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Sym021 Monotherapy and in Combination With Sym022 or Sym023 in Patients With Advanced Solid Tumor Malignancies or Lymphomas

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ClinicalTrials.gov Identifier: NCT03311412
Recruitment Status : Recruiting
First Posted : October 17, 2017
Last Update Posted : June 11, 2019
Sponsor:
Information provided by (Responsible Party):
Symphogen A/S

Brief Summary:
The primary purpose of this study is to see if Sym021 is safe and tolerable as monotherapy and in combination with either Sym022 or Sym023 for patients with locally advanced/unresectable or metastatic solid tumor malignancies or lymphomas that are refractory to available therapy or for which no standard therapy is available.

Condition or disease Intervention/treatment Phase
Metastatic Cancer Solid Tumor Lymphoma Drug: Sym021 Drug: Sym022 Drug: Sym023 Phase 1

Detailed Description:

Part 1 of this study will evaluate the preliminary safety, tolerability, and dose-limiting toxicities (DLTs) of Sym021, an anti-programmed cell death protein 1 (PD-1) monoclonal antibody (mAb). The goal is to establish the maximum tolerated dose (MTD) and/or recommended Phase 2 dose (RP2D) of sequential escalating doses of Sym021 when administered once every 2 weeks (Q2W) by 30-minute intravenous (IV) infusion. Sym021 will be given to patients in escalating dose cohorts; each patient will be given one fixed dose level.

Part 2 of this study will evaluate the safety, tolerability, and DLTs to establish the MTD and/or RP2D of sequential escalating doses of Sym022 and Sym023 when administered Q2W in combination with the RP2D of Sym021, each by IV infusion. Dose levels of Sym021+Sym022 and Sym021+Sym023 will be evaluated until for each combination the MTD is identified, a maximum administered dose (MAD) is reached, or until a RP2D for the added mAb (Sym022 or Sym023) in combination with Sym021 is selected. Each patient will be given one fixed dose level of an assigned combination.


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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 102 participants
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1, Open-Label, Multicenter Trial Investigating the Safety, Tolerability, and Preliminary Antineoplastic Activity of Sym021 (Anti-PD-1) as Monotherapy and in Combination With Either Sym022 (Anti-LAG-3) or Sym023 (Anti-TIM-3) in Patients With Advanced Solid Tumor Malignancies or Lymphomas
Actual Study Start Date : December 7, 2017
Estimated Primary Completion Date : November 2019
Estimated Study Completion Date : November 2020

Resource links provided by the National Library of Medicine

MedlinePlus related topics: Lymphoma

Arm Intervention/treatment
Experimental: Sym021 Dose Level 1
Part 1, Sym021 monotherapy dose level 1
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Experimental: Sym021 Dose Level 2
Part 1, Sym021 monotherapy dose level 2
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Experimental: Sym021 Dose Level 3
Part 1, Sym021 monotherapy dose level 3
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Experimental: Arm A: Sym021+Sym022 Dose Level 1
Part 2, Arm A: Sym021 RP2D in combination with dose level 1 of Sym022
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym022
Sym022 is a recombinant, fully human antibody that binds LAG-3 and blocks the LAG-3/major histocompatibility complex class II (MHC-II) interaction, thus allowing for increased T-cell proliferation and cytokine production.
Other Name: Anti-LAG-3

Experimental: Arm A: Sym021+Sym022 Dose Level 2
Part 2, Arm A: Sym021 RP2D in combination with dose level 2 of Sym022
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym022
Sym022 is a recombinant, fully human antibody that binds LAG-3 and blocks the LAG-3/major histocompatibility complex class II (MHC-II) interaction, thus allowing for increased T-cell proliferation and cytokine production.
Other Name: Anti-LAG-3

Experimental: Arm A: Sym021+Sym022 Dose Level 3
Part 2, Arm A: Sym021 RP2D in combination with dose level 3 of Sym022
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym022
Sym022 is a recombinant, fully human antibody that binds LAG-3 and blocks the LAG-3/major histocompatibility complex class II (MHC-II) interaction, thus allowing for increased T-cell proliferation and cytokine production.
Other Name: Anti-LAG-3

Experimental: Arm A: Sym021+Sym022 Dose Level 4
Part 2, Arm A: Sym021 RP2D in combination with dose level 4 of Sym022
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym022
Sym022 is a recombinant, fully human antibody that binds LAG-3 and blocks the LAG-3/major histocompatibility complex class II (MHC-II) interaction, thus allowing for increased T-cell proliferation and cytokine production.
Other Name: Anti-LAG-3

Experimental: Arm B: Sym021+Sym023 Dose Level 1
Part 2, Arm B: Sym021 RP2D in combination with dose level 1 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3

Experimental: Arm B: Sym021+Sym023 Dose Level 2
Part 2, Arm B: Sym021 RP2D in combination with dose level 2 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3

Experimental: Arm B: Sym021+Sym023 Dose Level 3
Part 2, Arm B: Sym021 RP2D in combination with dose level 3 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3

Experimental: Arm B: Sym021+Sym023 Dose Level 4
Part 2, Arm B: Sym021 RP2D in combination with dose level 4 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3

Experimental: Arm B: Sym021+Sym023 Dose Level 5
Part 2, Arm B: Sym021 RP2D in combination with dose level 5 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3

Experimental: Arm B: Sym021+Sym023 Dose Level 6
Part 2, Arm B: Sym021 RP2D in combination with dose level 6 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3

Experimental: Arm B: Sym021+Sym023 Dose Level 7
Part 2, Arm B: Sym021 RP2D in combination with dose level 7 of Sym023
Drug: Sym021
Sym021 is a humanized antibody that binds PD-1 with sub-nanomolar affinity and blocks binding of the inhibitory ligands PD-L1 and PD-L2, thus releasing PD-1-mediated inhibition of the immune response.
Other Name: Anti-PD-1

Drug: Sym023
Sym023 is a recombinant, fully human antibody that binds TIM-3 and induces activation of immune cells.
Other Name: Anti-TIM-3




Primary Outcome Measures :
  1. Part 1: Assessment of treatment emergent adverse events (AEs) meeting DLT criteria. [ Time Frame: 12 months ]
    Assess the safety and tolerability of Sym021 monotherapy on a Q2W schedule. Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1.

  2. Part 2: Assessment of treatment emergent adverse events (AEs) meeting DLT criteria. [ Time Frame: 12 months ]
    Assess the safety and tolerability of the Sym021 RP2D in combination with sequential escalating doses of Sym022 and Sym023 on a Q2W schedule. Assessment based on the occurrence of AEs meeting DLT criteria measured during Cycle 1.


Secondary Outcome Measures :
  1. Evaluation of the immunogenicity of Sym021 as a single agent and in combination with Sym022 and Sym023. [ Time Frame: 24 months ]
    Serum sampling to assess the potential for anti-drug antibody (ADA) formation.

  2. Evaluation of objective response (OR) or stable disease (SD). [ Time Frame: 24 months ]
    Assessed by Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST v1.1), Response Evaluation Criteria in Lymphomas 2017 (RECIL 2017), or Immunotherapeutics Response Evaluation Criteria in Solid Tumors (iRECIST), depending on tumor type.

  3. Time to progression (TTP) of disease. [ Time Frame: 24 months ]
    Based on time of enrollment to first evidence of progression on imaging studies, as assessed by RECIST v1.1, RECIL 2017, or iRECIST, depending on tumor type.

  4. Area under the concentration-time curve in a dosing interval (AUC) [ Time Frame: 24 months ]
    Will be estimated using non-compartmental methods and actual timepoints.

  5. Maximum concentration (Cmax) [ Time Frame: 24 months ]
    Will be derived from observed data.

  6. Time to reach maximum concentration (Tmax) [ Time Frame: 24 months ]
    Will be derived from observed data.

  7. Trough concentration (Ctrough) [ Time Frame: 24 months ]
    Will be derived from observed data.

  8. Terminal elimination half-life (T½) [ Time Frame: 24 months ]
    Will be estimated using non-compartmental methods and actual timepoints.

  9. Clearance (CL) [ Time Frame: 24 months ]
    Will be estimated using non-compartmental methods and actual timepoints.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   18 Years and older   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Male or female patients, ≥ 18 years of age at the time of obtaining informed consent.
  • Documented (histologically- or cytologically-proven) solid tumor malignancy that is locally advanced or metastatic; patients with documented lymphoma.
  • Malignancy (solid tumor or lymphoma) that is currently not amenable to surgical intervention due to either medical contraindications or non-resectability of the tumor.
  • Refractory to or intolerant of existing therapy(ies) known to provide clinical benefit.
  • Measurable or non-measurable disease according to RECIST v1.1 or RECIL 2017.
  • Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
  • Persons of childbearing potential agreeing to use a highly effective method of contraception during the study beginning within 2 weeks prior to the first dose and continuing until 6 months after the last dose of study drug(s); men agreeing to refrain from sperm donation during this period.

Exclusion Criteria:

  • Women who are pregnant or intending to become pregnant before, during, or within 6 months after the last dose of study drug; women who are breastfeeding; persons of childbearing potential and not willing to use a highly effective method of contraception.
  • Central nervous system (CNS) malignancies; patients with known, untreated CNS or leptomeningeal metastases, or spinal cord compression, patients with any of the above not controlled by prior surgery or radiotherapy, or patients with symptoms suggesting CNS involvement for which treatment is required.
  • Hematologic malignancies other than lymphoma.
  • Active thrombosis, or a history of deep vein thrombosis (DVT) or pulmonary embolism (PE) within 4 weeks prior to Cycle 1/Day 1 (C1/D1) unless adequately treated and considered stable.
  • Active uncontrolled bleeding or a known bleeding diathesis.
  • Clinically significant cardiovascular disease or condition.
  • Significant ocular disease or condition, including history of an autoimmune or inflammatory disorder.
  • Significant pulmonary disease or condition.
  • Current or recent (within 6 months) significant gastrointestinal (GI) disease or condition.
  • An active, known, or suspected autoimmune disease, or a documented history of autoimmune disease or syndrome, requiring systemic steroids or other immunosuppressive medications.
  • History of organ transplantation (e.g., stem cell or solid organ transplant).
  • History of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy.
  • Patients with unresolved > Grade 1 toxicity associated with any prior antineoplastic therapy except for persistent Grade 2 alopecia, peripheral neuropathy, decreased hemoglobin, lymphopenia, hypomagnesemia, and/or end-organ failure being adequately managed by hormone replacement therapy.
  • Inadequate recovery from any prior surgical procedure, or having undergone any major surgical procedure within 4 weeks prior to C1/D1.
  • Known history of human immunodeficiency virus (HIV) or known active infection with hepatitis B virus (HBV) or hepatitis C virus (HCV).

Drugs and Other Treatments Exclusion Criteria:

  • Part 2 Combination Dose-Escalations ONLY: Prior therapy with:

    • Sym021 or other inhibitors of PD-1/PD-L1.
    • Sym022 or other inhibitors of LAG-3, if participating in Arm A.
    • Sym023 or other inhibitors of TIM-3, if participating in Arm B.
  • 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 first study drug administration and during study, with exceptions.
  • Any other investigational treatments within 2 weeks prior to and during study; includes participation in any medical device or supportive care therapeutic intervention trials.
  • Radiotherapy, with exceptions.
  • Use of live vaccines against infectious diseases 4 weeks prior to first study drug administration and during study.
  • Immunosuppressive or systemic hormonal therapy within 2 weeks prior to first study drug administration and during study, with exceptions.
  • Prophylactic use of hematopoietic growth factors within 1 week prior to first study drug administration and during Cycle 1 of study.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT03311412


Contacts
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Contact: Ulla Holm Hansen, RN +45 8838 2600 uhh@symphogen.com

Locations
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United States, Michigan
South Texas Accelerated Research Therapeutics (START) Midwest Recruiting
Grand Rapids, Michigan, United States, 49503
Contact: Kathy Estkowski, CCRP    616-954-5551    kathy.estkowski@startmidwest.com   
Contact: Yvette C. Cole, RN, BSN, OCN    616-389-1652    yvette.cole@startmidwest.com   
Principal Investigator: Nehal Lakhani, MD, PhD         
United States, Texas
The University of Texas MD Anderson Cancer Center Recruiting
Houston, Texas, United States, 77030
Contact: Yunfang Jiang    713-794-1751    yjiang@mdanderson.org   
Principal Investigator: Jordi Rodon Ahnert, MD         
NEXT Oncology Recruiting
San Antonio, Texas, United States, 78240
Contact: Sarah Gomez    210-595-5670      
Principal Investigator: Anthony W Tolcher, MD         
Canada, Ontario
Princess Margaret Cancer Centre Recruiting
Toronto, Ontario, Canada, M5G 2M9
Contact: Lillian Siu, MD    416-946-2911      
Principal Investigator: Lillian Siu, MD         
Sponsors and Collaborators
Symphogen A/S
Investigators
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Principal Investigator: Lillian Siu, MD, FRCPC Princess Margaret Cancer Centre

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Responsible Party: Symphogen A/S
ClinicalTrials.gov Identifier: NCT03311412     History of Changes
Other Study ID Numbers: Sym021-01
First Posted: October 17, 2017    Key Record Dates
Last Update Posted: June 11, 2019
Last Verified: June 2019
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Symphogen A/S:
Locally advanced/unresectable
Metastatic solid tumor
Lymphoma
Anti-PD-1
PD-1
PD1
Anti-LAG-3
LAG-3
LAG3
Anti-TIM-3
TIM-3
TIM3
Additional relevant MeSH terms:
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Lymphoma
Neoplasms by Histologic Type
Neoplasms
Lymphoproliferative Disorders
Lymphatic Diseases
Immunoproliferative Disorders
Immune System Diseases