Phase I Study of MOv18 IgE

Study Overview
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Brief Summary
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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.

Detailed Description
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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.

Official Title
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A Cancer Research UK Phase I Study of MOv18 IgE, a First in Class Chimeric IgE Antibody Against Folate Receptor-alpha, in Patients With Advanced Solid Tumours

Conditions
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Human Cancers

Intervention / Treatment
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* Drug: MOv18 IgE
* Drug: MOv18 IgE
* Drug: MOv18 IgE
* Drug: MOv18 IgE
* Drug: MOv18 IgE
* Drug: MOv18 IgE
* Drug: MOv18 IgE


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Histologically or cytologically-proven advanced, unresectable solid tumour of a type known to express FRα in a percentage of cases 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). Advanced disease for which no alternative therapy is felt to be appropriate. Measurable disease or disease evaluable by tumour marker. Measurable disease is preferred for patients entering higher cohorts to facilitate efficacy assessments. World Health Organisation (WHO) performance status of 0 or 1 and a life expectancy of at least 12 weeks. 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 Aged 16 years or over at the time consent is given. Written (signed and dated) informed consent and capable of co-operating with treatment and follow-up. Exclusion Criteria: 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. 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. Patients on bisphosphonates or treated with bisphosphonates in the last 18 months. 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). Known brain metastases that have not been previously treated and been stable for at least 2 months. 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. 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. Major thoracic or abdominal surgery from which the patient has not yet recovered. 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. 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. 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. Known to be serologically positive for hepatitis B, hepatitis C or human immunodeficiency virus (HIV). 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). 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. Any other condition which in the Investigator's opinion would not make the patient a good candidate for the clinical study. 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.

Ages Eligible for Study
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Minimum Age: 16 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MOv18 IgE Cohort 1<br> | Drug: MOv18 IgE<br>* The allocated dose of 70 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by an intradermal injection of 0.1 mL of a 2 µg/mL MOv18 IgE solution for safety assessment.<br>|
| Experimental: MOv18 IgE Cohort 2<br> | Drug: MOv18 IgE<br>* The allocated dose of 250 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by either an intradermal injection of 0.1 mL of a 2 µg/mL MOv18 IgE solution or a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.<br>|
| Experimental: MOv18 IgE Cohort 3<br> | Drug: MOv18 IgE<br>* The allocated dose of 500 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.<br>|
| Experimental: MOv18 IgE Cohort 4<br> | Drug: MOv18 IgE<br>* The allocated dose of 700 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.<br>|
| Experimental: MOv18 IgE Cohort 5<br> | Drug: MOv18 IgE<br>* The allocated dose of 1.5 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.<br>|
| Experimental: MOv18 IgE Cohort 6<br> | Drug: MOv18 IgE<br>* The allocated dose of 3 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 6 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.<br>|
| Experimental: MOv18 IgE Cohort 7<br> | Drug: MOv18 IgE<br>* Cycle 1 - The allocated dose of 6 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 3 weeks. Cycle 2 - The allocated dose of 12 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for 3 weeks, followed by fortnightly for 6 weeks if the patient appears to be benefiting from MOv18 IgE. Each IV infusion will be preceded by a skin prick test with 2 µg/mL MOv18 IgE solution, for safety assessment.<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Serious Adverse Events (SAEs) and Non-serious Adverse Events (AEs) Considered to be at Least Possibly Related to MOv18 IgE | Reported safety information in the form of AEs, categorised according to Medical Dictionary for Regulatory Activities (MedDRA) version (v) 24.0 and graded for severity according to National Cancer Institute - Common Terminology Criteria for Adverse Events (NCI CTCAE) v4.02. AEs will be assessed by the reporting study doctors for a causal relationship to MOv18 IgE. Count of AEs by arm. | From the date of written informed consent and until the end of safety follow up period for MOv18 IgE, a median of 88.5 days (range: 13 to 181 days). | 
| Number of Participants Who Experienced Dose Limiting Toxicities (DLTs) | DLTs graded for severity using the NCI CTCAE v4.02, measured by count of participants per arm. Two DLTs were reported; however, following review of the data, it was determined that events of this nature did not constitute DLTs. The trial protocol was updated so that if further similar events occurred then would not be considered as DLTs but the events already reported remain categorised as DLTs. | From first dose onwards until completion of Cycle 1 (3 weeks). | 
| Number of Dose Independent Significant Toxicities | AEs judged to be due to systemic mast cell degranulation (i.e. anaphylaxis). No dose independent significant toxicities were reported. However, one event of anaphylactic reaction was classified as a DLT at the time of occurrence but, following review of the data, the trial protocol was updated. This meant that any future events of anaphylaxis would have been classified as dose independent toxicities, but the event already reported remained as a DLT. | From the date of written informed consent and until the end of safety follow up period for MOv18 IgE, a median of 88.5 days (range: 13 to 181 days). | 
| Number of Participants With Grade ≥2 Laboratory Parameter AEs Reported | Reported safety information in the form of haematological or biochemical abnormalities that were reported as AEs and graded for severity according to NCI CTCAE v4.02. | From the date of written informed consent and until the end of safety follow up period for MOv18 IgE, a median of 88.5 days (range: 13 to 181 days). | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Antitumour Activity (Best Response) of MOv18 IgE Measured According to the Response Evaluation Criteria in Solid Tumours (RECIST) v 1.1 | Best radiological response observed according to RECIST v1.1, presented per arm by count of participants. RECIST responses include complete response (CR), partial response (PR), stable disease (SD) and progressive disease (PD). For a response to be defined as SD, the criteria must have been met at least once at a minimum interval of 6 weeks after study entry. | Radiological disease response assessment at screening/baseline and every 6 weeks to end of treatment, a median of 56.5 days (range: 38 to 124 days). | 
| Antitumour Activity Measured by the Percentage Change in Cancer Antigen 125 (CA125) Tumour Marker Levels During the Trial, in Participants With Elevated CA125 at Baseline | The percentage change in CA125 levels from baseline to the last measurement taken on-treatment, presented as a median (minimum, maximum) for each arm. | Disease response assessment at screening/baseline and every six weeks, if clinically appropriate for tumour type, to end of treatment, for a median of 34 days (range: 5 to 91 days). | 
| Measurement of Pharmacokinetic (PK) Parameter Area Under the Concentration-Time Curve From Time 0 to 24 Hours of MOv18 IgE | Area under the serum concentration-time curve from time 0 to 24 hours after IV MOv18 IgE administration, evaluated using an enzyme linked immunosorbent assay (ELISA) method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 within 24 hours (h) predose, then 30 mins postdose and 2, 4, 6 and 24 h postdose. Cohort 7 only (intrapatient dose escalation): Cycle 2 Day 1 predose, then 30 mins postdose and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 
| Measurement of PK Parameter Maximum Observed Serum Concentration (Cmax) of MOv18 IgE | Cmax in serum following IV MOv18 IgE administration was analysed using an ELISA method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 <24 h predose, then 30 mins postdose and 2, 4, 6, 24 and 48 h postdose; Cycle 1 Day 8 predose. Cohort 7 only (intrapatient escalation): Cycle 2 Day 1 predose, then 30 mins and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 
| Measurement of PK Parameter Time to Reach Maximum Observed Serum Concentration (Tmax) of MOv18 IgE | Serum samples were analysed to determine the Tmax of MOv18 IgE following IV administration using an ELISA method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 <24 h predose, then 30 mins postdose and 2, 4, 6, 24 and 48 h postdose; Cycle 1 Day 8 predose. Cohort 7 only (intrapatient escalation): Cycle 2 Day 1 predose, then 30 mins and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 
| Measurement of PK Parameter Terminal Half Life for MOv18 IgE | Serum samples were analysed to determine the concentrations of MOv18 IgE using a previously developed ELISA method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 <24 h predose, then 30 mins postdose and 2, 4, 6, 24 and 48 h postdose; Cycle 1 Day 8 predose. Cohort 7 only (intrapatient escalation): Cycle 2 Day 1 predose, then 30 mins and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 
| Measurement of the PK Parameter Mean Residence Time (MRT) of MOv18 IgE | Serum samples were analysed to determine the MRT of MOv18 IgE following IV administration, using an ELISA method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 <24 h predose, then 30 mins postdose and 2, 4, 6, 24 and 48 h postdose; Cycle 1 Day 8 predose. Cohort 7 only (intrapatient escalation): Cycle 2 Day 1 predose, then 30 mins and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 
| Measurement of the PK Parameter Total Body Clearance (CLT) of MOv18 IgE | Serum samples were analysed to determine the CLT of MOv18 IgE following IV administration, using an ELISA method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 <24 h predose, then 30 mins postdose and 2, 4, 6, 24 and 48 h postdose; Cycle 1 Day 8 predose. Cohort 7 only (intrapatient escalation): Cycle 2 Day 1 predose, then 30 mins and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 
| Measurement of the PK Parameter Volume of Distribution (Vss) of MOv18 IgE | Serum samples were analysed to determine the Vss of MOv18 IgE following IV administration, using an ELISA method. Not all participants were analysed at all time points. | Cohorts 1-7: Cycle 1 Day 1 <24 h predose, then 30 mins postdose and 2, 4, 6, 24 and 48 h postdose; Cycle 1 Day 8 predose. Cohort 7 only (intrapatient escalation): Cycle 2 Day 1 predose, then 30 mins and 2, 4, 6 and 24 h postdose. Each cycle = 21 days. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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IgE antibody, Folate receptor, Cancer Immunotherapy, First in class