Study of NG-641 in Combination With Nivolumab in Metastatic or Advanced Epithelial Tumours (NEBULA)

• ClinicalTrials.gov Identifier: NCT05043714
• Recruitment Status: Recruiting
• First Posted: September 14, 2021
• Last Update Posted: March 31, 2022
• Sponsor: Akamis Bio
• Collaborator: Bristol-Myers Squibb
• Information provided by (Responsible Party): Akamis Bio

Study Description

Brief Summary:

This is a phase 1a/1b, multicentre, open-label, non-randomized study of NG-641 in combination with nivolumab in patients with metastatic or advanced epithelial tumours.

To characterize the safety and tolerability of NG-641 in combination with nivolumab in patients with metastatic or advanced epithelial tumours and to determine the recommended dose of NG-641 in combination with nivolumab for further development in patients with metastatic or advanced epithelial tumours

Condition or disease	Intervention/treatment	Phase
Metastatic Cancer; Epithelial Tumor	Biological: NG-641 in combination with Nivolumab	Phase 1

Detailed Description:

The Phase 1a part of the study is is a dose-escalation phase investigating NG-641 administration by intravenous (IV) infusion in combination with fixed doses of nivolumab in a range of tumour types. Patients eligible for Phase 1a will have metastatic or advanced disease after failure of prior anti-programmed cell death 1 (PD-1) or anti-programmed cell death ligand 1 (PD-L1) therapy. Dose escalation will be governed by the Bayesian Optimal Interval (BOIN) design, with up to four dose-escalation cohorts planned, plus an optional dose de-escalation cohort.

The Phase 1b part of the study will further investigate the efficacy and safety of the selected dose regimen in up to three of the tumour types evaluated in phase 1b (tumour-specific Dose Expansion Cohorts A, B and C). Patients eligible for Phase 1b will have metastatic or advanced disease and primary resistance to anti-PD-1 or anti-PD-L1 therapy.

Following treatment, patients will be followed every 8 weeks for 12 months for tumour imaging and evaluation (until disease progression), overall survival and outcomes on further treatment.

Study Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 30 participants
• Allocation: N/A
• Intervention Model: Sequential Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: A Multicentre, Open-label, Non-randomized, Phase 1a/1b Study of NG-641, a Tumour-selective and Transgene-expressing Adenoviral Vector, in Combination With Nivolumab in Patients With Metastatic or Advanced Epithelial Tumours (NEBULA)
• Actual Study Start Date: December 1, 2021
• Estimated Primary Completion Date: October 6, 2022
• Estimated Study Completion Date: December 15, 2022

Arms and Interventions

Arm

Intervention/treatment

Experimental: Intravenous; Patients will receive a first study treatment cycle consisting of one IV infusion of NG-641 on Days 1, 3 and 5 and one IV infusion of nivolumab on Day 15. Patients will then receive nivolumab monotherapy given once every four weeks (on Day 15 of each 28-day cycle), until progression, unacceptable toxicity, withdrawal of consent, completion of 8 cycles of treatment, or the study ends, whichever occurs first.

Biological: NG-641 in combination with Nivolumab; Patients will receive a first study treatment cycle consisting of one IV infusion of NG-641 on Days 1, 3 and 5 and one IV infusion of nivolumab on Day 15. Patients will then receive nivolumab monotherapy given once every four weeks on Day 15 of each 28-day cycle up to 8 cycles

Outcome Measures

Primary Outcome Measures :

1. Incidence of adverse events (safety and tolerability) in study of NG-641 in combination with nivolumab [ Time Frame: 30 days after last dose of study drug ]
   Assess the safety and tolerability of NG-641 in combination with nivolumab by review of adverse events including serious adverse events, 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

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

Criteria

Inclusion Criteria:

• Provide written informed consent to participate

• Patients must have one of eleven histologically or cytologically confirmed metastatic/advanced carcinoma or adenocarcinoma that has progressed after at least one line of systemic therapy and are incurable by local therapy (contact Sponsor for more details regarding the tumour types)

  a. Tumour types included are: urothelial carcinoma, squamous cell carcinoma of the head and neck (SCCHN), microsatellite instability (MSI)-high/deficient mismatch repair (dMMR) cancer, non-small cell lung cancer (NSCLC), uterine/endometrial cancer, cervical cancer, oesophageal cancer, gastric cancer, triple-negative breast cancer (TNBC), cutaneous squamous cell carcinoma and hepatocellular carcinoma

• At least one measurable site of disease according to RECIST Version 1.1 criteria; this lesion must be either (i) outside a previously irradiated area or (ii) progressive if it is in a previously irradiated area
• Prior treatment with a PD-1/PD-L1 inhibitor (prior PD-1/PD-L1 may have been given as monotherapy or combination therapy)
• Tumour accessible for biopsy
• Aged 18 years or over
• ECOG performance status 0 or 1
• Predicted life expectancy of ≥6 months
• Adequate lung reserve (Oxygen saturation on ambient air at sea level ≥95% or the equivalent based on altitude (i.e. ≥90% at 5000 feet))

• Adequate renal function:

  1. Creatinine ≤1.5 × upper limit of normal (ULN) and estimated glomerular filtration rate (eGFR) ≥60 mL/minute/1.73m2 (or measured creatinine clearance ≥60 mL/minute)
  2. Spot albumin-to-creatinine ratio (ACR) for proteinuria at screening and baseline ≤30 mg/g. Patients with a spot ACR >30 mg/g who undergo a subsequent 24-hour urinary protein test with a result of <1 g/24 h may be included

• Adequate hepatic function:

  1. Serum total bilirubin ≤1.5 × ULN OR direct bilirubin ≤1 × ULN
  2. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤3 × ULN range
  3. Albumin ≥3 g/dL

• Adequate bone marrow function:

  1. Absolute neutrophil count ≥1.5 × 109/L
  2. Platelets ≥100 × 109/L
  3. Haemoglobin ≥90 g/L (9 g/dL)
• Coagulation profile within the normal range

• Meeting reproductive status requirements:

  1. Must not be pregnant or breastfeeding
  2. Female patients of childbearing potential, must have a negative serum or urine pregnancy test (minimum sensitivity 25 IU/L or equivalent units of human chorionic gonadotrophin) within 24 hours before the first dose of study treatment
  3. Female patients of childbearing potential who are heterosexually active must agree to use a highly effective method of contraception to prevent pregnancy, for the duration of study treatment and 6 months following the last dose of study treatment. Female patients who are continuously not heterosexually active are exempt from contraceptive requirements, but must still undergo pregnancy testing
  4. Female patients who are heterosexually active, irrespective of childbearing status, must ensure their male partner agrees to use a condom with spermicide during sexual intercourse for the duration of study treatment and 6 months following the last dose of study treatment
  5. Patients must be willing to refrain from egg donation during treatment and for at least 6 months following the last dose of study treatment
  6. Male patients who are sexually active with men or women must agree to use a condom with spermicide during intercourse for the duration of study treatment and 6 months following the last dose of study treatment. In addition, patients must be willing to refrain from sperm donation during this time.
• Exclusion Criteria:
• Prior or planned allogeneic or autologous bone marrow or organ transplantation
• Splenectomy
• Active infections requiring antibiotics, physician monitoring or systemic therapy within 1 week of the anticipated first dose of study drug, or recurrent fevers (>38.0˚C) associated with a clinical diagnosis of active infection
• Treatment with the antiviral agents: ribavirin, adefovir, lamivudine or cidofovir within 10 days prior to the first dose of study treatment; or pegylated interferon in the 4 weeks before the first dose of study treatment
• Active viral disease or positive test for hepatitis B virus using hepatitis B surface antigen test or positive test for HCV using HCV ribonucleic acid (RNA) or HCV antibody test indicating acute or chronic infection. Positive test for HIV or AIDS

• Patients who have active, known or suspected autoimmune disease that has required systemic therapy in the past 2 years, are immunocompromised in the opinion of the Investigator, or are receiving systemic immunosuppressive treatment

  a. Patients with vitiligo, type I diabetes mellitus, asthma/atopy, residual hypothyroidism due to autoimmune disease (which only requires hormone replacement therapy), 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. Use of inhaled corticosteroids, local steroid injection, or steroid eye drops is allowed

• Treatment with any live, live-attenuated or COVID-19 vaccine in the 30 days before the first dose of NG-641 or nivolumab (COVID-19 vaccines known not to be live/live-attenuated or based on an adenoviral vector (e.g. mRNA vaccines) are not subject to the 30-day exclusion)
• Treatment with any other vaccine (including known non-live/live-attenuated and non-adenoviral COVID-19 vaccines) in the 7 days before the first dose of NG-641
• History of prior Grade 3-4 acute kidney injury or other clinically significant renal impairment
• History of clinically significant interstitial lung disease or non-infectious pneumonitis
• Lymphangitic carcinomatosis (clinically suspected or radiographic evidence)
• Infectious or inflammatory bowel disease in the 3 months before the first dose of study treatment
• Myocardial infarction, stroke or other significant cardiovascular or cerebrovascular event in the 12 months before the first dose of study treatment
• Pulmonary embolism, deep vein thrombosis, or other uncontrolled thromboembolic event in the 12 months before the first dose of study treatment, or current treatment with therapeutic or prophylactic anticoagulation therapy
• Grade 3 or 4 gastrointestinal bleeding (or risk factors for gastrointestinal bleeding) or haemoptysis in the 3 months before first dose of study treatment, or any history of bleeding requiring an investigative procedure (e.g. endoscopy), transfusion or hospitalisation in the 12 months before the first dose of study treatment
• Tumour location/extent considered by the Investigator to present a significant risk if tumour flare or necrosis were to occur (e.g. an initial increase in tumour size that may lead to intestinal, airway or ureter obstruction, or penetrating tumour infiltration of major blood vessels, or other hollow organs potentially at risk of perforation)

• Use of the following prior therapies/treatments:

  1. Treatment with any other enadenotucirev-based virus (parent virus or transgene-modified variants), or fibroblast activation protein (FAP) targeting agent at any time
  2. Treatment with an investigational or licensed anti-cancer monoclonal antibody (mAb), immune checkpoint inhibitor, immune stimulatory treatment or other biological therapy in the 28 days prior to the first dose of study treatment.
• Prior anti-PD-1/PD-L1 therapy is permitted without a 'washout' phase c. Treatment with an investigational or licensed chemotherapy, targeted small molecule or other investigational drug in the 14 days or five half-lives (whichever is shorter) before the first dose of study treatment d. Major surgery in the 28 days before the first dose of study treatment e. Radiation therapy in the 14 days before the first dose of study treatment f. Treatment with complementary medications (e.g. herbal supplements or traditional Chinese medicines) to treat the disease under study within the 14 days prior to first study treatment. Such medications are permitted if they are used as supportive care g. Bisphosphonate therapy or treatment with Receptor Activator of Nuclear factor Kappa-Β (RANK)-ligand inhibitors for metastatic bone disease is permitted
• All toxicities attributed to prior anti-cancer therapy (including radiation therapy) other than alopecia must have resolved to Grade 1 or baseline before the first dose of study treatment
• Known allergy or hypersensitivity (Grade ≥3) to NG-641 transgene, immune checkpoint inhibitor products or formulation, or other monoclonal antibodies
• Discontinuation from prior treatment with an immune therapy due to a Grade ≥3 immune-related AE, or any history of life-threatening toxicity related to prior immune therapy
• 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
• Symptomatic brain metastases or any leptomeningeal metastases that are symptomatic and/or requires treatment
• 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

Contacts and Locations

Contacts

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

Contact: Behnaz Ravanfar; +44 1235835328; behnaz.ravanfar@psioxus.com

Locations

United States, California

UCLA Department of Medicine; Recruiting

Santa Monica, California, United States, 90404

Contact: Lee Rosen, MD 424-413-2244 irosen@mednet.ucla.edu

United Kingdom

The Clatterbridge Cancer Centre NHS Foundation Trust; Not yet recruiting

Liverpool, Lancashire, United Kingdom, L7 8YA

Contact: Christian Ottensmeier +44 1517951475 c.ottensmeier@liverpool.ac.uk

Oxford University Hospitals NHS Foundation Trust; Not yet recruiting

Oxford, Oxfordshire, United Kingdom, OX3 7LE

Contact: Eileen Parkes +44 1865617411 eileen.parkes@oncology.ox.ac.uk

Sponsors and Collaborators

Akamis Bio

Bristol-Myers Squibb

More Information

• Responsible Party: Akamis Bio
• ClinicalTrials.gov Identifier: NCT05043714
• Other Study ID Numbers: NG-641-03
• First Posted: September 14, 2021
• Last Update Posted: March 31, 2022
• Last Verified: March 2022

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

Keywords provided by Akamis Bio:

Metastatic Cancer; Epithelial Tumor; Viral vector; Advanced

Additional relevant MeSH terms:

Neoplasm Metastasis; Neoplasms, Glandular and Epithelial; Neoplasms; Neoplastic Processes; Pathologic Processes; Neoplasms by Histologic Type; Nivolumab; Antineoplastic Agents, Immunological; Antineoplastic Agents; Immune Checkpoint Inhibitors; Molecular Mechanisms of Pharmacological Action