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Sym021 in Combination With Either Sym022 or Sym023 or Sym023 and Irinotecan in Patients With Recurrent Advanced Selected Solid Tumor Malignancies

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ClinicalTrials.gov Identifier: NCT04641871
Recruitment Status : Active, not recruiting
First Posted : November 24, 2020
Last Update Posted : March 1, 2023
Sponsor:
Information provided by (Responsible Party):
Symphogen A/S

Study Description
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Brief Summary:
The study will evaluate the preliminary efficacy of 3 combinations (Sym021+Sym022, Sym021+Sym023 and Sym021+Sym023+irinotecan) in patients with biliary tract carcinomas (BTC) and with esophageal squamous cell carcinoma (ESCC) by assessing overall response rates (ORRs) per Investigator assessment using Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 The study will also evaluate the safety and tolerability profile of the 3 combinations

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

Detailed Description:

The study will evaluate safety and efficacy in patients with:

  • Biliary tract carcinomas patients who have progressed on one prior line of gemcitabine and platinum-based chemotherapy in the metastatic setting.
  • Esophageal squamous cell carcinoma patients who have progressed on one prior line of platinum-based chemotherapy in the metastatic setting.

The trial is set up as 3 sub-studies.

  • Sub-study 1 includes biliary tract carcinoma patients and is composed of 2 investigational combination treatment arms (Sym021+Sym022 [Arm A] and Sym021+Sym023 [Arm B]).
  • Sub-study 2, includes biliary tract carcinoma patients and is composed of one investigational combination treatment arm:Sym021+Sym023+irinotecan. A safety lead- in phase is included to assess tolerability of the combination. A Study Safety Team will review clinical and laboratory safety data and will make decisions regarding the continued enrollment after the safety lead-in phase.
  • Sub-Study 3, includes esophageal squamous cell carcinoma patients and is composed of one investigational combination treatment arm: Sym021+Sym023+irinotecan. Dose of irinotecan in this arm will be selected based upon the safety lead in in sub-study 2 period.

August 2021 : Based upon results from a recent per protocol Interim Analysis (IA) it is has been decided as of 3rd of August 2021 to stop further enrollment into Sub-study 1 Arm A (Sym021+Sym022). Future patients will be allocated to either Sub-study 1 Arm B (Sym021+Sym023) or Sub-study 2 (Sym021+Sym023+irinotecan).

Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 148 participants
Allocation: Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: An Exploratory, Open-label, Multicenter Phase 1b Trial to Evaluate Safety and Efficacy of Sym021 (Anti-PD 1) in Combination With Either Sym022 (Anti-LAG-3) or Sym023 (Anti-TIM-3) or Sym023 and Irinotecan in Patients With Recurrent Advanced Selected Solid Tumor Malignancies
Actual Study Start Date : October 12, 2020
Estimated Primary Completion Date : April 2024
Estimated Study Completion Date : January 2025

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Sym021+Sym022 [ARM A] for BTC patients
Sym021 will be infused over approximately 30 minutes (+10 minutes), followed by a 30-minute post-dosing interval before infusion of Sym022 over approximately 30 minutes (+10 minutes). The duration of each infusion may be extended by 30 minutes, or longer, if indicated.
 Drug: Sym021
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-PD-1

Drug: Sym022
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-LAG-3
Experimental: Sym021+Sym023 [ARM B] for BTC patients
Sym021 will be infused over approximately 30 minutes (+10 minutes), followed by a 30-minute post-dosing interval before infusion of Sym023 over approximately 30 minutes (+10 minutes). The duration of each infusion may be extended by 30 minutes, or longer, if indicated.
 Drug: Sym021
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-PD-1

Drug: Sym023
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-TIM-3
Experimental: Sym021+Sym023+irrinotecan for BTC patients
Sym021 will be infused over approximately 30 minutes (+10 minutes), followed by a 30-minute post-dosing interval before infusion of Sym023 over approximately 30 minutes (+10 minutes). The duration of each infusion may be extended by 30 minutes, or longer, if indicated. After another 30-minute post-dosing interval, irinotecan will be infused over 90 minutes.
 Drug: Sym021
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-PD-1

Drug: Sym023
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-TIM-3

Drug: Irinotecan Hydrochloride
IV infusion over 90 min on day 1 and 15 of the first 2 cycles. After 2 cycles of treatment, irinotecan may be discontinued at the Investigator's discretion
Experimental: Sym021+Sym023+irrinotecan for ESCC patients
Sym021 will be infused over approximately 30 minutes (+10 minutes), followed by a 30-minute post-dosing interval before infusion of Sym023 over approximately 30 minutes (+10 minutes). The duration of each infusion may be extended by 30 minutes, or longer, if indicated. After another 30-minute post-dosing interval, irinotecan will be infused over 90 minutes.
 Drug: Sym021
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-PD-1

Drug: Sym023
IV infusion over 30 minutes on day 1 and 15 of each cycle.
Other Name: Anti-TIM-3

Drug: Irinotecan Hydrochloride
IV infusion over 90 min on day 1 and 15 of the first 2 cycles. After 2 cycles of treatment, irinotecan may be discontinued at the Investigator's discretion


Outcome Measures
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Primary Outcome Measures :
  1. To evaluate the preliminary efficacy of the combinations Sym021+Sym022, Sym021+Sym023 and Sym021+Sym023+irinotecan in patients with BTC or ESCC by assessing overall response rates (ORRs) per Investigator assessment using RECISTv.1.1 [ Time Frame: Until disease progression or end of study, whichever comes first, assessed up to 24 months ]
    Objective Response Rate (ORR) per Investigator assessment of antitumor activity (based on radiological evidence per RECIST v1.1)

  2. To evaluate the incidence, severity, and relationship of (S)AEs collected from administration of the first dose of study drug until 30 days after the last dose of the 3 combinations (Sym021+Sym022, Sym021+Sym023 and Sym021+Sym023+irrinotecan) [ Time Frame: Through study completion up to 30 days after last dose of the three combinations ]
    Calculation of AE incidence will be based on the number of patients per AE category; AEs in total and sorted by frequency, AEs by relationship, SAEs in total and by relationship, Immune mediated AEs, Fatal AEs

  3. To evaluate the AEs leading to dose interruption, dose delays, and permanent treatment stop of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023 +irinotecan) [ Time Frame: Through study completion up to a maximum of 24 months ]
    Calculation of AE incidence will be based on the number of patients per AE category ; AEs leading to dose interruption, dose delays, and permanent treatment stop


Secondary Outcome Measures :
  1. Peak plasma (irinotecan) and serum( mAbs) Concentration (Cmax) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023+irinotecan) [ Time Frame: First study dose and throughout the trial, up to 2 years ]
    Peak serum concentration (Cmax) for each mAbs in each combination.

  2. Area under the serum concentration versus time curve (AUC) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023+ irinotecan) [ Time Frame: First dose of study drug and throughout the trial, up to 2 years ]
    Area under the serum concentration versus time curve (AUC) for each mAbs in each combination.

  3. Time to reach maximum concentration (Tmax) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023+irinotecan) [ Time Frame: First dose of study drug and throughout the trial, up to 2 years ]
    Time to reach maximum concentration (Tmax) for each mAbs in each combination.

  4. Trough concentration (Ctrough) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023 + irinotecan) [ Time Frame: First dose of study drug and throughout the trial, up to 2 years ]
    Trough concentration (Ctrough) for each mAbs in each combination.

  5. Plasma concentration for irinotecan and its metabolite in the combination Sym021+Sym023+ Irinotecan [ Time Frame: First dose of study drug and throughout the trial, up to 2 years ]
    Plasma concentration at the end of infusion for irinotecan and its metabolite in the combination Sym021+Sym023+ Irinotecan

  6. To confirm the RP2D of each combination [ Time Frame: 36 month ]
    Confirmation of the RP2D, based on the dose-response relationship (in case more than one dose level is implemented), overall tolerability and safety profile, and the PK and pharmacodynamic data

  7. Evaluation of Duration of Response (DOR) [ Time Frame: Until disease progression or end of study, whichever comes first, assessed up to 24 months ]
    Duration of the OR will be determined from the day initial response is observed to day of progression is observed. Number and percentages of patients with documented OR will be presented.

  8. Evaluation of Progression-Free Survival (PFS) [ Time Frame: From first study drug dose until disease progression or end of study, whichever comes first, assessed up to 24 months ]
    Will be calculated as from the first study drug dose to the day progression of disease is confirmed radiological or date of death.

  9. Evaluation of Disease Control Rate (DCR), defined as CR, PR, or stable disease (SD) ≥6 months [ Time Frame: Until disease progression or end of study, whichever comes first, assessed up to 6 months ]
    Will be calculated according to standard response criteria

  10. Evaluation of duration of response. [ Time Frame: Until disease progression or end of study, whichever comes first, assessed up to 24 months ]
    Will be calculated from the day the initial response is observed to the day progression of disease is observed

  11. Evaluation of Objective Response Rate (ORR) per Investigator assessment (based on Immunotherapeutics Response Evaluation Criteria in Solid Tumors [iRECIST]) [ Time Frame: Until disease progression or end of study, whichever comes first, assessed up to 24 months ]
    Will be based on Investigators assessment on Immunotherapeutic Response Evaluation Criteria in Solid Tumors (iRECIST)

  12. Evaluation Overall Survival (OS) [ Time Frame: From first dose of study drug until death or latest survival follow-up assessed up to 30 month ]
    Overall survival will be derived from start of treatment until death or latest survival follow-up.

  13. Evaluation of immunogenicity of each antibody drug in the combinations [ Time Frame: From screening up to 30 months ]
    Occurrence of antidrug antibody (ADA) measured in serum at selected time points during the study


Eligibility Criteria
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Information from the National Library of Medicine

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

Inclusion Criteria:

For Sub-study 1 and 2:

  • Patients with locally advanced or metastatic biliary tract carcinoma including adenocarcinoma of the intra- and/or extra-hepatic bile ducts and gallbladder carcinoma. Patients with ampullary cancers are excluded.
  • Patients must only have received and progressed on or be intolerant of first-line gemcitabine and platinum-based chemotherapy in metastatic/advanced setting and should not have received prior anti-PD-(L)1 therapy. Patients with known fibroblast growth factor receptor 2 (FGFR2) fusion or rearrangement, or isocitrate dehydrogenase 1 (IDH1) mutation will be excluded. Prior anti-PD-(L)1 therapy may be allowed during the trial if regulatory approval for such therapy is obtained while this trial is enrolling.

For Sub-study 3:

  • Patients with with locally advanced or metastatic esophageal squamous cell carcinoma
  • Patients must only have received and progressed on or be intolerant of first-line platinum-based chemotherapy in metastatic/advanced setting and should have received prior anti-PD-(L)1 therapy. Patients with mixed adenosquamous histology cancers are excluded.

For all Sub-studies :

  • Patients with measurable disease according to RECIST v1.1
  • Patients with an ECOG PS of 0 or 1, and anticipated life expectancy of ≥3 months
  • Patients must have adequate organ function as indicated by laboratory values
  • Adequate contraception required as appropriate

Exclusion Criteria:

  • Patients with central nervous system (CNS) malignancy, untreated or unstable metastases
  • Patients with significant cardiovascular disease

  • Patients with

    1. Active thrombosis, or a history of deep vein thrombosis or pulmonary embolism, within 4 weeks prior to the first study drug dose
    2. Active uncontrolled bleeding or a known bleeding diathesis
  • Patients with a significant pulmonary disease or condition
  • Patients with a current or recent (within 6 months) significant gastrointestinal disease or condition
  • Patients with Gilbert's syndrome or patients with UGT1A1*28 homozygosity (also known as UGT1A1 7/7 genotype)
  • Patients with a significant ocular disease or condition
  • Patients with an active, known or suspected autoimmune disease
  • Patients with any other serious/active/uncontrolled infection
  • Patients with a history of organ transplantation
  • Patients with human immunodeficiency virus (HIV) (HIV 1/2 antibodies) or active infection with hepatitis B virus or hepatitis C virus
  • Prior therapy with irinotecan
  • For Sub-study 1 and Sub-study 2: Anti-PD-(L)1, anti -LAG-3* or anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other immuno-oncology (IO) therapies.
  • For Sub-study 3: Anti-TIM-3 containing regimen, or combination with any other systemic or localized therapy or any other IO therapies (other than anti-PD-(L)1 agents).
  • Patients must not be on warfarin, if they have a history of acute immune-related thrombocytopenia; patients must not be on strong cytochrome P450 (CYP) 3A4 inducers, strong CYP3A4 inhibitors, or strong UGT1A1 inhibitors.
  • Patients with a known or suspected hypersensitivity to any of the excipients of formulated study drug
  • Patients with unresolved >Grade 1 toxicity associated with any prior antineoplastic therapy
  • Sub-study 1 and Sub-study 2: Patients with known FGFR2 fusion or rearrangement, or IDH1 mutation.
  • For Sub-study 3: Patients with a history of significant toxicities associated with previous administration of immune checkpoint inhibitors that necessitated permanent discontinuation of that therapy.
Contacts and Locations
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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): NCT04641871


Locations
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Sponsors and Collaborators
Symphogen A/S
Investigators
Layout table for investigator information
Principal Investigator: Nehal Lakhani, MD START Midwest
More Information
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Responsible Party: Symphogen A/S
ClinicalTrials.gov Identifier: NCT04641871    
Other Study ID Numbers: Sym021-02
First Posted: November 24, 2020    Key Record Dates
Last Update Posted: March 1, 2023
Last Verified: February 2023
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
Anti-PD-1
PD-1
PD1
Anti-TIM-3
TIM-3
TIM3
 Cholangiocarcinoma
CCA
Biliary Tract Carcinomas
Gallbladder
Esophageal Squamous Cell Carcinoma
ESCC
Irinotecan
Additional relevant MeSH terms:
Layout table for MeSH terms
Neoplasms
Neoplasm Metastasis
Neoplastic Processes
Pathologic Processes
Irinotecan
 Topoisomerase I Inhibitors
Topoisomerase Inhibitors
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Antineoplastic Agents