Clinical trial NCT04641871: Sym021 in Combination With Either Sym022 or Sym023 or Sym023 and Irinotecan in Patients With Recurrent Advanced Selected Solid Tumor Malignancies
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
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
Conditions: Metastatic Cancer
Solid Tumor
Keywords: 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
Lead sponsor: Symphogen A/S
Sponsor class: INDUSTRY
First posted: 2020-11-24
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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

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).

Eligibility 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.

Primary outcomes:
measure: 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
timeFrame: Until disease progression or end of study, whichever comes first, assessed up to 24 months
measure: 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)
timeFrame: Through study completion up to 30 days after last dose of the three combinations
measure: 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)
timeFrame: Through study completion up to a maximum of 24 months
Secondary outcomes:
measure: Peak plasma (irinotecan) and serum( mAbs) Concentration (Cmax) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023+irinotecan)
timeFrame: First study dose and throughout the trial, up to 2 years
measure: Area under the serum concentration versus time curve (AUC) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023+ irinotecan)
timeFrame: First dose of study drug and throughout the trial, up to 2 years
measure: Time to reach maximum concentration (Tmax) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023+irinotecan)
timeFrame: First dose of study drug and throughout the trial, up to 2 years
measure: Trough concentration (Ctrough) of the 3 combinations (Sym021+Sym022 and Sym021+Sym023 and Sym021+Sym023 + irinotecan)
timeFrame: First dose of study drug and throughout the trial, up to 2 years
measure: Plasma concentration for irinotecan and its metabolite in the combination Sym021+Sym023+ Irinotecan
timeFrame: First dose of study drug and throughout the trial, up to 2 years
measure: To confirm the RP2D of each combination
timeFrame: 36 month
measure: Evaluation of Duration of Response (DOR)
timeFrame: Until disease progression or end of study, whichever comes first, assessed up to 24 months
measure: Evaluation of Progression-Free Survival (PFS)
timeFrame: From first study drug dose until disease progression or end of study, whichever comes first, assessed up to 24 months
measure: Evaluation of Disease Control Rate (DCR), defined as CR, PR, or stable disease (SD) ≥6 months
timeFrame: Until disease progression or end of study, whichever comes first, assessed up to 6 months
measure: Evaluation of duration of response.
timeFrame: Until disease progression or end of study, whichever comes first, assessed up to 24 months
measure: Evaluation of Objective Response Rate (ORR) per Investigator assessment (based on Immunotherapeutics Response Evaluation Criteria in Solid Tumors [iRECIST])
timeFrame: Until disease progression or end of study, whichever comes first, assessed up to 24 months
measure: Evaluation Overall Survival (OS)
timeFrame: From first dose of study drug until death or latest survival follow-up assessed up to 30 month
measure: Evaluation of immunogenicity of each antibody drug in the combinations
timeFrame: From screening up to 30 months
Other outcomes:
Locations:
city: Aurora
country: United States
facility: University of Colorado
state: Colorado
city: Jacksonville
country: United States
facility: Mayo Clinic - Jacksonville
state: Florida
city: Tampa
country: United States
facility: Moffitt Cancer Center
state: Florida
city: Chicago
country: United States
facility: University of Chicago
state: Illinois
city: Westwood
country: United States
facility: University of Kansas Medical Center (KUMC)
state: Kansas
city: Grand Rapids
country: United States
facility: START Midwest
state: Michigan
city: Rochester
country: United States
facility: Mayo Clinic
state: Minnesota
city: Bronx
country: United States
facility: Montefiore Medical Center PRIME
state: New York
city: New York
country: United States
facility: Mount Sinai - PRIME
state: New York
city: Cincinnati
country: United States
facility: University of Cincinnati Medical Center
state: Ohio
city: Houston
country: United States
facility: MD Anderson
state: Texas
city: Fairfax
country: United States
facility: Virginia Cancer Specialists, PC
state: Virginia
city: Toronto
country: Canada
facility: Princess Margaret Cancer Centre
state: Ontario
city: Dijon
country: France
facility: Centre Georges-François Leclerc, Department of Medical Oncology
city: Saint-Herblain
country: France
facility: Institut de Cancerologie de L'Ouest
city: Barcelona
country: Spain
facility: Vall d'Hebron Institute of Oncology
city: Madrid
country: Spain
facility: Hospital Universitario San Carlos
Study officials:
affiliation: START Midwest
name: Nehal Lakhani, MD
role: PRINCIPAL_INVESTIGATOR
References: