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

• ClinicalTrials.gov Identifier: NCT04219254
• Recruitment Status: Recruiting
• First Posted: January 7, 2020
• Last Update Posted: January 12, 2023
• Sponsor: BioInvent International AB
• Collaborator: Merck Sharp & Dohme LLC
• Information provided by (Responsible Party): BioInvent International AB

Study Description

Brief Summary:

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

Condition or disease	Intervention/treatment	Phase
Solid Tumor, Adult	Drug: Pembrolizumab 25 MG/ML(MK-3475)	Phase 1; Phase 2

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: N/A
• Intervention Model: Single Group Assignment
• Intervention Model Description: Phase 1/2a, dose escalation, consecutive-cohort, open-label study trial of BI-1206 in combination with pembrolizumab
• Masking: None (Open Label)
• Masking Description: open label
• Primary Purpose: Treatment
• Official Title: 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)
• Actual Study Start Date: June 29, 2020
• Estimated Primary Completion Date: November 2025
• Estimated Study Completion Date: January 2026

Arms and Interventions

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

Outcome Measures

Primary Outcome Measures :

1. Documenting AEs and SAEs and determining causality in relation to BI-1206 and/or pembrolizumab [ Time Frame: Up to 2 year ]
   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
2. 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) [ Time Frame: During the 42-day treatment period on induction therapy ]
   Select the RP2D dose for BI-1206 using mTPI-2 design.

Secondary Outcome Measures :

1. Evaluation of PK parameters for BI-1206. Maximum observed plasma concentration (Cmax) [ Time Frame: Up to 2 year ]
   Study the PK profile of BI-1206 according to a non-compartmental analysis using a validated software
2. Evaluation of PK parameters for BI-1206. Area under the plasma concentration-time curve (AUC) [ Time Frame: Up to 2 year ]
   Study the PK profile of BI-1206 according to a non-compartmental analysis using a validated software
3. Evaluation of ADA response to BI 1206 [ Time Frame: Up to 2 year ]
   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.
4. Measurement of CD32b receptor occupancy on B cells. [ Time Frame: Up to 2 year ]
   Evaluate the effect of BI-1206 administered in combination with pembrolizumab on CD32b receptor occupancy on B cells in subjects with advanced solid tumors.

Other Outcome Measures:

1. Assessment of best disease responses according to Immunological Response Evaluation Criteria in Solid Tumors (iRECIST). [ Time Frame: 8 weeks after first dose BI1206 and every 9 weeks for subjects who continue on therapy ]
   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.
2. Measurement of progression free survival. [ Time Frame: Up to 2 year ]
   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.
3. Measurement of duration of objective response [ Time Frame: Up to 2 year ]
   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
4. Measurement of objective response rate [ Time Frame: Up to 2 year ]
   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
5. Measurement of peripheral blood B-lymphocyte depletion. [ Time Frame: Up to 2 year ]
   Evaluate the effect of BI-1206 in combination with pembrolizumab measuring B Lymphocyutes CD19 in absolut value.
6. Measurement of expression levels of immunological markers such as CD32b, PD-1 in tissue biopsies. [ Time Frame: Up to 2 year ]
   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.
7. Evaluate BI-1206 and pembrolizumab tumor penetrance in biopsies [ Time Frame: Up to 2 year ]
   Evaluate BI-1206 and pembrolizumab tumor penetrance in biopsies using immunohistochemistry
8. Measurement of cytokine levels [ Time Frame: Up to 2 year ]
   Study the potential cause of infusion related reaction (IRR) by measure serum cytokine levels
9. Measurement of serum cytokine levels and/or soluble CD32b. [ Time Frame: Up to 2 year ]
   • Study the potential cause of infusion related reaction (IRR), such as cytokine release and/or soluble CD32b

Eligibility Criteria

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

Criteria

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.

Contacts and Locations

Contacts

Contact: Susanne Gertsson; +46709 102 267; susanne.gertsson@bioinvent.com

Contact: McAllister, PhD; andres.mcallister@bioinvent.com

Locations

United States, Colorado

Sarah Cannon Research Institute; Recruiting

Denver, Colorado, United States, 80218

Principal Investigator: Falchook

United States, Minnesota

HealthPartners Institute - Regions Cancer Care Center,; Recruiting

Saint Paul, Minnesota, United States, 55101

Principal Investigator: Dudek

United States, Oklahoma

Oklahoma University , Stephenson Cancer Center; Recruiting

Oklahoma City, Oklahoma, United States, 73104

Principal Investigator: Aljumaily, MD

United States, Texas

NEXT Oncology; Recruiting

San Antonio, Texas, United States, 78229

Principal Investigator: Tolcher

Sweden

Sahlgrenska University Hospital; Recruiting

Göteborg, Sweden

Principal Investigator: Ny, MD

Lund University Hospital; Recruiting

Lund, Sweden

Principal Investigator: Carneiro, PhD

Karolinska University Hospital, Solna; Recruiting

Stockholm, Sweden

Principal Investigator: Yachnin, PhD

Sponsors and Collaborators

BioInvent International AB

Merck Sharp & Dohme LLC

Investigators

• Principal Investigator: Carneiro, PhD; Lund University Hospital

More Information

• Responsible Party: BioInvent International AB
• ClinicalTrials.gov Identifier: NCT04219254
• Other Study ID Numbers: 18-BI-1206-03
• First Posted: January 7, 2020
• Last Update Posted: January 12, 2023
• Last Verified: January 2023

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Yes
• 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.
• Supporting Materials: Study Protocol
• Time Frame: Within one year from end of study
• Access Criteria: Paper copy of CSR

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

Additional relevant MeSH terms:

Neoplasms; Pembrolizumab; Antineoplastic Agents, Immunological; Antineoplastic Agents