Advanced Malignancies, Ovarian Cancer, T-cell Lymphoma, Melanoma
Conditions
Keywords
Advanced Malignancies, T-cell Lymphoma
Brief summary
The goal of this first in human clinical trial is to test BI-1808 administered as single agent and in combination with pembrolizumab in subjects with advanced malignancies whose disease has progressed after standard therapy. The main questions it aims to answer are: * how safe and tolerable is BI-1808 * what is maximum tolerated or administrated dose * to determine recommended dose for further clinical trials. Participants will receive infusions of with BI-1808 as a single agent, BI-1808 in combination with pembrolizumab and BI-1808 in combination with pembrolizumab and paclitaxel every 3 weeks. For the purpose of this study, subjects with advanced malignancies includes subjects with advanced solid tumors and subjects with T-cell lymphoma (TCL),
Detailed description
This is a Phase 1/2a, dose-escalation, multicenter, first-in-human, consecutive-cohort, open-label study of BI-1808, as a single agent, in combination with pembrolizumab, and in BI-1808 in combination with pembrolizumab and paclitaxel in subjects with advanced malignancies, whose disease has progressed after standard therapy. The study will consist of 2 phases: a Phase 1 with Parts A and B, and a Phase 2a with Parts A , B and C. Phase 1 Part A consists of a dose escalation of BI-1808 as a single agent to evaluate safety and tolerability and to determine the RP2D as a single agent (sRP2D) in subjects with advanced malignancies whose disease has progressed after standard therapy. Phase 1 Part B consists of a dose escalation of BI-1808 in combination with pembrolizumab to evaluate the safety and tolerability of the combination treatment and to allow selection of the RP2D for BI-1808 in combination with pembrolizumab (cRP2D) in subjects with advanced malignancies whose disease has progressed after standard therapy. Phase 2a will assess BI-1808 administered as a single agent (Part A), in combination with pembrolizumab (Part B), and in combination with pembrolizumab and paclitaxel (Part C) at the respective hypothesized RP2D(s) determined in Phase 1. Phase 2a expansion will be conducted in indication specific signal seeking cohorts and indication specific Dose Optimization Cohorts) of subjects. The Phase 2a study aims to further evaluate the safety and tolerability of BI-1808 as monotherapy (Part A), in combination with pembrolizumab (Part B), and in combination with pembrolizumab and paclitaxel (Part C). Including characterization of the PK and PD profiles of BI-1808, evaluation of preliminary antitumor activity based on ORR, DoR, and progression-free survival (PFS) as assessed by RECIST v1.1 and iRECIST, and determination of the recommended Phase 2 dose (RP2D).
Interventions
DRUGBI-1808
BI-1808 administered as a flat-dose IV infusion once every 3 weeks
DRUGPembrolizumab (KEYTRUDA® ) 25 Mg/mL Solution for Injection
Pembrolizumab administered as a flat-dose IV infusion once every 3 weeks.
Paclitaxel administered as a flat-dose IV infusion weekly.
Sponsors
BioInvent International AB
Merck Sharp & Dohme LLC
Study design
Allocation
NON_RANDOMIZED
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
Phase 1/2a, dose escalation, consecutive-cohort, open-label study trial of BI-1808 as a Single Agent in Combination with Pembrolizumab and in combination with Pembrolizumab and Paclitaxel in Subjects with advanced malignancies.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Able and willing to provide written informed consent. * Aged 18 years or older. * Histologically confirmed advanced or metastatic malignancy eligible for an enrolling study cohort. * Disease progression following, intolerance of, ineligibility for, or refusal of applicable standard therapy. * At least one measurable lesion according to the response criteria specified in the protocol. * Eastern Cooperative Oncology Group performance status of 0 or 1. * Life expectancy of at least 12 weeks. * Adequate organ function. * Willing and medically suitable to provide required tumor or skin biopsies. * Meets the disease-specific and treatment-history requirements of the applicable Phase 2a cohort. * For Phase 2a Part C: Histologically confirmed platinum-resistant high-grade serous or clear-cell ovarian carcinoma, prior platinum-based treatment as specified in the protocol, and suitability for paclitaxel treatment.
Exclusion criteria
1\. Active central nervous system metastases or carcinomatous meningitis. * Active or clinically significant autoimmune disease, immunodeficiency, or use of prohibited immunosuppressive treatment. * Prior treatment-related toxicity not recovered to the level specified in the protocol. * Prior anticancer therapy, radiotherapy, immunotherapy, investigational treatment, or live vaccine within the protocol-defined washout period. * History of clinically significant immune-mediated toxicity, including pneumonitis, associated with previous immune-checkpoint inhibitor treatment. * Uncontrolled or clinically significant cardiovascular disease, serious infection, or another condition that could compromise safety or study participation. * Major surgery without adequate recovery. * Prior allogeneic tissue or solid-organ transplantation or active graft-versus-host disease. * Pregnancy or breastfeeding, or unwillingness to comply with protocol-defined contraceptive requirements. * Known hypersensitivity to a study treatment or its components. * Another active malignancy, except for protocol-defined permitted malignancies. * Participation in another interventional clinical trial that conflicts with this study. * Unable or unlikely to comply with study procedures and requirements. * For Phase 2a Part C: Receipt of prohibited colony-stimulating factors within the protocol-defined period before treatment.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Occurrence of adverse events (AEs) | From the start of the study treatment for up to 2 years and 90 days. | AEs will be assessed by the investigators by severity and will be graded according to the NCI CTCAE v5.0 or higher and causality between AEs and the exposure to the study treatment. |
| Identify DLTs, determine the maximum tolerated dose and select a recommended Phase 2 dose (RP2D) of BI-1808, given via intravenous (IV) infusion, as a single agent (Phase 1, Part A), and in combination with pembrolizumab (Phase 1, Part B) | Up to 104 weeks (2 years) | Determine the hypothesized RP2D dose for BI-1808 Phase 2a according to mTPI-2 design |
| Occurrence of serious adverse events (SAEs) | Up to 104 weeks (2 years) | SAEs will be assessed by the investigators by severity and will be graded according to the NCI CTCAE v5.0 or higher and causality between SAEs and the exposure to the study treatment |
| To identify the recommended Phase 2 dose (RP2D) of BI-1808, | up to 104 weeks (2 years) | Select the RP2D dose for BI-1808 derived from the totality of PK, PD, clinical response, safety,and tolerability observed in signal seeking and dose optimization cohorts. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of PK parameters for BI-1808. Maximum observed plasma concentration (Cmax) | Up to 104 weeks (2 years) | Study the PK profile of BI-1808 according to a non-compartmental analysis using a validated software |
| Evaluation of ADA response to BI-1808 in serum with validated method | Up to 104 weeks (2 years) | The detection and characterization of antibodies to BI-1808 will be performed using a validated method and will be evaluated for BI-1808 serum concentration to enable interpretation of the antibody data |
| Measurement of TNFR2 receptor occupancy on CD14+ and/CD16+ cells in serum with validated method | Up to 104 weeks (2 years) | evaluate the receptor occupancy of BI-1808 as a single agent and in combination with pembrolizumab or pembrolizumab and paclitaxel on T-cells expressing TNFR2 in absolute value |
Countries
Denmark, Hungary, Russia, Spain, Sweden, United Kingdom, United States
Contacts
CONTACTSusanne Gertsson
CONTACTMona Welschof, PhD
STUDY_DIRECTORAndres McAllister, PhD
BioInvent International AB
Outcome results
None listed