BI-1607 in Combination With Trastuzumab in Subjects With HER2-positive Advanced Solid Tumors (CONTRAST)

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

HER2+ breast and gastric cancer patients' survival is significantly improved by trastuzumab alone or in combination with chemotherapy. However, many patients remain uncured and develop resistance to trastuzumab resulting in relapse or progression of the disease. BI-1607, a human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) targets CD32b (Fc Gamma Receptor IIB), it is intended to enhance the efficacy and overcome resistance to existing cancer treatments such as trastuzumab.

This is a Phase 1/2a, first-in-human, open-label, multicenter, dose-escalation, consecutive-cohort study of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors whose tumor has progressed after standard therapy.

Study Overview

• Status: Active, not recruiting
• Conditions: HER2-positive Breast Cancer; HER2-positive Gastric Cancer; Metastatic Gastric Adenocarcinoma; Metastatic Gastroesophageal Junction Adenocarcinoma; HER2-positive Metastatic Breast Cancer
• Intervention / Treatment: Drug: BI-1607; Drug: BI-1607; Drug: Trastuzumab

Detailed Description

This is a Phase 1/2a, first-in-human, open-label, multicenter, dose-escalation, consecutive-cohort study of BI-1607 in combination with trastuzumab in subjects with HER2+ advanced solid tumors whose tumor has progressed after standard therapy.

The Phase 1 part of the trial is a dose escalation study of BI-1607 combined with trastuzumab in HER2+ advanced or metastatic solid tumors, the aim is to assess safety and tolerability and to determine the recommended phase II dose of BI-1607 in combination with trastuzumab.

The selected dose of BI-1607 will be studied in a subsequent Phase 2a part of the trial along with trastuzumab in 2 open-label, expansion cohorts of 15 evaluable subjects each. The first cohort will enroll subjects with locally advanced or metastatic HER2+ breast cancer, and the second will recruit subjects with HER2+ metastatic gastric or gastroesophageal junction adenocarcinoma. The aim of the phase 2a is to collect additional safety data to further support the recommended dose, and to detect early signs of clinical activity.

• Study Type: Interventional
• Enrollment (Estimated): 18
• Phase: Phase 2; Phase 1

Contacts and Locations

Study Locations

• Germany
  • Essen, Germany, 45136
    • Evang. Kliniken Essen-Mitte
  • Frankfurt, Germany, 60488
    • Krankenhaus Nordwest
• Spain
  • Barcelona, Spain, 08035
    • Hospital Vall d'Hebron
  • Madrid, Spain, 28034
    • Complejo Hospitalario Ruber Juan Bravo
• United Kingdom
  • Oxford, United Kingdom, OX3 7LE
    • Churchill Hospital
  • Southampton, United Kingdom, SO16 6YD
    • Southampton General Hospital

Participation Criteria

Eligibility Criteria

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

Description

Main 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 received standard of care or is intolerant to standard of care antineoplastic therapy. Subjects who are intolerant to trastuzumab cannot be enrolled in the study.
• Has at least 1 measurable disease lesion as defined by RECIST v1.1 criteria.
• Has a locally confirmed HER2+ tumor.

• Must have progressive disease after the last line of treatment. In addition, subjects must have received the following previous lines of treatment:

  1. Prior lines of treatment including trastuzumab and chemotherapy.
  2. At least one prior line of treatment with an antibody-drug conjugate (ADC) (eg, trastuzumab-emtansine [TDM-1, or trastuzumab-deruxtecan]).

Main Exclusion Criteria:

• Needs doses of prednisolone >10 mg daily (or equipotent doses of other corticosteroids) while on the trial other than as premedication.
• Has known active central nervous system (CNS) metastases and/or carcinomatous meningitis.
• Has cardiac or renal amyloid light-chain amyloidosis.
• Has had clinically significant lung disease requiring systemic corticosteroid treatment within the last 6 months of enrollment.
• Has an active, known, or suspected autoimmune disease.
• Is at high medical risk because of nonmalignant 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 uncontrolled or significant cardiovascular disease.
• Has a known additional malignancy of another type, except for adequately treated cone-biopsied carcinoma in situ (eg, breast carcinoma, cervical cancer in situ), adequately controlled superficial bladder cancer, and basal or squamous cell carcinoma of the skin.
• Has a diagnosis of primary or acquired immunodeficiency disorder or is taking any other form of immunosuppressive therapy.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Phase I -Dose escalation; Dose escalation study of BI-1607 combined with trastuzumab in HER2+ advanced or metastatic solid tumors.	Drug: BI-1607; administered at different doses in Phase I by intravenous infusions every 3 weeks.; Drug: BI-1607; administered at the recommended dose in Phase 2a by intravenous infusions every 3 weeks.; Drug: Trastuzumab; administered at 8mg/kg for the first infusion and at 6mg/kg in subsequent infusions by intravenous infusions every 3 weeks.; Other Names: Herceptin
Experimental: Phase 2a - Expansion cohorts; Dose expansion study of BI-1607 combined with trastuzumab in cohort 1: HER2 positive locally advanced or metastatic HER2+ breast cancer and cohort 2: metastatic gastric or gastroesophageal junction adenocarcinoma	Drug: BI-1607; administered at different doses in Phase I by intravenous infusions every 3 weeks.; Drug: BI-1607; administered at the recommended dose in Phase 2a by intravenous infusions every 3 weeks.; Drug: Trastuzumab; administered at 8mg/kg for the first infusion and at 6mg/kg in subsequent infusions by intravenous infusions every 3 weeks.; Other Names: Herceptin

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the safety and tolerability profile of BI-1607 in combination with trastuzumab	Adverse events (AEs) and serious adverse events (SAEs) (graded according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] v5.0) and their causality in relation to BI-1607 or to the combination with trastuzumab	End of treatment visit or 30 days after last dose of study drug.
Identify Dose limiting toxicities, determine the maximum tolerate dose of BI-1607 and propose a recommended Phase 2 dose (RP2D) for evaluation of BI-1607 in combination with trastuzumab.	Occurrence of DLTs	22 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of the pharmacokinetic (PK) profile of BI-1607 when administered every 3 weeks in combination with trastuzumab	The PK parameters will include area under the serum concentration-time curve, maximum concentration, time to maximum concentration, and terminal half-life	90 days after the last dose of BI-1607
Assessment of the immunogenicity of BI-1607 when administered in combination with trastuzumab	Antidrug antibody response to BI-1607 in blood serum	90 days after the last dose of BI-1607
Assessment of the CD32b receptor occupancy (RO) of BI-1607 on B cells when administered in combination with trastuzumab	RO on circulating B lymphocytes	30 days after the last dose of BI-1607
Assessment of the possible antitumor activity of BI-1607 in combination with trastuzumab	Best tumor response, objective response rate (ORR) according to Response Evaluation Criteria in Solid Tumors (RECIST) v1.1, progression-free survival (PFS), time to response, duration of response (DOR) and OS	1 year after the last treatment

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Exploratory: investigate expression levels of Fc receptors, and other immunological markers on immune cells infiltrating the tumor	Expression levels of Fc receptors (eg, CD32b) and other markers of immunological activity using immunohistochemistry (IHC) and/or nucleotide-based assays using tissue samples	1 day
Exploratory: investigate the genetic background of subjects with respect to FcgammaR isoforms and explore a potential correlation of the genetic background with clinical responses	Determination of Fcgamma receptor isoforms using nucleotide-based assays on genetic material extracted from whole blood	1 day
Exploratory: explore any exposure-response and/or exposure-safety relationship between BI-1607 serum concentrations and clinical outcome	Correlation of BI-1607 PK and antitumor activity measures, as well as to safety measures of interest	1 day

Collaborators and Investigators

• Sponsor: BioInvent International AB
• Investigators: Study Director: Andres McAllister, MD, PhD, BioInvent International AB

Study record dates

Study Major Dates

• Study Start (Actual): July 28, 2022
• Primary Completion (Actual): February 7, 2024
• Study Completion (Estimated): April 1, 2024

Study Registration Dates

• First Submitted: September 22, 2022
• First Submitted That Met QC Criteria: September 22, 2022
• First Posted (Actual): September 26, 2022

Study Record Updates

• Last Update Posted (Actual): February 20, 2024
• Last Update Submitted That Met QC Criteria: February 16, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Keywords: HER2-positive; solid tumours
• Additional Relevant MeSH Terms: Skin Diseases; Neoplasms by Histologic Type; Neoplasms; Neoplasms by Site; Carcinoma; Neoplasms, Glandular and Epithelial; Breast Diseases; Breast Neoplasms; Adenocarcinoma; Antineoplastic Agents; Antineoplastic Agents, Immunological; Trastuzumab
• Other Study ID Numbers: 21-BI-1607-01

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No