First in Human Study of NVG-111 in Chronic Lymphocytic Leukaemia and Mantle Cell Lymphoma
Study Details
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 |
|---|---|---|
|
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
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
- Phase 1: Number of treatment-emergent adverse events (TEAEs) [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) [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) [Up to 7 months]
Safety parameter: specific protocol-defined AEs of Grade >=3
- Phase 1: Number of dose limiting toxicities (DLTs) [Up to 28 days]
Safety parameter assessed by protocol-defined adverse events
- Phase 1: Laboratory safety abnormalities [Up to 7 months]
Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments
- Phase 1: Vital sign abnormalities [Up to 7 months]
Safety parameter assessed by absolute values and change from baseline in vital signs
- Phase 1: ECG abnormalities [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 [Up to 7 months]
Safety parameter assessed by change from baseline in ECOG performance status
- Phase 2: Complete response rate (CRR) in CLL [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 [Up to 6 months]
Efficacy parameter defined as proportion of patients with complete metabolic response (CMR) by Lugano criteria
Secondary Outcome Measures
- Phase 1 and 2: Area under the serum concentration versus time curve (AUC) [Up to 7 months]
Pharmacokinetic parameter derived from systemic concentrations of NVG-111
- Phase 1 and 2: AUC0-t [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 [Up to 7 months]
Pharmacokinetic parameter: clearance of NVG-111 derived from systemic concentrations
- Phase 1 and 2: Cmax [Up to 7 months]
Pharmacokinetic parameter: maximum systemic concentration of NVG-111
- Phase 1 and 2: tmax [Up to 7 months]
Pharmacokinetic parameter: time to Cmax of NVG-111 derived from systemic concentrations
- Phase 1 and 2: t1/2 [Up tp 7 months]
Pharmacokinetic parameter: half-life of NVG-111 derived from systemic concentrations
- Phase 1 and 2: Vz [Up tp 7 months]
Pharmacokinetic parameter: volume of distribution of NVG-111 derived from systemic concentrations
- Phase 2: Progression free survival (PFS) [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) [Up to 31 months]
Efficacy parameter defined as time from first response to death (all cause) or progressive disease
- Phase 2: Overall Survival (OS) [Up to 31 months]
Efficacy parameter defined as time from first dose to death (all cause)
- Phase 2: EORTC QLQ-C30 [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 [Up to 31 months]
Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire
- Phase 2: EQ-5D-3L [Up to 31 months]
Efficacy parameter: HRQoL assessed by change from baseline in EQ-5D-3L questionnaire
- Phase 2: Number of TEAEs [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 [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 [Up to 7 months]
Safety parameter: specific protocol-defined AEs of Grade >=3
- Phase 2: Laboratory safety abnormalities [Up to 7 months]
Safety parameter assessed by absolute values and change from baseline in laboratory safety assessments
- Phase 2: Vital sign abnormalities [Up to 7 months]
Safety parameter assessed by absolute values and change from baseline in vital signs
- Phase 2: Adverse ECG findings [Up to 7 months]
Safety parameter assessed by absolute value and change from baseline in ECG intervals including QTcF
Eligibility Criteria
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 109 /L (without growth factors) and platelets ≥ 30 x 109 /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
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University College London Hospital | London | United Kingdom | W1T 7HA |
Sponsors and Collaborators
- NovalGen Ltd.
Investigators
- Principal Investigator: Parag Jasani, MBBS, FRCP, FRCPath, Royal Free London NHS Foundation Trust and University College London Hospitals
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- NVG111-101
- 2020-000820-20