/S
4. Oversight
Studies a U.S. FDA-regulated Drug Product
Yes
Studies a U.S. FDA-regulated Device Product
No
Data Monitoring Committee
Yes
5. Study Description
Brief Summary
This trial is designed as a multi-centre, open label, dose-escalation, phase I trial and consists of five parts.
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.
6. Conditions and Keywords
Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Metastatic Colorectal Cancer
Keywords
Advanced solid tumors, Metastatic colorectal Cancer
7. Study Design
Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
111 (Actual)
8. Arms, Groups, and Interventions
Arm Title
Sym004
Arm Type
Experimental
Intervention Type
Drug
Intervention Name(s)
Sym004
Intervention Description
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.
Primary Outcome Measure Information:
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)
Secondary Outcome Measure Information:
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
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
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
10. Eligibility
Sex
All
Minimum Age & Unit of Time
18 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
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:
Patients with refractory or recurrent advanced mCRC and wild-type KRAS who have progressed on epidermal growth factor receptor (EGFR) Ab treatment.
Patients wit confirmed response while on treatment anti-EGFR Ab treatment.
Documented disease progression during or within 6 months after cessation of anti-EGFR Ab treatment.
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:
Histologically or cytologically confirmed diagnosis of cancer
Failure and/or intolerance to standard chemotherapy
Life expectancy of at least 3 months
Eastern Cooperative Oncology Group (ECOG) performance status ≤2
Exclusion Criteria:
Patients with clinically symptomatic brain metastases.
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
Diarrhea CTCAE >1
Skin rash CTCAE >1
Abnormal organ or bone marrow function.
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.
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).
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.
Known HIV positive
Known active hepatitis B or C
Patients with known uncontrolled allergic conditions or allergy to the study drug and/or their components.
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.
Significant concurrent, uncontrolled medical condition evaluated by the investigator to interfere with effect of the trial drug.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Josep Tabernero, MD, PhD
Organizational Affiliation
Vall d´Hebron University Hospital
Official's Role
Principal Investigator
Facility Information:
Facility Name
South Texas Accelerated Research Therapeutics (START)
City
San Antonio
State/Province
Texas
ZIP/Postal Code
78229
Country
United States
Facility Name
UZ Brussel, Medische Oncologie
City
Brussel
ZIP/Postal Code
1090
Country
Belgium
Facility Name
UZ Gasthuisberg, Digestive Oncology Unit
City
Brussel
ZIP/Postal Code
3000
Country
Belgium
Facility Name
UZ Antwerp, Oncologie
City
Edegem
ZIP/Postal Code
2650
Country
Belgium
Facility Name
Medical Oncology Department, Vall d´Hebron University Hospital
City
Barcelona
ZIP/Postal Code
08035
Country
Spain
Facility Name
Servicio de Oncología Médica, Hospital Universitario Virgen del Rocío
City
Sevilla
ZIP/Postal Code
41013
Country
Spain
Facility Name
Hospital Clínico Universitario de Valencia
City
Valencia
ZIP/Postal Code
46010
Country
Spain
12. IPD Sharing Statement
Plan to Share IPD
No
Citations:
PubMed Identifier
25962717
Citation
Dienstmann R, Patnaik A, Garcia-Carbonero R, Cervantes A, Benavent M, Rosello S, Tops BB, van der Post RS, Argiles G, Skartved NJ, Hansen UH, Hald R, Pedersen MW, Kragh M, Horak ID, Braun S, Van Cutsem E, Tolcher AW, Tabernero J. Safety and Activity of the First-in-Class Sym004 Anti-EGFR Antibody Mixture in Patients with Refractory Colorectal Cancer. Cancer Discov. 2015 Jun;5(6):598-609. doi: 10.1158/2159-8290.CD-14-1432. Epub 2015 May 11.
Results Reference
derived
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Sym004 in Patients With Advanced Solid Tumors
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