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Study of SRF388 in Patients With Advanced Solid Tumors

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Know the risks and potential benefits of clinical studies and talk to your health care provider before participating. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT04374877
Recruitment Status : Recruiting
First Posted : May 5, 2020
Last Update Posted : February 6, 2023
Sponsor:
Collaborator:
Merck Sharpe & Dohme Corp.
Information provided by (Responsible Party):
Surface Oncology

Study Description
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Brief Summary:
This is a Phase 1/1b, open-label, first-in-human, dose-escalation and expansion study of SRF388, a monoclonal antibody that targets IL-27, as a monotherapy and in combination in patients with solid tumors.

Condition or disease Intervention/treatment Phase
Advanced Solid Tumor Clear Cell Renal Cell Carcinoma Hepatocellular Carcinoma Non-small Cell Lung Cancer Drug: SRF388 Drug: Pembrolizumab Phase 1

Detailed Description:

This is a Phase 1/1b, open-label, first-in-human (FIH), dose-escalation and expansion study of SRF388, a monoclonal antibody targeting IL-27, as a monotherapy and in combination in patients with solid tumors that will be conducted in 3 parts:

  • Part A: SRF388 monotherapy dose-escalation portion of the study will evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of SRF388 as monotherapy in patients with advanced solid tumors.
  • Part B: SRF388 monotherapy expansion cohorts will evaluate the safety, efficacy, tolerability, PK, and pharmacodynamics of SRF388 monotherapy in patients with advanced or metastatic ccRCC, advanced or metastatic HCC, and advanced or metastatic NSCLC in indication specific cohorts.
  • Part C will evaluate the safety, preliminary efficacy, tolerability, and PK of SRF388 in combination with pembrolizumab in patients with advanced RCC,HCC, or NSCLC.
Study Design
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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 220 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: A Phase 1/1b Study of SRF388 in Patients With Advanced Solid Tumors
Actual Study Start Date : April 22, 2020
Estimated Primary Completion Date : July 2023
Estimated Study Completion Date : July 2023

Resource links provided by the National Library of Medicine


Arms and Interventions
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Arm Intervention/treatment
Experimental: Part A Monotherapy Dose Escalation
The Part A monotherapy dose escalation portion of the study will evaluate the safety, tolerability, PK, pharmacodynamics, and preliminary efficacy of SRF388 as monotherapy in up to 42 patients with advanced solid tumors.
 Drug: SRF388
SRF388 is a fully human IgG1 antibody against IL-27. Inhibition of IL-27 with SRF388 reduces STAT1 phosphorylation leading to increased pro-inflammatory (anti-tumor) cytokine secretion (e.g., IFN-g, TNF-a) and decreased expression of inhibitory immune checkpoint receptors (e.g., PD-L1, TIGIT, LAG3) on immune cells that may result in anticancer therapeutic activity.
Experimental: Part B Indication-specific SRF388 Monotherapy Expansion
Part B monotherapy expansion will evaluate the safety, tolerability, PK, pharmacodynamics, and efficacy of SRF388 monotherapy at the recommended phase 2 dose (RP2D) in up to 40 patients with ccRCC, up to 40 patients with HCC, and up to 40 patients with NSCLC.
 Drug: SRF388
SRF388 is a fully human IgG1 antibody against IL-27. Inhibition of IL-27 with SRF388 reduces STAT1 phosphorylation leading to increased pro-inflammatory (anti-tumor) cytokine secretion (e.g., IFN-g, TNF-a) and decreased expression of inhibitory immune checkpoint receptors (e.g., PD-L1, TIGIT, LAG3) on immune cells that may result in anticancer therapeutic activity.
Experimental: Part C SRF388 in Combination with Pembrolizumab
Part C will evaluate the safety, preliminary efficacy, tolerability, and PK of SRF388 in combination with pembrolizumab in patients with advanced RCC or HCC, or anti-PD(L)1 relapsed/refractory advanced NSCLC.
 Drug: SRF388
SRF388 is a fully human IgG1 antibody against IL-27. Inhibition of IL-27 with SRF388 reduces STAT1 phosphorylation leading to increased pro-inflammatory (anti-tumor) cytokine secretion (e.g., IFN-g, TNF-a) and decreased expression of inhibitory immune checkpoint receptors (e.g., PD-L1, TIGIT, LAG3) on immune cells that may result in anticancer therapeutic activity.

Drug: Pembrolizumab
Pembrolizumab by intravenous (IV) infusion
Other Name: Keytruda®


Outcome Measures
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Primary Outcome Measures :
  1. [Part A] Dose Limiting Toxicity (DLT) [ Time Frame: Assessed during first 28 days of treatment ]
    Evaluation of DLT of SRF388 as a monotherapy.

  2. [Part B] Confirmed objective response rate (ORR) [ Time Frame: Up to 24 months ]
    ORR will be estimated by the percentage of patients achieving a best overall response of CR or PR per RECIST v1.1 and iRECIST.

  3. [Part C] DLT [ Time Frame: Assessed during first 21 days of treatment ]
    Evaluation of DLT of SRF388 in combination with pembrolizumab.

  4. [Part C] Summary of adverse events (AEs) based on treatment emergent AEs (TEAEs) [ Time Frame: Up to 24 months ]
    Safety and tolerability of SRF388 + pembrolizumab will be assessed by summarizing AEs and will be based on TEAEs. A TEAE is an AE that emerges or worsens in the period from the first dose of study treatment to 30 days after the last dose of study drug assessed by per CTCAE version 5.0 or higher.

  5. [Part C -NSCLC Cohort] Objective response rate (ORR) [ Time Frame: Up to 24 months ]
    ORR will be estimated by the percentage of patients achieving a best overall response of CR or PR per RECIST v1.1 and iRECIST.


Secondary Outcome Measures :
  1. [Part A, Part B] Safety Analysis: Summary of adverse events (AEs) and based on treatment-emergent AEs (TEAEs) [ Time Frame: Up to 24 months ]
    Safety and tolerability of SRF388 will be assessed by summarizing adverse events (AEs) and will be based on treatment-emergent AEs (TEAEs).

  2. [Part A, Part B, Part C] Pharmacokinetics (PK) of SRF388 [ Time Frame: Up to 24 months ]
    Serum concentrations of SRF388 will be collected and analyzed to evaluate the PK of SRF388.

  3. [Part A, Part B] Pharmacodynamics of SRF388 (pSTAT levels) [ Time Frame: Up to 24 months ]
    Pharmacodynamics of SRF388 will be evaluated in immune cell subsets via whole blood.

  4. [Part A, Part C] Objective response rate (ORR) [ Time Frame: Up to 24 months ]
    ORR will be estimated by the percentage of patients achieving a best overall response of CR or PR per RECIST v1.1 and iRECIST.

  5. [Part A, Part B, Part C] Duration of response (DoR) [ Time Frame: Up to 24 months ]
    DoR is defined as the time from the first documented response (CR or PR) to documented disease progression as determined by applicable disease criteria, or documented death due to any cause, whichever occurs first.

  6. [Part A, Part B, Part C] Disease control rate (DCR) [ Time Frame: Up to 24 months ]
    DCR is defined as the percentage of patients with CR, partial PR, or stable disease lasting a minimum of 12 weeks.

  7. [Part A, Part B, Part C] Progression-free survival (PFS) [ Time Frame: Up to 24 months ]
    PFS is defined as the time from the first treatment on study with study drug to documented disease progression as determined by applicable disease criteria or death.

  8. [Part C] Serum concentration of EBI3 [ Time Frame: Up to 24 months ]
    Serum will be collected to assess EBI3 correlation with outcomes.

  9. [Part C] Anti-drug Antibodies (ADAs) to SRF388 [ Time Frame: Up to 24 months ]
    Serum will be collected and assessed for the development of ADAs to SRF388.

  10. [Part C - NSCLC Cohort] Summary of adverse events (AEs) based on treatment emergent AEs (TEAEs) [ Time Frame: Up tp 24 months ]
    Safety and tolerability of SRF388 + pembrolizumab will be assessed by summarizing AEs and will be based on TEAEs.


Eligibility Criteria
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Information from the National Library of Medicine

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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

Part A and Part B Abbreviated Inclusion Criteria:

  • ≥ 18 years of age
  • Locally advanced or metastatic (Stage IV) solid tumor that has progressed during or after standard therapy, and for whom no available therapies are appropriate (based on investigator judgment)
  • Patients in Part B with advanced or metastatic ccRCC, HCC, or NSCLC must have at least 1 measurable lesion per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1
  • Patients with HCC in Part B must have at least 1 measurable target lesion according to modified RECIST (mRECIST)
  • Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC1) Stage B (not eligible for transcatheter arterial chemoembolization [TACE]) or Stage C
  • For patients in Part B with ccRCC, demonstrated progressive disease (PD) during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with regimen(s) that have included a vascular endothelial growth factor (VEGF)-targeted agent and an immune checkpoint inhibitor. Patients who did not progress on but discontinued the VEGF-targeted agent for toxicity or intolerability are permitted.
  • For patients in Part B with HCC, demonstrated PD during or after the most recent treatment regimen. Prior treatment history must include progression during or after treatment with a VEGF-targeted agent. Patients who did not progress on but discontinued the VEGF-targeted agent for toxicity or intolerability are permitted.
  • For Part B patients in the tumor biopsy subsets only, must have tumor tissue that is accessible for pretreatment and on-treatment tumor biopsy in the opinion of the Investigator and be willing to undergo pretreatment and on-treatment biopsies per protocol
  • Serum creatinine clearance ≥ 30 mL/min per Cockcroft-Gault formula or serum creatinine ≤ 2.0 x the upper limit of normal (ULN)
  • Total bilirubin ≤ 1.5 x ULN (≤ 3 x ULN if elevated because of Gilbert's syndrome and ≤ 2 x ULN for patients with HCC or patients with known liver metastases)
  • Aspartate aminotransferase (AST/SGOT) and alanine aminotransferase/serum glutamic pyruvic transaminase (ALT/SGPT) < 2.5 x ULN (< 5 x ULN if liver metastasis or for patients with HCC)
  • For patients with HCC, Child-Pugh class A or B7 with a serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
  • Adequate hematologic function, defined as absolute neutrophil count (ANC) ≥ 1.0 x 109/L, hemoglobin ≥ 9.0 g/dL, and platelet count ≥ 100 x 109/L. For patients with HCC, platelet count ≥ 75 x 109/L without transfusion
  • Eastern Cooperative Oncology Group (ECOG) performance status 0-1
  • Patients with NSCLC must have histologically confirmed locally advanced and/or metastatic Stage IV NSCLC
  • Patients with NSCLC must have demonstrated progressive disease during or after the most recent treatment regimen

Part C Abbreviated Inclusion Criteria:

  • ≥ 18 years of age
  • Advanced RCC of any histology or advanced HCC previously treated with at least one systemic anticancer therapy OR histologically or cytologically confirmed metastatic or unresectable adenocarcinoma or squamous cell NSCLC
  • Patients with HCC must have unresectable disease, Barcelona Clinic Liver Cancer (BCLC) Stage B (not eligible for transcatheter arterial chemoembolization) or Stage C
  • At least 1 measurable lesion per RECIST 1.1
  • Patients with HCC must have at least 1 measurable target lesion according to modified RECIST (mRECIST)
  • ECOG performance status of 0-1
  • ANC ≥1500/µL (1.5 x 109/L)
  • Platelets ≥100 000/µL (≥ 100 x 109/L)
  • Hemoglobin for participants with RCC: ≥9.0 g/dL; for participants with HCC: ≥8.5 g/dL
  • Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels >1.5 × institutional ULN
  • Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels >1.5 × ULN
  • AST (SGOT) and ALT (SGPT) ≤2.5 × ULN (≤5 × ULN for participants with liver metastases)
  • International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
  • For patients with HCC, Child-Pugh Class A or B7 with a serum albumin ≥ 2.8 g/dL (≥ 28 g/L)
  • Willingness of male and female patients who are not surgically sterile or postmenopausal to use medically acceptable methods of birth control for the duration of the study drug period (or beginning 14 days before the initiation of pembrolizumab for oral contraception), including 75 days after the last dose of SRF388 or 120 days after the last dose of pembrolizumab; male patients must refrain from donating sperm during this period. Sexually active men, and women using oral contraceptive pills, should also use barrier contraception with spermicide. Azoospermic male patients and WCBP who are continuously not heterosexually active are exempt from contraceptive requirements. However, female patients must still undergo pregnancy testing as described in this section.

Part C Abbreviated Inclusion Criteria Specific to Patients with RCC or HCC from Part A or Part B:

  • Progressed on SRF388 by RECIST 1.1
  • Did not experience prior Grade ≥ 3 toxicity related to SRF388
  • Willingness to undergo pretreatment core or excisional biopsy if deemed safe and tumor is accessible, in the opinion of the Investigator
  • Has received no systemic anticancer therapies between SRF388 doses

Part C Abbreviated Inclusion Criteria specific to NSCLC Patients:

  • No more than 3 prior lines of systemic therapy for unresectable or metastatic disease with prior radiologic progression on or following platinum-based chemotherapy and prior anti-PD-(L)1 therapy whether given alone or in combination

Part A and Part B Abbreviated Exclusion Criteria:

  • Previously received an anti-IL-27 antibody or anti-IL-27 targeted therapy
  • For patients in Part B with renal cell carcinoma (RCC), non-clear cell RCC histology
  • For patients with HCC, known fibrolamellar or mixed hepatocellular cholangiocarcinoma
  • History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
  • Major surgery within 4 weeks prior to Screening
  • Unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition including pneumonitis and/or interstitial lung disease, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study

Part C Abbreviated Exclusion Criteria:

  • Is currently participating in or has participated in a study of an investigational agent or has used an investigational device within 4 weeks prior to the first dose of study drug
  • Previously received an anti-IL 27 antibody or anti-IL 27 targeted therapy (exception to patients who received SRF388 in Part A or Part B)
  • No prior systemic therapy for unresectable or metastatic disease
  • Received > 4 prior systemic regimens for unresectable or metastatic disease (prior PD-(L)1 inhibitors are allowed if the patient did not discontinue therapy due to ≥ Grade 3 drug-related toxicity)
  • For patients with HCC, fibrolamellar histology or mixed hepatocellular cholangiocarcinoma
  • For patients with HCC, moderate or severe ascites
  • For patients with HCC, inability to undergo disease evaluation with triphasic computed tomography or magnetic resonance imaging because of contrast allergy or other contraindication
  • For patients with HCC, imaging findings consistent with ≥ 50% liver occupation by HCC tumors
  • History of Grade 4 allergic or anaphylactic reaction to any monoclonal antibody therapy or any excipient in the study drugs
  • Surgeries that required general anesthesia must be completed at least 2 weeks before first study drug administration
  • Prior autologous stem cell transplant ≤ 3 months before the first dose
  • Prior allogeneic hematopoietic cell transplant within 6 months of the first dose or with a history of or current clinical Graft-Versus-Host Disease
  • Has had an allogenic tissue/solid organ transplant
  • Other unstable or severe uncontrolled medical condition (eg, unstable cardiac function, unstable pulmonary condition, uncontrolled diabetes) or any important medical illness or abnormal laboratory finding that would, in the Investigator's judgment, increase the risk to the patient associated with his or her participation in the study
Contacts and Locations
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Top of Page Study Description Study Design Arms and Interventions Outcome Measures Eligibility Criteria Contacts and Locations More Information

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): NCT04374877


Contacts
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Contact: Beth Bowers 1-978-954-7207 bbowers@surfaceoncology.com

Locations
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Sponsors and Collaborators
Surface Oncology
Merck Sharpe & Dohme Corp.
Investigators
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Study Chair: Lauren Harshman, MD Surface Oncology
More Information
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Responsible Party: Surface Oncology
ClinicalTrials.gov Identifier: NCT04374877    
Other Study ID Numbers: SRF388-101
KEYNOTE-C16 ( Other Identifier: Merck Sharp & Dohme Corp. )
First Posted: May 5, 2020    Key Record Dates
Last Update Posted: February 6, 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 Surface Oncology:
metastatic solid tumors
advanced solid tumors
Phase 1
SRF388
IL-27
safety
efficacy
immunotherapy
cancer
 immuno-oncology
kidney cancer
renal cell carcinoma
liver cancer
hepatocellular carcinoma
non-small cell lung cancer
pembrolizumab
PD-1
Additional relevant MeSH terms:
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Carcinoma
Carcinoma, Non-Small-Cell Lung
Carcinoma, Hepatocellular
Carcinoma, Renal Cell
Neoplasms, Glandular and Epithelial
Neoplasms by Histologic Type
Neoplasms
Lung Neoplasms
Respiratory Tract Neoplasms
Thoracic Neoplasms
Neoplasms by Site
Lung Diseases
Respiratory Tract Diseases
Carcinoma, Bronchogenic
Bronchial Neoplasms
 Adenocarcinoma
Liver Neoplasms
Digestive System Neoplasms
Digestive System Diseases
Liver Diseases
Kidney Neoplasms
Urologic Neoplasms
Urogenital Neoplasms
Female Urogenital Diseases
Female Urogenital Diseases and Pregnancy Complications
Urogenital Diseases
Kidney Diseases
Urologic Diseases
Male Urogenital Diseases
Pembrolizumab