Clinical trial NCT04763083: First in Human Study of NVG-111 in Relapsed/Refractory ROR1+ Malignancies
Official title: An Open-label, Phase 1, First in Human Study Investigating the Safety, Tolerability, Pharmacokinetics and Efficacy of NVG-111 in Subjects With Relapsed/Refractory ROR1+ Malignancies
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Chronic Lymphocytic Leukaemia
Small Lymphocytic Lymphoma
Mantle Cell Lymphoma
Follicular Lymphoma
Diffuse Large B Cell Lymphoma
Non-small Cell Lung Cancer (NSCLC)
Malignant Melanoma
Keywords: ROR1 positive cancers
Bispecific T cell engagers
Lead sponsor: NovalGen Ltd.
Sponsor class: INDUSTRY
First posted: 2021-02-21
Enrollment: 90
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: 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. This is the first clinical trial of the drug NVG-111, and will include patients with certain types of cancer including chronic lymphocytic leukaemia (CLL), small lymphocytic lymphoma (SLL) mantle cell lymphoma (MCL), follicular lymphoma (FL) and diffuse large B cell lymphoma (DLBCL) in Group A. Subjects with solid tumours, focusing initially on stage IV non-small cell lung cancer (NSCLC) or malignant melanoma.

Detailed description: Receptor tyrosine kinase-like Orphan Receptor 1 (ROR1) is a protein which is expressed at high levels on many types of 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 first in human study to assess the safety, pharmacokinetics and efficacy of NVG-111 in patients with subjects with relapsed/refractory ROR1+ malignancies.

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. Additional cycles may be given depending on the response seen.

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.

Eligibility criteria: Inclusion criteria:

* Personally signed informed consent document.
* Male or female, age ≥18 years.
* Relapsed or refractory ROR1+ malignancies
* 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 active disease.
* High tumour bulk as defined in the protocol.
* Allogeneic or autologous organ transplant 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 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.

Primary outcomes:
measure: Number of treatment-emergent adverse events (TEAEs)
timeFrame: Up to 10 months
measure: Number of serious adverse events (SAEs)
timeFrame: Up to 10 months
measure: Number of adverse events of special interest (AESI)
timeFrame: Up to 10 months
measure: Number of dose limiting toxicities (DLTs)
timeFrame: Up to 28 days
measure: Laboratory safety abnormalities
timeFrame: Up to 10 months
measure: Vital sign abnormalities
timeFrame: Up to 10 months
measure: ECG abnormalities
timeFrame: Up to 10 months
measure: Changes from baseline in ECOG
timeFrame: Up to 10 months
Secondary outcomes:
Other outcomes:
Locations:
city: London
country: United Kingdom
facility: University College London Hospital
city: London
country: United Kingdom
facility: Royal Marsden Hospital
city: Manchester
country: United Kingdom
facility: The Christie NHS Foundation Trust
Study officials:
affiliation: Royal Free London NHS Foundation Trust and University College London Hospitals
name: Parag Jasani, MBBS, FRCP, FRCPath
role: PRINCIPAL_INVESTIGATOR
References: