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Sym004 Versus Futuximab or Modotuximab in Patients With mCRC

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ClinicalTrials.gov Identifier: NCT03549338
Recruitment Status : Terminated (Study was terminated due to administrative reasons)
First Posted : June 8, 2018
Last Update Posted : April 15, 2019
Sponsor:
Information provided by (Responsible Party):
Symphogen A/S

Tracking Information
First Submitted Date  ICMJE May 25, 2018
First Posted Date  ICMJE June 8, 2018
Last Update Posted Date April 15, 2019
Actual Study Start Date  ICMJE November 30, 2018
Actual Primary Completion Date March 9, 2019   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: April 11, 2019)
Assess the safety profile of a weekly dosing regimen of Sym004 versus single agent futuximab or single agent modotuximab based on the occurrence of treatment emergent adverse events (AEs). [ Time Frame: 4 months ]
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology and the severity of the toxicities will be graded according to the Common Terminology Criteria for Adverse Events (Version 5) (CTCAE v5), where applicable.
Original Primary Outcome Measures  ICMJE
 (submitted: May 25, 2018)
Evaluate the relative contribution of futuximab and modotuximab to the antitumor activity of Sym004 as assessed by the Response Evaluation Criteria in Solid Tumors (Version 1.1) (RECIST v1.1). [ Time Frame: 12 months ]
Evaluation following 8 weeks of treatment based on percentage change from baseline in the sum of the diameters of tumors designated as target lesions, as documented at the EOC2 tumor assessment.
Change History Complete list of historical versions of study NCT03549338 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE
 (submitted: May 25, 2018)
Assess the safety profile of a weekly dosing regimen of Sym004 versus single agent futuximab or single agent modotuximab based on the occurrence of treatment emergent adverse events (AEs). [ Time Frame: 12 months ]
AEs will be coded according to the Medical Dictionary for Regulatory Activities (MedDRA) terminology and the severity of the toxicities will be graded according to the Common Terminology Criteria for Adverse Events (Version 5) (CTCAE v5), where applicable.
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Sym004 Versus Futuximab or Modotuximab in Patients With mCRC
Official Title  ICMJE A Phase 2, Randomized, Open-Label, Multicenter, Three-Arm Trial of Sym004 Versus Each of Its Component Monoclonal Antibodies, Futuximab and Modotuximab, in Patients With Chemotherapy-Refractory Metastatic Colorectal Carcinoma and Acquired Resistance to Anti-EGFR Monoclonal Antibody Therapy
Brief Summary This is a Phase 2, randomized, open-label, 3-arm trial in the ratio of 1:1:1 to either Sym004 (Arm A) versus each of its component monoclonal antibodies (mAbs), futuximab (Arm B) or modotuximab (Arm C), in genomically-selected patients with chemotherapy-refractory metastatic colorectal carcinoma (mCRC) and acquired resistance to anti-epidermal growth factor receptor (anti-EGFR) mAb therapy. The study is designed to evaluate the relative antitumor activity of each agent as assessed by imaging studies performed after 8 weeks of treatment.
Detailed Description

Following consent and prior to randomization, genomic analysis will be conducted on blood samples obtained from each potential patient. Triple-negative (TN) results as defined in trial eligibility criteria will be required for initial eligibility. Patients with TNmCRC will continue in the screening process. Once deemed fully eligible, patients will be randomized to Arm A, Arm B, or Arm C.

Dosing cycles of 28 days will continue until documented disease progression (PD) or another criterion for discontinuation is met. Antitumor activity will be assessed at the end of every 2 cycles (every 8 weeks [Q8W]). At the End of Cycle 2 (EOC2) tumor assessment:

  • Patients assigned to Arm A (Sym004) with a documented objective response (OR) or stable disease (SD) will continue to receive Sym004; patients at the EOC2 with documented PD will be discontinued from study
  • Patients assigned to Arm B (futuximab) or Arm C (modotuximab) with a documented OR or SD will be crossed-over to receive Sym004; patients with documented PD at the EOC2 (or prior to the EOC2) will be offered the opportunity to crossover to receive Sym004 or will be discontinued from study

To be considered evaluable for antitumor activity assessment, patients must have completed 2 cycles of dosing inclusive of EOC2 disease imaging studies and must have received any amount of their assigned investigational medicinal product (IMP) during that period, or have PD documented by imaging studies prior to the EOC2. Non-evaluable patients and patients discontinuing from study prior to the EOC2 for reasons other than documented PD will not be replaced.

Note: In December 2018, the decision was made to terminate the trial and enrollment was prematurely discontinued. The primary, secondary, and exploratory objectives are no longer applicable. Only clinical safety-related evaluations will be conducted.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Metastatic Colorectal Cancer
  • Colorectal Cancer Metastatic
  • Carcinoma
Intervention  ICMJE
  • Drug: Sym004
    Sym004 is a 1:1 mixture of two recombinant mAbs (futuximab and modotuximab) which bind specifically to non-overlapping epitopes located in the extracellular domain (ECD) of the EGFR.
  • Drug: Futuximab
    Futuximab is one of two mAb components that constitute Sym004.
  • Drug: Modotuximab
    Modotuximab is one of two mAb components that constitute Sym004.
Study Arms  ICMJE
  • Experimental: Arm A (Sym004)
    Sym004 will be administered as a loading dose of 9 mg/kg on Cycle 1/Day 1 (C1D1), followed by weekly doses of 6 mg/kg beginning C1D8.
    Intervention: Drug: Sym004
  • Experimental: Arm B (Futuximab)

    Futuximab will be administered as a loading dose of 4.5 mg/kg on C1D1, followed by weekly doses of 3 mg/kg beginning C1D8.

    At the End of Cycle 2 (EOC2), ongoing patients from Arm B will be crossed-over from futuximab to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of progressive disease (PD).

    Upon crossover, Sym004 will be administered at the dose level that contains the corresponding dose level of the individual antibody futuximab as was previously being administered (prior to crossover).

    Interventions:
    • Drug: Sym004
    • Drug: Futuximab
  • Experimental: Arm C (Modotuximab)

    Modotuximab will be administered as a loading dose of 4.5 mg/kg on C1D1, followed by weekly doses of 3 mg/kg beginning C1D8.

    At the EOC2, ongoing patients from Arm C will be crossed-over from modotuximab to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of PD.

    Upon crossover, Sym004 will be administered at the dose level that contains the corresponding dose level of the individual antibody modotuximab as was previously being administered (prior to crossover).

    Interventions:
    • Drug: Sym004
    • Drug: Modotuximab
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Terminated
Actual Enrollment  ICMJE
 (submitted: January 14, 2019)
2
Original Estimated Enrollment  ICMJE
 (submitted: May 25, 2018)
54
Actual Study Completion Date  ICMJE March 9, 2019
Actual Primary Completion Date March 9, 2019   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  • Male or female patients, ≥ 18 years of age at the time of obtaining informed consent.
  • Histologically- or cytologically-confirmed mCRC.
  • Microsatellite instability-high (MSI-H) / mismatch repair-deficient (dMMR) tumors must have received prior therapy with pembrolizumab, nivolumab, or other programmed cell death protein-1 (PD-1)/programmed death-ligand 1 (PD-L1) pathway blocker, and must have progressed on that therapy.
  • Meeting the protocol definition of TNmCRC assessed in the screening blood test.
  • mCRC currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor.
  • Measurable disease according to RECIST v1.1, and willingness to undergo a total of 2 biopsies of a primary or metastatic tumor site(s) considered safely accessible for biopsy.
  • Must have received at least 2 prior regimens of standard chemotherapy for mCRC and must have been refractory to or failed (includes intolerance to) those regimens. Prior standard chemotherapy may not have included TAS-102 or regorafenib, but must have included agents as specified in the protocol.
  • "Acquired" resistance to commercially available anti-EGFR mAbs approved for the treatment of mCRC must have:

    1. Received treatment with an anti-EGFR for ≥16 weeks
    2. Progressive disease (PD) documented by imaging or clinical findings less than or equal to 6 calendar months after cessation of previous anti-EGFR mAb treatment
    3. No more than 6 calendar months from last dose of previous anti-EGFR mAb treatment to date of consent for this trial (regardless of the line of therapy in which it was used)
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
  • Not of childbearing potential or who agree to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 3 months after the last dose of study drug.

Exclusion Criteria:

  • Women who are pregnant or lactating or intending to become pregnant before, during, or within 3 months after the last dose of study drug.
  • Prior history of specific mutations (specified in the protocol) in the tumor at the time of any previous assessment.
  • Known, untreated central nervous system (CNS) or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required
  • An active second malignancy or history of another malignancy within the last 5 years, with exceptions.
  • Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to first administration of study drug unless adequately treated and considered by the Investigator to be stable.
  • Active uncontrolled bleeding or a known bleeding diathesis
  • Known clinically significant cardiovascular disease or condition.
  • Non-healing wounds on any part of the body.
  • Significant gastrointestinal abnormality.
  • Skin rash > Grade 1 from prior anti-EGFR therapy at the time of randomization.
  • Unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy

Drugs and Other Treatments Exclusion Criteria:

  • Prior treatment with TAS-102 or regorafenib
  • Any antineoplastic agent for the primary malignancy (standard or investigational) without delayed toxicity within 4 weeks prior to first administration of IMP and during study with exceptions
  • Any other investigational treatments within 4 weeks prior to and during study; includes participation in any medical device or other therapeutic intervention clinical trials
  • Radiotherapy as specified in the protocol
  • Immunosuppressive or systemic hormonal therapy (> 10 mg daily prednisone equivalent) within 2 weeks prior to first administration of IMP and during study; allowed therapies are specified in the protocol.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE Contact information is only displayed when the study is recruiting subjects
Listed Location Countries  ICMJE Germany,   Italy,   Spain,   United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT03549338
Other Study ID Numbers  ICMJE Sym004-13
2018-000618-39 ( EudraCT Number )
Has Data Monitoring Committee No
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Symphogen A/S
Study Sponsor  ICMJE Symphogen A/S
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Scott Kopetz, MD,PhD,FACP The University of Texas MD Anderson Cancer Center
PRS Account Symphogen A/S
Verification Date April 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP