Sym004 in Patients With Advanced Solid Tumors

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

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

Study Overview

• Status: Completed
• Conditions: Metastatic Colorectal Cancer
• Intervention / Treatment: Drug: Sym004

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 Type: Interventional
• Enrollment (Actual): 111
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Belgium
  • Brussel, Belgium, 1090
    • UZ Brussel, Medische Oncologie
  • Brussel, Belgium, 3000
    • UZ Gasthuisberg, Digestive Oncology Unit
  • Edegem, Belgium, 2650
    • UZ Antwerp, Oncologie
• Spain
  • Barcelona, Spain, 08035
    • Medical Oncology Department, Vall d´Hebron University Hospital
  • Sevilla, Spain, 41013
    • Servicio de Oncología Médica, Hospital Universitario Virgen del Rocío
  • Valencia, Spain, 46010
    • Hospital Clinico Universitario de Valencia
• United States
  • Texas
    • San Antonio, Texas, United States, 78229
      • South Texas Accelerated Research Therapeutics (START)

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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
3. Diarrhea CTCAE >1
4. Skin rash CTCAE >1
5. Abnormal organ or bone marrow function.
6. 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.
7. 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).
8. 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.
9. Known HIV positive
10. Known active hepatitis B or C
11. Patients with known uncontrolled allergic conditions or allergy to the study drug and/or their components.
12. 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.
13. Significant concurrent, uncontrolled medical condition evaluated by the investigator to interfere with effect of the trial drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / 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.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Visit 2 until first follow-up visit (up to 66 weeks)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
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.	Up to 62 weeks
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.	Up to 62 weeks
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).	See Time Frame in the Outcome Measure Description

Collaborators and Investigators

• Sponsor: Symphogen A/S
• Investigators: Principal Investigator: Josep Tabernero, MD, PhD, Vall d´Hebron University Hospital

Publications and helpful links

General Publications

• 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.

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2010
• Primary Completion (Actual): February 1, 2015
• Study Completion (Actual): May 1, 2015

Study Registration Dates

• First Submitted: April 23, 2010
• First Submitted That Met QC Criteria: May 3, 2010
• First Posted (Estimate): May 5, 2010

Study Record Updates

• Last Update Posted (Actual): October 15, 2018
• Last Update Submitted That Met QC Criteria: September 13, 2018
• Last Verified: September 1, 2018

More Information

Terms related to this study

• Keywords: Advanced solid tumors; Metastatic colorectal Cancer
• Additional Relevant MeSH Terms: Digestive System Diseases; Neoplasms; Neoplasms by Site; Gastrointestinal Neoplasms; Digestive System Neoplasms; Gastrointestinal Diseases; Colonic Diseases; Intestinal Diseases; Intestinal Neoplasms; Rectal Diseases; Colorectal Neoplasms
• Other Study ID Numbers: Sym004-01; 2009-017119-13 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No