Phase I Study of MOv18 IgE, a First in Class Chimeric IgE Antibody in Patients With Advanced Solid Tumours
Phase I Study of MOv18 IgE, a First in Class Chimeric IgE Antibody in Patients With Advanced Solid Tumours
This first in human study of the new therapeutic antibody MOv18 IgE 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 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.

 MOv18 IgE antibodies are designed to recognise and attach to a particular protein called the
 folate receptor alpha. 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 and to a
 lesser extent cancers of the kidney, pleura, 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 folate receptor protein 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 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. The majority of 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.
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 if 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.