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

Primary Purpose

Chronic Lymphocytic Leukaemia, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma

Status

Recruiting

Phase

Phase 1

Locations

United Kingdom

Study Type

Interventional

Intervention

NVG-111

About this trial

This is an interventional treatment trial for Chronic Lymphocytic Leukaemia focused on measuring ROR1 positive cancers, Bispecific T cell engagers

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion criteria:

Personally signed informed consent document.
Male or female, age ≥18 years.
Relapsed or refractory CLL/SLL or MCL:
- CLL/SLL patients on at least 2nd line therapy, with a partial response at Screening to ≥12 months ongoing treatment with Bruton's Tyrosine kinase inhibitor (BTKi), venetoclax ± anti-CD20 MAb or phosphoinositide 3-kinase inhibitor (PI3Ki). OR have evidence of disease progression using these therapies OR have stopped therapy due to intolerance.
- MCL patients on at least 2nd line therapy, with a partial response at Screening to ≥6 months ongoing treatment with a BTKi or evidence of disease progression on a BTKi or achieved PR but stopped therapy due to intolerance.
MCL and SLL patients must have archived tumour biopsy tissue available, or have a new biopsy unless blood or bone marrow tests at Screening show detectable ROR1.
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 lymphoma.
High tumour bulk as defined in the protocol.
Allogeneic or autologous hematopoietic stem cell transplant or donor lymphocyte infusion 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 Covid-19, 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.

Sites / Locations

University College London HospitalRecruiting
Royal Marsden HospitalRecruiting
The Christie NHS Foundation TrustRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Arm Label

Group A: Haematological malignancies

Group B: Solid tumours

Arm Description

Outcomes

Primary Outcome Measures

Number of treatment-emergent adverse events (TEAEs)

Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing

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

Number of adverse events of special interest (AESI)

Safety parameter: specific protocol-defined AEs of Grade >=3

Number of dose limiting toxicities (DLTs)

Safety parameter assessed by protocol-defined adverse events

Laboratory safety abnormalities

Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments

Vital sign abnormalities

Safety parameter assessed by absolute values and change from baseline in vital signs

ECG abnormalities

Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF

Changes from baseline in ECOG

Safety parameter assessed by change from baseline in ECOG performance status

Secondary Outcome Measures

Full Information

NCT ID

NCT04763083

First Posted

February 12, 2021

Last Updated

July 5, 2023

Sponsor

NovalGen Ltd.

1. Study Identification

Unique Protocol Identification Number

NCT04763083

Brief Title

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

Official Title

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

Study Type

Interventional

2. Study Status

Record Verification Date

September 2022

Overall Recruitment Status

Recruiting

Study Start Date

May 14, 2021 (Actual)

Primary Completion Date

December 2023 (Anticipated)

Study Completion Date

December 2025 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

NovalGen Ltd.

4. Oversight

Studies a U.S. FDA-regulated Drug Product

Studies a U.S. FDA-regulated Device Product

Data Monitoring Committee

Yes

5. Study Description

Brief Summary

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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Chronic Lymphocytic Leukaemia, Small Lymphocytic Lymphoma, Mantle Cell Lymphoma, Follicular Lymphoma, Diffuse Large B Cell Lymphoma, Non-small Cell Lung Cancer (NSCLC), Malignant Melanoma

Keywords

ROR1 positive cancers, Bispecific T cell engagers

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 1

Interventional Study Model

Parallel Assignment

Masking

None (Open Label)

Allocation

Non-Randomized

Enrollment

90 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title

Group A: Haematological malignancies

Arm Type

Experimental

Arm Title

Group B: Solid tumours

Arm Type

Experimental

Intervention Type

Drug

Intervention Name(s)

NVG-111

Intervention Description

Open label, continuous iv infusion, escalating doses of NVG-111 for minimum 3 cycles

Primary Outcome Measure Information:

Title

Number of treatment-emergent adverse events (TEAEs)

Description

Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing

Time Frame

Up to 10 months

Title

Number of serious adverse events (SAEs)

Description

Time Frame

Up to 10 months

Title

Number of adverse events of special interest (AESI)

Description

Safety parameter: specific protocol-defined AEs of Grade >=3

Time Frame

Up to 10 months

Title

Number of dose limiting toxicities (DLTs)

Description

Safety parameter assessed by protocol-defined adverse events

Time Frame

Up to 28 days

Title

Laboratory safety abnormalities

Description

Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments

Time Frame

Up to 10 months

Title

Vital sign abnormalities

Description

Safety parameter assessed by absolute values and change from baseline in vital signs

Time Frame

Up to 10 months

Title

ECG abnormalities

Description

Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF

Time Frame

Up to 10 months

Title

Changes from baseline in ECOG

Description

Safety parameter assessed by change from baseline in ECOG performance status

Time Frame

Up to 10 months

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

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.

Central Contact Person:

First Name & Middle Initial & Last Name or Official Title & Degree

Amit C Nathwani, MBChB, FRCP, FRCPath, PhD

Phone

0044 207 139 8639

a.nathwani@novalgen.co.uk

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Parag Jasani, MBBS, FRCP, FRCPath

Organizational Affiliation

Royal Free London NHS Foundation Trust and University College London Hospitals

Official's Role

Principal Investigator

Facility Information:

Facility Name

University College London Hospital

City

London

ZIP/Postal Code

W1T 7HA

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

William Townsend

william.townsend@nhs.net

First Name & Middle Initial & Last Name & Degree

Heather Shaw

First Name & Middle Initial & Last Name & Degree

Martin Forster

Facility Name

Royal Marsden Hospital

City

London

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Juanita Lopez

Juanita.Lopez@icr.ac.uk

Facility Name

The Christie NHS Foundation Trust

City

Manchester

Country

United Kingdom

Individual Site Status

Recruiting

Facility Contact:

First Name & Middle Initial & Last Name & Degree

Fiona Thistlethwaite

fiona.thistlethwaite@nhs.net

12. IPD Sharing Statement

Plan to Share IPD

Undecided

IPD Sharing Plan Description

The company is developing an IPD sharing plan which will be completed and posted prior to primary completion date of the study

Learn more about this trial

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

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