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

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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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) in Subjects With Advanced Malignancies (Keynote-D20)

Conditions
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Advanced Malignancies

Intervention / Treatment
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* Drug: BI-1808
* Drug: Pembrolizumab 25 Mg/mL Solution for Injection


Participation Criteria
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Eligibility Criteria
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Target population: Phase 1, Parts A and Part B of the trial will recruit subjects with all types of malignancies whose tumors have progressed after standard anticancer treatment. Phase 2a, Parts A and Part B of the trial will recruit patients with NSCLC, OC, and CTCL (specifically MF or SS). Inclusion Criteria: Is willing and able to provide written informed consent for the trial. Is ≥18 years of age on the day of signing informed consent. Has a histologically confirmed advanced malignancy. Subjects with CTCL [MF or SS] who satisfy the Phase 2a, Cohort 3-specific eligibility criteria may be enrolled into the Phase 1 part of the study. Is intolerant of, refuses, or is not eligible for standard antineoplastic therapy. Has at least 1 measurable disease lesion as defined by RECIST. Is able to safely undergo a baseline tumor tissue biopsy prior to first dose of BI-1808 (on non previously irradiated lesions only). The biopsy must be performed at least 4 weeks following the last dose of tumor directed therapy. Has a life expectancy of ≥12 weeks. Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Has adequate organ function as confirmed by laboratory values. Phase 2: Inclusion criteria in addition to above. Cohort 1 and Cohort 4 (NSCLC): For subjects whose tumors have programmed death-ligand 1 (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 standard of care chemotherapy either combined with anti PD 1/PD-L1 therapy or given separately. For subjects with known anaplastic lymphoma kinase, ROS proto-oncogene 1, receptor tyrosine kinase (ROS1) or epidermal growth factor receptor sensitizing molecular rearrangements, 1 line of targeted therapy will be required in addition to anti-PD-1/PD-L1 therapy. Cohort 2 and Cohort 5 (OC): Histologically confirmed and documented recurrent ovarian, fallopian tube, and peritoneal cancer. Platinum-resistant OC (defined as relapsing within 6 months after the last administration of platinum-based chemotherapy) or platinum-refractory OC (defined as progressing while on a platinum-based chemotherapy). At least treated with 1 line of platinum-based chemotherapy. Prior treatment with poly-ADP ribose polymerase inhibitors is allowed. Cohort 3 (CTCL - MF or SS) Stage IB-IV MF or SS with failure of at least 1 systemic therapy. No current large cell transformation. Prior therapy - No prior allo hematopoietic stem cell transplantation (HSCT); >90 days since auto HSCT; >4 weeks since systemic therapy and >2 weeks since skin-directed therapy. Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of low-to-medium potency topical steroids permitted (no change in preceding 4 weeks). Prior lines with mogamulizumab or vorinostat are allowed 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 known or suspected hypersensitivity to BI-1808 or pembrolizumab Has cardiac or renal amyloid light-chain amyloidosis. Has received the following: Chemotherapy or small molecule products within 4 weeks of first dose of BI-1808. Radiotherapy within 2 weeks of first dose of BI-1808. 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-1808. Has not recovered from AEs to at least Grade 1 by NCI CTCAE Has had Grade ≥3 autoimmune manifestations of previous immune checkpoint inhibitor treatments (eg, anti-PD-1, anti-PD-L1, or anti-CTLA-4). Has a history of (noninfectious) 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). However, those female subjects who have a negative serum or urine pregnancy test before enrollment and agree to use a highly effective method of birth control for 4 weeks before entering the trial, during the trial, and for 12 months after last dose of BI-1808, are considered eligible. Is a male subject with partner(s) of childbearing potential (unless he agrees to take measures not to father children by using 1 form of highly effective contraception [condom plus spermicide gel] during the trial and for 12 months after completing treatment). Has had major surgery from which the subject has not yet recovered. 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 known human immunodeficiency (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 trial. Has a history or current evidence of any condition, therapy, or laboratory abnormality that might confound the results of the trial, interfere with the subject's participation for the full duration of the trial, 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. Has a known additional malignancy of another type, with the exception of adequately treated cone biopsied carcinoma in situ (eg, breast carcinoma, cervical cancer in situ) and basal or squamous cell carcinoma of the skin. Male subjects with asymptomatic prostate cancer without known metastatic disease and with no requirement for therapy or requiring only hormonal therapy and with normal prostate-specific antigen for >1 year prior to start of trial therapy are eligible. 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.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Interventional Model Description: Phase 1/2a, dose escalation, consecutive-cohort, open-label study trial of BI-1808 as a Single Agent and in Combination with Pembrolizumab
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Phase I, Part A - Dose escalation and safety of BI-1808 alone<br>Dose escalation with repeated administrations of BI-1808 infusions as a single agent, in patients with advanced malignacy. | Drug: BI-1808<br>* BI-1808, a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets TNFR2 administered at different dose [Phase I, Part A] and at Recommended Dose for Part B [Phase I, Part B and Phase IIa] by intravenous (IV) infusions every 3 weeks.<br>|
| Experimental: Phase I, Part B - Dose escalation and Safety of BI-1808 in combination with pembrolizumab<br>Dose escalation and safety with repeated administrations of BI-1808 infusions in combination with infusions of pembrolizumab in patients with advanced malignacy. | Drug: BI-1808<br>* BI-1808, a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets TNFR2 administered at different dose [Phase I, Part A] and at Recommended Dose for Part B [Phase I, Part B and Phase IIa] by intravenous (IV) infusions every 3 weeks.<br>Drug: Pembrolizumab 25 Mg/mL Solution for Injection<br>* Pembrolizumab a programmed death receptor (PD-1) blocking antibody administered at 200mg by intravenous (IV) infusions every 3 weeks.<br>|
| Experimental: Phase IIa - Part A Expansion cohorts of BI-1808 alone<br>Repeated administrations of BI-1808 infusions as a singel dose in 3 cohorts of patients with defined advanced malignacy : ovarian cancer, non-small cell lung cancer , Cutaneous T-cell lymphoma (Sézary Syndrome and Mycosis Fungoides). | Drug: BI-1808<br>* BI-1808, a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets TNFR2 administered at different dose [Phase I, Part A] and at Recommended Dose for Part B [Phase I, Part B and Phase IIa] by intravenous (IV) infusions every 3 weeks.<br>|
| Experimental: Phase IIa, Part B - Expansion cohorts of BI-1808 in combination with pembrolizumab<br>Repeated administrations of BI-1808 infusions in combination with infusions of pembrolizumab in 2 cohorts of patients with defined advanced malignacy : ovarian cancer, non-small cell lung cancer. | Drug: BI-1808<br>* BI-1808, a fully human immunoglobulin G1 (IgG1) monoclonal antibody (mAb) that targets TNFR2 administered at different dose [Phase I, Part A] and at Recommended Dose for Part B [Phase I, Part B and Phase IIa] by intravenous (IV) infusions every 3 weeks.<br>Drug: Pembrolizumab 25 Mg/mL Solution for Injection<br>* Pembrolizumab a programmed death receptor (PD-1) blocking antibody administered at 200mg by intravenous (IV) infusions every 3 weeks.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Documenting AEs and SAEs and determining causality in relation to BI-1808 and/or pembrolizumab | Asess the safety and tolerability profile of increasing doses of BI-1808, as a single agent (Phase 1, Part A), and in combination with pembrolizumab (BI-1808 with pembrolizumab, graded according to National Cancer Institute [NCI]-CTCAE version 50 | Up to 1 year | 
| 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) | Select the RP2D dose for BI-1808ing mTPI-2 design. | Up to 1 year | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Evaluation of PK parameters for BI-1808. Maximum observed plasma concentration (Cmax) | Study the PK profile of BI-1808 according to a non-compartmental analysis using a validated software | Up to 1 year | 
| Evaluation of ADA response to BI-1808 in serum with validated method | assess the immunogenicity of BI-1808. 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 | Up to 1 year | 
| Measurement of TNFR2 receptor occupancy on CD14+ and/CD16+ cells in serum with validated method | evaluate the receptor occupancy of BI-1808 as a single agent and in combination with pembrolizumab on T-cells expressing TNFR2 in absolute value | Up to 1 year |