Clinical Trials /

Sym004 Versus Futuximab or Modotuximab in Patients With mCRC

NCT03549338

Description:

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.

Related Conditions:
  • Colorectal Carcinoma
Recruiting Status:

Terminated

Phase:

Phase 2

Trial Eligibility

Document

Title

  • Brief Title: Sym004 Versus Futuximab or Modotuximab in Patients With mCRC
  • Official Title: 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

Clinical Trial IDs

  • ORG STUDY ID: Sym004-13
  • SECONDARY ID: 2018-000618-39
  • NCT ID: NCT03549338

Conditions

  • Metastatic Colorectal Cancer
  • Colorectal Cancer Metastatic
  • Carcinoma

Interventions

DrugSynonymsArms
Sym004Arm A (Sym004)
FutuximabArm B (Futuximab)
ModotuximabArm C (Modotuximab)

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Arm A (Sym004)ExperimentalSym004 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.
  • Sym004
Arm B (Futuximab)ExperimentalFutuximab 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).
  • Sym004
  • Futuximab
Arm C (Modotuximab)ExperimentalModotuximab 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).
  • Sym004
  • Modotuximab

Eligibility Criteria

        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

          -  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.
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Secondary Outcome Measures

Measure: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
Safety Issue:
Description: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.

Details

Phase:Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:Symphogen A/S

Trial Keywords

  • Metastatic Colorectal Cancer
  • Colorectal Cancer
  • Carcinoma

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