First in Human Study of NG-350A (an Oncolytic Adenoviral Vector Which Expresses an Anti-CD40 Antibody) (FORTITUDE)

• Sponsor: PsiOxus Therapeutics Ltd
• Information provided by (Responsible Party): PsiOxus Therapeutics Ltd

Study Description

Brief Summary:

This study is to evaluate the safety and tolerability of an oncolytic adenoviral vector which expresses a full length anti-CD40 antibody at the site of virus replication in patients with metastatic or advanced epithelial tumours. This study will evaluate the safety, tolerability and preliminary efficacy and also pharmacokinetics, immunogenicity and other pharmacodynamic effects to elucidate the mechanism of action of NG-350A in patients with advanced or metastatic epithelial tumours.

Condition or disease	Intervention/treatment	Phase
Metastatic Cancer; Epithelial Tumor	Biological: NG-350A	Phase 1

Detailed Description:

The aim of the study is to characterise the safety and tolerability of NG-350A in patients with metastatic or advanced epithelial tumours.

Phase Ia of the study is a dose escalation and safety expansion phase investigating NG 350A administration by intratumoural injection and intravenous infusion. Phase Ib of the study is to investigate efficacy in separate efficacy cohorts of patients with specific epithelial tumour types.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	125 participants
Allocation:	Non-Randomized
Intervention Model:	Sequential Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Multicentre, Open-label, Non Randomised First in Human Study of NG-350A in Patients With Metastatic or Advanced Epithelial Tumours
Actual Study Start Date :	February 19, 2019
Estimated Primary Completion Date :	June 2021
Estimated Study Completion Date :	June 2021

Arms and Interventions

Arm	Intervention/treatment
Experimental: Intratumoural; In the IT cohort, patients will receive a single dose of NG-350A by IT injection on Day 1. The dose given to each patient will be dependent on the size of the tumour lesion to be injected. The total injection volume should be up to a maximum of 2 mL of diluted virus.	Biological: NG-350A; NG-350A is oncolytic adenoviral vector which, following replication in permissive tissues, expresses a full length agonist anti-CD40 antibody at the site of virus replication. NG-350A is derived from the Group B oncolytic platform virus enadenotucirev.
Experimental: Intravenous; In the IV cohort, patients will receive a single cycle of study treatment, with three single doses of NG-350A on Days 1, 3 and 5 by IV infusion.	Biological: NG-350A; NG-350A is oncolytic adenoviral vector which, following replication in permissive tissues, expresses a full length agonist anti-CD40 antibody at the site of virus replication. NG-350A is derived from the Group B oncolytic platform virus enadenotucirev.

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events (safety and tolerability) in study NG-350A-01 [ Time Frame: End of study treatment visit Day 57 ]
   Assess the safety and tolerability of NG-350A by review of adverse events including serious adverse events (SAEs), adverse events meeting protocol defined DLT criteria, severe adverse events, adverse events leading to study treatment or study discontinuation, and adverse events resulting in death.

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Provide written informed consent to participate
2. Males or females aged 18 years or over
3. Histologically or cytologically documented metastatic or advanced epithelial cancer (carcinoma or adenocarcinoma) that has relapsed from, or is refractory to, standard treatment, or for which no standard treatment is available

4. a) For patients undergoing surgical excision/resection:

   • Excisable tumour/tumour lesion accessible for baseline biopsies and biopsies deemed safe by the Investigator
   • Willing to consent for baseline biopsies and surgical procedure
   • Patient able to undergo surgical procedure and appropriate anaesthesia b) For patients not undergoing surgical excision/resection:
   • Tumour accessible for biopsy and biopsies deemed safe by the Investigator
   • Willing to consent to tumour biopsies at baseline and during the study
5. Safety expansion and efficacy cohorts only: at least one measurable site of disease according to RECIST criteria; this lesion must be either (i) outside a previously irradiated area or (ii) progressive if it is in a previously irradiated area (not applicable in patients undergoing surgical excision/resection if the lesion to be resected is the target lesion)
6. Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1
7. Predicted life expectancy of 3 months or more
8. Ability to comply with study procedures in the Investigator's opinion
9. Recovered to Grade 1 from the effects (excluding alopecia) of any prior therapy for their malignancies

10. Non-impaired renal function

    • Creatinine ≤1.5 mg/dL and estimated glomerular filtration rate (eGFR) using the Cockroft Gault formula ≥60 mL/min/1.73m2 (or measured creatinine clearance ≥60 mL/min)
    • Urine dipstick for proteinuria at screening and baseline negative or trace. Patients may be included with results of 1+ if they have a spot urinary albumin: creatinine ratio (ACR) of either (i) ≤3 mg/mmol or (ii) >3 mg to <70 mg/mmol with a 24 hour urinary protein <0.2 g/24hours
    • Serum complement components C3 and C4 above the lower limit of normal range

11. Adequate hepatic function:

    • Serum bilirubin <1.5 mg/dL (except patients with Gilbert's syndrome who may have total bilirubin <3.0 mg/mL)
    • Aspartate aminotransferase and alanine aminotransferase ≤3 x upper limit of normal
    • Albumin ≥3 g/dL

12. Adequate bone marrow function:

    • Absolute neutrophil count ≥1.5 x 109/L
    • Platelets ≥100 x 109/L
    • Haemoglobin ≥90 g/L (9 g/dL)
13. Prothrombin time and activated partial thromboplastin time within normal range or international normalised ratio ≤1.5, as appropriate

14. Meeting reproductive status requirements:

    • Females must not be pregnant or breastfeeding
    • Females of childbearing potential must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotrophin [hCG]) within 24 hours before the first dose of study treatment
    • Females of childbearing potential must agree to use a highly effective method of contraception, for the duration of study treatment with NG-350A and 6 months following the last dose of study treatment. Females of childbearing potential who are continuously not heterosexually active are exempt from contraceptive requirements, but must still undergo pregnancy testing
    • Fertile males who are sexually active with females of childbearing potential must agree to follow instructions for method(s) of contraception, for the duration of study treatment with NG-350A and 6 months following the last dose of study treatment. In addition, males must be willing to refrain from sperm donation during this time. Azoospermic males are exempt from contraceptive requirements

Exclusion Criteria:

1. Known history or evidence of significant immunodeficiency due to underlying illness (e.g. human immunodeficiency virus [HIV]/acquired immunodeficiency syndrome [AIDS]) and/or medication (e.g. systemic corticosteroids or other immunosuppressive medications, including cyclosporine, azathioprine, interferons in the 4 weeks before the first dose of study treatment). Patients with a condition requiring systemic treatment with either corticosteroids (>10 mg daily prednisolone equivalent) or other immunosuppressive medications within 14 days of the first dose of study treatment. Inhaled or topical steroids and adrenal replacement steroid doses are permitted in the absence of autoimmune disease
2. Splenectomy
3. Prior allogeneic or autologous bone marrow or organ transplantation
4. Active infections requiring antibiotics, physician monitoring or recurrent fevers (>38.0˚C) associated with a clinical diagnosis of active infection
5. Active viral disease or positive test for hepatitis B virus using hepatitis B surface antigen test or positive test for hepatitis C virus (HCV) using HCV RNA or HCV antibody test indicating acute or chronic infection. Positive test for HIV or AIDS; testing is not required in the absence of history
6. Use of the following antiviral agents: ribavirin, adefovir, lamivudine or cidofovir within 7 days prior to the first dose of study treatment; or pegylated interferon in the 14 days before the first dose of study treatment
7. Administration of an investigational drug in the 28 days, or six half-lives (whichever is longer) before the first dose of study treatment
8. Major surgery or treatment with any chemotherapy, radiation therapy, biologics for cancer or investigational therapy in the 28 days before the first dose of study treatment. All toxicities attributed to prior anti-cancer therapy other than alopecia must have resolved to Grade 1 or baseline before the first dose of study treatment. Patients with toxicities (other than renal toxicities) attributed to prior anti-cancer therapy which are not expected to resolve and result in long lasting sequelae, such as neuropathy after platinum based therapy, are permitted to enrol
9. Other prior malignancy active within the previous 3 years except for local or organ confined early stage cancer that has been definitively treated with curative intent, does not require ongoing treatment, has no evidence of residual disease and has a negligible risk of recurrence and is therefore unlikely to interfere with the primary and secondary endpoints of the study, including response rate and safety
10. Symptomatic brain metastases or any leptomeningeal metastasis that is symptomatic and/or requires treatment. Patients with brain metastases are eligible if these have been locally treated (surgery, radiotherapy). There must also be no requirement for immunosuppressive doses of systemic corticosteroids (>10 mg/day prednisone equivalent) for at least 2 weeks before the first dose of study treatment
11. Any history of renal disease or renal injury or autoimmune disease. Patients with active, known or suspected auto-immune disease or a syndrome that requires systemic or immunosuppressive agents; patients with vitiligo, type I diabetes mellitus, residual hypothyroidism due to autoimmune disease only requiring hormone replacement, psoriasis not requiring systemic treatment or conditions not expected to recur in the absence of an external trigger are permitted to enrol providing they comply with the other eligibility criteria relating to renal function
12. Any serious or uncontrolled medical disorder that, in the opinion of the Investigator or the Medical Monitor, may increase the risk associated with study participation or study treatment administration, impair the ability of the patient to receive protocol therapy or interfere with the interpretation of study results
13. History of coagulopathy, transient ischaemic attacks, cerebrovascular accidents or venous thromboembolism
14. Previous treatment with enadenotucirev or an anti-CD40 antibody
15. Known allergy to NG-350A transgene products or formulation
16. Any other medical or psychological condition that would preclude participation in the study or compromise ability to give informed consent

Contacts and Locations

Contacts

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Contact: PsiOxus Therapeutics	+44 1235835328	enquiries@psioxus.com

Locations

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United States, Texas
The University of Texas MD Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact: Aung Naing, MD 713-563-0803 anaing@mdanderson.org

Sponsors and Collaborators

PsiOxus Therapeutics Ltd

Investigators

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Principal Investigator:	Aung Naing, MD	The University of Texas MD Anderson Cancer Center

More Information

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Responsible Party:	PsiOxus Therapeutics Ltd
ClinicalTrials.gov Identifier:	NCT03852511 History of Changes
Other Study ID Numbers:	NG-350A-01
First Posted:	February 25, 2019
Last Update Posted:	February 28, 2019
Last Verified:	February 2019

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Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by PsiOxus Therapeutics Ltd:

metastatic; epithelial; virus; advanced

Additional relevant MeSH terms:

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Neoplasm Metastasis; Neoplasms, Glandular and Epithelial; Neoplastic Processes	Neoplasms; Pathologic Processes; Neoplasms by Histologic Type