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

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ClinicalTrials.gov Identifier: NCT04763083
Recruitment Status : Recruiting
First Posted : February 21, 2021
Last Update Posted : June 23, 2021
Sponsor:
Information provided by (Responsible Party):
NovalGen Ltd.

Tracking Information
First Submitted Date  ICMJE February 12, 2021
First Posted Date  ICMJE February 21, 2021
Last Update Posted Date June 23, 2021
Actual Study Start Date  ICMJE May 14, 2021
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: February 17, 2021)
  • 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
  • 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
  • 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
  • Phase 1: Number of dose limiting toxicities (DLTs) [ Time Frame: Up to 28 days ]
    Safety parameter assessed by protocol-defined adverse events
  • 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
  • Phase 1: Vital sign abnormalities [ Time Frame: Up to 7 months ]
    Safety parameter assessed by absolute values and change from baseline in vital signs
  • 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
  • Phase 1: Changes from baseline in ECOG [ Time Frame: Up to 7 months ]
    Safety parameter assessed by change from baseline in ECOG performance status
  • 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
  • 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
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: February 17, 2021)
  • 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
  • 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
  • Phase 1 and 2: CL [ Time Frame: Up to 7 months ]
    Pharmacokinetic parameter: clearance of NVG-111 derived from systemic concentrations
  • Phase 1 and 2: Cmax [ Time Frame: Up to 7 months ]
    Pharmacokinetic parameter: maximum systemic concentration of NVG-111
  • Phase 1 and 2: tmax [ Time Frame: Up to 7 months ]
    Pharmacokinetic parameter: time to Cmax of NVG-111 derived from systemic concentrations
  • Phase 1 and 2: t1/2 [ Time Frame: Up tp 7 months ]
    Pharmacokinetic parameter: half-life of NVG-111 derived from systemic concentrations
  • Phase 1 and 2: Vz [ Time Frame: Up tp 7 months ]
    Pharmacokinetic parameter: volume of distribution of NVG-111 derived from systemic concentrations
  • 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
  • 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
  • Phase 2: Overall Survival (OS) [ Time Frame: Up to 31 months ]
    Efficacy parameter defined as time from first dose to death (all cause)
  • 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
  • Phase 2: EORTC QLQ-CLL17 [ Time Frame: Up to 31 months ]
    Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire
  • Phase 2: EQ-5D-3L [ Time Frame: Up to 31 months ]
    Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire
  • 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
  • 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
  • Phase 2: Number of AESI [ Time Frame: Up to 7 months ]
    Safety parameter: specific protocol-defined AEs of Grade >=3
  • 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
  • Phase 2: Vital sign abnormalities [ Time Frame: Up to 7 months ]
    Safety parameter assessed by absolute values and change from baseline in vital signs
  • 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
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE First in Human Study of NVG-111 in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma
Official Title  ICMJE 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
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.

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 Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Phase 2
Study Design  ICMJE Allocation: Non-Randomized
Intervention Model: Parallel Assignment
Masking: None (Open Label)
Primary Purpose: Treatment
Condition  ICMJE
  • Chronic Lymphocytic Leukaemia
  • Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma
Intervention  ICMJE
  • Drug: NVG-111
    Open label, continuous iv infusion, escalating doses of NVG-111 for minimum 3 cycles, 21 days on, 7 days off
  • Drug: NVG-111 (RP2D)
    Open label, continuous iv infusion at RP2D
Study Arms  ICMJE
  • Experimental: Phase 1 Dose escalation
    Up to 9 sequential cohorts including both CLL/SLL and MCL patients
    Intervention: Drug: NVG-111
  • Experimental: Phase 2
    CLL/SLL and MCL cohorts
    Intervention: Drug: NVG-111 (RP2D)
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: February 17, 2021)
90
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE December 2025
Estimated Primary Completion Date December 2023   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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) or venetoclax ± anti-CD20 MAb
    • MCL patients on at least 2nd line therapy, with a partial response at Screening to ≥6 months ongoing treatment with a BTKi
  • MCL and SLL patients must have archived tumor 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
  • 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
  • Presence of other major cancer
  • Any other concurrent cancer treatments
  • Recent or planned live vaccines
  • 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
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
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
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04763083
Other Study ID Numbers  ICMJE NVG111-101
2020-000820-20 ( EudraCT Number )
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
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
Responsible Party NovalGen Ltd.
Study Sponsor  ICMJE NovalGen Ltd.
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Parag Jasani, MBBS, FRCP, FRCPath Royal Free London NHS Foundation Trust and University College London Hospitals
PRS Account NovalGen Ltd.
Verification Date June 2021

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP