First in Human Study of NVG-111 in Relapsed/Refractory ROR1+ Malignancies

An Open-label, Phase 1, First in Human Study Investigating the Safety, Tolerability, Pharmacokinetics and Efficacy of NVG-111 in Subjects With Relapsed/Refractory ROR1+ Malignancies

NVG-111 is a bispecific antibody drug, having two "arms", one arm attaches to a substance on cancer cells called ROR1, the other arm attaches to the body's immune cells directing them to kill the cancer cells. This is the first clinical trial of the drug NVG-111, and will include patients with certain types of cancer including chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) in Group A. Subjects with solid tumours, focusing initially on stage IV non-small cell lung cancer (NSCLC) or malignant melanoma.

Study Overview

• Status: Recruiting
• Conditions: Follicular Lymphoma; Mantle Cell Lymphoma; Diffuse Large B Cell Lymphoma; Non-small Cell Lung Cancer (NSCLC); Small Lymphocytic Lymphoma; Malignant Melanoma; Chronic Lymphocytic Leukaemia
• Intervention / Treatment: Drug: NVG-111

Detailed Description

Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a protein which is expressed at high levels on many types of cancers but is absent or expressed at low levels in normal adult organs. NVG-111 is a bispecific antibody T cell engager, comprising tandem single chain variable fragments (scFv), one arm binding to ROR1 on cancer cells, the other to cell surface CD3 on lymphocytes. Dual binding of NVG-111 causes MHC-independent immunological synapse formation, releasing perforins, granzyme B and cytokines, resulting in targeted killing of the cancer cells.

This is a Phase 1 first in human study to assess the safety, pharmacokinetics and efficacy of NVG-111 in patients with subjects with relapsed/refractory ROR1+ malignancies.

A range of doses will be studied in sequential cohorts to understand safety, pharmacokinetics and pharmacodynamics of the drug and establish the recommended phase 2 dose (RP2D). At each dose level, patients will receive 3 cycles of NVG-111 by continuous intravenous infusion, each cycle consists of 21 days treatment. Additional cycles may be given depending on the response seen.

All patients will have a safety follow up visit 4 weeks after completion of treatment with NVG-111, and will then enter long term follow up for up to two years to evaluate the duration of efficacy.

• Study Type: Interventional
• Enrollment (Estimated): 90
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Amit C Nathwani, MBChB, FRCP, FRCPath, PhD; Phone Number: 0044 207 139 8639; Email: a.nathwani@novalgen.co.uk

Study Locations

• United Kingdom
  • London, United Kingdom
    • Recruiting
    • Royal Marsden Hospital
    • Contact: Juanita Lopez; Email: Juanita.Lopez@icr.ac.uk
  • London, United Kingdom, W1T 7HA
    • Recruiting
    • University College London Hospital
    • Contact: William Townsend; Email: william.townsend@nhs.net
    • Sub-Investigator: Heather Shaw
    • Sub-Investigator: Martin Forster
  • Manchester, United Kingdom
    • Recruiting
    • The Christie NHS Foundation Trust
    • Contact: Fiona Thistlethwaite; Email: fiona.thistlethwaite@nhs.net

Participation Criteria

Eligibility Criteria

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

Description

Inclusion criteria:

• Personally signed informed consent document.
• Male or female, age ≥18 years.
• Relapsed or refractory ROR1+ malignancies
• ECOG performance status ≤2.

• Adequate organ function.

  • Bilirubin ≤1.5 x ULN (unless Gilbert's syndrome).
  • AST and ALT ≤2.5 x ULN (if no hepatic CLL or MCL), or AST and ALT ≤5 x ULN (if hepatic CLL or MCL).
  • APTT and PT ≤1.5 x ULN.
  • ANC ≥0.5 x 10^9 /L (without growth factors) and platelets ≥ 30 x 10^9 /L (without transfusion).
  • Serum creatinine ≤2 x ULN.
  • Estimated creatinine clearance ≥30 mL/min.
• In females of childbearing potential, a negative serum pregnancy test.
• For both males and females, willingness to use adequate contraception.
• Willingness and ability to comply with study procedures.

Exclusion Criteria:

• Richter's transformation.
• CNS or leptomeningeal active disease.
• High tumour bulk as defined in the protocol.
• Allogeneic or autologous organ transplant within prior 6 months.
• Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura within 8 weeks of screening.
• Clinically significant neurological disease.
• Clinically significant cardiovascular disease or ECG abnormalities.
• Severe chronic lung disease.
• Positive test at Screening for HIV, hepatitis B or hepatitis C infection.
• Any other concurrent cancer or cancer treatments.
• Uncontrolled ongoing infection
• Recent major surgery
• Concurrent participation in another clinical trial, or experimental therapy within 5 half-lives of Screening
• Pregnant or currently breastfeeding.
• Any other medical condition that in the opinion of the investigator contraindicates participation in the study.

Study Plan

How is the study designed?

Design Details

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

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Group A: Haematological malignancies	Drug: NVG-111; Open label, continuous iv infusion, escalating doses of NVG-111 for minimum 3 cycles
Experimental: Group B: Solid tumours	Drug: NVG-111; Open label, continuous iv infusion, escalating doses of NVG-111 for minimum 3 cycles

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Number of treatment-emergent adverse events (TEAEs)	Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing	Up to 10 months
Number of serious adverse events (SAEs)	Safety parameter defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent disability/incapacity, is a congenital anomaly/birth defect, or is medically significant/important	Up to 10 months
Number of adverse events of special interest (AESI)	Safety parameter: specific protocol-defined AEs of Grade >=3	Up to 10 months
Number of dose limiting toxicities (DLTs)	Safety parameter assessed by protocol-defined adverse events	Up to 28 days
Laboratory safety abnormalities	Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments	Up to 10 months
Vital sign abnormalities	Safety parameter assessed by absolute values and change from baseline in vital signs	Up to 10 months
ECG abnormalities	Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF	Up to 10 months
Changes from baseline in ECOG	Safety parameter assessed by change from baseline in ECOG performance status	Up to 10 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Phase 1 and 2: Area under the serum concentration versus time curve (AUC)	Pharmacokinetic parameter derived from systemic concentrations of NVG-111	Up to 7 months
Phase 1 and 2: AUC0-t	Pharmacokinetic parameter derived from systemic concentrations of NVG-111 defined as AUC up to time t	Up to 7 months
Phase 1 and 2: CL	Pharmacokinetic parameter: clearance of NVG-111 derived from systemic concentrations	Up to 7 months
Phase 1 and 2: Cmax	Pharmacokinetic parameter: maximum systemic concentration of NVG-111	Up to 7 months
Phase 1 and 2: tmax	Pharmacokinetic parameter: time to Cmax of NVG-111 derived from systemic concentrations	Up to 7 months
Phase 1 and 2: t1/2	Pharmacokinetic parameter: half-life of NVG-111 derived from systemic concentrations	Up tp 7 months
Phase 1 and 2: Vz	Pharmacokinetic parameter: volume of distribution of NVG-111 derived from systemic concentrations	Up tp 7 months
Phase 2: Progression free survival (PFS)	Efficacy parameter defined as time from first dose to death (all cause) or progressive disease by iwCLL criteria for CLL/SLL and Lugano criteria for MCL	Up to 31 months
Phase 2: Duration of Response (DoR)	Efficacy parameter defined as time from first response to death (all cause) or progressive disease	Up to 31 months
Phase 2: Overall Survival (OS)	Efficacy parameter defined as time from first dose to death (all cause)	Up to 31 months
Phase 2: EORTC QLQ-C30	Efficacy parameter: Health Related Quality of Life (HRQoL) assessed by change from baseline in EORTC QLQ-C30 questionnaire	Up to 31 months
Phase 2: EORTC QLQ-CLL17	Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire	Up to 31 months
Phase 2: EQ-5D-3L	Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire	Up to 31 months
Phase 2: Number of TEAEs	Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing	Up to 7 months
Phase 2: Number of SAEs	Safety parameter defined as any untoward medical occurrence that, at any dose results in death, is life threatening, requires inpatient hospitalisation or prolongation of existing hospitalisation, results in persistent disability/incapacity, is a congenital anomaly/birth defect, or is medically significant/important	Up to 7 months
Phase 2: Number of AESI	Safety parameter: specific protocol-defined AEs of Grade >=3	Up to 7 months
Phase 2: Laboratory safety abnormalities	Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments	Up to 7 months
Phase 2: Vital sign abnormalities	Safety parameter assessed by absolute values and change from baseline in vital signs	Up to 7 months
Phase 2: Adverse ECG findings	Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF	Up to 7 months

Collaborators and Investigators

• Sponsor: NovalGen Ltd.
• Investigators: Principal Investigator: Parag Jasani, MBBS, FRCP, FRCPath, Royal Free London NHS Foundation Trust and University College London Hospitals

Study record dates

Study Major Dates

• Study Start (Actual): May 14, 2021
• Primary Completion (Estimated): December 1, 2023
• Study Completion (Estimated): December 1, 2025

Study Registration Dates

• First Submitted: February 12, 2021
• First Submitted That Met QC Criteria: February 17, 2021
• First Posted (Actual): February 21, 2021

Study Record Updates

• Last Update Posted (Actual): July 7, 2023
• Last Update Submitted That Met QC Criteria: July 5, 2023
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Keywords: ROR1 positive cancers; Bispecific T cell engagers
• Additional Relevant MeSH Terms: Pathologic Processes; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Lymphoma, Non-Hodgkin; Disease Attributes; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Leukemia, Lymphoid; Leukemia; Leukemia, B-Cell; Neuroendocrine Tumors; Nevi and Melanomas; Lymphoma, B-Cell; Chronic Disease; Lymphoma; Lymphoma, Large B-Cell, Diffuse; Lymphoma, Mantle-Cell; Leukemia, Lymphocytic, Chronic, B-Cell; Melanoma
• Other Study ID Numbers: NVG111-101; 2020-000820-20 (EudraCT Number)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: UNDECIDED
• IPD Plan Description: The company is developing an IPD sharing plan which will be completed and posted prior to primary completion date of the study

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No