CURATE.AI Optimized Modulation for Multiple Myeloma

Phenotypic Personalized Medicine: Systematically Optimized Combination Therapy in Multiple Myeloma Using CURATE.AI

Clinical trial applying CURATE.AI, a Phenotypic Precision Medicine (PPM) platform, to Bortezomib, Thalidomide, Cyclophosphamide and Lenalidomide dosing in multiple myeloma patients to show improvement in response.

Study Overview

• Status: Recruiting
• Conditions: Multiple Myeloma
• Intervention / Treatment: Drug: Bortezomib; Drug: Cyclophosphamide; Drug: Dexamethasone; Drug: Thalidomide; Drug: Bortezomib; Drug: Cyclophosphamide; Drug: Thalidomide; Drug: Dexamethasone; Drug: Lenalidomide; Drug: Lenalidomide; Other: CURATE.AI-Guided dosage modulation

Detailed Description

In conventional combination chemotherapy, drug doses are typically determined using dose escalation to reach a maximum tolerated dose (MTD) or via dose expansion to identify suitable regimen administration guideline, and the combinations are subsequently administered at fixed doses. During the course of treatment, the patient's response to therapy evolves and changes due to the time-dependent, dose dependent, and patient-specific nature of drug synergy and resulting efficacy and tolerability. To overcome this challenge, we have developed CURATE.AI, a Phenotypic Precision Medicine (PPM) platform, which has been clinically validated and used to prospectively optimize patient liver transplant immunosuppression, and tuberculosis therapy, among other indications. In this study, CURATE.AI may improve patient response by providing dose recommendations for Bortezomib, Thalidomide, Cyclophosphamide and Lenalidomide to the clinical team over the course of the patient's treatment.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2; Phase 3

Contacts and Locations

• Study Contact: Name: Wee Joo Chng, Prof; Phone Number: 67795555; Email: mdccwj@nus.edu.sg
• Study Contact Backup: Name: Sanjay de Mel, Dr; Phone Number: 67795555; Email: sanjay_widanalage@nuhs.edu.sg

Study Locations

• Singapore
  • Singapore, Singapore, 119228
    • Recruiting
    • National University Hospital
    • Contact: Wee Joo Chng, Prof; Phone Number: 67795555; Email: mdccwj@nus.edu.sg
    • Contact: Sanjay de Mel, Dr; Phone Number: 67795555; Email: sanjay_widanalage@nuhs.edu.sg
    • Principal Investigator: Wee Joo Chng, Prof
    • Sub-Investigator: Edward Chow, Dr
    • Sub-Investigator: Dean Ho, Prof
    • Sub-Investigator: Sanjay de Mel, Dr
    • Sub-Investigator: Melissa Ooi, Dr

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 21 years to 99 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Multiple myeloma diagnosed according to standard criteria, without prior anti-myeloma treatment at study entry. Both transplant eligible and ineligible patients may be included.

2. Patients must have evaluable multiple myeloma with at least one of the following (within 21 days of starting treatment)

   1. Serum M-protein ≥ 0.5g/dL, or
   2. In subjects without detectable serum M-protein, Urine M-protein ≥ 200mg/24 hour, or serum free light chai (sFLC) > 100mg/L (involved light chain) and an abnormal kappa/Lambda ratio
3. Males and females ≥ 18 years of age or > country's legal age for adult consent
4. Eastern Cooperative Oncology Group (ECOG) Performance Status of 0 to 2

5. Patients must meet the following clinical laboratory criteria with 21 days of starting treatment:

   1. Absolute neutrophil count (ANC) ≥ 1,000/mm3 and platelet ≥ 50,000/mm3 (≥ 30,000/mm3 if myeloma involvement in the bone marrow is >50%)
   2. Total bilirubin ≤ 1.5 x the upper limit of the normal range (ULN). Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤ 3 x ULN.
   3. Calculated creatinine clearance ≥ 30mL/min or creatinine < 3mg/dL.
6. Written informed consent in accordance with federal, local and institutional guidelines

Exclusion Criteria:

1. Female patients who are lactating or pregnant
2. Multiple Myeloma of IgM subtype
3. Glucocorticoid therapy (prednisolone > 30mg/day or equivalent) within 14 days prior to informed consent obtained
4. POEMS syndrome
5. Plasma cell leukaemia or circulating plasma cells ≥ 2 x 109/L
6. Waldenstrom's Macroglobulinaemia
7. Patients with known amyloidosis
8. Chemotherapy with approved or investigation anticancer therapeutics within 21 days prior to starting bortezomib treatment
9. Focal radiation therapy within 7 days prior to start of treatment. Radiation therapy to an extended field involving a significant volume of bone marrow within 21 days prior to start of treatment
10. Immunotherapy (excluding steroids) 21 days prior to start of treatment
11. Major surgery (excluding kyphoplasty) within 28 days prior to start of treatment
12. Active congestive heart failure (New York Heart Association [NYHA] Class III or IV), symptomatic ischaemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 4 months prior to informed consent obtained
13. Known HIV seropositive, hepatitis C infection, and/or hepatitis B (except for patients with hepatitis B surface antigen or core antibody receiving and responding to antiviral therapy directed at hepatitis B: these patients are allowed)
14. Patients with known cirrhosis

15. Second malignancy within the past 3 years except:

    1. Adequately treated basal cell or squamous cell skin cancer
    2. Carcinoma in situ of the cervix
    3. Breast carcinoma in situ with full surgical resection
16. Patients with myelodysplastic syndrome
17. Patients with steroid, cyclophosphamide, bortezomib, lenalidomide or thalidomide hypersensitivity
18. Patients with a calculated creatinine clearance less than 30ml/min by the Cockroft Galt method.
19. Prior treatment with Bortezomib
20. Contraindication to any of the required concomitant drugs or supportive treatments
21. Any clinically significant medical disease or psychiatric condition that, in the investigator's opinion, may interfere with protocol

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: Standard of Care; Dosing of VCD(bortezomib, cyclophosphamide,dexamethasone), VTD (bortezomib,thalidomide, dexamethasone), or VRD (Bortezomib, Lenalidomide, Dexamethasone) combinations according to standard of care	Drug: Bortezomib; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Other Names: Velcade; Drug: Cyclophosphamide; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Drug: Dexamethasone; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Drug: Thalidomide; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Drug: Bortezomib; Dose in a range of 0.7,1.0,1.3 mg/m2 subcutaneous (SC) injection on Day 1, 8, 15 ,22 for cycles 1 to 4 , as determined and guided by CURATE.AI and approved by the clinical care team; Other Names: Velcade; Drug: Cyclophosphamide; Dosing in a range of 100, 300, 500 mg PO on Day 1, 8, 15, 22 for cycles 1 to 4 as determined and guided by CURATE.AI and approved by the clinical care team.; Drug: Thalidomide; Dose in a range of 50-200mg PO on day 1-28 for cycles 1 to 4 as determined and guided by CURATE.AI and approved by the clinical care team.; Drug: Dexamethasone; 40 mg PO on Day 1 ,8 , 15, 22 for cycles 1 to 4, as determined and guided by the clinical care team according to standard of care; Drug: Lenalidomide; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Other Names: Revlimid; Drug: Lenalidomide; Dose in a range of 5-25mg PO on day 1-21 for cycles 1 to 4, as determined and guided by CURATE.AI and approved by the clinical care team.; Other Names: Revlimid
Experimental: CURATE.AI-guided dosing; CURATE.AI optimized modulation of bortezomib and cyclophosphamide dosages in the VCD (bortezomib, cyclophosphamide, dexamethasone), bortezomib and thalidomide in the VTD (bortezomib, thalidomide, dexamethasone) or bortezomib and lenalidomide in the VRD (bortezomib, lenalidomide, dexamethasone) combinations	Drug: Bortezomib; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Other Names: Velcade; Drug: Cyclophosphamide; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Drug: Dexamethasone; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Drug: Thalidomide; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Drug: Bortezomib; Dose in a range of 0.7,1.0,1.3 mg/m2 subcutaneous (SC) injection on Day 1, 8, 15 ,22 for cycles 1 to 4 , as determined and guided by CURATE.AI and approved by the clinical care team; Other Names: Velcade; Drug: Cyclophosphamide; Dosing in a range of 100, 300, 500 mg PO on Day 1, 8, 15, 22 for cycles 1 to 4 as determined and guided by CURATE.AI and approved by the clinical care team.; Drug: Thalidomide; Dose in a range of 50-200mg PO on day 1-28 for cycles 1 to 4 as determined and guided by CURATE.AI and approved by the clinical care team.; Drug: Dexamethasone; 40 mg PO on Day 1 ,8 , 15, 22 for cycles 1 to 4, as determined and guided by the clinical care team according to standard of care; Drug: Lenalidomide; Standard dosing based on product insert and subjected to dose adjustments as determined by clinical care team; Other Names: Revlimid; Drug: Lenalidomide; Dose in a range of 5-25mg PO on day 1-21 for cycles 1 to 4, as determined and guided by CURATE.AI and approved by the clinical care team.; Other Names: Revlimid; Other: CURATE.AI-Guided dosage modulation; CURATE.AI-guided modulation of Velcade and Cyclophosphamide dosages for VCD regimen, Velcade and Thalidomide dosages for VTD regimen, and Velcade and Lenalidomide dosages for VRD regimen

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate	Complete response (CR), or stringent complete response (sCR), or very good partial response (VGPR), or partial response (PR) based on IMWG criteria at the end of cycle 4	Up to 16 weeks or at the end of cycle 4 of treatment (each cycle is 28 days)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of Treatment-Emergent Adverse Events (Safety and Tolerability)	Occurrence of adverse events throughout the study, graded via Common Terminology Criteria for Adverse Events (CTCAE) v 4.03 criteria.	Up to 16 weeks or at the end of cycle 4 of treatment (each cycle is 28 days)

Collaborators and Investigators

• Sponsor: National University Hospital, Singapore
• Collaborators: National University of Singapore

Publications and helpful links

General Publications

• Pantuck, A.J., Lee, D.K., Kee, T., Wang, P., Lakhotia, S., Silverman, M.H., Mathis, C., Drakaki, A., Belldegrun, A.S., Ho, C.M. and Ho, D., 2018. Modulating BET Bromodomain Inhibitor ZEN-3694 and Enzalutamide Combination Dosing in a Metastatic Prostate Cancer Patient Using CURATE. AI, an Artificial Intelligence Platform. Advanced Therapeutics, 1(6), p.1800104.

Study record dates

Study Major Dates

• Study Start (Estimated): September 10, 2023
• Primary Completion (Estimated): September 10, 2025
• Study Completion (Estimated): September 10, 2025

Study Registration Dates

• First Submitted: November 20, 2018
• First Submitted That Met QC Criteria: November 28, 2018
• First Posted (Actual): November 29, 2018

Study Record Updates

• Last Update Posted (Actual): September 6, 2023
• Last Update Submitted That Met QC Criteria: August 31, 2023
• Last Verified: August 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Anti-Infective Agents; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Angiogenesis Inhibitors; Angiogenesis Modulating Agents; Growth Substances; Growth Inhibitors; Anti-Bacterial Agents; Leprostatic Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Cyclophosphamide; Thalidomide; Lenalidomide; Bortezomib
• Other Study ID Numbers: 2015/00280

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No