Clinical Trials /

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

NCT04763083

Description:

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.

Related Conditions:
  • Chronic Lymphocytic Leukemia
  • Mantle Cell Lymphoma
  • Small Lymphocytic Lymphoma
Recruiting Status:

Recruiting

Phase:

Phase 1/Phase 2

Trial Eligibility

Document

Title

  • Brief Title: First in Human Study of NVG-111 in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma
  • 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

Clinical Trial IDs

  • ORG STUDY ID: NVG111-101
  • SECONDARY ID: 2020-000820-20
  • NCT ID: NCT04763083

Conditions

  • Chronic Lymphocytic Leukaemia
  • Small Lymphocytic Lymphoma
  • Mantle Cell Lymphoma

Interventions

DrugSynonymsArms
NVG-111Phase 1 Dose escalation
NVG-111 (RP2D)Phase 2

Purpose

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.
    

Trial Arms

NameTypeDescriptionInterventions
Phase 1 Dose escalationExperimentalUp to 9 sequential cohorts including both CLL/SLL and MCL patients
  • NVG-111
Phase 2ExperimentalCLL/SLL and MCL cohorts
  • NVG-111 (RP2D)

Eligibility 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) 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
      
Maximum Eligible Age:N/A
Minimum Eligible Age:18 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Phase 1: Number of treatment-emergent adverse events (TEAEs)
Time Frame:Up to 7 months
Safety Issue:
Description:Safety parameter assessed by: type, frequency, severity and treatment-relatedness of AEs following commencement of dosing

Secondary Outcome Measures

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

Details

Phase:Phase 1/Phase 2
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:NovalGen Ltd.

Trial Keywords

  • Non Hodgkin Lymphoma

Last Updated

May 17, 2021