A Phase I/IIa trial of NVG-222 in blood cancers
| ISRCTN | ISRCTN14974342 |
|---|---|
| DOI | https://doi.org/10.1186/ISRCTN14974342 |
| IRAS number | 1012182 |
| Secondary identifying numbers | CRUKD/24/003, CPMS 67880 |
- Submission date
- 17/06/2025
- Registration date
- 30/09/2025
- Last edited
- 07/10/2025
- Recruitment status
- Not yet recruiting
- Overall study status
- Ongoing
- Condition category
- Cancer
Plain English summary of protocol
Background and study aims
This clinical trial is testing a new cancer drug called NVG-222, which is designed to help the body's immune system find and kill cancer cells. NVG-222 is a type of drug called a bispecific T-cell engager. Bispecific T-cell engagers work by recognising and attaching to two different types of cells at the same time: cancer cells and immune cells in the body called T cells. NVG-222 has been designed to work by attaching to a protein called ROR1, which is found in high levels on certain types of cancer cells, and to CD3, a protein found on T cells. By connecting the cancer cells to the T cells, NVG-222 should help the immune system to target and kill the cancer cells more effectively. NVG-222 also contains an ‘off switch’ designed to reduce the risk of serious side effects by turning the drug off if early signs of side effects appear.
The main aims of the clinical trial are to find out:
1. The best dose of NVG-222 that can be given safely to participants in the trial.
2. What the side effects of NVG-222 are.
3. What happens to NVG-222 inside the body.
4. Whether NVG-222 can shrink or control cancer.
Who can participate?
Patients aged 18 years and over with certain types of blood cancer (also called haematological malignancies) that are expected to have ROR1 proteins on their cancer cells. Patients must have cancer that has come back (relapsed) or is no longer responding to standard treatment (refractory). Patients can also participate if the Investigator doesn’t think any standard treatment is right for them, or if the patient decides not to have the treatment that has been offered to them.
What does the study involve?
This clinical trial is split into two phases.
Phase I is the ‘dose escalation’ phase and is split into two parts. In Part I, one participant at a time will receive NVG-222, starting with a low dose. If there are no serious side effects, the next participant will receive a higher dose, and so on. Part II will start after Part I has finished. In Part II, small groups of participants will receive NVG-222 at different dose levels, starting with a low dose. After reviewing the results from each group, it will be decided if the dose of NVG-222 can be increased for the next group of participants. This phase of the trial aims to find out the best dose of NVG-222 that can be given safely.
Phase II is the ‘dose expansion’ phase. This will start when the dose escalation phase has worked out the best dose of NVG-222 to give participants in the trial. In the dose expansion phase, this dose will be given to a larger number of participants who have specific types of blood cancer. This phase of the trial aims to find out more about how NVG-222 works against cancer. This phase of the trial may include testing NVG-222 in combination with other cancer treatments.
What are the possible benefits and risks of participating?
NVG-222 is a new drug that has never been given to humans before. Possible risks and benefits are based on laboratory tests and experience with similar drugs but there is not yet any information about the effects of NVG-222 in humans. Participants in the trial will be monitored closely to find out the effects of NVG-222, and the study has been carefully designed to keep participants safe.
Where is the study run from?
Cancer Research UK
When is the study starting and how long is it expected to run for?
June 2025 to October 2030
Who is funding the study?
1. Cancer Research UK
2. NovalGen Ltd
Who is the main contact?
Dr William Townsend, william.townsend@nhs.net
Plain English summary under review with external organisation
Contact information
Scientific
Centre for Drug Development
2 Redman Place
London
E20 1JQ
United Kingdom
| Phone | +44 (0)20 34696878 |
|---|---|
| stuart.smith@cancer.org.uk |
Scientific
Centre for Drug Development
2 Redman Place
London
E20 1JQ
United Kingdom
| Phone | +44 (0)20 34695417 |
|---|---|
| jenny.king@cancer.org.uk |
Principal Investigator
250 Euston Road
London
NW1 2PG
United Kingdom
| Phone | +44 (0)20 34479443 |
|---|---|
| william.townsend@nhs.net |
Study information
| Study design | Multi-centre first-in-human non-randomized Phase I/IIa open-label dose escalation and dose expansion adaptive design trial |
|---|---|
| Primary study design | Interventional |
| Secondary study design | Non randomised study |
| Study setting(s) | Hospital |
| Study type | Safety, Efficacy |
| Participant information sheet | Not available in web format, please use the contact details to request a participant information sheet |
| Scientific title | A Cancer Research UK Phase I/IIa, first-in-human dose escalation and expansion trial of NVG-222, an autoregulating, half-life extended bispecific ROR1-directed CD3 T-Cell engager, given in participants with haematological malignancies |
| Study objectives | Primary objectives: 1. To propose the optimal dose range and/or schedule for NVG-222 that can be given safely to participants with blood cancers. 2. To make an initial assessment of how safe and tolerable NVG-222 is in participants with blood cancers over a 12-month dosing period. Secondary objectives: 1. To monitor the levels of NVG-222 in the blood. 2. To make an initial assessment of the anti-tumour activity of NVG-222. 3. To make a further assessment of how safe and tolerable NVG-222 is in participants with blood cancers. |
| Ethics approval(s) |
Approved 25/07/2025, London – City & East Research Ethics Committee (2nd Floor, 2 Redman Place, Stratford, London, E20 1JQ, United Kingdom; +44 (0)207 1048171, +44 (0)207 1048 170; cityandeast.rec@hra.nhs.uk), ref: 25/LO/0512 |
| Health condition(s) or problem(s) studied | Haematological malignancies |
| Intervention | The dose escalation phase (Phase I) will consist of two parts. In Part I, NVG-222 will be administered in single participant cohorts. These participants will follow accelerated dose escalation with intra-participant dose escalation permitted. In Part II, NVG-222 will be administered in multiple participant cohorts consisting of 3 to 6 participants each. Participants will receive NVG-222 as an intravenous infusion once every 2 weeks. The starting dose will be 6 µg. In the dose expansion phase (Part III; Phase IIa), participants will receive NVG-222 as an intravenous infusion at a dose and schedule that will be determined based on data from the dose escalation phase. All participants may receive NVG-222 for up to 12 cycles. If a participant is benefiting from treatment with NVG-222, a maximum of 6 further cycles may be given. Participants will be followed up for up to 100 days after the last administration of NVG-222. |
| Intervention type | Drug |
| Pharmaceutical study type(s) | Pharmacokinetic, Pharmacodynamic |
| Phase | Phase I/II |
| Drug / device / biological / vaccine name(s) | NVG-222 |
| Primary outcome measure | 1. Nature and frequency of dose-limiting toxicities (DLTs). DLTs are defined and assessed according to specific criteria in the trial protocol. Evaluation of this endpoint will occur when sufficient participants have completed the DLT assessment period (first 28 days of administration) and all relevant data have been collected. 2. Determination of the maximum tolerated dose (MTD) and/or optimal biological dose (OBD) and/or therapeutic dose range and/or optimal dose schedule for NVG-222. The Bayesian optimal interval model will recommend the NVG-222 dose with an estimated DLT rate within the target range of 20% to 33%. In the absence of DLT, the single agent recommended Phase II dose or OBD and schedule will be determined based upon the maximum administered dose and all available safety, pharmacokinetic (PK) and pharmacodynamic data. Evaluation of this endpoint will occur when sufficient participants have completed the DLT assessment period (first 28 days of administration) and all clinically relevant data have been reviewed by the Sponsor, Chief Investigator and Principal Investigators. 3. Frequency of adverse events (AEs) considered at least possibly related to NVG-222 and number of Grade 3, 4 and 5 AEs considered at least possibly related to NVG-222 over the first 12 months of dosing. AEs, including relatedness, seriousness and severity (graded according to National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 5.0 with the exception of cytokine release syndrome [CRS] and neurotoxicity [ICANS], which will be graded according to American Society for Transplantation and Cellular Therapy [ASTCT] consensus grading) will be assessed by the Investigator. |
| Secondary outcome measures | 1. PK parameters of NVG-222, including minimum concentration (Cmin), maximum concentration (Cmax), area under the curve (AUC), clearance (CL), volume of distribution (Vd) and terminal elimination half-life (t1/2), in blood (serum) for intravenous administration, measured using a standard ligand binding assay. Additional PK parameters may be determined as appropriate. Samples for PK analysis will be taken at up to 30 timepoints for each participant over the duration of the trial. 2. Objective response rate, defined as the proportion of participants who achieve complete response (CR), partial response (PR)/partial remission as the best overall response according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and the end of trial (EoT). 3. Complete response rate, defined as the proportion of participants with a best overall response of CR according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 4. Disease control rate, defined as the percentage of participants who achieve CR, PR/partial remission or a minimum of stable disease/no progressive disease for 12 weeks based on disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 5. Duration of response, defined as the time from the initial occurrence of a documented PR/partial remission or CR until documented disease progression or death due to any cause, whichever occurs first, according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 6. Duration of complete response, defined as the time from the initial occurrence of a documented CR until documented disease progression, relapse, or death due to any cause, whichever occurs first, according to disease-specific assessment criteria. This endpoint will be evaluated at 12 months and EoT. 7. Progression-free survival, defined as the time from the date of administration of the first dose of NVG 222 on this trial to disease progression or death from any cause or the date of censoring at the last time the participant was known to be progression-free. Participants who are lost to follow-up will be censored at the time of last contact; participants who start a new anti-cancer treatment will not be censored. This endpoint will be evaluated at 12 months and EoT. 8. Overall survival, defined as the time from the date of administration of the first dose of NVG 222 on this trial to the date of death due to any cause, or to the date of censoring at the last time the participant was known to be alive. Participants who are lost to follow-up will be censored at the time of last contact; participants who start a new anti-cancer treatment will not be censored. This endpoint will be evaluated at 12 months and EoT. 9. Frequency of AEs considered at least possibly related to NVG 222 and number of Grade 3, 4 and 5 AEs considered at least possibly related to NVG-222 over the entire trial period. AEs, including relatedness, seriousness and severity (graded according to NCI CTCAE Version 5.0 with the exception of CRS and neurotoxicity [ICANS], which will be graded according to ASTCT consensus grading) will be assessed by the Investigator. AEs will be collected from the date of informed consent until 100 days after the last administration of NVG-222 or until the participant starts another anti-cancer therapy. |
| Overall study start date | 13/06/2025 |
| Completion date | 15/10/2030 |
Eligibility
| Participant type(s) | Patient |
|---|---|
| Age group | Adult |
| Lower age limit | 18 Years |
| Sex | Both |
| Target number of participants | 60 |
| Key inclusion criteria | 1. Written (signed and dated) informed consent and be capable of co-operating with Investigational Medicinal Product (IMP) administration and follow-up. 2. All patients must have relapsed or have refractory disease. Patients must have received at least two prior lines of treatment including, as appropriate, high-dose chemoimmunotherapy, CAR T-cell therapy, CD20 bispecific antibody therapy, haemopoietic stem cell transplant, targeted therapies including BTKi and BCL2 inhibitors. Approved therapies should have been received unless these therapies are contraindicated, intolerable to the patient, or declined by the patient. Histologic documentation of disease and/or flow cytometry of disease: Patients with documented diagnosis for one of the following B-cell malignancies anticipated to express ROR1 according to the World Health Organization Classification of Haematolymphoid Tumours, 5th Edition (WHO-HAEM5) and requiring treatment: 2.1. Chronic lymphocytic leukaemia (CLL)/small lymphocytic lymphoma (SLL) 2.2. Richter’s 2.3. Large B-cell lymphoma (LBCL; including all subtypes and high-grade B cell not otherwise specified) 2.4. Burkitt lymphoma 2.5. Follicular lymphoma (FL; including all sub-types) 2.6. Marginal zone lymphoma (MZL; extranodal and nodal) 2.7. Splenic B-cell lymphomas and leukaemias 2.8. Mantle cell lymphoma (MCL) 2.9. Lymphoplasmacytic lymphoma, including Waldenström macroglobulinaemia (WM) 2.10. Transformed indolent NHL (iNHL) 3. Objectively evaluable or measurable disease, defined by the appropriate disease response criteria as follows: 3.1. iwCLL for participants with CLL/SLL, 3.2. IWWM-6 for participants with WM 3.3. Lugano classification for participants with LBCL, MCL, MZL, splenic B-cell lymphomas and leukaemias, Burkitt lymphoma, lymphoplastic lymphoma (excluding WM), transformed iNHL, and FL 4. Life expectancy of at least 12 weeks. 5. Eastern Cooperative Oncology Group performance status of 0–1. 6. Haematological and biochemical indices within prescribed ranges. 7. Aged 18 years or over at the time consent is given. |
| Key exclusion criteria | 1. Patient has received any of the following: 1.1. Radiotherapy (except for palliative reasons), chemotherapy or other IMPs during the previous 4 weeks before first dose of IMP (or last dose of an immunotherapy during the previous 4 weeks). 1.2. Therapeutic antibodies (for any indication), within 4 weeks prior to first NVG-222 administration. 1.3. Prior treatment with CAR-T therapy within 4 weeks prior to first NVG-222 administration. 1.4. Autologous haematopoeitic stem cell transplantation (HSCT) within 100 days prior to first NVG-222 administration, or solid organ transplantation. 1.5. Allogeneic HSCT or donor lymphocyte infusion within 6 months prior to first NVG-222 administration. 2. Ongoing toxic manifestations of previous treatments greater than CTCAE Grade 1 with certain exceptions permitted as per protocol. 3. Active central nervous system (CNS) involvement. Primary CNS lymphoma, CNS involvement by lymphoma at screening, CNS metastasis that requires treatment or leptomeningeal involvement of the tumour under study with certain exceptions permitted as per protocol. 4. History or presence of dementia, or psychosis with certain exceptions permitted as per protocol. 5. Women who are pregnant or breastfeeding (or planning to breastfeed). 6. Women of childbearing potential. However, those patients who are not pregnant or breastfeeding are eligible provided they have a negative highly sensitive serum pregnancy test within 7 days before enrolment and agree to follow the trial’s contraceptive requirements. 7. Male patients with partners of childbearing potential. However, those patients who agree to follow the trial’s contraceptive guidance are eligible. 8. Any major surgery from which the patient has not yet recovered (excluding biopsy collection if applicable). 9. Active uncontrolled infection. 10. Uncontrolled autoimmune haemolytic anaemia or idiopathic thrombocytopenic purpura within 8 weeks of Screening. 11. Patient is unable to receive at least one of the following prophylactic medications for tumour lysis syndrome: allopurinol, febuxostat or rasburicase. 12. Patients with history of significant AEs related to prior immunotherapies. 13. The use of corticosteroids treatment ≤10 mg/day prednisone or equivalent is permitted; however, there must be documentation that the patient was on a stable dose of at least 14 days duration prior to trial enrolment. Inhaled and topical steroids are permitted. 14. Known to be serologically positive for hepatitis B virus (HBV), hepatitis C virus (HCV), or human immunodeficiency virus (HIV). 14.1. Active hepatitis B infection. Patients with negative serologic or PCR test results for acute or chronic HBV infection are eligible. 14.2. Active hepatitis C infection. Patients who test positive for hepatitis C antibody with a detectable HCV load are not eligible. 14.3. Patients with known HIV are excluded unless viral load is undetectable and CD4 count is above 300 cells/mm3 on stable Highly Active Antiretroviral Therapy. 15. Known or suspected hypersensitivity reaction to previous biological therapy or any of the NVG-222 excipients that, in the opinion of the Investigator, is a contraindication for participation in this trial. 16. Significant cardiovascular disease as defined within the protocol. 17. Clinically significant lung disease as defined within the protocol. 18. Participating in or plans to participate in another interventional clinical trial whilst taking part in this Phase I/IIa trial of NVG-222. Certain exceptions are permitted as per protocol. 19. Current or prior malignancy that could affect safety or efficacy assessment of the IMP or compliance with the protocol or interpretation of results. Certain exceptions are permitted as per protocol. 20. Live vaccine or live-attenuated vaccine within 28 days of trial enrolment. 21. Any other condition that, in the Investigator’s opinion, would mean that the trial is not in the best interests of the patient. |
| Date of first enrolment | 30/11/2025 |
| Date of final enrolment | 01/11/2029 |
Locations
Countries of recruitment
- England
- United Kingdom
Study participating centres
London
NW1 2PQ
United Kingdom
London
SE1 9RT
United Kingdom
Sponsor information
Charity
2 Redman Place
London
E20 1JQ
England
United Kingdom
| Phone | +44 (0)20 34696878 |
|---|---|
| regulatory@cancer.org.uk | |
| Website | http://www.cancerresearchuk.org/ |
"ROR" |
https://ror.org/054225q67 |
Funders
Funder type
Charity
Private sector organisation / Other non-profit organizations
- Alternative name(s)
- CR_UK, Cancer Research UK - London, Cancer Research UK (CRUK), CRUK
- Location
- United Kingdom
No information available
Results and Publications
| Intention to publish date | 15/10/2031 |
|---|---|
| Individual participant data (IPD) Intention to share | Yes |
| IPD sharing plan summary | Available on request |
| Publication and dissemination plan | Peer-reviewed scientific journals Internal report Conference presentation Publication on website Submission to regulatory authorities It is intended that the results of the trial will be published on a publicly accessible database (ISRCTN) and in peer-reviewed journals, at conferences and in press releases as appropriate. A lay summary of the results will also be published on patient-facing websites (such as the Cancer Research UK website). Anonymised individual participant data may be shared with researchers whose proposed use of the data is approved by a review committee of the Sponsor. All requests made within 5 years from the end of the trial will be considered, requests made subsequently will be considered where possible. |
| IPD sharing plan | The datasets generated during and/or analysed during the current study will be available upon request |
Editorial Notes
07/10/2025: Date of first enrolment was changed from 15/10/2025 to 30/11/2025.
03/10/2025: Internal review.
07/08/2025: ISRCTN received notification of combined HRA/MHRA approval for this trial on 07/08/2025.
17/06/2025: Study's existence confirmed by the HRA.
