Neoadjuvant INBRX-106 (Hexavalent OX40 Agonist) in Combination With Pembrolizumab as a Chemotherapy-sparing Regimen for Stage II TNBC (Triple Negative Breast Cancer) Patients

Eligibility Criteria

• 1. Age ≥ 18 years, inclusive of all genders.
• 2. Have an Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 or 1.
• 3. Patients must have histologically confirmed TNBC (ER/PR ≤ 10% allowed, HER2- as defined by ASCO guidelines). HER2 negative permitted to enroll as IHC 0, 1, or 2+ with negative ISH.
• 4. Primary breast tumor at least 2cm (at least clinical T2 based on pathology, imaging, or clinical exam) and measurable by ultrasound.
• 5. No clinical evidence of regional nodal involvement (N0).
• 6. Multifocal/multicentric disease is allowed if all suspicious sites have been biopsied and are consistent with TNBC OR, if in the opinion of the investigator, all suspicious sites represent the same disease process and biopsy is not clinically indicated.
• 7. No prior therapy of any kind for TNBC.
• 8. Willingness to undergo serial ultrasounds, serial biopsies, and blood draws.
• 9. Patients must have adequate organ function as defined below. Specimens must be collected within 28 days prior to the start of study treatment.
• * Absolute neutrophil count (ANC) ≥1500/µL
• * Platelets ≥100 000/µL
• * Hemoglobin ≥8.0 g/dL or ≥5.0 mmol/L
• * Creatinine OR measured or calculated creatinine clearance (GFR can also be used in place of creatinine or CrCl) ≤1.5 × ULN OR ≥30 mL/min for participant with creatinine levels \>1.5 × institutional ULN
• * Total bilirubin ≤1.5 × ULN OR direct bilirubin ≤ULN for participants with total bilirubin levels \>1.5 × ULN. Patients with elevated LFTs that are suggestive of Gilbert's disease (a benign process) are eligible.
• * AST (SGOT) and ALT (SGPT) ≤2.5 × ULN
• * International normalized ratio (INR) OR prothrombin time (PT) Activated partial thromboplastin time (aPTT) ≤1.5 × ULN unless participant is receiving anticoagulant therapy as long as PT or aPTT is within therapeutic range of intended use of anticoagulants
• * TSH and free T4 levels should be drawn within 14 days prior to start of treatment. Patients must have adequate thyroid function as demonstrated by free T4 values, regardless of TSH.
• 10. Fertile male patients and female patients of childbearing potential must agree to avoid impregnating a partner or becoming pregnant, respectively. They must be willing to employ highly effective contraception methods (with a failure rate of less than 1% when used consistently and correctly) at least 28 days before the first dose of study treatment until 4 months after the last dose of study treatment.
• * Combined (estrogen and progestogen containing) hormonal contraception associated with inhibition of ovulation: Oral. Intravaginal. Transdermal.
• * Progestogen-only hormonal contraception associated with inhibition of ovulation: Oral. Injectable. Implantable.
• * Intrauterine device (IUD).
• * Intrauterine hormone-releasing system (IUS).
• * Bilateral tubal occlusion.
• * Vasectomized partner. (Only considered to be highly effective contraception if he is the sole sexual partner of the female patient of childbearing potential and if the vasectomized partner has received medical assessment of the surgical success.)
• * Sexual abstinence. (Only considered to be highly effective contraception if defined as refraining from heterosexual intercourse during the entire period of risk associated with the study treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the preferred and usual lifestyle of the patient and if considered acceptable by local regulatory agencies and IRBs/IECs.
• 11. Pre-menopausal women must have a negative urinary or serum pregnancy test within 72 hours prior to start of treatment. If screening serum pregnancy test collected outside of 72 hours prior to start of treatment, this may be accepted for determination of eligibility, but must be re-checked prior to treatment C1D1. If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required. The following age-specific requirements apply:
• * Women \< 50 years of age are considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of exogenous hormonal treatments and if they have luteinizing hormone and follicle-stimulating hormone levels in the post-menopausal range for the institution or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• * Women ≥ 50 years of age are considered post-menopausal if they have been amenorrhoeic for 12 months or more following cessation of all exogenous hormonal treatments, had radiation-induced menopause with last menses \>1 year ago, had chemotherapy-induced menopause with last menses \>1 year ago, or underwent surgical sterilization (bilateral oophorectomy, bilateral salpingectomy or hysterectomy).
• 12. TIL score \> 1%.
• 1. Bilateral breast cancer.
• 2. Prior malignancies that require ongoing active therapy or are at clinically significant risk of systemic recurrence in the opinion of the investigator.
• 3. Suspicion for, or histologically confirmed metastatic disease.
• 4. Symptomatic primary tumor.
• 5. Primary tumor with potential for skin ulceration or invasion of the chest wall, or with pain that would suggest rapid progression or imminent muscle/skin involvement in the opinion of the enrolling investigator.
• 6. Prior therapy with an anti-PD-1, anti-PD-L1, or antiPDL2 agent or with an agent directed to another stimulatory or co-inhibitory T-cell receptor (e.g., CTLA-4, OX40, CD137). Patients who have received these agents more than 3 years prior for other malignancies may be considered if they are not still at clinically significant risk of systemic recurrence in the opinion of the investigator.
• 7. Known allergy or hypersensitivity to any of the study drugs or any of the study drug excipients.
• 8. Diagnosis of immunodeficiency or is receiving chronic systemic steroid therapy (in dosing exceeding 10 mg daily of prednisone equivalent) or any other form of immunosuppressive therapy within 7 days prior to the first dose of study drug.
• 9. Active autoimmune disease that has required systemic treatment in excess of prednisone 10mg daily or equivalent in the past 2 years (i.e., with use of disease modifying agents, corticosteroids or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment and is allowed.
• 10. 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.
• 11. Participants with a condition requiring systemic treatment with either corticosteroids (\> 10 mg daily prednisone equivalents) or other immunosuppressive medications within 14 days of study drug administration. Inhaled or topical steroids and adrenal replacement doses \> 10 mg daily prednisone equivalents are permitted in the absence of active autoimmune disease.
• 12. Known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial.
• 13. Pregnant or breastfeeding.
• 14. History of (non-infectious) pneumonitis that required steroids or has current pneumonitis.
• 15. History of allogenic tissue/solid organ transplantation.
• 16. Has active autoimmune disease that has required systemic treatment in the past 2 years (i.e., with use of disease modifying agents, corticosteroids, or immunosuppressive drugs). Replacement therapy (e.g., thyroxine, insulin, or physiologic corticosteroid replacement therapy for adrenal or pituitary insufficiency, etc.) is not considered a form of systemic treatment. Has a known additional malignancy (other than their current breast cancer diagnosis) that is progressing or has required active systemic treatment within the past 3 years.
• 17. History or current evidence of any condition, therapy, or clinically significant laboratory abnormality that might confound the results of the study, interfere with the subject's participation for the full duration of the study, or is not in the best interest of the subject to participate, in the opinion of the treating investigator.
• 18. Active infection requiring systemic therapy with the exception of UTI requiring oral antibiotic therapy and prophylactic anti-viral therapy (e.g. Acyclovir).
• 19. Known history of Human Immunodeficiency Virus (HIV) infection.
• 20. Known history of Hepatitis B (defined as Hepatitis B surface antigen \[HBsAg\] reactive) or known active Hepatitis C virus (defined as HCV RNA \[qualitative\] is detected) infection. Patients with naturally acquired immunity are allowed (i.e. HBsAg(-); HBcAb(+); HBsAb(+/-). Note: no testing for Hepatitis B and Hepatitis C is required unless mandated by local health authority.
• 21. Any known history of active TB (Bacillus Tuberculosis).