BI-1808 as a Single Agent and With Pembrolizumab in Treatment of Advanced Malignancies

• Status: Recruiting
• Trial end date: 2025-05-01
• Target enrollment: 0
• Participant gender: All

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.

• Phase: Phase 1/Phase 2
• Accepts Healthy Volunteers?: No

Details

• Lead Sponsor: BioInvent International AB
• Treatments: Pembrolizumab

Criteria

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

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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.