BI-1808 as a Single Agent and With Pembrolizumab (KEYTRUDA® ) in Treatment of Advanced Malignancies(Keynote-D20)

Advanced Malignancies Clinical Trial

Official title: Phase 1/2a Open-Label, Dose-Escalation, Multicenter, FIH, Consecutive-Cohort, Clinical Trial of BI-1808, a Monoclonal Antibody to TNFR 2 as a Single Agent and in Combination With Pembrolizumab (MK-3475-D20) in Subjects With Advanced Malignancies

Status Recruiting

Clinical Trial Summary

This is a Phase 1/2a, dose-escalation, multicenter, first-in-human, consecutive-cohort, open-label study of BI-1808, as a single agent and in combination with pembrolizumab in subjects with advanced malignancies, whose disease has progressed after standard therapy.

For the purpose of this study, subjects with advanced malignancies includes subjects with advanced solid tumors (where iRECIST can be applied for efficacy assessment) and subjects with cutaneous T-cell lymphoma (CTCL), specifically Sézary Syndrome (SS) and mycosis fungoides (MF).

The study will consist of 2 phases: a Phase 1 with Parts A and B, and a Phase 2a with Parts A and B.

All subjects participating in the trial will complete a follow-up portion of the trial and an End of Treatment (EOT) Visit 30 days (±3 days) after their last dose of BI-1808.

Clinical Trial 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 and in combination with pembrolizumab in subjects with advanced malignancies, whose disease has progressed after standard therapy.

For the purpose of this study, subjects with advanced malignancies includes subjects with advanced solid tumors and subjects with cutaneous T-cell lymphoma (CTCL), specifically Sézary Syndrome (SS) and mycosis fungoides (MF).

The study will consist of 2 phases: a Phase 1 with Parts A and B, and a Phase 2a with Parts A and B.

For the purpose of making dose-escalation decisions, DLTs will be evaluated from the first dose through Day 22. Data will be regularly reviewed by the SMC; the outcome of these reviews will drive the dose-escalation process.

b Subjects in the first cohort of Phase 1, Part B will be administered BI-1808 at the single-agent dose level of RP2D 1 (1 dose level lower than the sRP2D) as the starting dose. Thereafter, escalation (or de-escalation) will follow the same rules as those of Phase 1, Part A of the trial, according to the mTPI-2 design.

All subjects participating in the trial will complete a follow-up portion of the trial and an End of Treatment (EOT) Visit 30 days (±3 days) after their last dose of BI-1808.

Phase 1, Parts A and B of the trial will recruit patients with all types of malignancies whose tumors have progressed after standard anticancer treatment and who meet the inclusion/exclusion criteria. A minimum number of subjects with non-small-cell lung cancer (NSCLC), ovarian cancer (OC), and CTCL may be included in the Phase 1 (dose escalation) part of the trial.

For any subjects with CTCL included in Phase 1, Parts A and B of the study, efficacy assessments will be performed as detailed for Phase 2a, Part A - Cohort 3.

Phase 1, Part A consists of a dose-escalation phase, using the modified toxicity probability interval dose-escalation design, version 2 (mTPI 2) for selection of the single-agent recommended Phase 2 dose (sRP2D).

An underlying target DLT rate of 30% will be applied for the decision-making rules of the mTPI 2 design and to determine an sRP2D for BI-1808.

In Phase 1, Part A, consecutive cohorts of subjects with all types of malignancies will receive IV infusions of ascending doses of BI-1808 at the doses of 25 mg, 75 mg, 225 mg, and 675 mg, every 3 weeks (Q3W). Six additional subjects will receive BI-1808 at the sRP2D.

Subjects in Phase 1, Part A will initially receive 3 doses of therapy with BI-1808 (ie, administered on Day 1 [Week 1], Day 22 [Week 4], and Day 43 [Week 7]). During this period, subjects will undergo PK, pharmacodynamic, and safety assessments at regular intervals. For the purpose of making dose escalation decisions, DLTs will be evaluated from the first dose through Day 22. Data will be regularly reviewed by a Safety Monitoring Committee (SMC), the outcome of these reviews will drive the dose escalation process.

The data obtained in Phase 1, Part A will be used to inform the BI-1808 dose to be taken forward for the Phase 2a expansion phase of the trial. In order to determine the sRP2D, and upon recommendation of the SMC, additional cohorts with intermediate doses or regimens can be added in Phase 1. In the event that available PK and pharmacodynamic results are compelling, an optimal therapeutic dose can be estimated, and upon recommendation by the SMC, Phase 1 of the trial may be stopped and the Phase 2a part of the trial can begin.

Subjects who show clinical benefit (CR, PR or SD) at the Week 9 Visit shall continue on therapy with BI-1808. Starting at Week 10, these subjects will receive infusions every 3 weeks (±3 days) for up to 32 additional doses from first dose of BI-1808 therapy, or until PD or unacceptable toxicity. Subjects with PD at the Week 9 Visit may continue on therapy until a confirmatory scan is performed at least 4 weeks after the Week 9 scan. If PD is not confirmed, the subject shall continue on treatment; if PD is confirmed, the subject will be discontinued from the trial.

Subjects completing the initial treatment period with PD at the Week 9 assessment (confirmed by scan at least 4 weeks later), will be discontinued from treatment and the EOT Visit will be performed within 30 days (±3 days) after the Week 9 Visit.

In Phase 1, Part B of the trial, additional subjects with all types of malignancies will be enrolled and the safety and tolerability profile of the combination of BI-1808 with pembrolizumab will be assessed. Successive cohorts will receive an ascending dose of BI-1808 in combination with pembrolizumab at the standard dose of 200 mg. The pembrolizumab infusion will be given before the BI-1808 infusion.

Subjects in the first cohort of Phase 1, Part B will be administered BI-1808 at the dose level of sRP2D 1 (1 dose level lower than the sRP2D) as the starting dose, in combination with pembrolizumab 200 mg. Thereafter, escalation (or de-escalation) will follow the same rules as those of Phase 1, Part A of the trial, according to the mTPI-2 design.

For Phase 1, Part B, and for the purpose of making dose-escalation decisions, the DLT period will be evaluated through Day 43.

Dose-escalation and confirmation of the recommended Phase 2 dose for BI-1808 in combination with pembrolizumab (cRP2D) of BI-1808 in combination with pembrolizumab will end using the same rules as in Phase 1, Part A. Once the cRP2D of the BI-1808 in combination with pembrolizumab treatment has been determined, Cohort 4 of Phase 2a Part B may begin.

Subjects who show clinical benefit (CR, PR or SD) at the Week 9 Visit shall continue treatment with BI-808 in combination with pembrolizumab. Starting at Week 10, these subjects will receive infusions every 3 weeks (±3 days) for up to 32 additional doses from first dose of BI-1808 therapy,or until PD or unacceptable toxicity. Subjects with PD at the Week 9 Visit may continue on combination therapy until a confirmatory scan is performed at least 4 weeks after the Week 9 scan. If PD is not confirmed, the subject shall continue on treatment; if PD is confirmed, the subject will be discontinued from the trial.

Subjects completing the initial treatment period with PD at the Week 9 assessment (confirmed by scan at least 4 weeks later), will be discontinued from treatment and the EOT Visit will be performed within 30 days (±3 days) after the Week 9 Visit.

Phase 2a, Part A consists of 3 expansion cohorts of 12 subjects each: expansion Cohorts 1 and 2 will enroll subjects with NSCLC, and OC respectively. Additional cohorts with other specified malignancy types may be enrolled, based on Phase 1 results.

Subjects in these cohorts will be treated at the sRP2D of BI-1808 (as a single agent), as determined in Phase 1, Part A. Subjects will receive IV infusions of BI-1808 administered on Day 1 [Week 1], Day 22 [Week 4], and Day 43 [Week 7].

From Week 1 until Week 9 subjects will undergo PK, pharmacodynamic, and safety assessments at regular intervals. At the Week 9 Visit, subjects will also undergo disease response assessments to determine the potential clinical benefit (CR, PR, or SD).

Subjects who show clinical benefit (CR, PR or SD) at the Week 9 Visit shall continue on BI-1808 therapy. Starting at Week 10, these subjects will receive infusions every 3 weeks (±3 days) for up to 32 additional doses from first dose of BI-1808 therapy, or until PD or unacceptable toxicity. Subjects with PD at the Week 9 Visit may continue on therapy until a confirmatory scan is performed at least 4 weeks after the Week 9 scan. If PD is not confirmed, the subject shall continue on treatment; if PD is confirmed, the subject will be discontinued from the trial.

In Phase 2a, Part A, expansion Cohort 3 will study the activity of BI-1808 as a single agent in subjects with CTCL (specifically MF or SS). Subjects in this cohort will initially receive 3 doses of therapy with BI-1808 (ie, administered on Day 1 [Week 1], Day 22 [Week 4], and Day 43 [Week 7]). From Week 1 until Week 9 subjects will undergo PK, pharmacodynamic, and safety assessments at regular intervals. At the Week 9 Visit, subjects will also undergo disease response assessments to determine the potential clinical benefit (CR, PR or SD) of the combination therapy.

For all subjects with CTCL, the modified Severity Weighted Assessment Tool (mSWAT) (Olsen et al 2011) will be used for quantitative assessment of disease burden in the skin of all subjects, and blood samples will be collected for circulating Sézary cells. The presence or absence of measurable (extracutaneous) disease will be determined from the computed tomography (CT)/magnetic resonance imaging (MRI) scan performed at Screening/Baseline. For subjects with CTCL with nonmeasurable disease, subsequent scans will occur only at the discretion of the Investigator (eg, if there is a suggestion of new nodal or visceral involvement during the study). Subjects in Cohort 3 with measurable (extracutaneous) disease will have a CT/MRI scan at the Week 9 Visit (can be performed within 1 week prior to the Week 9 visit). For subjects with measurable (extracutaneous) disease who continue in the trial, a CT scan will be performed every third BI-1808 dose (ie, every 9 weeks [±1 week] after Week 10).

Subjects who show clinical benefit (CR, PR, or SD) at the Week 9 Visit shall continue on BI-1808 therapy. Starting at Week 10, these subjects will receive infusions every 3 weeks (±3 days) for up to 32 additional doses from first dose of BI-1808 therapy. Subjects with PD at the Week 9 Visit may continue on therapy until a confirmatory scan is performed at least 4 weeks after the Week 9 scan. If PD is not confirmed, the subject shall continue on treatment; if PD is confirmed, the subject will be discontinued from the trial.

Subjects completing the initial treatment period with PD at the Week 9 assessment (confirmed by scan at least 4 weeks later), will be discontinued from treatment and the EOT Visit will be performed within 30 days (±3 days) after the Week 9 Visit.

In Phase 2a, Part B expansion Cohorts 4 and 5 will explore the activity of BI-1808 in combination with pembrolizumab in subjects with NSCLC (Cohort 4) or OC (Cohort 5). Additional cohorts with other specified malignancy types may be enrolled, based on Phase 1, Part B results. These cohorts will only be opened when the cRP2D of the combination therapy (BI-1808 in combination with pembrolizumab) has been determined (Phase 1, Part B). Subjects in these cohorts will receive IV infusions of BI-1808 administered on Day 1 [Week 1], Day 22 [Week 4], and Day 43 [Week 7], in combination with 200 mg of pembrolizumab on the same days. The pembrolizumab infusion will be given before the BI-1808 infusion.

From Week 1 until Week 9, subjects will undergo PK, pharmacodynamic, and safety assessments at regular intervals. At the Week 9 Visit, subjects will also undergo disease response assessments to determine the potential clinical benefit (CR, PR or SD) of the combination therapy.

Subjects who show clinical benefit (CR, PR or SD) at the Week 9 Visit shall continue on combination therapy (BI-1808 in combination with pembrolizumab). Starting at Week 10, these subjects will receive infusions every 3 weeks (±3 days) for up to 32 additional doses from first dose of BI-1808 therapy, or until PD or unacceptable toxicity. Subjects with PD at the Week 9 Visit may continue on combination therapy until a confirmatory scan is performed at least 4 weeks after the Week 9 scan. If PD is not confirmed, the subject shall continue on treatment; if PD is confirmed, the subject will be discontinued from the trial.

Subjects completing the initial treatment period with PD at the Week 9 assessment (confirmed by scan at least 4 weeks later), will be discontinued from treatment and the EOT Visit will be performed within 30 days (±3 days) after the Week 9 Visit. ;

Related Conditions & MeSH terms

• Advanced Malignancies
• Neoplasms

• NCT number: NCT04752826
• Study type: Interventional
• Source: BioInvent International AB
• Contact: Susanne Gertsson
• Phone: +46462868550
• Email: susanne.gertsson@bioinvent.com
• Status: Recruiting
• Phase: Phase 1/Phase 2
• Start date: January 25, 2021
• Completion date: December 15, 2026