Multiple myeloma and diffuse large B cell lymphoma Cancer Multiple myeloma, Diffuse large B-cell lymphoma
Conditions
Interventions
The initial stage will involve the first patient being given the study drug (DTP3) at a particular starting dose. If this is well tolerated for one treatment cycle (4 weeks), the next patient will be
Sponsors
Imperial College London
Eligibility
Sex/Gender
All
Age
16 Years to 99 Years
Inclusion criteria
Inclusion criteria: Disease-specific inclusion criteria (MM): 1. Documented diagnosis of multiple myeloma (IMWG 2014 criteria) 2. Any R-ISS stage 3. Measurable disease as determined by at least one of: 3.1. Serum M-protein =500 mg/dL 3.2. Urine M-protein =200 mg/24 hour 3.3. Involved serum free light chain (sFLC) level =10 mg/dL, provided that serum sFLC ratio is abnormal 4. Has previously been treated with an ImiD, a proteasome inhibitor and an anti-CD38 antibody 5. Previous treatment with at least two prior regimens 6. Relapsed (after most recent regimen) or refractory disease [refractory defined as either best response of progression on previous regimen or progression within 6 months of achieving PR (or better) on previous regimen] 7. Requires active therapeutic intervention (in the judgement of the investigator) 8. Not currently a candidate for stem cell transplantation or CAR T-cell therapy Disease-specific inclusion criteria [DLBCL]: 9. Documented diagnosis of DLBCL [WHO 2016 criteria] 9.1. Diffuse large B-cell lymphoma – de novo or transformed (from follicular lymphoma only) 9.2. High-grade B-cell lymphoma (MYC with BCL2 and/or BCL6); High-grade B-cell lymphoma (NOS) 9.3. Primary mediastinal B-cell lymphoma 10. Non-GCB by local IHC [Dose Expansion Only] 11. Measurable disease as determined by CT (or MRI) documentation of two or more clearly demarcated lesions/nodes with a long axis >1.5 cm and short axis >1.0 cm or one clearly demarcated lesion/node with a long axis >2.0 cm and short-axis =1.0 cm AND baseline FDG-PET scans must demonstrate positive lesion compatibility with CT (or MRI) defined anatomical tumour sites 12. No available standard of care therapeutic regimens in the opinion of the investigator 13. Relapsed (after most recent regimen) or refractory disease [refractory defined as either best response of progression on previous regimen or progression within 6 months of achieving PR (or better) on previous regimen] 14. Requires active therapeutic intervention (in the judgement of the investigator) 15. Not currently a candidate for stem cell transplantation or CAR T-cell therapy General inclusion criteria: 16. Adequate hematologic function: 16.1. ANC = 1 x 10e9/l (no restriction on prior growth factor support) 16.2. Platelet count =50 x 10e9/l (no platelet transfusions permitted in 7 last days prior to assessment). Platelet counts of 16 years 21. Written informed consent prior to admission into the study
Exclusion criteria
Exclusion criteria: 1. Primary or secondary CNS lymphoma 2. T-cell rich B-cell lymphoma 3. Plasma cell leukaemia 4. POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin changes) 5. Primary amyloidosis 6. Clinically significant (in the opinion of the investigator) cardiovascular disease, such as: • History of myocardial infarction, acute coronary syndromes (including unstable angina), coronary angioplasty/stenting/bypass grafting within the past 6 months prior to the date of consent • Class III or IV heart failure as defined by the New York Heart Association (NYHA) functional classification system • Severe cardiac arrhythmia requiring medication or severe conduction abnormalities • Poorly controlled hypertension (resting diastolic blood pressure >100 mmHg) • Clinically significant valvular disease, cardiomegaly, ventricular hypertrophy, or cardiomyopathy, QTc prolongation [defined as a QTc interval >450 msec (males) or >470 msec (females)] or other significant ECG abnormalities including 2nd degree (type II) or 3rd degree AV block or bradycardia (ventricular rate 10 mg/day (or steroid equivalent) at time of starting the first dose of study drug. Higher doses are permitted for primary disease symptomatic control during the screening period, after discussion with the medical monitor, but this must have been tapered to a dose of =10 mg/day by the time treatment with DTP3 starts 12. Sem cell transplant (autologous/allogeneic) or CAR T-cell regimen within 12 weeks of the date of consent 13. Participation in another clinical trial with any investigational drug within 28 days prior to the date of consent 14. Prior (non-experimental) MM or DLBCL therapy within 28 days of the date of consent. Concomitant bisphosphonate therapy is permitted 15. Prior radiotherapy within 28 days of the date of consent. Localised palliative radiation therapy to a single site for symptomatic control is acceptable within this period 16. Anticipated need for concurrent radiotherapy during the study 17. Past or current history of other neoplasms, except for: 17.1. Curatively treated non-melanoma skin cancer 17.2. Adequately treated in situ carcinoma of the cervix 17.3. Prostate adenocarcinoma with documented PSA value of <0.1 ng/ml within 6 weeks of the date of consent 17.4. Other cancer curatively treated and with no evidence of disease for at least 3 years before the date of consent. 18. Known HIV infection 19. Active hepatitis C virus (HCV) or hepatitis B virus (HBV). Patients who are positive for hepatitis B core antibody, hepatitis B surface antigen or hepatitis C antibody must have a negative polymerase chain reaction (PCR) result 20. Ability to become pregnant (or already pregnant or lactating). However, those female patients who have a negative serum or urine pregnancy test before enrolment and agree to use two highly effective forms of contraception: 20.1. Oral, injected or implanted hormonal contraception and condom 20.2. Have an intra-uterine device and condom 20.3. Vasectomised partner 20.4. Sexual abstine
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| 1. Incidence, nature, and severity of all adverse events (AEs), serious adverse events (SAEs) and dose-limiting toxicities (DLTs): Common Terminology Criteria for Adverse Events (CTCAE) V5.0 will be assessed at each clinic visit and other assessments, including laboratory parameters, ECGs, and vital signs will be assessed at designated intervals during each cycle of treatment 2. Overall Response Rate (ORR): response will be evaluated using IMWG 2016 (MM) and Lugano Criteria 2014 (DLBCL). MM disease evaluation will occur 4 weekly and DLBCL imaging evaluation will occur 8 weekly 3. MM: best overall response of stringent complete response (sCR), complete response (CR), very good partial response (VGPR) or partial response (PR); response will be evaluated using IMWG 2016 (MM) - MM disease evaluation will occur 4 weekly 4. DLBCL: best overall response of PR or CR; response will be evaluated using Lugano Criteria 2014 (DLBCL). DLBCL imaging evaluation will occur 8 weekly | — |
Secondary
| Measure | Time frame |
|---|---|
| Current secondary outcome measures as of 12/11/2024: 1. Laboratory parameters, ECGs, and vital signs assessed at designated intervals during each cycle of treatment 2. Extent of exposure to DTP3: relative DTP3 dose intensity (delivered dose versus intended dose) will be calculated for each patient and presented descriptively at the end of a patient's participation in the trial: 2.1. Dose intensity = Delivered dose / Intended dose (expressed as a percentage) 2.2. Delivered dose = cumulative total dose the patient actually received over the duration of the study participation (affected by dose reduction/delay) 2.3. Intended and delivered dose values are calculated at the end of a patient's participation in the trial - after the drug has been permanently withdrawn 3. Pharmacokinetic (PK) parameters of DTP3 will be examined on Day 1, Day 3, and Day 5 of Cycle 1. Derived PK parameters will include: Cmax, Tmax, t1/2, AUC 0-t, AUC 0-‚àû, Vd, Vss 4. Pharmacodynamic (PD) biomarkers of pathway-specific response measured at screening and 24 hours (range 18-36 hours) after the 4th dose (C1W2D2). Tissue collection for PD marker analysis (phospho-JNK and phospho-ERK, cleavedcaspase-3, propidium iodide nuclear staining, propidium iodide nuclear staining ) 4.1 MM: 50 ml of blood and 10ml bone marrow aspirate 4.2 DLBCL: 50ml blood and tumour biopsy (if accesible), 28G core biopsy 5. Efficacy through disease evaluation with CT/FDG PET for MM (IMWG) and DLBCL (lugano criteria). _____ Previous secondary outcome measures: 1. Laboratory parameters, ECGs, and vital signs assessed at designated intervals during each cycle of treatment 2. Extent of exposure to DTP3: relative DTP3 dose intensity (delivered dose versus intended dose) will be calculated for each patient and presented descriptively at the end of a patient's participation in the trial: 2.1. Dose intensity = Delivered dose / Intended dose (expressed as a percentage) 2.2. Delivered dose = cumulative total dose the patient act | — |
Countries
England, United Kingdom, Wales
Contacts
Public ContactElena Ferrer
Outcome results
None listed