CONTRAST
Research type
Research Study
Full title
Phase 1/2a Open-label Clinical Trial of BI-1607, an Fc-Engineered Monoclonal Antibody to CD32b (FcγRIIB), in Combination with Trastuzumab in Subjects with HER2-positive Advanced Solid Tumors - CONTRAST
IRAS ID
310197
Contact name
Anna Ropenga
Contact email
Sponsor organisation
BioInvent International AB
Eudract number
2021-005646-15
ISRCTN Number
ISRCTN00000000
Clinicaltrials.gov Identifier
Duration of Study in the UK
4 years, 0 months, 0 days
Research summary
Research Summary:
BioInvent International AB is conducting a study of a study drug called BI-1607 as a possible treatment for HER2-positive advanced solid tumours. This is the first time BI-1607 is being tested in humans.\n\nThe main goal of Phase 1 of this study is to learn how safe and tolerable the study drug is when combined with trastuzumab in participants with HER2- positive advanced solid tumours, to find the highest tolerated dose of the study drug, and to determine the recommended dose of the study drug to use in Phase 2a of this study. \n\nThe study will take place in approximately 7 to 12 sites in the EU, the United Kingdom, and the United States (US), with up to 116 participants with HER2- positive advanced solid tumours participating. This study includes 2 parts (Phase 1 and Phase 2a). In Phase 1, up to 36 participants with HER2- positive advanced solid tumours will be participating.\n\nParticipants will be in this study for at least 3 months, and will need to visit their study centre at least 9 times over this period. If their cancer shows improvement at the end of the period and throughout the study (e.g., Cycle 2, 4, 6, 9 or at the disease assessment every 12 cycles afterwards), participants may be able to continue receiving the study drug for up to 2 years.\n \nThe study is divided into 3 periods: a screening period, a treatment period, and a follow-up period. At 6 months and 1 year after a participant has completed study treatment, they will be contacted to see how they are doing.\n
Summary of Results:
• Screening and Treatment: 27 subjects were screened; 18 were treated with at least a dose of BI-1607. The main reason for stopping treatment was progressive disease.
• Demographics: Median age was 63 years, with most subjects under 65. Most were female (77.8%).
• Cancer Types: Most had breast cancer (44.4%) or stomach cancer (16.7%) at advanced stages (Stage III or IV).
• Performance Status: Subjects had good performance status (ECOG PS of 0 or 1).
• Treatment Details: Subjects received a median of 2 infusions of BI-1607 and trastuzumab.Safety Results:
Overall for Phase 1:
• Adverse Events: 17 subjects (94.4%) experienced at least one adverse event, mostly mild (Grade 1) or moderate (Grade 2). Common issues included anemia, weakness, and increased liver enzymes.
• Infusion Related Reactions: 8 subjects had mild to moderate infusion-related reactions including itching and rash (Grade 1 to 3).
• Drug-Related Events: 13 subjects (72.2%) had a BI-1607 related adverse events, mostly mild or moderate. Common issues included rash and increased liver enzymes.
• Serious Events: 2 subjects had serious adverse events, but none were related to the drug.
• Discontinuations: 3 subjects stopped treatment due to adverse events, including condition aggravated, acute kidney injury and infusion related reaction rash.
• Deaths: 4 subjects died, 2 from disease progression and 2 from adverse events (condition aggravated and acute kidney injury).
• Lab Results: No significant changes in blood tests or heart function were observed.
• Performance Status: All subjects maintained a good performance status throughout the study.Efficacy Results:
Overall, in Phase 1:
• Response: No subjects had a complete or partial response. The best response was stable disease in 7 subjects (77.8%).
• Stable Disease: At Month 3, 2 subjects had stable disease (22.2%), and at Month 6, 1 subject had stable disease (11.1%).
• Tumor Size: The average decrease in tumor size was 3.94% (-15.3% to 20%).
• Progression-Free Survival: Seven subjects (77.8%), 5 subjects (55.6%), and 4 subjects (44.4%) were alive with no disease progression for 60, 120, and 180 days, respectively.
• Time to Response: The median time to response was 2.6 months.
• Overall Survival: The median overall survival was 3.7 months. Survival rates were: 17 subjects (94.4%) were alive at 30 days, 16 subjects (88.9%) at 60 days, and 14 subjects (77.9%) at 120, 150, and 180 days.Pharmacokinetic (PK) Results:
• Dose and Concentration: BI-1607 concentrations increased with higher doses. Most subjects had measurable BI-1607 levels during and after infusion, peaking between 1.95 to 10 hours after the first dose and 4.05 to 9.57 hours after multiple doses.
• Exposure: BI-1607 exposure increased with dose, but the increase was more than expected. This might be due to the small sample size.
• Steady-State: Steady-state levels were reached by Cycle 2 for doses of 500 mg, 700 mg, and 900 mg.
• QTc Interval: No link was found between BI-1607 levels and changes in the QTc interval.Pharmacodynamic (PDc) Results:
• Receptor Occupancy: No receptor occupancy was detected before the first dose. Full receptor occupancy was observed 24 hours after dosing and declined gradually. Higher doses maintained near full occupancy between doses.
• C-Reactive Protein (CRP): No major changes in CRP levels were observed.
• Immunoglobulins: No significant changes in serum immunoglobulin levels (IgA, IgG1, IgM) were noted.
• Cytokines: Low levels of 13 cytokines were detected, with no increase in inflammatory cytokines IL-6 or TNF-α.
• FcγRIIB Expression: Increased expression on B cells peaked at 6 hours post-infusion and returned to baseline for lower doses but remained high for higher doses.
• Genotypic Analysis: No link was found between specific genetic polymorphisms and treatment response.Immunogenicity Results:
• All subjects tested negative for antidrug antibodies (ADAs) at baseline and during follow-up assessments.Conclusions:
• Safety: BI-1607 was safe up to 900 mg when administered in combination with trastuzumab.
• Antibodies: No antidrug antibodies were detected.
• Study Termination: The study ended early due to a change in development strategy.
• Efficacy: Stable disease was the best response; no complete or partial responses were observed.
• Pharmacodynamics: Full receptor occupancy was achieved.
• Pharmacokinetics: BI-1607 concentrations increased with dose. Steady-state was reached by Cycle 2 for higher doses.REC name
South Central - Oxford A Research Ethics Committee
REC reference
22/SC/0050
Date of REC Opinion
14 Jun 2022
REC opinion
Further Information Favourable Opinion