BSI-082 Alone and in Combination with Trastuzumab Deruxtecan for the Treatment of Locally Advanced or Metastatic Solid Tumors

Inclusion Criteria

• Read, understood, and provided written informed consent and must be willing to comply with all study requirements and procedures
• Adults ≥ 18 years of age at the time of informed consent form is signed
• Patients with histologically or cytologically confirmed locally advanced or metastatic solid tumors who have relapsed, or been non-responsive, or have developed disease progression through standard systemic therapy, or have been ineligible for standard systemic therapy known to confer clinical benefit
• Patients having an Food and Drug Administration (FDA)-approved indication for T-DXd (only for phase 1b dose expansion)
• With 4 weeks or 5 half-lives (whichever is shorter) of prior anticancer therapies (only for phase 1a dose escalation)
• Life expectancy ≥ 12 weeks
• Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
• Presence of at least 1 measurable lesion based on computed tomography (CT) or magnetic resonance imaging (MRI) per Response Evaluation Criteria in Solid Tumors (RECIST) version (V) 1.1
• Has a left ventricular ejection fraction (LVEF) ≥ 50% by either an echocardiogram (ECHO) or multigated acquisition (MUGA) scan within 28 days before enrollment
• Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L
• Platelet counts ≥ 100 x 10^9/L
• Hemoglobin ≥ 9 g/dL (without recent red blood cell transfusion within 2 weeks prior to study entry)
• Creatinine clearance ≥ 40 mL/min per the Cockcroft and Gault formula
• Aspartate aminotransferase (AST) ≤ 2.5 x upper limit normal (ULN) or patients with hepatic metastasis ≤ 5 x ULN
• Alanine aminotransferase (ALT) ≤ 2.5 x ULN or patients with hepatic metastasis ≤ 5 x ULN
• Total bilirubin ≤ 1.5 x ULN, except for patients with Gilbert’s syndrome (for patients with Gilbert’s syndrome, total bilirubin < 3.0 x ULN or direct bilirubin < 1.5 x ULN)
• Both male and female of childbearing potential patients enrolled in this trial as well as their partners must agree to use highly effective contraception during the study and for at least 10 months after discontinuing study treatment. Patients and/or partners who are surgically sterile or postmenopausal are exempt from this requirement

Exclusion Criteria

• Known allergies, hypersensitivity, or intolerance to monoclonal antibodies (mAbs) or formulation components of BSI-082
• Prior therapy with any signal-regulatory protein alpha (SIRPalpha) or CD47 targeting agents
• Has active autoimmune disease or a documented history of autoimmune disease, or history of potential autoimmune syndrome that required systemic steroids or immunosuppressive medications, except for patients with vitiligo, endocrinopathies, type 1 diabetes, or patients with resolved childhood asthma/atopy or other syndromes which would not be expected to recur in the absence of an external trigger (e.g., drug-related serum sickness or post-streptococcal glomerulonephritis). Patients with mild asthma who require intermittent use of bronchodilators (such as albuterol) and those who have not been hospitalized for asthma in the preceding 3 years will not be excluded from this study
• Toxicities of prior anticancer therapies have not resolved to ≤ grade 1 or to baseline prior to the first dose of study treatment (excluding alopecia, vitiligo, endocrinopathies on stable hormone replacement therapy, grade 2 neuropathy from taxanes or platinum containing therapies and grade 2 hearing loss from platinum-containing therapies)
• Has other malignancy, except for adequately treated basal or squamous cell skin cancer or in situ cancers; or any other cancer from which the patient has been disease-free for at least 5 years
• Occurrence of immune related toxicity necessitating permanent discontinuation or immune related toxicity that required treatment with a tumor necrosis factor (TNF) inhibitor (e.g., infliximab) in patients with previous immunotherapy
• Medical history of myocardial (MI) within 6 months before study enrollment, symptomatic congestive heart failure (CHF) (New York Heart Association [NYHA] class II to IV)
• Any of the following within 6 months of enrollment: cerebrovascular accident, transient ischemic attack, other arterial thromboembolic events, or pulmonary embolism
• Has a QT interval corrected with Fridericia's formula (QTcF) prolongation to > 470 ms based on average of the screening triplicate 12-lead electrocardiogram (ECG)
• Uncontrolled hypertension (resting systolic blood pressure > 180 mmHg or diastolic blood pressure > 110 mmHg) and/or severe arrhythmia within 28 days before enrollment
• Has a history of (non-infectious) interstitial lung disease (ILD)/pneumonitis that required steroids, has current ILD/pneumonitis, or where suspected ILD/pneumonitis cannot be ruled out by imaging at screening
• Has lung-specific intercurrent clinically significant illnesses including, but not limited to, any underlying pulmonary disorder
• Any autoimmune, connective tissue or inflammatory disorders where there is documented or suspicion of pulmonary involvement at the time of screening
• Prior complete pneumonectomy
• Has spinal cord compression or clinically active central nervous system metastases, defined as untreated and symptomatic, or requiring therapy with corticosteroids or anticonvulsants to control associated symptoms
• Has uncontrolled infection requiring intravenous (IV) antibiotics, antivirals, or antifungals
• Has active primary immunodeficiency or active human immunodeficiency virus (HIV) infection as determined by plasma HIV ribonucleic acid (RNA) viral load and CD4 count. For the dose- expansion phase only, participants with undetectable viral load or normalized CD4 count (CD4+ T-cell counts ≥ 350 cells/μL) and no opportunistic infection within the past 12 months will be eligible. These participants must be on established antiretroviral therapy for at least 4 weeks and have an HIV viral load < 400 copies/mL prior to enrollment
• Has active hepatitis B or C infection. Participants with past hepatitis C virus (HCV) infection and positive for HCV antibody are eligible only if polymerase chain reaction (PCR) is negative for HCV RNA. Participants with past or resolved hepatitis B virus infection are eligible only if confirmed by the investigator
• Has received a live, attenuated vaccine (messenger ribonucleic acid [mRNA] and replication- deficient adenoviral vaccines are not considered live, attenuated vaccines) within 30 days prior to first exposure to study drug(s)
• Has any other acute or chronic medical or psychiatric condition or laboratory abnormality that could increase the risk associated with trial participation or trial drug administration or could interfere with the interpretation of trial results would make the patient inappropriate for entry into the trial
• Has substance abuse or any other medical conditions such as clinically significant cardiac or psychological conditions, that may interfere with the participant's participation in the clinical study or evaluation of the clinical study results
• Women who are pregnant or lactating. All female patients of childbearing potential must have a negative serum pregnancy test prior to the first dose of study treatment