A Study of BI-1206 in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors (KEYNOTE-A04)

A Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to CD32b (FcγRIIB), in Combination With Pembrolizumab in Subjects With Advanced Solid Tumors Previously Treated With Anti-PD-1 or Anti-PD-L1 Antibodies (KEYNOTE-A04)

Phase 1/2a Clinical Trial of BI-1206, a Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Pembrolizumab in Subjects with Advanced Solid Tumors Previously Treated with Anti-PD-1 or Anti-PD-L1 Antibodies

Study Overview

• Status: Recruiting
• Conditions: Solid Tumor, Adult
• Intervention / Treatment: Drug: Pembrolizumab 25 MG/ML(MK-3475)

Detailed Description

This is a Phase 1/2a, multicenter, dose-finding, consecutive-cohort, open-label trial of BI-1206 in combination with pembrolizumab in subjects with advanced solid tumors who have previously received treatment with a PD-1/PD-L1 immune checkpoint inhibitor.

The trial will consist of 2 main parts: Phase 1 (with dose escalation cohorts and selection of the RP2D), and Phase 2a (with 3 expansion cohorts at the RP2D).

Subjects in each phase will initially receive 3 planned doses of therapy with BI-1206 in combination with pembrolizumab.

Subjects who show clinical benefit (CR, PR or SD) at the Week 9 Visit may continue on combination therapy. Starting at Week 10, these subjects will receive infusions every 3 weeks for up to 32 additional doses or up to 2 years from first dose of BI-1206 therapy or until progression.

• Study Type: Interventional
• Enrollment (Anticipated): 90
• Phase: Phase 2; Phase 1

Contacts and Locations

• Study Contact: Name: Susanne Gertsson; Phone Number: +46709 102 267; Email: susanne.gertsson@bioinvent.com
• Study Contact Backup: Name: McAllister, PhD; Email: andres.mcallister@bioinvent.com

Study Locations

• Sweden
  • Göteborg, Sweden
    • Recruiting
    • Sahlgrenska University Hospital
    • Principal Investigator: Ny, MD
  • Lund, Sweden
    • Recruiting
    • Lund University Hospital
    • Principal Investigator: Carneiro, PhD
  • Stockholm, Sweden
    • Recruiting
    • Karolinska University Hospital, Solna
    • Principal Investigator: Yachnin, PhD
• United States
  • Colorado
    • Denver, Colorado, United States, 80218
      • Recruiting
      • Sarah Cannon Research Institute
      • Principal Investigator: Falchook
  • Minnesota
    • Saint Paul, Minnesota, United States, 55101
      • Recruiting
      • HealthPartners Institute - Regions Cancer Care Center,
      • Principal Investigator: Dudek
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • Oklahoma University , Stephenson Cancer Center
      • Principal Investigator: Aljumaily, MD
  • Texas
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • NEXT Oncology
      • Principal Investigator: Tolcher

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Is willing and able to provide written informed consent for the trial.
• Is ≥18 years of age on day of signing informed consent.
• Has a histologically confirmed advanced solid tumor. Subjects must have received at least 2 doses of an approved anti-PD-1/L1 mAb, and have documented progression on or within 12 weeks from the last dose of anti-PD-1/L1 mAb.
• Is intolerant of, refuses, or is not eligible for standard antineoplastic therapy.
• Has at least 1 measurable disease lesion as defined by Response Evaluation Criteria in Solid Tumors
• Is able to safely undergo a baseline tumor tissue biopsy prior to first dose of BI-1206
• Has a life expectancy of ≥12 weeks.
• Has an ECOG performance status of 0-1.
• Has adequate organ function as confirmed by laboratory values listed in the main body of the protocol

Expansion Cohort-Specific Inclusion Criteria:

In addition to the general inclusion criteria above, subjects must also meet the criteria for the specific cohort.

• Cohort 1 (Non-small cell lung cancer):

  • For subjects whose tumor has PD-L1 ≥ 50%: Required prior therapies will include anti-PD-1 therapy as monotherapy. Prior standard of care chemotherapy will be allowed but not required.
  • For tumors with unknown PD-L1 or PD-L1 < 50% , required prior therapies will include anti-PD 1/PD-L1 therapy and SOC chemotherapy either combined with anti PD-1/PD-L1 therapy or given separately.
  • For subjects with known anaplastic lymphoma kinase, ROS1 or epidermal growth factor receptor sensitizing molecular rearrangements, one line of targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy.

• Cohort 2 (Metastatic Melanoma):

  • Required prior therapies will include anti-PD-1 therapy either as monotherapy or as part of a combination regimen.
  • For subjects with a known BRAF V600-activating mutation combination targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy.

• Cohort 3 (Other Tumor Types):

  • All subjects will require prior anti-PD-1/PD-L1 therapy

Exclusion Criteria:

• Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids)
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has known or suspected hypersensitivity to pembrolizumab or BI-1206 or any of their excipients.
• Has cardiac or renal amyloid light-chain (AL) amyloidosis.

• Has received the following:

  • Chemotherapy or small molecule products within 4 weeks of first dose of BI 1206.
  • Radiotherapy within 2 weeks of first dose of BI-1206. A 1-week washout is permitted for palliative radiation (≤2 weeks of radiotherapy) for non-CNS disease. Subjects who have previously had radiation pneumonitis are not allowed.
  • Immunotherapy within 4 weeks prior to the first dose of BI-1206.
• Has not recovered from AEs to at least Grade 1 by Common Terminology Criteria for Adverse Events v4.0 due to prior anti-cancer therapies.
• Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments .
• Has a history of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• Has an active, known or suspected autoimmune disease.
• Is a female subject and has the ability to become pregnant (or already pregnant or lactating/ breastfeeding). o Intravaginal
• Is a male subject with partner(s) of child-bearing potential• Has had major surgery from which the subject has not yet recovered.
• Is at high medical risk because of non-malignant systemic disease including severe active infections on treatment with antibiotics, antifungals or antivirals.
• Has presence of chronic graft versus host disease.
• Has had an allogenic tissue/solid organ transplant.
• Has known human immunodeficiency virus (HIV) and / or history of hepatitis B or C infections, or has a positive test for HIV antibody, hepatitis B antigen / hepatitis B virus DNA or hepatitis C antibody or RNA.
• Has a history of active tuberculosis (bacillus tuberculosis).
• Has received a live vaccine within 30 days before the first dose of study treatment.
• Has uncontrolled or significant cardiovascular disease
• Has a known psychiatric or substance abuse disorder that would interfere with the subject's ability to cooperate with the requirements of the study.
• Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• Is participating or planning to participate in another interventional clinical trial, or has participated in a trial of an investigational agent or has used an investigational device within 4 weeks prior to first dose of study drug. Subjects who have entered the follow-up phase of an investigational study may participate as long as it has been 4 weeks after the last dose of the previous investigational agent. Participation in an observational trial is acceptable.
• Has a known additional malignancy of another type
• Has a diagnosis of primary or acquired immunodeficiency disorder or taking any other form of immunosuppressive therapy within 7 days prior the first dose of study drug.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: BI-1206; BI-1206 administrated IV with a starting dose of 1 mg/kg every third week using mTPI2 Design in escalation Phase I. RP2D to be used i Phase IIa.	Drug: Pembrolizumab 25 MG/ML(MK-3475); Pembrolizumab 200mg administrated IV every third week as a fixed dose will be used in Phase I and IIa

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Documenting AEs and SAEs and determining causality in relation to BI-1206 and/or pembrolizumab	Assess the safety and tolerability profile of increasing doses of BI-1206 in combination with pembrolizumab, graded according to National Cancer Institute [NCI]-CTCAE version 4.0	Up to 2 year
Determining the MTD of BI-1206 at the same dose level experiencing a BI-1206 or pembrolizumab-related or possibly related dose-limiting toxicity (DLT)	Select the RP2D dose for BI-1206 using mTPI-2 design.	During the 42-day treatment period on induction therapy

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluation of PK parameters for BI-1206. Maximum observed plasma concentration (Cmax)	Study the PK profile of BI-1206 according to a non-compartmental analysis using a validated software	Up to 2 year
Evaluation of PK parameters for BI-1206. Area under the plasma concentration-time curve (AUC)	Study the PK profile of BI-1206 according to a non-compartmental analysis using a validated software	Up to 2 year
Evaluation of ADA response to BI 1206	Assess the immunogenicity of BI-1206. Detection and characterization of antibodies to BI-1206 will be performed using a validated method and will be evaluated for BI-1206 serum concentration to enable interpretation of the antibody data.	Up to 2 year
Measurement of CD32b receptor occupancy on B cells.	Evaluate the effect of BI-1206 administered in combination with pembrolizumab on CD32b receptor occupancy on B cells in subjects with advanced solid tumors.	Up to 2 year

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of best disease responses according to Immunological Response Evaluation Criteria in Solid Tumors (iRECIST).	Initially assess possible anti-tumor activity of BI-1206 administered in combination with pembrolizumab 8 weeks after first dose of BI-1206 (i.e., the Week 9 Visit [including follow-up confirmation for progressive disease (PD)]) in subjects with advanced solid tumors. Anti-tumor activity will also be evaluated every 9 weeks for subjects whocontinue on therapy.	8 weeks after first dose BI1206 and every 9 weeks for subjects who continue on therapy
Measurement of progression free survival.	Patients who complete a baseline and at least one post-treatment disease assessment will be evaluable.PFS will be measured from the date of administration of the first dose of BI-1206 to the first date of progression, date of death from any cause, or the last response assessment date, whichever comes first.	Up to 2 year
Measurement of duration of objective response	Time-to-event estimates will be generated using the Kaplan-Meier method. In the context of this single arm study, these analyses will be only descriptive	Up to 2 year
Measurement of objective response rate	ORR is defined as the percentage of subjects who achieved a response of CR or PR. ORR and the associated 2-sided 95% exact confidence limits will be provided	Up to 2 year
Measurement of peripheral blood B-lymphocyte depletion.	Evaluate the effect of BI-1206 in combination with pembrolizumab measuring B Lymphocyutes CD19 in absolut value.	Up to 2 year
Measurement of expression levels of immunological markers such as CD32b, PD-1 in tissue biopsies.	Study expression levels of immunological markers (e.g., CD32b, PD-1) in the tumor and study a potential correlation of levels of expression with clinical responses.	Up to 2 year
Evaluate BI-1206 and pembrolizumab tumor penetrance in biopsies	Evaluate BI-1206 and pembrolizumab tumor penetrance in biopsies using immunohistochemistry	Up to 2 year
Measurement of cytokine levels	Study the potential cause of infusion related reaction (IRR) by measure serum cytokine levels	Up to 2 year
Measurement of serum cytokine levels and/or soluble CD32b.	• Study the potential cause of infusion related reaction (IRR), such as cytokine release and/or soluble CD32b	Up to 2 year

Collaborators and Investigators

• Sponsor: BioInvent International AB
• Collaborators: Merck Sharp & Dohme LLC
• Investigators: Principal Investigator: Carneiro, PhD, Lund University Hospital

Study record dates

Study Major Dates

• Study Start (Actual): June 29, 2020
• Primary Completion (Anticipated): November 1, 2025
• Study Completion (Anticipated): January 1, 2026

Study Registration Dates

• First Submitted: October 21, 2019
• First Submitted That Met QC Criteria: January 3, 2020
• First Posted (Actual): January 7, 2020

Study Record Updates

• Last Update Posted (Actual): January 12, 2023
• Last Update Submitted That Met QC Criteria: January 11, 2023
• Last Verified: January 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms; Antineoplastic Agents; Antineoplastic Agents, Immunological; Pembrolizumab
• Other Study ID Numbers: 18-BI-1206-03

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: Yes
• IPD Plan Description: All information concerning the product as well as any matter concerning the operation of the Sponsor, such as clinical indications for the drug, its formula, methods of manufacture and other scientific data relating to it, that have been provided by the Sponsor and are unpublished, are confidential and must remain the sole property of the Sponsor. The Investigator will agree to use the information only for the purposes of carrying out this studytrial and for no other purpose unless prior written permission from the Sponsor is obtained.
• IPD Sharing Time Frame: Within one year from end of study
• IPD Sharing Access Criteria: Paper copy of CSR
• IPD Sharing Supporting Information Type: Study Protocol

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No