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Immunoglobulins

DI-B4 will be administered once weekly for up to a total of four weeks. The starting dose will be 0.02 mg given as an intravenous infusion. A cycle is 1 week in duration and patients should expect to receive a maximum of 4 cycles.

DI-B4

The main aims of this clinical study are to find out the maximum dose that can be given safely to patients, the potential side effects of the drug and how they can be managed. The study will also look at what happens to Anti-CD19 (DI-B4) inside the body.

DI-B4 is a type of drug called an Anti-CD19 monoclonal antibody which is being used to stop the growth and kill cancerous immune cells by targeting the B-cell marker (CD-19) expressed on their surface. This drug has not been given to patients before.

DI-B4 will be given weekly by intravenous infusion for four weeks. The study is in two parts. In Part 1, small groups of patients will be treated at increasing doses to find the highest safest dose and best dose for part 2 of the study. Approximately 16-20 patients will be treated in this part. In Part 2, the dose identified in Part 1 will be given to approximately 20 patients.

Patients recruited to the study will receive four weeks (cycles) of treatment. They will attend an end of therapy visit eight weeks after their last dose of DI-B4, and attend follow-up visits up to eighteen months after their first dose of DI-B4. Information on the overall and progression free survival will be collected for a period up to eighteen months after the final patient is treated on the study.

Patients will have blood and urine samples taken each week during treatment amongst other clinical tests. CT scans will be performed at the start of the study, at eight weeks post treatment and six months after the study start. Bone marrow biopsies and FDG-PET scans will only be taken if needed. Research blood samples will also be taken to look at what happens to the drug inside the body.

It is important to explain that patients will have advanced cancer so it is unlikely that patients will benefit directly from taking part but the study may help improve future treatment of cancer.

Patients with relapsed or refractory CD19 positive indolent B-cell lymphoma, Waldenström Macroglobulinaemia or chronic lymphocytic leukaemia will be entered into this study.

For the vast majority of patients, B-cell non Hodgkin lymphoma and chronic lymphocytic leukaemia are incurable using existing therapeutic approaches.

Although anti-CD20 directed therapy has improved outcomes, more than fifty percent of patients still relapse following treatment or are refractory to it and therefore additional novel non-cross resistant therapies are urgently required.

DI-B4 is a humanised, low-fucosylated anti-CD19 Immunoglobulin (Ig) G1 monoclonal antibody with potent antibody-dependent cell-mediated cytotoxicity (ADCC) but minimal complement dependent cytotoxicity (CDC). The target antigen, CD19, is the canonical B-cell marker that is expressed on all B-cells including the malignant B-cells in NHL, CLL and acute lymphoblastic leukaemia (ALL). The CD19 antigen is therefore an attractive B-cell lineage specific target for monoclonal antibody therapy. DI-B4 is expected to act through the depletion of normal and malignant CD19 positive cells, primarily via ADCC.

This is a multi-centre, Phase I, dose escalation/dose expansion study. For the first three cohorts, an intra-patient dose escalation scheme will be followed unless a DLT is observed. From Cohort 4 onwards, a standard 3 + 3 dose escalation schedule of DI-B4 will be continued until the maximum tolerated dose (MTD) is defined, up to a maximum dose of 1000mg.

A Phase I Trial of DI-B4 in Patients With Advanced CD19 Positive Indolent B-cell Malignancies

A Cancer Research UK Phase I Trial of the Anti-CD19 DI-B4 Monoclonal Antibody Given Intravenously, Weekly for Four Weeks, in Patients With Advanced CD19 Positive Indolent B-cell Malignancies

Cancer Research UK

Antineoplastic Agents

Amino Acids

Capecitabine

Irinotecan

Oxaliplatin

Ibrutinib

Myeloma Proteins

Paraproteins

Antimetabolites

Tyrosine Kinase Inhibitors

Protein Kinase Inhibitors

Enzyme Inhibitors

Tyrosine

- Cohort 1: Capecitabine in solid tumours. In this cohort, participants will receive the treatment in three-week cycles. Only the dose of capecitabine will be modulated with CURATE.AI, based on measurements of the tumour marker (CEA/CA19-9). CT scans for radiological assessment will be performed according to standard of care, usually after every 2 to 3 cycles of chemotherapy for Cohort 1 only.

Cohort 2: Ibrutinib in Waldenström macroglobulinaemia In this cohort, participants will receive the treatment in four-week cycles. The total cumulative dose of Ibrutinib will be modulated with CURATE.AI, based on measurements of the tumour marker (IgM paraprotein).

Efficacy and toxicity measurements at the end of each dosing cycle, together with an information on given drugs and their doses, and other patient data, will be used by CURATE.AI to recommend the dose of capecitabine and Ibrutinib for the next cycle. The clinical investigators will decide whether or not to administer or prescribe the dose recommendation from CURATE.AI.

CURATE.AI

Treatment with the selected regimen will take up to a maximum duration of 12 months, in 3-week cycles. CURATE.AI dose recommendations will be generated before each chemotherapy cycle; fixed throughout the cycle; and within 1) the predetermined safety range (50% to 100% of dose used in standard of care treatment) and 2) subject-specific dosing range. Maximum total cumulative dose per cycle of capecitabine in the predetermined safety range is set at 100% of standard starting dose (i.e. , 1250mg/m2 twice daily for single agent capecitabine regimen). Minimum total cumulative dose per cycle of capecitabine in the predetermined safety range is set at 50% of the standard starting dose (i.e. 625mg/m2 twice daily for single agent capecitabine). Subject-specific dosing range may alter those numbers to suit the specific circumstances of the subject, thus giving the subject specific safe dosing range.

Treatment with the selected regimen will take up to a maximum duration of 12 months, in 3-week cycles. CURATE.AI dose recommendations will be generated before each chemotherapy cycle; fixed throughout the cycle; and within 1) the predetermined safety range (50% to 100% of dose used in standard of care treatment) and 2) subject-specific dosing range. Maximum dose of capecitabine in the predetermined safety range is set at 100% of standard starting dose (i.e. 1000 mg/m2 twice daily for XELOX regimen). Minimum dose of capecitabine in the predetermined safety range is set at 50% of the standard starting dose (i.e. 500 mg/m2 twice daily for XELOX regimen). Subject-specific dosing range may alter those numbers to suit the specific circumstances of the subject, thus giving the subject specific safe dosing range. The doses of other drug in the XELOX regimen (oxaliplatin) will be held constant or adjusted at the clinical investigator's discretion, as per standard of care.

XELOX

Treatment with the selected regimen will take up to a maximum duration of 12 months, in 3-week cycles. CURATE.AI dose recommendations will be generated before each chemotherapy cycle; fixed throughout the cycle; and within 1) the predetermined safety range (50% to 100% of dose used in standard of care treatment) and 2) subject-specific dosing range. Maximum dose of capecitabine in the predetermined safety range is set at 100% of standard starting dose (i.e. 1000 mg/m2 twice daily for XELIRI regimen). Minimum dose of capecitabine in the predetermined safety range is set at 50% of the standard starting dose (i.e. 500 mg/m2 twice daily for XELIRI regimen). Subject-specific dosing range may alter those numbers to suit the specific circumstances of the subject, thus giving the subject specific safe dosing range.

The doses of other drug in the XELIRI regimen (irinotecan) will be held constant or adjusted at the clinical investigator's discretion, as per standard of care.

XELIRI

Treatment with the selected regimen will take up to a maximum duration of 12 months, in 4-week cycles. CURATE.AI dose recommendations will be generated before each chemotherapy cycle; fixed throughout the cycle; and within 1) the predetermined safety range (50% to 100% of dose used in standard of care treatment) and 2) subject-specific dosing range.

Maximum total cumulative dose per cycle of Ibrutinib in the predetermined safety range is set at 100% of standard starting dose (i.e. 420 mg once daily for 4 weeks, which constitutes the total of 11760 mg per cycle). Minimum total cumulative dose per cycle of Ibrutinib in the predetermined safety range is set at 50% of the standard starting dose (i.e. 280 mg once daily on alternative days with 140 mg once daily, which constitutes the total of 5880 mg per cycle). The dosing range may be altered to suit the specific circumstances of the participant, thus giving the participant-specific safe dosing range.

Raghav Sundar

Michelle Au

Cheng Ean Chee, Dr

Wei Peng Yong, Dr

Raghav Sundar, Dr

Hon Lyn Tan, Dr

Jingshan Ho, Dr

Gloria Chan, Dr

Joan Choo, Dr

Hui Sin Tan

Yi Wan Lim

Wan Qin Chong

Hon Lyn Tan

Angela Shien Ling Pang

Samuel Guan Wei Ow

Yvonne Li En Ang

Natalie Yan Li Ngoi

Gloria Hui Jia Chan

Joline Si Jing Lim

Yiqing Huang

Joan Rou-en Choo

Matilda Xinwei Lee

Jingshan Ho

Alvin Seng Cheong Wong

In the current clinical context, drug dosing in oncology is dictated by toxicity. The optimal dosages of drugs in combinatory regimens for solid tumours are not clear, and the typical physician's decision on dose adjustment is a clinical judgement based on the degree of toxicity experienced by the patient. CURATE.AI - a small data, AI-derived technology platform - allows personalised guidance of an individual's dose modulations based only on that individual's data. Additionally, CURATE.AI is mechanism-independent, and dynamically adapts to changes experienced by the subject, providing dynamic dose optimisation throughout the duration of the subject's treatment. This study aims to demonstrate the feasibility of applying CURATE.AI in standard of care settings for treatment of solid tumours. An additional objective is to explore tumour markers in serial measurements at weekly frequency of probing, with modulated doses.

Cancer patients are given drug combinations that promote cancer cell elimination. The final drug concentration in the body must fall within a narrow range that maximises cancer elimination while minimizing toxic side effects. The complexity of this task increases significantly with the number of drugs given in combination due to increasing parameters and stochastic behaviour of a biological system. Currently, the established approach is to select maximum tolerated doses (MTD) - the highest drug doses that do not cause unacceptable side effects. Treatment efficacy does not guide dose selection. Combined with limited personalisation, this dosing strategy often results in suboptimal outcomes of the treatment.

CURATE.AI is an AI-derived, mechanism-independent, small data technology platform for personalised, dynamic dosing. CURATE.AI uses a quadratic equation to generate individualised CURATE.AI profile and dosing recommendation based on only that individual's medical data: drug doses and the corresponding response marker (e.g. blood tumour markers). Profile recalibration via CURATE.AI facilitates dynamic dosing and personalised care throughout the treatment duration, aimed at achieving the highest efficacy within pre-specified safe dose ranges.

CURATE.AI is an indication-agnostic platform that has already been applied clinically for a range of indications including in oncology. CURATE.AI can be applied to indications that demonstrate regularly measured dose-dependent relationship between the treatment dose and the treatment response (i.e. biomarker level). Currently, the gold standard of monitoring treatment response in solid tumour is via radiology (using criteria such as RECIST), which is usually done at the end of a few cycles of systemic therapy and therefore not suitable to be used as a CURATE.AI input signal for drug dose adjustment between cycles.. Additionally, haematological neoplasms often cannot be monitored with imaging. Waldenström macroglobulinaemia treatment response is assessed using an adaptation of the response criteria from the Eighth International Workshop on Waldenström macroglobulinaemia (IWWM-8) that includes blood markers. Blood-based tumour markers, e.g. carcinoembryonic antigen (CEA) and carbohydrate antigen 19-9 (CA19-9) and immunoglobulin M (IgM) markers, are more suitable to be implemented into CURATE.AI. Apart from these traditional tumour markers, recent advances in genomic sequencing have led to the application of plasma circulating tumour DNA (ctDNA) level as a novel marker of tumour burden. In addition, the serum free light chain (sFLC) has been widely used to assess treatment response for patients with multiple myeloma and other plasma cell dyscrasias, and has shown potential as a novel marker for disease burden in Waldenström macroglobulinaemia. Therefore, serial ctDNA and sFLC measurements, may be an appropriate input for CURATE.AI.

This Pilot Clinical Trial aims to set foundation to investigate the applicability and feasibility of the CURATE.AI platform within the current clinical setting for guided dosing of various systemic therapies commonly used for solid and haematological neoplasms

Individualised CURATE.AI profiles will be generated based on each participant's response to a set of drug doses. Subsequently, the personalised CURATE.AI profile will be used to recommend the efficacy-driven dose. CURATE.AI will operate only within the safety range for each drug prespecified for each participant.

This Pilot Clinical Trial and feasibility study will inform the investigators on the logistical and practical aspects of performing a large-scale randomised study and on the suitability of CURATE.AI for guided dosing of a wider range of chemotherapy regimens. An additional objective is to explore the utility of CEA, CA19-9, Ig M, ctDNA and sFLC as tumour markers in serial measurements at weekly frequency of probing, with modulated doses. ctDNA and sFLC will be also explored as an input for CURATE.AI to generate dose recommendations, however this analysis will not be used to prospectively guide dosing.

This is a multi-centre, one-arm, prospective pilot study of participants diagnosed with either solid organ or haematological neoplasm.The participants will be enrolled for the duration of their treatment with the selected regimens, XELOX, XELIRI and single agent capecitabine regimens or single-agent ibrutinib . At 12-month mark, the decision on the patient engagement with the study will be made by the principal investigator in consultation with the study sponsors and treating physician.

PRECISE CURATE.AI Pilot Clinical Trial

Personalised, Rational, Efficacy-driven Cancer Drug Dosing Via an Artificial Intelligence SystEm - CURATE.AI (PRECISE CURATE.AI Trial)

CT scans for radiological assessment will be performed according to standard of care, usually after every 2 to 3 cycles of chemotherapy

Percentage of trial participants with clinical progressive disease(which is defined as the clinical investigator deeming that the patient will not benefit any further from the chemotherapy regimen and considering stopping it) at the time of the first radiological assessment performed as per standard-of-care.

Mandatory blood draws for the measurement of tumour marker(s)as per standard of care.Additional blood draws solely for the purposes of the trial for measurements of tumour markers(s)

Tumour marker measurements at higher frequency will be analysed to inform about temporal dynamics of tumour response to modulated dosing.

For CURATE.AI profile generation, a minimum of 3 dose levels and corresponding tumour marker (CEA/CA19-9/Ig M) readouts are needed for the modulated drug. After obtaining the first tumour marker readout a set of potential doses of capecitabine or Ibrutinib to pick from will be recommended by the CURATE.AI team with calibration-intent, based on the mathematical requirements of the method.

If the modulations do not yield a dose-dependent response (e.g. biomarker readouts were affected by the factors unrelated to capecitabine or Ibrutinib modulation) a new data pair will have to be acquired according to calibration-intent recommendation from the CURATE.AI team.

When dose-dependent response is obtained, the profile will be checked for actionability - an ability to recommend an optimum dose within the pre-specified personal safety range.

Percentage of trial participants with clinically relevant toxicities of grades 3-4 based on CTCAE version 4.0.

Data collection and explorative analysis of the ctDNA and/or sFLC as: (1) a tumour marker in serial measurements at given clinical context and after modulated dosing; (2) potential input for CURATE.AI

Data collection and explorative analysis of CEA , CA19-9 , Ig M and/or other traditional tumour markers in higher frequency serial measurements after modulated dosing in relation to standard frequency readings and other efficacy measures, e.g RECIST criteria or IWWM-8

CURATE.AI applicability: Percentage of participants in whom we successfully apply CURATE.AI profile. Based on percentages, outcomes will be classified as Green (\>70%) / Yellow (10-70%) / Red (\<10%).

A decision on whether we "successfully apply" the CURATE.AI profile requires expert judgement and cannot be made based on a purely numerical process. The expert panel will consider the following factors with careful regard for the individual circumstances of each participant:

1. Error/variance (biological/analytical) is sufficiently small to allow accurate predictions
2. Profile can be generated sufficiently early for the participant to potentially benefit;
3. Dose-dependent relationship is observed;
4. Profile is actionable (i.e. fulfils the clinical investigator's pre-specified safety requirements);
5. Systemic changes in the participant which require profile recalibration are rare or readily assimilated into the CURATE.AI algorithm.

Percentage of participants who always adhered to the prescribed dose whenever they took their medication, as measured by the standardised pharmacovigilance protocol. Based on percentages, outcomes will be classified as Green (\>90%) / Yellow (10-90%) / Red (\<10%).

Percentage of CURATE.AI recommendations provided in time for the next chemotherapy cycle, across all participants and cycles. Based on percentages, outcomes will be classified as Green (100%) / Yellow (10-99%) / Red (\<10%).

Percentage of dosing events across all participants and cycles in which CURATE.AI recommendation is considered in the clinical decision-making process. Based on percentages, outcomes will be classified as Green (100%) / Yellow (10-99%) / Red (\<10%).

Percentage of CURATE.AI recommended doses that were used by the clinical investigator. Based on percentages, outcomes will be classified as Green (\>70%) / Yellow (10-70%) / Red (\<10%).

Percentage of participants in whom the CURATE.AI-guided cumulative dose is substantially (≥10%) different from the projected standard-of-care cumulative dose. Based on percentages, outcomes will be classified as Green (\>20%) / Yellow (1-20%) / Red (0%).

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization
A Phase I Trial of DI-B4 in Patients With Advanced CD19 Positive Indolent B-cell Malignancies	NCT01805375	Indolent B-cell... Chronic Lymphoc... Waldenström Mac...	DI-B4	18 Years -	Cancer Research UK
PRECISE CURATE.AI Pilot Clinical Trial	NCT04522284	Solid Tumor	CURATE.AI Capecitabine XELOX XELIRI Ibrutinib	21 Years - 99 Years	National University Hospital, Singapore
A Phase I Trial of DI-B4 in Patients With Advanced CD19 Positive Indolent B-cell Malignancies	NCT01805375	Indolent B-cell... Chronic Lymphoc... Waldenström Mac...	DI-B4	18 Years -	Cancer Research UK

Spots Global Cancer Trial Database for waldenström macroglobulinaemia