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Anti-Infective Agents

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Antibodies, Monoclonal

Trifluridine

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Sym004 will be administered as a loading dose of 9 mg/kg on Cycle 1 Day 1, followed by weekly doses of 6 mg/kg beginning Cycle 1 Day 8.

TAS-102 is commercially available and will be administered as per local prescribing instructions.

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.

Sym004

TAS-102 is a combination of trifluridine, a thymidine-based nucleic acid analogue, and tipiracil, a thymidine phosphorylase inhibitor.

TAS-102

Josep Tabernero, MD, PhD

This is a Phase 3, randomized, open-label, 2-arm trial designed to evaluate overall survival (OS) following treatment with Sym004, an investigational medicinal product (IMP), versus TAS-102 (trifluridine/tipiracil), a comparator (control) agent.

Randomization is in the ratio of 1:1 to either Sym004 (Arm A) or TAS-102 (Arm B) in genomically-selected patients with chemotherapy-refractory or relapsed metastatic colorectal carcinoma (mCRC) and acquired resistance to anti-epidermal growth factor receptor (EGFR) monoclonal antibody (mAb) therapy.

Following consent, centralized genomic analysis will be conducted on blood samples obtained from each potential patient. Double-negative (DN) results as defined in trial inclusion criteria will be required for initial eligibility prior to randomization. Patients with DNmCRC will continue in the screening process. Once deemed fully eligible, patients will be randomized to either Arm A or Arm B (collectively referred to as protocol therapy).

Dosing cycles of 28 days with the assigned protocol therapy will continue until a protocol-specified discontinuation criterion is met. Following treatment discontinuation, patients will continue to be followed for OS.

Sym004 Versus TAS-102 in Patients With mCRC

A Phase 3, Randomized, Open-Label, Multicenter Trial of Sym004 Versus Trifluridine/Tipiracil (TAS-102) in Patients With Chemotherapy-Refractory or Relapsed Metastatic Colorectal Carcinoma and Acquired Resistance to Anti-EGFR Monoclonal Antibody Therapy

Time (in months) from the date of randomization to the date of death. In the absence of death confirmation or for patients alive as of the OS data cut-off date (i.e., date upon reaching 445 deaths), OS will be censored at the date of last study follow-up, or the cut-off date, whichever is earlier.

Time (in months) from the date of randomization until the date of the investigator-assessed radiological disease progression or death due to any cause.

Investigator-assessed radiological disease progression (per RECIST v1.1) with the following key censoring rules:

* Patients who are alive with no disease progression as of the analysis cut-off date will be censored at the date of the last tumor assessment.
* Patients who receive non-study cancer treatment before disease progression will be censored at the date of the last evaluable tumor assessment before the initiation of non-study cancer treatment.
* Patients with clinical, but not radiologic, evidence of progression will be censored at the date of the last evaluable tumor assessment before the clinical progression assessment.

Defined as the proportion of patients with objective evidence of complete response (CR) or partial response (PR). Assessed approximately every 8 weeks (at the end of even-numbered cycles).

Defined as the proportion of patients with objective evidence of CR, PR, or stable disease (SD). Assessed approximately every 8 weeks (at the end of even-numbered cycles).

Time (in months) from the first documentation of response (CR or PR) to the first documentation of objective tumor progression or to death due to any cause, with the same censoring rules as for PFS.

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, from signing of informed consent up to 30 days after the final dose of Sym004.

Serum sampling to assess the potential for ADA formation are planned on the following visits: Cycle 1 Day 1, Cycle 1 Day 15, Cycle 2 Day 1, Day 1 of odd numbered cycles thereafter, the End of Treatment Visit, and the 1-Month Follow-up Visit.

Cmin is defined as the serum concentration at the start of infusion. The serum concentration of Sym004 is the sum of the two constituting mAbs, futuximab and modotuximab. Sparse sampling at 7 timepoints are planned on the following visits: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment Visit.

Cmax is defined as the serum concentration at the end of infusion. The serum concentration of Sym004 is the sum of the two constituting mAbs, futuximab and modotuximab. Sparse sampling at 7 timepoints are planned on the following visits: Cycle 1 Day 1, Cycle 1 Day 8, Cycle 2 Day 1, Cycle 3 Day 1, End of Treatment Visit.

Symphogen A/S

Sym004 will be given as a loading dose of 9 mg/kg on Cycle 1 Day 1 (C1D1), followed by weekly doses of 6 mg/kg beginning C1D8.

For patients that crossover from Arm B and Arm C, Sym004 will be given at the dose level that contains the corresponding dose level of the respective individual antibody (futuximab or modotuximab) prior to crossover.

Futuximab will be given 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 will crossover to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of progressive disease (PD).

Modotuximab will be given 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 will crossover to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of PD.

Futuximab is one of two mAb components that constitute Sym004.

Futuximab

Modotuximab is one of two mAb components that constitute Sym004.

Modotuximab

Scott Kopetz, MD,PhD,FACP

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.

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.

Sym004 Versus Futuximab or Modotuximab in Patients With mCRC

A Ph2, Randomized, Open-Label, Multicenter, Three-Arm Trial of Sym004 Versus Each of Its Component Futuximab and Modotuximab, in Patients With Chemotherapy-Refractory Metastatic Colorectal Carcinoma and Acquired Resistance to Anti-EGFR mAb

Measured From Baseline to End of Trial Participation, as Assessed by the Common Terminology Criteria for AEs (Version 5) (CTCAE v5). 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 CTCAE v5, where applicable.

Sym004 will be given as a loading dose of 9 mg/kg on Cycle 1 Day 1 (C1D1), followed by weekly doses of 6 mg/kg beginning C1D8. For patients that crossover from Arm B and Arm C, Sym004 will be given at the dose level that contains the corresponding dose level of the respective individual antibody (futuximab or modotuximab) prior to crossover.

Arm A (Sym004)

Arm B (Futuximab)

Sym004 will be given as a loading dose of 9 mg/kg on Cycle 1/Day 1 (C1D1), followed by weekly doses of 6 mg/kg beginning C1D8.

Futuximab will be given 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 will be crossed-over to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of progressive disease (PD). Sym004 will be given at the dose level that contains the corresponding dose level of the individual antibody futuximab prior to crossover.

Modotuximab will be given 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 will be crossed-over to Sym004; crossover may occur prior to the EOC2 in the event of early radiographic documentation of PD. Sym004 will be given at the dose level that contains the corresponding dose level of the individual antibody modotuximab prior to crossover.

Arm C (Modotuximab)

Total

Age, Categorical

Sex: Female, Male

Ethnicity (NIH/OMB)

Race (NIH/OMB)

United States

Region of Enrollment

No patients were treated in Arm C due to the early termination of the trial.

Early termination changed the primary objective to assess the safety of the allocated treatment. Collection of data for secondary and exploratory objectives was omitted. The crossover dose plan as detailed was no longer in effect.

Vice President, Global Oncology

At least one AE

At least one SAE

At least one AE related to Sym004

At least one AE related to futuximab

At least one SAE related to Sym004

At least one SAE related to futuximab

The first patient was randomized to Arm B prior to the trial termination date and crossed over to Sym004 at the EOC1. The second patient was randomized to Arm B after the trial termination date, but enrolled to Arm A per Sponsor decision.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
Sym004 Versus TAS-102 in Patients With mCRC	NCT03717038	Metastatic Colo... Colorectal Canc... Carcinoma	Sym004 TAS-102	18 Years -	Symphogen A/S
Sym004 Versus Futuximab or Modotuximab in Patients With mCRC	NCT03549338	Metastatic Colo... Colorectal Canc... Carcinoma	Sym004 Futuximab Modotuximab	18 Years -	Symphogen A/S
Sym004 Versus Futuximab or Modotuximab in Patients With mCRC	NCT03549338	Metastatic Colo... Colorectal Canc... Carcinoma	Sym004 Futuximab Modotuximab	18 Years -	Symphogen A/S
Sym004 Versus Futuximab or Modotuximab in Patients With mCRC	NCT03549338	Metastatic Colo... Colorectal Canc... Carcinoma	Sym004 Futuximab Modotuximab	18 Years -	Symphogen A/S

Spots Global Cancer Trial Database for modotuximab

Every month we try and update this database with for modotuximab cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Spots Global Cancer Trial Database for modotuximab

Every month we try and update this database with for modotuximab cancer trials from around the world to help patients and their families find trials that might be right for them. We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.

Every month we try and update this database with for modotuximab cancer trials from around the world to help patients and their families find trials that might be right for them.
We offer this 100% free of charge and do not endorse any of the trials listed here, we hope it helps you or a loved one.