SL03-OHD-105

1. Subject has voluntarily agreed to participate by giving written informed consent in accordance with ICH/GCP guidelines and applicable local regulations.

2. Age ≥ 18 years.

3. [PLD Cohort] Subject has a histologically confirmed diagnosis of high grade EOC, primary peritoneal cancer, or fallopian tube cancer.

NOTE: non-epithelial tumors and ovarian tumors with low malignant potential are excluded.

4. [PLD Cohort] Subject must have platinum-resistant disease, defined as disease progression within 180 days (6 months) following the last administered dose of platinum therapy.

NOTE: Subjects that are primary platinum refractory, defined by progressing during or within 1 month of upfront platinum therapy, are excluded.

5. [PLD Cohort] Subjects must have received no more than 1 prior line of systemic anticancer therapy for platinum-resistant disease and have either received bevacizumab, be medically-ineligible for bevacizumab, or bevacizumab is not indicated per local standard of care. Lines of therapy are defined in this study as:

· Adjuvant ± neoadjuvant is considered 1 line of therapy.

· Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (i.e., not counted independently).

· Therapy changed due to toxicity in the absence of progression will be considered part of the same line (i.e., not counted independently).

· Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.

6. [MIRV Cohort] Subject has a histologically confirmed diagnosis of high grade serous EOC, primary peritoneal cancer, or fallopian tube cancer.

NOTE: non-epithelial tumors and ovarian tumors with low malignant potential are excluded.

7. [MIRV Cohort] Subject must have platinum-resistant disease as defined by:

· Subjects who have only had 1 line of platinum-based therapy must have received at least 4 cycles of platinum, must have had a response (complete response/remission [CR] or partial response/remission [PR]) and then progressed between > 3 months and ≤ 6 months after the date of the last dose of platinum.

· Subjects who have received 2 or 3 lines of platinum therapy must have progressed on or within 6 months after the date of the last dose of platinum.

NOTE: Progression should be calculated from the date of the last administered dose of platinum therapy to the date of the radiographic imaging showing progression.

NOTE: Patients who are platinum refractory during front-line treatment are excluded [primary platinum-refractory disease, defined as disease that did not respond to (CR or PR) or has progressed within ≤3 months of the last dose of first-line platinum-containing chemotherapy].

8. [MIRV Cohort] Subjects must have received at least 1 but no more than 3 prior systemic lines of anticancer therapy, including at least 1 line of therapy containing bevacizumab or be medically-ineligible for bevacizumab. Lines of therapy are defined in this study as:

· Adjuvant ± neoadjuvant is considered 1 line of therapy.

· Maintenance therapy (e.g., bevacizumab, PARP inhibitors) will be considered part of the preceding line of therapy (i.e., not counted independently).

· Therapy changed due to toxicity in the absence of progression will be considered part of the same line (i.e., not counted independently).

· Hormonal therapy will be counted as a separate line of therapy unless it was given as maintenance.

9. [MIRV Cohort] Willing to provide an archival tumor tissue block or slides or undergo new biopsy using a low-risk, medically routine procedure for IHC confirmation of FRα positivity.

10. [MIRV Cohort] Subject’s tumor must be positive for FRα expression as defined by the Ventana FOLR1 Assay.

11. Eastern Cooperative Oncology Group Performance Status (ECOG PS) of 0 or 1.

12. Measurable disease by RECIST v1.1 using radiologic assessment.

13. Laboratory values must meet the following criteria:

- Absolute neutrophil count (ANC)≥1.5 x 109/L without GCSF in prior 10 days or long-acting WBC growth factors in prior 20 days.

- Platelet count ≥100 x 109/L without platelet transfusion in prior 10 days.

- Hemoglobin (Hgb) >9.0 g/dL without packed RBC transfusion in the prior 7 days.

- Creatinine clearance (CrCl) ≥30 mL/min (using modified Cockcroft-Gault formula; Appendix Section 16.3).

- ALT/AST ≤ 3 x ULN.

- Total bilirubin ≤ 1.5 x ULN; subjects with isolated indirect hyperbilirubinemia are permitted if direct bilirubin ratio is < 35% and total bilirubin is ≤ 3.0 x ULN.

- Serum albumin [MIRV cohort only] ≥ 2 g/dL.

- Left ventricular ejection fraction (LVEF) [PLD Cohort only] >50% by echocardiography (ECHO).

14. Females of childbearing potential (FCBP) must have a negative serum or urine pregnancy test within 4 days of the first dose of study treatment. FCBP must use 2 highly effective methods of contraception starting at least 14 days prior to the first dose of study treatment, throughout the study, and for at least 6 months (or for the duration required by local regulatory guidance) after the last dose of PLD or at least 3 months after the last dose of SL-172154 or MIRV, whichever is longer.

15. Subjects must have stabilized or recovered (Grade 1 or baseline) from all prior anti-cancer therapy-related toxicities. NOTE: Grade 2 alopecia is acceptable for either cohort; Grade 2 sensory neuropathy [PLD Cohort only] or Grade 1 sensory neuropathy [MIRV Cohort only] is acceptable.

16. [MIRV and PLD Cohorts, Dose Expansion only] Willing to consent to 1 mandatory pre-treatment and 1 on-treatment tumor biopsy, unless there is excessive risk from the procedure as determined by the investigator. 

1. Prior treatment with a signal-regulatory protein alpha (SIRPα) targeting agent, anti-CD47 agent or CD40 agonist.

2. [PLD Cohort] Prior treatment with doxorubicin or PLD.

3. [MIRV Cohort] Prior treatment with MIRV or another FRα-targeting agent.

4. Any anti-cancer therapy within the time intervals noted below prior to first dose (Day 1) of study treatment:

- Chemotherapy (4 weeks or 5 half-lives, whichever is shorter)

- Hormonal therapy (4 weeks or 5 half-lives, whichever is shorter)

- PD-1/L1 inhibitor and other immunotherapies not otherwise specified (4 weeks or 5 half-lives, whichever is shorter)

- Tumor vaccine (4 weeks)

- Cell-based therapy (8 weeks)

- Other mAbs or biologic therapies (4 weeks or 5 half-lives, whichever is shorter)

- Other investigational agents not covered above (4 weeks or 5 half-lives whichever is shorter)

- Major surgery (2 weeks)

- Radiation (except palliative intent which does not require washout) (2 weeks).

5. Concurrent chemotherapy, immunotherapy, biologic or hormonal therapy for cancer treatment is prohibited. Concurrent use of hormones for non-cancer related conditions is acceptable.

6. Receipt of live attenuated vaccine (including live attenuated vaccines for COVID-19) within 28 days of the first dose of study treatment.

7. Current or prior use of immunosuppressive medication within 7 days prior to first dose of study treatment. The following are exceptions to this exclusion criterion:

· Intranasal, inhaled, topical steroids, or local steroid injections (e.g., intra-articular injection)

· Steroids as premedication for HSRs (e.g., CT scan premedication).

8. [MIRV Cohort] Requires use of folate-containing supplements (e.g., folate deficiency).

9. Active or documented history of autoimmune disease, history of multiple sclerosis (MS) or other demyelinating disease and/or Lambert-Eaton syndrome (paraneoplastic syndrome). Exceptions include controlled Type I diabetes, vitiligo, alopecia areata or hypo/hyperthyroidism.

10. Ongoing or active infection (e.g., no systemic antimicrobial therapy for treatment of infection within 5 days of D1 of study treatment).

11. Known severe hypersensitivity to the active drug substance or to any of the excipients for the agents to be administered or subjects with known hypersensitivity to Chinese hamster ovary cell products. Prior severe hypersensitivity to monoclonal antibodies [MIRV Cohort only] or liposomal preparations [PLD Cohort only].

12. Severe gastrointestinal conditions such as clinical or radiological evidence of bowel obstruction within 4 weeks prior to study entry.

13. Clinically significant or uncontrolled cardiovascular disease including any of the following:

· Myocarditis

· Unstable angina within 6 months from first dose of study treatment

· Acute myocardial infarction within 6 months from first dose of study treatment

· Uncontrolled hypertension

· NYHA Class III or IV congestive heart failure

· Clinically significant (symptomatic) cardiac arrhythmias (e.g., sustained ventricular tachycardia, second- or third- degree atrioventricular block without a pacemaker, circulatory collapse requiring vasopressor or inotropic support, or arrhythmia requiring therapy)

· History of haemorrhagic or ischemic stroke within 6 months prior to enrollment

· Prior anthracycline-related cardiotoxicity or prior anthracycline exposure approaching the lifetime limit [PLD cohort only].

14. [MIRV Cohort] History of cirrhotic liver disease (Child-Pugh Class B or C).

15. [MIRV Cohort] Active or chronic corneal disorders, history of corneal transplantation, or active ocular conditions requiring ongoing treatment/monitoring, such as uncontrolled glaucoma, wet age-related macular degeneration requiring intravitreal injections, active diabetic retinopathy with macular edema, macular degeneration, presence of papilledema, and/or monocular vision.

16. Previous clinical diagnosis of noninfectious interstitial lung disease (ILD), including noninfectious pneumonia.

17. Untreated CNS or leptomeningeal metastases. Subjects with treated CNS metastases must have completed definitive treatment (radiotherapy and/or surgery) >2 weeks prior to first dose of study treatment and no longer require steroids.

18. Women who are pregnant or breast feeding, or who plan to become pregnant or breast feed while receiving study treatment.

19. Psychiatric illness/social circumstances that would limit compliance with study requirements and substantially increase the risk of AEs or compromised ability to provide written informed consent.

20. Another malignancy that requires active therapy and that, in the opinion of the investigator and Sponsor, would interfere with monitoring of radiologic assessments of response to the study treatment.

21. Has undergone allogeneic stem cell transplantation or organ transplantation.

22. Known history or positive test for human immunodeficiency virus (HIV), or positive test for hepatitis B (positive for hepatitis B surface antigen [HBsAg]) or hepatitis C virus ([HCV]; if HCV antibody (Ab) test is positive check for HCV ribonucleic acid [RNA]).

NOTE: Hepatitis B virus (HBV): Subjects who are hepatitis B core antibody [HBcAb] positive, but HBsAg negative are eligible for enrollment. HCV: Subjects who are HCV Ab positive, but HCV RNA negative are eligible for enrollment. 

Research Nurse: Lizzie Coates (x2031) Elizabeth.Coates@LTHTR.nhs.uk