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Phase I Study of MOv18 IgE, a First in Class Chimeric IgE Antibody in Patients With Advanced Solid Tumours

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details.
 
ClinicalTrials.gov Identifier: NCT02546921
Recruitment Status : Completed
First Posted : September 11, 2015
Last Update Posted : May 25, 2022
Sponsor:
Information provided by (Responsible Party):
Cancer Research UK

Brief Summary:
This first in human study of the new therapeutic antibody MOv18 immunoglobulin (Ig) E 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.

Condition or disease Intervention/treatment Phase
Human Cancers Drug: MOv18 IgE Phase 1

Detailed Description:

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.

MOv18 IgE antibodies are designed to recognise and attach to a particular protein called the Folate Receptor alpha (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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 26 participants
Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Official Title: 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
Study Start Date : September 2015
Actual Primary Completion Date : July 30, 2021
Actual Study Completion Date : July 30, 2021

Resource links provided by the National Library of Medicine


Arm Intervention/treatment
Experimental: MOv18 IgE Cohort 1 Drug: MOv18 IgE
The allocated dose of 70 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for six weeks, followed by fortnightly for six 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.

Experimental: MOv18 IgE Cohort 2 Drug: MOv18 IgE
The allocated dose of 250 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for six weeks, followed by fortnightly for six 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.

Experimental: MOv18 IgE Cohort 3 Drug: MOv18 IgE
The allocated dose of 500 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for six weeks, followed by fortnightly for six 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.

Experimental: MOv18 IgE Cohort 4 Drug: MOv18 IgE
The allocated dose of 700 µg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for six weeks, followed by fortnightly for six 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.

Experimental: MOv18 IgE Cohort 5 Drug: MOv18 IgE
The allocated dose of 1.5 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for six weeks, followed by fortnightly for six 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.

Experimental: MOv18 IgE Cohort 6 Drug: MOv18 IgE
The allocated dose of 3 mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for six weeks, followed by fortnightly for six 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.

Experimental: MOv18 IgE Cohort 7 Drug: MOv18 IgE

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 three weeks.

Cycle 2 - The allocated dose of 12mg MOv18 IgE will be diluted in 250 mL saline and administered by IV infusion once weekly for three weeks, followed by fortnightly for six 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.





Primary Outcome Measures :
  1. Serious Adverse Events (SAEs) and non-serious adverse events (AEs) considered to be at least possibly related to MOv18 IgE [ Time Frame: From the date of written informed consent and until the end of safety follow up period for MOv18 IgE, a median of 89 days (range: 13 to 181 days). ]
    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.

  2. Number of Dose Independent Significant Toxicities [ Time Frame: From the date of written informed consent and until the end of safety follow up period for MOv18 IgE, a median of 89 days (range: 13 to 181 days). ]
    AEs judged to be due to systemic mast cell degranulation (i.e. anaphylaxis).

  3. Number of Patients with Grade ≥2 Laboratory Parameter AEs Reported [ Time Frame: From the date of written informed consent and until the end of safety follow up period for MOv18 IgE, a median of 89 days (range: 13 to 181 days). ]
    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.


Secondary Outcome Measures :
  1. Number of participants who experienced dose limiting toxicities (DLTs) [ Time Frame: From first dose onwards until completion of Cycle 1 (3 weeks). ]
    DLTs graded for severity using the NCI CTCAE v4.02, measured by count of participants per arm.

  2. Antitumour activity (best response) of MOv18 IgE measured according to the Response Evaluation Criteria in Solid Tumours (RECIST) v 1.1 [ Time Frame: 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). ]
    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.

  3. 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 [ Time Frame: 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). ]
    The percentage change in CA125 levels from baseline to the last measurement taken on-treatment, presented as a median (minimum, maximum) for each arm.

  4. Measurement of pharmacokinetic (PK) parameter Area Under the Concentration-Time curve from time 0 to 24 hours of MOv18 IgE [ Time Frame: 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. ]
    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.

  5. Measurement of PK parameter Maximum Observed Serum Concentration (Cmax) of MOv18 IgE [ Time Frame: 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. ]
    Cmax in serum following IV MOv18 IgE administration was analysed using an ELISA method. Not all participants were analysed at all time points.

  6. Measurement of PK Parameter Time to Reach Maximum Observed Serum Concentration (Tmax) of MOv18 IgE [ Time Frame: 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. ]
    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.

  7. Measurement of PK Parameter Terminal Half Life for MOv18 IgE [ Time Frame: 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. ]
    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.

  8. Measurement of the PK parameter Mean Residence Time (MRT) of MOv18 IgE [ Time Frame: 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. ]
    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.

  9. Measurement of the PK parameter Total Body Clearance (CLT) of MOv18 IgE [ Time Frame: 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. ]
    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.

  10. Measurement of the PK parameter Volume of Distribution (Vss) of MOv18 IgE [ Time Frame: 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. ]
    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.



Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.


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Ages Eligible for Study:   16 Years and older   (Child, Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
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.

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02546921


Locations
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United Kingdom
Addenbrooke's Hospital, Cambridge
Cambridge, United Kingdom
Guy's and St Thomas's Hospital
London, United Kingdom, SE1 9RT
University College London Hospital
London, United Kingdom
Sponsors and Collaborators
Cancer Research UK
Investigators
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Principal Investigator: James Spicer, Dr Guy's and St Thomas's Hospital
Additional Information:
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Responsible Party: Cancer Research UK
ClinicalTrials.gov Identifier: NCT02546921    
Other Study ID Numbers: CRUKD14/001
2014-000070-19 ( EudraCT Number )
First Posted: September 11, 2015    Key Record Dates
Last Update Posted: May 25, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Cancer Research UK:
IgE antibody
Folate receptor
Cancer Immunotherapy
First in class
Additional relevant MeSH terms:
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Immunoglobulin E
Immunologic Factors
Physiological Effects of Drugs