RELAPSED/REFRACTORY CHRONIC LYMPHOCYTIC LEUKAEMIA AND MANTLE CELL LYMPHOMA MedDRA version: 21.0 Level: LLT Classification code 10008976 Term: Chronic lymphocytic leukemia System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) MedDRA version: 21.1 Level: PT Classification code 10026801 Term: Mantle cell lymphoma refractory System Organ Class: 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Conditions
Interventions
Product Name: NVG-111
Product Code: NVG-111
Pharmaceutical Form: Solution for infusion
INN or Proposed INN: None
Current Sponsor code: NVG-111
Other descriptive name: NVG-111
Concentration unit: µg/ml
Sponsors
NovalGen Ltd
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: Principal inclusion criteria 1. Provide signed informed consent to participate in the study. 2. Adult males or females =18 years of age. 3. Subject has CLL/SLL or MCL with the following characteristics: CLL/SLL (i) Relapsed or refractory CLL or SLL according to iwCLL criteria [Hallek et al, 2019] (ii) Subject has achieved a best tumour response of PR, present at Screening, after at least 12 months ongoing treatment with a Bruton’s Tyrosine Kinase inhibitor (BTKi) or 6 months ongoing treatment with venetoclax (with or without anti-CD20 Mab), and has received at least 1 prior line of systemic therapy. MCL (i) Documented pathological diagnosis of MCL (including chromosome translocation t(11;14)(q13;q32) and/or overexpress cyclin D1) according to WHO criteria [Swerdlow et al, 2016]. (ii) Subject has relapsed or refractory MCL and has achieved a best tumour response of PR, present at Screening, with at least 6 months of ongoing treatment with a BTKi, and has received at least 1 prior line of systemic therapy. (iii) Subject has bone marrow involvement at Screening bone marrow biopsy and/or a positive PET scan at Screening, defined for this study as a score of 4 or 5 on the 5 point scale (Cheson et al, 2014) 4. MCL and SLL subjects must have archived tumor biopsy tissue available; a formalin fixed paraffin embedded sample at any time point since diagnosis is acceptable. If an archived biopsy tissue is not available, a new biopsy (core or excision) must be taken of at least one tumour-involved lymph node, unless FACs of blood or bone marrow aspirate/biopsy at Screening show detectable ROR1 expression. 5. All acute toxic effects of prior antitumor therapy resolved to Grade =1 (other than alopecia or vitiligo). 6. Life expectancy >6 months. 7. Eastern Cooperative Oncology Group (ECOG) Performance Status =2. 8. Body weight = 45 kg. 9. Adequate organ function defined by the following laboratory safety parameters: - bilirubin =1.5 x ULN, unless elevated bilirubin is due to Gilbert’s syndrome (and fractionated direct bilirubin is <35%), and - aspartate transaminase (AST) and alanine transaminase (ALT) =2.5 x ULN in subjects without hepatic CLL or MCL site of disease, or AST and ALT =5 x ULN in subjects with hepatic CLL or MCL site of disease, and - activated partial thromboplastin time (APTT) and prothrombin time (PT) =1.5 x ULN, and - neutrophils =0.5 x 109/L (independent of growth factor support) and platelets = 30 x 109/L (independent of transfusion within 14 days of screening), and - serum creatinine =2 x ULN, and - estimated creatinine clearance (eCCr) =30 mL/min using 24-hour creatinine clearance or modified Cockcroft-Gault equation (using Ideal Body Mass [IBM] instead of Mass) 10. Ability to adhere to the study visit schedule and other protocol requirements. 11. Must be willing and able to have a study-specific peripherally inserted central catheter (PICC line) or Hickman line inserted, unless pre-existing central venous access such as a port, PICC or Hickman line is already in situ. 12. If female, must be either: (i) of non-reproductive potential (i.e. post-menopausal by history with no menses for =1 year; or have a history of hysterectomy, bilateral tubal ligation or bilateral oophorectomy). (ii) OR, if of reproductive potential, have a negative pregnancy test result at screening AND be willing to use a highly effective method of birth control (<1% failure rate per year) throughout the study up to 28 days after last dose (see pro
Exclusion criteria
Exclusion criteria: Principal exclusion criteria 1. Diagnosis of Richter's transformation (note: subjects who have previously responded to therapy for Richter's transformation may be eligible at the investigators discretion). 2. History or presence of CNS or leptomeningeal lymphoma involvement. 3. Subject has either of the following: - any lymph node/site of disease >10 cm in diameter on Screening CT scan and/or - absolute lymphocyte count >50 x 109/L at Screening 4. Allogeneic or autologous hematopoietic stem cell transplant or donor lymphocyte infusion within 6 months prior to Screening. 5. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura within 8 weeks of Screening. 6. History or presence of clinically significant neurological disease such as epilepsy, generalised seizure disorder, paresis, aphasia, stroke, severe brain injuries, dementia, Parkinson's disease, cerebellar disease, organic brain syndrome or psychosis. 7. Currently active, clinically significant cardiovascular disease, such as uncontrolled arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction, uncontrolled hypertension or cardiac arrhythmia, unstable angina, or acute coronary syndrome within 6 months prior to Screening. 8. Known clinically significant lung disease potentially associated with high risk of complications from COVID-19, including but not limited to: - severe asthma according to GINA guidelines i.e. requiring at least high dose inhaled corticosteroids (>500µg per day of fluticasone propionate or equivalent)/long acting beta-2 agonists for disease control. - severe COPD according to GOLD guidelines (FEV1 2 infective exacerbations in prior year) 9. Active infection as demonstrated at Screening with COVID-19, HIV, hepatitis B or hepatitis C. This includes: - Positive for active COVID-19 infection with an approved diagnostic test - Positive HIV test result - Positive for hepatitis B surface antigen (HbsAg) - Negative HbsAg and positive for hepatitis B core antibody (HbcAb) - Positive Hepatitis C virus antibody (HCVAb) 10. Any other chronic or current active infectious disease requiring systemic antibiotics, antifungal or antiviral treatment such as, but not limited to, chronic renal infection, chronic chest infection with bronchiectasis or tuberculosis. 11. Live vaccines administered within 28 days of Screening or planned during the study up to Safety Follow-up. 12. Major surgery within 28 days prior to Screening or planned during the study up to Safety Follow-up. 13. History of hypersensitivity to therapeutic antibodies or any of the IMP components (e.g. excipients/buffer components such as histidine, polysorbate-80) to be administered in the study. 14. Subject is unable to receive at least one of the following prophylactic medications for tumour lysis syndrome: allopurinol, febuxostat or rasburicase e.g. due to contraindications in the respective product labels. Contraindications for each agent include known hypersensitivity. In addition, rasburicase is contraindicated in subjects with known glucose 6-phosphate dehydrogenase (G6PD) deficiency or other cellular metabolic disorder known to cause haemolytic anaemia. 15. Subject has received any of the foll
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Primary objectives (Part A): To establish the safety and tolerability, maximum tolerated dose and the recommended phase 2 dose in subjects with CLL/SLL and mantle cell lymphoma Primary objectives (Part B): To establish the efficacy of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma ;Secondary Objective: Secondary objectives (Part A): To establish the pharmacokinetic (PK) profile of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma Secondary objectives (Part B): • To establish the effect of NVG-111 on other parameters of efficacy in subjects with CLL/SLL and mantle cell lymphoma • To establish the safety and tolerability of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma • To establish the PK profile of NVG-111 in subjects with CLL/SLL and mantle cell lymphoma;Primary end point(s): Primary endpoint Part A • Frequency of treatment emergent adverse events (TEAEs), including SAEs and dose limiting toxicities (DLTs) • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status Part B • Complete response rate (CRR);Timepoint(s) of evaluation of this end point: Primary endpoint Part A • Frequency of treatment emergent adverse events (TEAEs), including SAEs and dose limiting toxicities (DLTs) Time point(s) of evaluation: 15 weeks • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status Time point(s) of evaluation: 15 weeks Part B • Complete response rate (CRR) Time point(s) of evaluation: 11 weeks | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Secondary endpoints Part A PK: AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz Part B Efficacy: • Progression Free Survival (PFS) as determined by iwCLL criteria for CLL/SLL and by Lugano criteria for MCL • Duration of Response (DoR) as determined by iwCLL criteria for CLL/SLL and by Lugano criteria for MCL • Overall survival (OS) • Health related quality of life (HRQoL) - EORTC QLQ-C30 and EQ-5D-3L (in CLL/SLL and MCL) - EORTC QLQ-CLL17 (in CLL/SLL) Safety: • Frequency of TEAEs, including SAEs • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status PK: • AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz;Timepoint(s) of evaluation of this end point: Secondary endpoints Part A PK: AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz Time point(s) of evaluation: 15 weeks Part B Efficacy: • PFS Time point(s) of evaluation: 28 months • DoR Time point(s) of evaluation: 28 months • Overall survival (OS) Time point(s) of evaluation: 28 months • HRQoL - EORTC QLQ-C30 and EQ-5D-3L (in CLL/SLL and MCL) - EORTC QLQ-CLL17 (in CLL/SLL) Time point(s) of evaluation: 28 months Safety: • Frequency of TEAEs, including SAEs • Safety laboratory tests (e.g. haematology, chemistry, urinalysis), vital signs, 12-lead ECGs, ECOG performance status Time point(s) of evaluation: 15 weeks PK: • AUC, AUC0-t, CL, Cmax, tmax, t1/2, and Vz Time point(s) of evaluation: 15 weeks | — |
Countries
United Kingdom
Contacts
Public ContactDr Peter Phillips
NovalGen
Outcome results
None listed