Phase I Study of MOv18 IgE

This first in human study of the new therapeutic antibody MOv18 immunoglobulin (Ig) E, which targets a protein called folate receptor alpha (FRa), in patients with advanced cancer seeks to demonstrate the potential for the use of this IgE antibody as an example of the use of the IgE class of antibodies for the treatment of cancer.

Therapeutic antibodies have significantly improved the prognosis of patients with a range of cancers. Currently available therapeutic antibodies belong to the IgG class. This study is looking at a new drug called MOv18 IgE which belongs to a different class of antibody, the IgE class. IgE antibodies may trigger a more powerful immune response to tumour cells than these available IgG antibodies and so be more effective in treating certain types of cancer. This is the first time an IgE antibody therapy will be given to patients with cancer.

The MOv18 IgE antibody is designed to recognise and attach to FRa. Scientists have found more of this protein on the surface of certain cancer cells than on the surface of normal cells, most commonly ovarian cancer but also cancers of the kidney, endometrium, lung, breast, bladder, colon and pancreas. Once attached, the MOv18 IgE antibody should trigger the body's own immune system to attack and kill the cancer cells.

Patients will be selected based on the presence of FRa on their tumour in a previous biopsy. The study is the first study of this new antibody treatment to be given to humans and will focus primarily on the assessment of safety confirming the findings of preclinical studies that exposure to MOv18 IgE will not trigger anaphylaxis. This is in addition to extensive pharmacokinetic (PK), biodistribution of the antibody and immunological response. The study will follow a dose escalation design where small groups of patients are treated at a set dose, starting with a very low dose followed by exponential increasing doses, to find a safe dose at which the drug has a good chance of effectively treating the cancer. Patients will receive a short course of treatment. Patients treated at the higher dose levels will be asked to provide a pre and post treatment biopsy to explore the effect of the treatment on the tumour.

Eligibility Criteria:
Inclusion Criteria:

1. Histologically or cytologically-proven advanced, unresectable solid tumour of a type known to express FRα in a percentage of cases
2. Archival tumour tissue expressing FRα (1+, 2+ or 3+ membrane staining on at least 5% of tumour cells by immunohistochemistry using the BN3.2 antibody, based on the technique described by Lawson \& Scorer, 2010).
3. Advanced disease for which no alternative therapy is felt to be appropriate.
4. Measurable disease or disease evaluable by tumour marker. Measurable disease is preferred for patients entering higher cohorts to facilitate efficacy assessments.
5. World Health Organisation (WHO) performance status of 0 or 1 and a life expectancy of at least 12 weeks.
6. Haematological and biochemical indices within the ranges shown below. These measurements should be performed within 7 days before the first dose of MOv18 IgE (Day -7 to Pre-dose on Day 1). Measurements performed before Day -7 may be accepted by the CDD to demonstrate eligibility if repeat testing is logistically difficult for the patient and is not considered necessary medically in the opinion of the Investigator or CDD.

   Laboratory Test Value required Haemoglobin (Hb) ≥ 9.0 g/dL Absolute neutrophil count ≥ 1.5 x 10\^9/L Platelet count ≥ 100 x 10\^9/L Serum bilirubin ≤ 1.5 x upper limit of normal (ULN) Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 2.5 x ULN unless raised due to liver metastases in which case up to 5 x ULN is permissible Serum creatinine ≤ 1.5 x ULN
7. Aged 16 years or over at the time consent is given.
8. Written (signed and dated) informed consent and capable of co-operating with treatment and follow-up.

Exclusion Criteria:

1. Radiotherapy (except for palliative reasons), endocrine therapy, immunotherapy or chemotherapy during the previous four weeks (six weeks for nitrosoureas and mitomycin-C) and investigational medicinal products during the previous 4 weeks, or 5 product half-lives before treatment.
2. Patients on beta-blockers and unable to interrupt beta-blockade (which may counteract the therapeutic effects of adrenaline), or 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 and for the duration of MOv18 IgE therapy.
3. Patients on bisphosphonates or treated with bisphosphonates in the last 18 months.
4. Ongoing toxic manifestations of previous treatments that have not resolved to Grade 1 or lower (other than alopecia of any grade or Grade 2 peripheral neuropathy).
5. Known brain metastases that have not been previously treated and been stable for at least 2 months.
6. Female patients who are able to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception (oral, injected or implanted hormonal contraception and condom; have an intra-uterine device and condom; diaphragm with spermicidal gel and condom) effective at the first administration of IMP, throughout the study and for six months afterwards are considered eligible.
7. Male patients with partners of child-bearing potential (unless they agree to take measures not to father children by using one form of highly effective contraception at the first administration of IMP, throughout the study and for six months afterwards) or agree to sexual abstinence\*. Men with pregnant or lactating partners should be advised to use barrier method contraception (for example, condom plus spermicidal gel) to prevent exposure to the foetus or neonate.

   \* Abstinence is only considered to be an acceptable method of contraception when this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not acceptable methods of contraception.
8. Major thoracic or abdominal surgery from which the patient has not yet recovered.
9. At high risk from the effects of anaphylaxis because of non-malignant systemic disease including active uncontrolled infection, cardiac failure, peripheral vascular disease, previous cerebrovascular accident (CVA), dyspnoea due to heart failure, extensive lung metastases, significant pleural effusions or other conditions.
10. History of laryngeal oedema, uncontrolled or high risk asthma (according to Global Initiative for Asthma (GINA) guidelines), or anaphylaxis. Patients with a history of hypersensitivity to carboplatin, taxanes, or contrast media may enter the study at the investigator's discretion.
11. Patients with any congenital or acquired immunodeficiency syndrome or receiving immunosuppressive therapy (including any dose of systemic corticosteroids), or who are immunosuppressed post organ transplant. However, patients receiving inhaled corticosteroids and patients with a history of allergy (other than anaphylaxis) are eligible, as are patients with a history of auto-immune disease.
12. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV).
13. Patients with baseline elevation in serum tryptase (indicating possible mastocytosis) or a positive baseline basophil activation test (indicating a hypothetical potential for anaphylaxis with MOv18 IgE).
14. Participating or planning to participate in another interventional clinical trial, whilst taking part in this study. Participation in an observational study or in the follow-up phase of a previous interventional trial is acceptable.
15. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical study.
16. Patients unwilling or unable to interrupt antihistamines (which may interfere with skin prick testing). Antihistamines should be discontinued at least 4 half-lives before the first skin prick test.