Sym013 (Pan-HER) in Patients With Advanced Epithelial Malignancies

Symphogen

Status and phase: Terminated; Phase 2; Phase 1

Conditions: Oncology

Treatments: Drug: Sym013

Study type: Interventional

Funder types: Industry

Identifiers

NCT02906670

Sym013-01

Details and patient eligibility

About

This is the first study to test Sym013 (Pan-HER) in humans. The primary purpose of this study is to see if Sym013 is safe and effective for patients with advanced epithelial malignancies without available therapeutic options.

Full description

This is an open-label, multicenter trial composed of 2 parts in which Sym013 will be evaluated when administered by intravenous infusion in patients with advanced epithelial malignancies without available therapeutic options.

Part 1 is a Phase 1a dose-escalation evaluating weekly (Q1W) and every second week (Q2W) schedules of administration in separate dose-escalation cohorts to determine the recommended phase 2 dose (RP2D) and regimen of Sym013.

Part 2 is a Phase 2a dose-expansion at the RP2D and regimen. Four (4) dose-expansion cohorts will be evaluated in this part of the trial and will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets. Patients will be entered, depending upon either a defined molecular profile or profiles, or their underlying malignancy, to 1 of 4 corresponding expansion cohorts: Cohort A, Cohort B, Cohort C, or Cohort D.

Enrollment: 32 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion criteria

Main inclusion criteria all patients, Part 1 and Part 2:

• Male or female, at least 18 years of age at the time of informed consent
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1
• Life expectancy >3 months assessed during Screening
• Documented (histologically- or cytologically-proven) epithelial malignancy that is locally advanced or metastatic, having received all therapy known to confer clinical benefit

Additional inclusion criteria applicable to Part 2 ONLY:

• Epithelial malignancy (tumor types to be determined), measurable according to RECIST v1.1 that has been confirmed by computed tomography (CT) or magnetic resonance imaging (MRI) within 4 weeks prior to C1/D1
• Willingness to undergo a pre-and post-dosing biopsy (total of 2 biopsies) from primary or metastatic tumor site(s) considered safe for biopsy

Exclusion criteria

• Any antineoplastic agent for the primary malignancy (standard or investigational) without delayed toxicity within 4 weeks or 5 plasma half-lives (whichever is shortest) prior to C1/D1, except nitrosoureas and mitomycin C within 6 weeks prior to C1/D1.

• Part 2 ONLY: Radiotherapy against target lesions within 4 weeks prior to C1/D1, unless there is documented progression of the lesion following radiotherapy

• Immunosuppressive or systemic hormonal therapy (>10 mg daily prednisone equivalent) within 2 weeks prior to C1/D1 with exceptions

• Use of hematopoietic growth factors within 2 weeks prior to C1/D1

• Active second malignancy or history of another malignancy within the last 3 years, with allowed exceptions

• Central nervous system (CNS) malignancies including:

  1. Primary malignancies of the CNS
  2. Known, untreated CNS or leptomeningeal metastases, or spinal cord compression; patients with any of these not controlled by prior surgery or radiotherapy, or symptoms suggesting CNS metastatic involvement for which treatment is required

• Inadequate recovery from an acute toxicity associated with any prior antineoplastic therapy

• Major surgical procedure within 4 weeks prior to C1/D1 or inadequate recovery from any prior surgical procedure

• Non-healing wounds on any part of the body

• Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to C1/D1, unless adequately treated and stable

• Active uncontrolled bleeding or a known bleeding diathesis

• Significant gastrointestinal abnormalities

• Significant cardiovascular disease or condition

• Abnormal hematologic, renal or hepatic function

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Parallel Assignment

Masking: None (Open label)

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32 participants in 14 patient groups

1 mg/kg Q1W

Experimental group

Description:

Phase 1a: Patients are administered a weekly dose of 1 mg/kg of Sym013 until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.

Treatment:

Drug: Sym013

2 mg/kg Q1W

Experimental group

Description:

Phase 1a: Patients are administered a weekly dose of 2 mg/kg of Sym013 until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.

Treatment:

Drug: Sym013

4 mg/kg Q1W

Experimental group

Description:

Phase 1a: Patients are administered a weekly dose of 4 mg/kg of Sym013 until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.

Treatment:

Drug: Sym013

6 mg/kg Q1W + Prophylaxis

Experimental group

Description:

Phase 1a: Patients are administered a weekly dose of 6 mg/kg of Sym013 + premedication until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw. Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.

Treatment:

Drug: Sym013

9 mg/kg Q1W + Prophylaxis

Experimental group

Description:

Phase 1a: Patients are administered a weekly dose of 9 mg/kg of Sym013 + premedication until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw. Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.

Treatment:

Drug: Sym013

6 mg/kg Q2W

Experimental group

Description:

Phase 1a: Patients are administered a dose of 6 mg/kg of Sym013 every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.

Treatment:

Drug: Sym013

9 mg/kg Q2W

Experimental group

Description:

Phase 1a: Patients are administered a dose of 9 mg/kg of Sym013 every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw.

Treatment:

Drug: Sym013

9 mg/kg Q2W + Prophylaxis

Experimental group

Description:

Phase 1a: Patients are administered a dose of 9 mg/kg of Sym013 + premedication every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw. Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.

Treatment:

Drug: Sym013

12 mg/kg Q2W + Prophylaxis

Experimental group

Description:

Phase 1a: Patients are administered a dose of 12 mg/kg of Sym013 + premedication every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw. Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.

Treatment:

Drug: Sym013

15 mg/kg Q2W + Prophylaxis

Experimental group

Description:

Phase 1a: Patients are administered a dose of 15 mg/kg of Sym013 + premedication every second week until unacceptable toxicity, progressive disease, termination of the trial or patient decision to withdraw. Premedications for infusion-related reactions included glucocorticoids and an antihistamine (H1 antagonist) prior to each dose of Pan-HER from the beginning of the study. As of Protocol Amendment 5, additional premedications were added which included montelukast, dexamethasone, antihistamine (H2 antagonist), and acetaminophen.

Treatment:

Drug: Sym013

Phase 2a Dose-Expansion Cohort A

Experimental group

Description:

Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.

Treatment:

Drug: Sym013

Phase 2a Dose-Expansion Cohort B

Experimental group

Description:

Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.

Treatment:

Drug: Sym013

Phase 2a Dose-Expansion Cohort C

Experimental group

Description:

Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.

Treatment:

Drug: Sym013

Phase 2a Dose-Expansion Cohort D

Experimental group

Description:

Part 2 is a Phase 2a dose-expansion with Sym013 at the RP2D and regimen. One (1) of 4 tumor types to be evaluated in this arm of the trial will be selected based upon findings from Part 1, additional preclinical data, and additional clinical data available at that time from other agents inhibiting these targets.

Treatment:

Drug: Sym013