A Study of MOv18 IgE in Patients With Solid Tumours That Express Folate Receptor Alpha

EPS101-10-02 is a two-part, Phase Ib, open-label, dose escalation and expansion trial in patients with platinum resistant ovarian cancer whose disease has progressed after no more than 4 lines of standard therapy.

In total, the trial will enrol approximately 45 patients. All enrolled patients will have biopsy accessible, measurable disease with a confirmed FRα expression of 5% or higher.

MOv18 IgE will be administered to approximately 30 patients in Part 1 and up to a further 15 in Part 2.

Patients will receive treatment on Days 1, 8 and 15 of a 21-day cycle and may continue treatment until radiological disease progression or unacceptable toxicity despite optimal medical management or dose or schedule modification, or withdrawal of consent.

The starting dose of MOv18 IgE is 3 mg.

Patient screening will occur during the 28 days prior to the first administration of MOv18 IgE. All patients will undergo PK, PD and safety assessments, as well as disease response (tumour) assessments to determine the potential clinical benefit of MOv18 IgE. In all instances, patients will be followed up for overall survival (OS) for a maximum of 270 days after their last dose of trial treatment, or until withdrawal of consent, lost to follow-up, death, or the overall end of trial, whichever is earliest.

In Part 1, MOv18 IgE will be administered at increasing dose levels in different patient cohorts of approximately 6 patients, until selection of the Part 2 dose. The dose of MOv18 IgE administered in Part 1 will be escalated following a Bayesian logistic regression model - Escalation with overdose control (BLRM-EWOC) trial design.

After determination of the Part 2 dose, up to 15 additional patients will be enrolled and treated with MOv18 IgE at that dose to further assess anti-tumour activity of MOv18 IgE and obtain additional information on its safety, PK and PD.

Inclusion criteria

Patients must meet all of the following criteria:

• Female ≥18 years of age.
• Written (signed and dated) informed consent.
• Histologically or cytologically confirmed advanced, recurrent or metastatic ovarian cancer, endometrial cancer, triple-negative breast cancer i. Ovarian cancer: must have epithelial ovarian cancer, primary peritoneal cancer, or fallopian tube cancer with high-grade serous or endometrioid features or a predominantly serous/endometrioid component ii. Endometrial cancer: must have advanced, recurrent or metastatic, endometrial cancer (any subtype excluding endometrial sarcoma) iii. Triple Negative Breast cancer: must have advanced, recurrent or metastatic triple-negative breast cancer (based on the most recently analyzed biopsy from locally recurrent or metastatic site, local laboratory) meeting the following criteria:

• HER2-negative in situ hybridization test or an immunohistochemistry (IHC) status of 0 or 1+
• ER and PgR expressions <10% as determined locally by IHC assay as per most recent ASCO/CAP guidelines
• Tumour tissue expressing FRα on at least 5% of tumour cells, as determined by immunohistochemistry using either (i) the BN3.2 antibody (Leica Biosystems) or (ii) the FOLR1 (FOLR1-2.1) antibody (Ventana) Note: All patients must be willing to provide an archival tumour tissue block, or undergo a procedure to obtain a new biopsy, using a low risk, medically routine procedure for immunohistochemistry (IHC) confirmation of FRα positivity using BN3.2 antibody (Leica Biosystems).

Note: Pre-screening for FRα positivity, using BN3.2 antibody (Leica Biosystems), may be performed at any point in advance of the first administration of MOv18 IgE i. Leica Biosystems BN3.2 antibody 1+ 2+ 3+ staining ii. Ventana FOLR1 antibody criteria 2+ 3+ membrane staining Note: Patients with a medical history confirming tumour tissue expression of FRα, as confirmed by the Ventana FOLR1 antibody, will be considered as meeting inclusion Criteria #4 and will not require a confirmation via Leica Biosystems assay prior to receiving MOv18 IgE. However, in all instances, confirmation of FRα expression using the BN3.2 antibody (Leica Biosystems), will be required to be tested during the trial. Confirmation is not required prior to C1D1.

Note: Discordant results between the two systems will not result in patient removal from the trial unless deemed appropriate by the treating Investigator.

• Negative basophil activation test (BAT) prior to the first administration of MOv18 IgE.

Note: this test will be performed at a reference laboratory.

• Ovarian cancer: platinum-free interval since last dose of platinum, of less than 6 months (182 days).
• Prior therapies:

Ovarian cancer: progressed following ≤2 prior regimens of anti-cancer therapy for platinum resistant ovarian cancer, and, at the time, no other authorised therapy is considered appropriate by the treating investigator.

i. Patients who received hyperthermic intraperitoneal chemotherapy (HIPEC) or other IP therapies are eligible.

Endometrial cancer: progressed after any prior line of systemic therapy, and, at the time, no other authorised therapy is considered appropriate by the treating investigator.

Breast cancer: progressed after any prior line of systemic therapy, and, at the time, no other authorised therapy is considered appropriate by the treating investigator.

• Has measurable disease as defined by RECIST v1.1 on CT or MRI scan i. Note: Baseline scans must be performed ≤28 days before the first administration of MOv18 IgE, after discontinuation of the prior regimen.

ii. Note: Lesions previously embolised, perfused, or irradiated without objective evidence of progression before the first administration of MOv18 IgE are not allowed to be considered for response assessment.

• No evidence of bowel obstruction.
• ECOG Performance Status Score 0-1 prior to the first administration of MOv18 IgE.
• Estimated life expectancy of >3 months, in the opinion of the Investigator.
• Adequate haematological function, including all of the following:

i. Absolute neutrophil count (ANC) ≥1.5 × 109/L (>1,500/mm3). G-CSF or GM-CSF may not be used to achieve this level.

ii. Platelets ≥100 × 109/L (>100,000 per mm3) iii. Haemoglobin level >9 g/dL obtained within 14 days before the first administration of MOv18 IgE. Packed red blood cell transfusion is acceptable, if the patient has a stable result of ≥9 g/dL for at least 1 week post-transfusion. Erythropoietin should not be used to achieve this level.

iv. Adequate coagulation function at screening as determined by prothrombin time (PT) ≤1.5 × upper limit of normal (ULN) or international normalised ratio (INR) <1.5 and activated partial thromboplastin time (aPTT) ≤1.5 × ULN. Does not apply to patients on an anti coagulant with a stable dose within 28 days prior to first dose.

v. Lymphocyte count ≥1000 cells/mm3, (1.0x10*9/L)

• Intact immune system as demonstrated by CD4 count ≥500 cells/mm3 and CD8 count ≥150 cells/mm3.
• Adequate renal function as demonstrated by either estimated glomerular filtration rate [eGFR] or calculated creatinine clearance >45 mL/min (Cockcroft Gault equation: creatinine clearance: (140-age [years]) × weight (kg)/(serum creatinine [mg/dL] × 72) × 0.85 ≤1.5 × ULN, or ≥60 mL/min for a patient with creatinine levels >1.5 × institutional ULN.
• Adequate hepatic function:

i. Serum total bilirubin ≤1.5 × ULN or direct bilirubin ≤ ULN for a patient with total bilirubin levels >1.5 × ULN.

ii. AST (SGOT) and ALT (SGPT) ≤2.5 × ULN or ≤5 × ULN for a patient with liver metastases.

iii. Albumin ≥3.0 g/dL.

• Recovered from all chemotherapy-related toxicities to Grade ≤1 according to CTCAE v5.0, excluding alopecia (any grade) and peripheral neuropathy (Grade ≤2).
• No history of significant cardiac or pulmonary dysfunction, including but not limited to interstitial pulmonary disease and chronic obstructive pulmonary disease.
• No active or history of autoimmune disease, (with exception of vitiligo, type I DM, residual hypothyroidism due to autoimmune condition only requiring hormone replacement) and/or no history of autoimmune disease that required treatment with steroids or immunosuppressive medication within 6 months of the first administration of MOv18 IgE.
• Negative serum or urine pregnancy test.
• Women of childbearing potential must have 2 negative pregnancy tests during Screening, the second within 24 hours prior to the first administration of MOv18 IgE. This criterion does not apply to patients who have had a previous hysterectomy or bilateral oophorectomy.
• Female patients of child bearing potential must agree to practice true abstinence or to use two forms of contraception, one of which must be highly effective. These forms of contraception must be used from the time of signing consent, throughout the treatment period, and for 6 months, (182 days), following the last dose of any study medication. Oral or injectable contraceptive agents cannot be the sole method of contraception.
• Willing and able to comply with all protocol-specified assessments and the trial visit schedule.
• Patient has been advised to take measures to avoid or minimise exposure of the skin to UV light, including sunbathing and solarium use for the duration of the trial and for 4 weeks following last administration of MOv18 IgE.

Exclusion criteria

Patients must not meet any of the following criteria:

• Non-epithelial tumour of the ovary, the fallopian tube, or the peritoneum (including germ cell tumours and sarcomas).
• Presence of ascites/pleural effusion requiring drainage within 28 days of first dose MOv18 IgE or persistent ongoing malignant ascites or pleural effusion requiring an in-dwelling drain.
• Taking beta-blockers (at PI discretion) and unable to interrupt beta-blockade (which may counteract the therapeutic effects of adrenaline), or full dose tricyclic anti-depressants/MAOIs (which can dangerously augment the effects of adrenaline). These agents should be discontinued at least 4 half-lives before administration of the first dose of MOv18 IgE. Treatment may be reintroduced 48 hours post dose administration.

i. Note: Beta blockers may continue if, in the opinion of the Investigator, it would not pose additional risk to the patient ii. Note: Only applies to full dose tricyclic anti-depressants. Low dose tricyclic anti-depressants to support conditions such as peripheral neuropathy, chronic pain, or insomnia, may be permitted at PI discretion

• History of laryngeal oedema, uncontrolled or high-risk asthma, or anaphylaxis. Patients with a history of hypersensitivity to carboplatin, taxanes, or contrast media may enter the trial at the Investigator's discretion.
• History of parasitic infections, such as helminthiasis within 5 years of the first administration of MOv18 IgE.
• Baseline elevation in serum tryptase (indicating possible mastocytosis) or a positive BAT. Tryptase normal range is 2-15 ng/mL.
• Receiving systemic anti-cancer therapy, including immunostimulatory agents (e.g., cytokine-based modality, antigen-specific peptide immunotherapy, immune checkpoint blockade, co-stimulatory agonists) within 28 days of the first administration of MOv18 IgE.
• Administration of other simultaneous chemotherapy drugs, anti-cancer therapy or anti-neoplastic hormonal therapy, or simultaneous radiotherapy during the trial treatment period (hormonal replacement therapy and denosumab is permitted).
• Receiving radiation therapy within 14 days prior to the first administration of MOv18 IgE. Local palliative radiotherapy is permitted; however, if the radiotherapy is to a target lesion, that lesion must be excluded from tumour response assessments.
• Chronic treatment with systemic corticosteroids or other systemic immunosuppressive medications (including but not limited to prednisone (>10 mg), cyclophosphamide, azathioprine, methotrexate, thalidomide, and anti-TNF agents) within 14 days prior to the first administration of MOv18 IgE, or anticipated requirement for systemic immunosuppressive medications during the trial.
• Administration of a live, attenuated vaccine within 28 days prior to Day 1 or anticipation that such a live attenuated vaccine will be required during the trial or within 5 months, (152 days), after the last dose of MOv18 IgE. Influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccination. COVID vaccination is permitted as necessitated.
• Previous allogeneic bone marrow transplant or previous solid organ transplantation.
• Historical positive serology test for human immunodeficiency virus (HIV).
• History of interstitial lung disease or active pneumonitis.
• Has a known hypersensitivity to a component of protocol therapy, MOv18 IgE or its vehicle (sodium citrate, L-arginine, sucrose and polysorbate 20).
• Positive serology for hepatitis B or C.
• Uncontrolled concurrent illness including, but not limited to, ongoing or active infection, or psychiatric illness.
• Has a history within last 12 months or ongoing clinically significant cardiovascular disease such as unstable angina, myocardial infarction, or acute coronary syndrome, symptomatic or uncontrolled arrhythmia, left ventricular failure, congestive heart failure, baseline ECG abnormalities that, in the Investigator's opinion, would be likely to interfere with their participation in the study, or with the interpretation of the results, including, but not limited to, QTc prolongation to greater than 470 ms (as determined by the Fridericia formula), or any Class III or IV cardiac disease as defined by the New York Heart Association Functional Classification.
• Concomitant use of drugs known to prolong QT/QTc interval (Appendix 1).
• Has a fever ≥38oC within 3 days before the first dose of MOv18 IgE.
• No other prior malignancy is allowed except for the following: adequately treated basal cell or squamous cell skin cancer, in-situ cervical cancer, surgically treated Stage I or II cancer from which the patient is currently in complete remission (at least to 5 years), or any other non-metastatic cancer controlled by surgery alone or surgery plus radiotherapy from which the patient has been disease-free for 5 years.
• Presence of CNS metastases (including spinal metastases) or CNS primary tumour, e.g., glioblastoma.
• Clinically significant illness or major surgery within 4 weeks before the administration of MOv18 IgE.
• Currently breastfeeding.
• Any condition which could interfere with, or the treatment for which might interfere with, the conduct of the trial, or which would, in the opinion of the Investigator, unacceptably increase the patient's risk by participating in the trial
• Patient is under legal custodianship.
• First-degree relatives of the Investigator, trial staff or Sponsor employees.