Intrathecal Dendritic Cell Vaccines in Combination with Trastuzumab or Nivolumab for the Treatment of Breast Cancer Patients with Leptomeningeal Disease

Inclusion Criteria

• Histologically or cytologically confirmed diagnosis of BC by American Society of Clinical Oncology (ASCO)/College of American Pathologists (CAP) guidelines (Wolff et al, 2018), or radiographically definite LMD from BC
• Confirmation of HER2 positivity. All patients with HER2+ cancers will be allowed to enroll if they have LMD. Patients may be immunohistochemistry (IHC) 3+ and/or fluorescent in situ hybridization (FISH)+. Patients with IHC 2+ HER2 are eligible with reflex FISH. Any patient who is HER2- (using the criteria above) is also eligible * Similarly, where available, HER2+ cells or amplification or other methods using CSF testing may be used for eligibility purposes * HER2+ is defined using conventional criteria and does not include the current designation of HER2 low as its own diagnostic and therapeutic entity
• Trial participants must have a diagnosis of LMD. They must have the presence of malignant cells in the CSF (CSF+; note now cytology is considered diagnostic of LMD if the cytology is read as positive or suspicious; [Chamberlain et al., 2017] OR characteristic radiographic abnormalities of LMD). Signs and symptoms of LMD in and of themselves are not sufficient for inclusion
• Patients must have an Eastern Cooperative Oncology Group (ECOG) performance scale of ≤ 2
• Proton cranial spinal radiation therapy (RT) OR cranial spinal RT using intensity-modulated radiation therapy (IMRT) are the preferred modalities of RT to treat LMD if possible, before study. At least whole brain radiation therapy (WBRT) is required for participation
• Coincident brain or spinal cord metastases are allowed if these are stable and do not require local therapy at the time of enrollment. Individuals with previously treated stable brain metastases are eligible to participate
• Stereotactic radiosurgery (SRS) and/or prior radiotherapy is permitted ≥ 2 weeks before the initial dendritic cell (DC) vaccine dose. A follow-up brain MRI should be obtained before the DC vaccine to determine the stability of the lesions. An interval of at least 2 weeks after the end of brain radiation or surgical resection of brain lesions or cytotoxic, targeted, immune, or investigational agent is required
• Must be ≥ 18 years of age on the day of signing the consent
• Life expectancy of ≥ 8 weeks
• Absolute neutrophil count ≥ 1000/mcL (within 14 days of treatment initiation)
• Platelets ≥ 75000/mcL (within 14 days of treatment initiation)
• Hemoglobin ≥ 9 g/dL or ≥ 5.6 mmol/L (within 14 days of treatment initiation)
• Either serum creatinine ≤ 1.5 x upper limit of normal (ULN) or measured ≤ 1.5 x ULN or calculated creatinine clearance ≥ 60 mL/min for subjects with creatinine levels > 1.5 x institutional ULN (within 14 days of treatment initiation)
• Serum total bilirubin ≤ 1.5 x ULN or direct bilirubin ≤ ULN for patients with total bilirubin levels > 1.5 x ULN or < 3 x ULN in the presence of documented Gilbert's syndrome unconjugated hyperbilirubinemia or ≤ 5.0 x ULN if liver metastases are present (within 14 days of treatment initiation)
• Aspartate aminotransferase (serum glutamic oxaloacetic transaminase [SGOT]) ≤ 2.5 x ULN (within 14 days of treatment initiation)
• Alanine aminotransferase (serum glutamic pyruvic transaminase [SGPT]) ≤ 2.5 x ULN (within 14 days of treatment initiation)
• Ability to understand and the willingness to sign a written informed consent document
• Corticosteroids at doses equivalent to ≤ 4 mg of dexamethasone daily or equivalent for symptom control are acceptable. This should be minimized when possible
• If the disease has progressed on current treatment before consent, patients may continue current systemic cancer therapies by principal investigator (PI) discretion
• Patients with systemic disease are eligible and will be managed
• Pregnancy test: negative serum or urine pregnancy test at screening for women of childbearing potential. Must be repeated once a month during treatment
• Contraception: Highly effective contraception for both male and female subjects throughout the study, and for the following specified durations after the last treatment administration as follows: highly effective contraception must be used by males for at least 90 days after the last treatment administration, if the risk of conception exists, to cover the spermatogenesis cycle, and at least 5 months after the last dose of nivolumab or 7 months after the last dose of trastuzumab for females
• The patient has an Ommaya reservoir or equivalent device that allows routine access to CSF and administration of DC1s
• Patient must be able to tolerate MRIs of brain with contrast for routine disease assessments

Exclusion Criteria

• Receiving other treatments specifically administered to treat LMD within the last 2 weeks or 5 half-lives of the agent, whichever is less. However, all other treatments to control systemic disease or bulk central nervous system (CNS) disease will be eligible, provided the therapy is not a phase I agent, an agent that significantly and unequivocally penetrates the CSF (eg, high-dose methotrexate, thiotepa, high-dose cytarabine [ara-C]) by PI discretion. History and physical (H & P) section: Patients may continue on IV trastuzumab, fam-trastuzumab deruxtecan-nxki, pertuzumab, tucatinib, or other HER2-directed, hormonal, or other therapeutic agents if controlling systemic disease and leptomeningeal metastases developed while on these therapies. In addition, at time of systemic progression, patients may start additional agents at the discretion of the treating physician and not start on new systemic therapies until LMD disease assessment
• Use of any immunotherapy within the last 4 weeks
• Unable or unwilling to have a contrast-enhanced brain MRI
• Known additional malignancy that is progressing or requires active treatment. Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or in situ cervical cancer that has undergone potentially curative therapy
• Has an active infection requiring systemic therapy which in the investigator’s opinion will increase the risk to the patient
• Had major surgical procedure, or significant traumatic injury within 2 weeks. Ommaya placement is allowed
• Patients with shunts are excluded from the study (including but not limited to ventriculoperitoneal and ventriculoatrial shunts)
• History of an intracranial thrombosis or thrombi extending up to the skull base. The choice of modality is at the investigator or provider’s discretion
• Has a history of 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
• Has known psychiatric or substance abuse disorders that would interfere with cooperation with the requirements of the trial
• Is pregnant or breastfeeding or expecting to conceive or father children within the projected duration of the trial, starting with the pre-screening or screening visit through 90 days after the last dose of trial treatment
• Has a known history of human immunodeficiency virus (HIV) (HIV 1, 2 antibodies). Testing is not mandatory
• Has known active or chronic hepatitis B (HBV) or hepatitis C virus (HCV). Testing is not mandatory
• Prior organ transplantation including allogenic stem-cell transplantation
• Other severe acute or chronic medical conditions or psychiatric conditions including recent (within the past year) or active suicidal ideation or behavior; or laboratory abnormalities that may increase the risk associated with study participation or study treatment administration or may interfere with the interpretation of study results and, in the judgment of the investigator, would make the patient inappropriate for entry into this study
• Has received a live vaccine within 30 days before 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 (eg, FluMist) are live attenuated vaccines and are not allowed. Current COVID vaccines are not live vaccines