CD40 Agonist, Flt3 Ligand, and Chemotherapy in HER2 Negative Breast Cancer

Exclusion Criteria

• •Among any patients enrolled in the first line treatment setting, tumors should not be PD-L1+ by 22C3 assays or eligible for FDA approved standard of care chemotherapy and anti-PD-1/PD-L1 combination therapy as alternative to this clinical trial. This does not apply if patients have previously received PD-1 or PD-L1 blockade as part of neoadjuvant or adjuvant therapy regimen.
• •History of severe hypersensitivity reactions to mAbs.
• •Prior treatment with any anti-CD40 antibody or rhuFlt3L product.
• •Treatment with anthracycline in the metastatic setting.
• •Prior progression while on anthracycline based therapy or within 6 months of completing neoadjuvant or adjuvant anthracycline.
• •Prior history of acute myeloid leukemia (AML), or tumor with known Flt3 mutation/amplification
• •Receipt of any antibody targeting T cell check point or co-stimulation pathways within 4 weeks, use of any other monoclonal based therapies within 4 weeks, and all other immunotherapy (tumor vaccine, cytokine, or growth factor given to control the cancer) within 2 weeks prior to the planned start of study treatment.
• •Prior T-cell or other cell-based therapies within 12 weeks (or 2 weeks if patient experienced disease progression on the prior treatment)
• •Systemic radiation therapy within 4 weeks, prior focal radiotherapy within 2 weeks, or radiopharmaceuticals (strontium, samarium) within 8 weeks prior to the first dose of study treatment.
• •Chemotherapy or antibody drug conjugate within 21 days or at least 5 half-lives (whichever is shorter) prior to the planned start of study treatment.
• •Any kinase inhibitors within 2 weeks prior to the first dose of study treatment.
• •Major surgery within 4 weeks prior to the first dose of study treatment. Surgery requiring local/epidural anesthesia must be completed at least 72 hours before study drug administration and patients should be recovered.
• •Use of other investigational drugs within 4 weeks or 5 half-lives (whichever is longer) prior to study treatment administration.
• •Use of immunosuppressive medications within 4 weeks or systemic corticosteroids within 2 weeks prior to first dose of study treatment. Topical, inhaled or intranasal corticosteroids (with minimal systemic absorption) may be continued if the patient is on a stable dose. Non-absorbed intraarticular corticosteroid and replacement steroids (≤ 10 mg/day prednisone or equivalent) will be permitted.
• •Other prior 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 3 years.
• •Active, untreated central nervous system metastases.
• •Patients with known treated brain metastases should be neurologically stable for 4 weeks post-treatment and prior to study enrollment. Continued use of steroids and/or anticonvulsants (in the absence of any suspicion of progressive brain metastases) is acceptable if ≤ equivalent of prednisone 10 mg daily. Brain MRI required on screening to document lack of progression.
• •Women who are pregnant or nursing. All female patients with reproductive potential must have a negative pregnancy test prior to starting treatment.
• •Active autoimmune disease or history of autoimmune disease or syndrome that required systemic steroids or immunosuppressive medications within the preceding 6 months, except for patients with vitiligo, endocrinopathies, or type 1 diabetes, Patients with mild asthma who require intermittent use of bronchodilators (such as albuterol) who have not been hospitalized for asthma in the preceding 6 months will not be excluded from this study.
• •Significant cardiovascular disease including unstable angina pectoris, uncontrolled hypertension or arrhythmia, congestive heart failure (New York Heart Association Class III or IV or EF\<50%) related to primary cardiac disease, uncontrolled ischemic or severe valvular heart disease or any of the following within 6 months prior to the first dose of study treatment: myocardial infarction, severe/unstable angina, coronary artery bypass graft, congestive heart failure, cerebrovascular accident, transient ischemic attack.
• •For patients with triple negative breast cancer- prior anthracycline therapy with a cumulative doxorubicin-equivalent dose greater than 240 mg/m2. 240 mg/m2 anthracycline is equivalent to 4 doses of anthracycline-based chemotherapy in the localized setting (generally 60 mg/m2 per dose). Notes from physicians demonstrating 4 prior cycles/doses of anthracycline or if less than 60 mg/m2 specifying as such to estimate the total anthracycline dose is sufficient. Exact calculation based on mg received originally is not required.
• •For patients with hormone receptor positive breast cancer who have received a prior anthracycline therapy with a cumulative doxorubicin-equivalent dose exceeding 240 mg/m2 (as was part of standard-of-care regimens in the past), a cardiology evaluation is recommended to minimize potential risks of heart damage.
• •Has received a live vaccine within 30 days prior to the first dose of study drug. Examples of live vaccines include, but are not limited to the following: measles, mumps, rubella, varicella/zoster (chicken pox), yellow fever, rabies, Bacillus Calmette-Guérin (BCG), and typhoid vaccine. Seasonal influenza vaccines for injection are generally killed virus vaccines and are allowed; however, intranasal influenza vaccines (e.g., FluMist®) are live attenuated vaccines and are not allowed. The COVID-19 vaccines available in the United States are not live vaccines and are allowed if the final vaccine dose (of a regimen that requires more than 1 dose) is received at least 1 week prior to study enrollment.
• •History of (non-infectious) pneumonitis or has current pneumonitis. This includes asymptomatic infiltrates on screening chest CT scan that are felt by the investigator to potentially be an inflammatory process (i.e. grade 1 pneumonitis).
• •Active infection requiring systemic therapy, known HIV infection, or positive test for hepatitis B surface antigen or hepatitis C (antibody screen and if positive confirmed by RNA analysis). If positive results are not indicative of a true active or chronic infection, the patient can be enrolled after discussion with and agreement by the Investigator.
• •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 and, in the judgment of the investigator, would make the patient inappropriate for entry into the trial.
• •Evidence of acute or chronic infection on screening chest radiography.