A Study of BRIA-OTS Cellular Immunotherapy in Metastatic Recurrent Breast Cancer

This is an open-label Phase 1/2a study. Once the safety of the BC1 cell line alone has been demonstrated in Phase 1, in Phase 2, patients will be treated with the Bria-OTS regimen (see below) and a clinically available check point inhibitor (CPI).

During the monotherapy phase of Phase 1, one patient will be treated intradermally every 2 weeks for 6 weeks (4 doses) with an initial dose of the BC1 cell line. If this dose is tolerated, the next patient will receive an increased dose of BC1. If once again tolerated, the third patient will receive a further dose increase of the BC1. Once at least 3 patients have been safely treated with the BC1 cell line, with no dose-limiting toxicity (DLT), the combinational phase of the study will commence.

Following the monotherapy phase, patients will be treated with BC1 and the Bria-OTS regimen (see below) every 3 weeks, plus a CPI at the FDA approved labelled dose and schedule. There will be at least a 2-week spacing between enrollment of each of the first three subjects in the study in order to assess for any early unanticipated risk(s).

During the Phase 1 combination and Phase 2 expansion phases, all patients will be treated with BC1 cells as part of the Bria-OTS regimen, which includes cyclophosphamide 300 mg/m2 2-3 days prior to BC1 cell inoculation, and peginterferon alpha-2a administered on the same day, following BC1 cell inoculation.

Open-label Phase 1/2a study.

Once the safety of the BC1 cell line alone has been demonstrated in Phase 1, in Phase 2, patients will be treated with the Bria-OTS regimen (see below) and a check point inhibitor (CPI).

During the monotherapy phase of Phase 1, one patient will be treated intradermally every 2 weeks for 6 weeks (4 doses) with an initial dose of the BC1 cell line. If this dose is tolerated, the next patient will receive an increased dose of BC1 cells. If once again tolerated, the third patient will receive a further increased dose of BC1. Once at least 3 patients have been safely treated with the BC1 cell line, with no dose-limiting toxicity (DLT), the combinational phase of the study will commence.

Following the monotherapy phase, patients will be treated with BC1 and the Bria-OTS regimen (see below) every 3 weeks, plus a CPI at the FDA approved labelled dose and schedule. There will be at least a 2-week spacing between enrollment of each of the first three subjects in the study in order to assess for any early unanticipated risk(s).

During the Phase 1 combination and Phase 2 expansion phases, all patients will be treated with BC1 cells as part of the Bria-OTS regimen, which includes cyclophosphamide 300 mg/m2 2-3 days prior to BC1 cell inoculation, and peginterferon alpha-2a administered on the same day, following BC1 cell inoculation.

Imaging studies will be performed at screening for baseline prior to first treatment; after the completion of the monotherapy phase just before starting the combination phase, and subsequently every 9 weeks for the first 6 months then q12 weeks thereafter while on treatment.

Patients who develop progressive disease on imaging, may remain on treatment as long as the Investigator feels they are deriving clinical benefit and there is no reasonable, meaningful, clinical alternative therapy available. Subjects will continue to be followed for time on subsequent therapy (PFS2) and survival by phone call or medical record review, every 3 months for up to 2 years.

Study Drug, Dosage, and Mode of Administration:

The Part 1 monotherapy phase of Phase 1 will proceed as follows for each patient:

Subject 1, Q2w for 4 doses Subject 2, Q2w for 4 doses Subject 3, Q2w for 4 doses

Initially, safety will be assessed on these 3 subjects. DLTs are defined as CTCAE Grade 3 or 4 adverse events that are suspected to be possibly related to study treatment.

If 1 of 3 Phase 1 subjects experience a DLT, that dose cohort will be expanded to another 3 patients before the combinational phase begins. If none of the patients in the expanded cohort experience a DLT (DLT rate of 1/4), the study will move into Bria-OTS and CPI combination. The dose for the combination will be either the highest dose at which no DLT is observed among the first 3 patients or the 3 patient expanded cohort dose level. In Phase 1, DLTs for determining the combinational BC1 dose will be observed until the first scheduled assessment. If the Phase 1 DLT rate is ≥ 2/4, an additional 3 patients will be dosed using the next lower dose level or 10 million cells (whichever is higher). If none of the 3 subjects experience dose-limiting toxicities (DLTs), that determined BC1 MTD dose will be included in the Part 2 combinational phase of Phase 1 along with a CPI. If a tolerated dose for BC1 cell line cannot be identified, further investigation will be paused, the data reviewed and may resume at a lower dose only with protocol amendment and IRB approval.

Following the Phase 1, Part 1 monotherapy phase, 3 patients will be treated every 3 weeks with the Bria-OTS regimen with a CPI in the Part 2 combination phase. The Bria-OTS regimen consists of cyclophosphamide 300 mg/m2 2-3 days prior to BC1 cell line inoculation. On the same day as the cell inoculation, subjects will receive peginterferon alpha-2a. Subjects will also receive the CPI on the same day of the cell inoculation according to approved dosing.

Once 3 patients have been safely treated with the Bria-OTS regimen and CPI for 2 cycles, Phase 2 will enroll an expansion cohort, consisting of up to an additional 9 subjects (for a total of 12 treated with the Bria-OTS regimen and CPI).

Eligibility Criteria:
Key Inclusion Criteria:

1. Histological confirmed recurrent metastatic breast cancer which has failed prior

   therapy defined as:
   1. Human epidermal growth factor 2 (EGFR2, HER2) positive tumors must have failed therapy with at least 2 anti-HER2 agents
   2. HER2 negative and either ER or PR positive tumors: must be refractory to hormonal therapy and previously treated with at least 2 hormone based targeted therapy containing regimens.
   3. Triple-negative and inflammatory tumors must have exhausted other curative intent therapies including prior treatment with a taxane and platinum-based agent
   4. All other MBC types must have exhausted other curative intent therapies including any genomic or germline directed targeted therapy having available approved drug(s)
   5. Patients with new or progressive breast cancer metastatic to the brain will be eligible, provided:

   i. The brain metastases must be clinically stable (without evidence of progressive disease by imaging) for at least 4 weeks, prior to first dose.

   ii. There is no need for steroids and patients have not had steroids for at least 2 weeks prior to the first dose.
2. Be 18 years of age or older.
3. Have expected survival of at least 4 months.
4. Have adequate performance status (up to and including ECOG 2)
5. Patients must be stable with all known or expected toxicities from previous treatment including:

   1. Prior immune related toxicity must not have exceeded Grade 2 with exception of stable endocrinopathy (endocrinopathy if well-managed, is not exclusionary).
   2. Toxicity of prior therapy that has not recovered to ≤ grade 1 or baseline (with the exception of any grade of alopecia, adequately treated endocrinopathy, and anemia not requiring transfusion support).

Exclusion Criteria:

1. Concurrent anti-cancer treatment.
2. Recent chemotherapy, radiotherapy, or other anti-cancer treatment within 3 weeks of first protocol treatment.
3. Participant has not recovered adequately from toxicities and/or complications from surgical intervention before starting study drug.
4. History of clinical hypersensitivity to the designated therapy, as specified in the protocol or to any components used in the preparation of any cell line in this study.
5. History of clinical hypersensitivity to any protocol specified therapy.
6. BUN \>30 in conjunction with a creatinine \>2, or calculated creatinine clearance (CrCl) \<30 mL/min (GFR can be used in place of creatinine or CrCl).
7. Absolute granulocyte count \< 1000; platelets \<50,000.
8. Bilirubin \>2.0; alkaline phosphatase \>4x upper limit of normal (ULN); ALT/AST \>2x ULN. For patients with hepatic metastases, ALT/AST \>5x ULN is exclusionary.
9. Proteinuria \>1+ on urinalysis or \>1 gm/24hr.
10. New York Heart Association stage 3 or 4 cardiac disease.
11. A pleural or pericardial effusion of moderate severity or worse.
12. Any woman of childbearing potential (i.e., has had a menstrual cycle within the past year and has not been surgically sterilized), unless she: agrees to take appropriate precautions to avoid becoming pregnant during the study and has a negative serum pregnancy test within 7 days prior to starting treatment.
13. Men who are fertile/reproductively competent, should take appropriate precautions to avoid fathering a child for the duration of the study.
14. Women who are pregnant or nursing.
15. Patients with concurrent second malignancy.
16. Persons with previous malignancies requiring treatment within the past 24 months.
17. Patients who have clinical or laboratory features indicative of AIDS and are HIV positive (by self-report).
18. Have a diagnosis of immunodeficiency, or is receiving chronic systemic steroid therapy (doses exceeding 10 mg daily of prednisone equivalent), or any other form of immunosuppressive therapy within 21 days prior to first dose of study treatment.
19. Patients who are on treatment for an autoimmune disease, unless specifically approved by the Investigator and the Sponsor.
20. Patients with severe psychiatric (e.g., schizophrenia, bipolar, or borderline personality disorder) or other clinically progressive major medical problems, unless approved by the Investigator and Sponsor.
21. Patients may not be on a concurrent clinical trial, unless approved by Investigator and Sponsor.