BI-1808 as a Single Agent and With Pembrolizumab in Treatment of Advanced Malignancies
BI-1808 as a Single Agent and With Pembrolizumab in Treatment of Advanced Malignancies
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.
Study design:

 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.

 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 14 additional doses or up to 1 year from first dose of BI-1808
 therapy, whichever comes first, 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 14 additional doses or up to 1 year
 from first dose of BI-1808 therapy, whichever comes first, 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 14 additional doses or up to 1 year from first dose of BI-1808 therapy,
 whichever comes first, 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 14 additional doses or up to 1 year from first dose of BI-1808 therapy,
 whichever comes first. 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 14 additional doses or up
 to 1 year from first dose of BI-1808 therapy, whichever comes first, 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.
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.

 Phase 2:

 1. Cohort 1 and Cohort 4 (NSCLC):

 1. 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.

 2. 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.

 3. 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):

 1. Histologically confirmed and documented recurrent ovarian, fallopian tube, and
 peritoneal cancer.

 2. 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).

 3. At least treated with 1 line of platinum-based chemotherapy.

 4. Prior treatment with poly-ADP ribose polymerase inhibitors is allowed. Cohort 3
 (CTCL - MF or SS)

 1. Stage IB-IV MF or SS with failure of at least 1 systemic therapy.

 2. No current large cell transformation.

 3. 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.

 4. Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of
 low-to-medium potency topical steroids permitted (no change in preceding 4
 weeks).

 5. Prior lines with mogamulizumab or vorinostat are allowed

 Has an Eastern Cooperative Oncology Group (ECOG) performance status of 0-1. Has
 adequate organ function as confirmed by laboratory values

 -

 Exclusion Criteria:

 -  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:

 The following inclusion criteria must be met for a subject to be eligible for
 inclusion in the trial:

 1. Is willing and able to provide written informed consent for the trial. 2. Is
 ≥18 years of age on the day of signing informed consent. 3. 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.

 4. Is intolerant of, refuses, or is not eligible for standard antineoplastic
 therapy.

 5. Has at least 1 measurable disease lesion as defined by RECIST. 6. 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.

 7. Has a life expectancy of ≥12 weeks. 8. Has an Eastern Cooperative Oncology
 Group (ECOG) performance status of 0-1. 9. Has adequate organ function as
 confirmed by laboratory values listed in the table below.

 Laboratory Test Value Required Hemoglobin ≥9.0 g/dL or ≥5.6 mmol/L (criteria must
 be met without erythropoietin dependency and without packed red blood cell
 transfusion within last 2 weeks) Absolute neutrophil count ≥1500/µL Platelet
 count ≥100,000/µL Total bilirubin ≤1.5 ×ULN or direct bilirubin ≤ULN for subjects
 with total bilirubin levels >1.5 × ULN ALT and AST ≤2.5 × ULN (≤5 × ULN for
 subjects with liver metastases) Creatinine or Measured or calculated creatinine
 clearance (per institutional standard [GFR can also be used in place of
 creatinine or creatinine clearance]) ≤1.5 × ULN or

 -  30 mL/min for subjects with creatinine levels >1.5 × institutional ULN INR
 or PT aPTT ≤1.5 × ULN unless subject is receiving anticoagulant therapy as
 long as PT or aPTT is within therapeutic range of intended use of
 anticoagulants

 ALT=alanine aminotransferase (serum glutamic-pyruvic transaminase);
 aPTT=activated partial thromboplastin time; AST=aspartate aminotransferase (serum
 glutamic-oxaloacetic transaminase); GFR=glomerular filtration rate;
 INR=international normalized ratio; PT=prothrombin time; ULN=upper limit of
 normal

 Phase 2a Expansion Cohort-Specific Inclusion Criteria:

 In addition to the general inclusion criteria above, subjects must also meet the
 criteria for the specific cohort. Additional requirements may be added or
 modified based on learnings from subjects enrolled in the Phase 1 portion of the
 trial.

 1. Cohort 1 and Cohort 4 (NSCLC):

 1. 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.

 2. 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.

 3. 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.

 2. Cohort 2 and Cohort 5 (OC):

 a. Histologically confirmed and documented recurrent ovarian, fallopian tube, and
 peritoneal cancer.

 b. 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).

 c. At least treated with 1 line of platinum-based chemotherapy. d. Prior treatment
 with poly-ADP ribose polymerase inhibitors is allowed. 3. Cohort 3 (CTCL - MF or SS)

 1. Stage IB-IV MF or SS with failure of at least 1 systemic therapy.

 2. No current large cell transformation.

 3. 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.

 4. Stable doses of systemic steroids (≤20 mg prednisone equivalent) and of
 low-to-medium potency topical steroids permitted (no change in preceding 4
 weeks).

 5. 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:

 1. Chemotherapy or small molecule products within 4 weeks of first dose of BI-1808.

 2. 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.

 3. 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. A 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.