First in Human Study of NVG-111 in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma

• ClinicalTrials.gov Identifier: NCT04763083
• Recruitment Status: Recruiting
• First Posted: February 21, 2021
• Last Update Posted: September 30, 2022
• Sponsor: NovalGen Ltd.
• Information provided by (Responsible Party): NovalGen Ltd.

Study Description

Brief Summary:

This is the first clinical trial of the drug NVG-111, and will include patients with certain types of blood cancer called chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL). 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.

The trial has two parts, the first part tests the safety of the drug at different dose levels. Once the first part of the study is complete a dose will be chosen for the second part of the study. The second part of the study will test how well NVG-111 works in treating these diseases.

Condition or disease	Intervention/treatment	Phase
Chronic Lymphocytic Leukaemia; Small Lymphocytic Lymphoma; Mantle Cell Lymphoma	Drug: NVG-111; Drug: NVG-111 (RP2D)	Phase 1; Phase 2

Detailed Description:

Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a protein which is expressed at high levels on many types of haematological 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 1/2 first in human study to assess the safety, pharmacokinetics and efficacy of NVG-111 in patients with debulked, relapsed or refractory CLL/SLL and MCL on at least 2nd line therapy. NVG-111 will be added on to existent therapy which will continue through the study.

In Phase 1, 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 followed by 7 days break. An additional 3 cycles may be given depending on the response seen.

In Phase 2, efficacy and safety of NVG-111 at the RP2D will be studied in separate cohorts of CLL/SLL and MCL patients.

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 Design

• Study Type: Interventional (Clinical Trial)
• Estimated Enrollment: 90 participants
• Allocation: Non-Randomized
• Intervention Model: Parallel Assignment
• Masking: None (Open Label)
• Primary Purpose: Treatment
• Official Title: An Open-label, Phase 1/2, First in Human Study Investigating the Safety, Tolerability, Pharmacokinetics and Efficacy of NVG-111 in Subjects With Relapsed/Refractory Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma
• Actual Study Start Date: May 14, 2021
• Estimated Primary Completion Date: December 2023
• Estimated Study Completion Date: December 2025

Arms and Interventions

Arm	Intervention/treatment
Experimental: Phase 1 Dose escalation; Up to 9 sequential cohorts including both CLL/SLL and MCL patients	Drug: NVG-111; Open label, continuous iv infusion, escalating doses of NVG-111 for minimum 3 cycles, 21 days on, 7 days off
Experimental: Phase 2; CLL/SLL and MCL cohorts	Drug: NVG-111 (RP2D); Open label, continuous iv infusion at RP2D

Outcome Measures

Primary Outcome Measures :

1. Phase 1: Number of treatment-emergent adverse events (TEAEs) [ Time Frame: Up to 7 months ]
   Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing
2. Phase 1: Number of serious adverse events (SAEs) [ Time Frame: Up to 7 months ]
   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
3. Phase 1: Number of adverse events of special interest (AESI) [ Time Frame: Up to 7 months ]
   Safety parameter: specific protocol-defined AEs of Grade >=3
4. Phase 1: Number of dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
   Safety parameter assessed by protocol-defined adverse events
5. Phase 1: Laboratory safety abnormalities [ Time Frame: Up to 7 months ]
   Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments
6. Phase 1: Vital sign abnormalities [ Time Frame: Up to 7 months ]
   Safety parameter assessed by absolute values and change from baseline in vital signs
7. Phase 1: ECG abnormalities [ Time Frame: Up to 7 months ]
   Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF
8. Phase 1: Changes from baseline in ECOG [ Time Frame: Up to 7 months ]
   Safety parameter assessed by change from baseline in ECOG performance status
9. Phase 2: Complete response rate (CRR) in CLL [ Time Frame: Up to 6 months ]
   Efficacy parameter defined as proportion of patients with complete response (CR) or CR with incomplete marrow recovery (CRi) by iwCLL criteria
10. Phase 2: CRR in MCL [ Time Frame: Up to 6 months ]
    Efficacy parameter defined as proportion of patients with complete metabolic response (CMR) by Lugano criteria

Secondary Outcome Measures :

1. Phase 1 and 2: Area under the serum concentration versus time curve (AUC) [ Time Frame: Up to 7 months ]
   Pharmacokinetic parameter derived from systemic concentrations of NVG-111
2. Phase 1 and 2: AUC0-t [ Time Frame: Up to 7 months ]
   Pharmacokinetic parameter derived from systemic concentrations of NVG-111 defined as AUC up to time t
3. Phase 1 and 2: CL [ Time Frame: Up to 7 months ]
   Pharmacokinetic parameter: clearance of NVG-111 derived from systemic concentrations
4. Phase 1 and 2: Cmax [ Time Frame: Up to 7 months ]
   Pharmacokinetic parameter: maximum systemic concentration of NVG-111
5. Phase 1 and 2: tmax [ Time Frame: Up to 7 months ]
   Pharmacokinetic parameter: time to Cmax of NVG-111 derived from systemic concentrations
6. Phase 1 and 2: t1/2 [ Time Frame: Up tp 7 months ]
   Pharmacokinetic parameter: half-life of NVG-111 derived from systemic concentrations
7. Phase 1 and 2: Vz [ Time Frame: Up tp 7 months ]
   Pharmacokinetic parameter: volume of distribution of NVG-111 derived from systemic concentrations
8. Phase 2: Progression free survival (PFS) [ Time Frame: Up to 31 months ]
   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
9. Phase 2: Duration of Response (DoR) [ Time Frame: Up to 31 months ]
   Efficacy parameter defined as time from first response to death (all cause) or progressive disease
10. Phase 2: Overall Survival (OS) [ Time Frame: Up to 31 months ]
    Efficacy parameter defined as time from first dose to death (all cause)
11. Phase 2: EORTC QLQ-C30 [ Time Frame: Up to 31 months ]
    Efficacy parameter: Health Related Quality of Life (HRQoL) assessed by change from baseline in EORTC QLQ-C30 questionnaire
12. Phase 2: EORTC QLQ-CLL17 [ Time Frame: Up to 31 months ]
    Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire
13. Phase 2: EQ-5D-3L [ Time Frame: Up to 31 months ]
    Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire
14. Phase 2: Number of TEAEs [ Time Frame: Up to 7 months ]
    Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing
15. Phase 2: Number of SAEs [ Time Frame: Up to 7 months ]
    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
16. Phase 2: Number of AESI [ Time Frame: Up to 7 months ]
    Safety parameter: specific protocol-defined AEs of Grade >=3
17. Phase 2: Laboratory safety abnormalities [ Time Frame: Up to 7 months ]
    Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments
18. Phase 2: Vital sign abnormalities [ Time Frame: Up to 7 months ]
    Safety parameter assessed by absolute values and change from baseline in vital signs
19. Phase 2: Adverse ECG findings [ Time Frame: Up to 7 months ]
    Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF

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:

• 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.

Contacts and Locations

Contacts

Contact: Amit C Nathwani, MBChB, FRCP, FRCPath, PhD; 0044 207 139 8639; a.nathwani@novalgen.co.uk

Contact: Sarah Cook, BSc; s.cook@novalgen.co.uk

Locations

United Kingdom

University College London Hospital; Recruiting

London, United Kingdom, W1T 7HA

Contact: William Townsend, MBBS 0203 447 9443 william.townsend@nhs.net

Sponsors and Collaborators

NovalGen Ltd.

Investigators

• Principal Investigator: Parag Jasani, MBBS, FRCP, FRCPath; Royal Free London NHS Foundation Trust and University College London Hospitals

More Information

• Responsible Party: NovalGen Ltd.
• ClinicalTrials.gov Identifier: NCT04763083
• Other Study ID Numbers: NVG111-101; 2020-000820-20 ( EudraCT Number )
• First Posted: February 21, 2021
• Last Update Posted: September 30, 2022
• Last Verified: September 2022

Individual Participant Data (IPD) Sharing Statement:

• Plan to Share IPD: Undecided
• Plan Description: The company is developing an IPD sharing plan which will be completed and posted prior to primary completion date of the study

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

Keywords provided by NovalGen Ltd.:

Non Hodgkin Lymphoma

Additional relevant MeSH terms:

Lymphoma; Leukemia; Leukemia, Lymphoid; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, Mantle-Cell; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases; Leukemia, B-Cell; Chronic Disease; Disease Attributes; Pathologic Processes; Lymphoma, Non-Hodgkin