CD1d-positive relapsed/refractory chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or acute myeloid leukemia (AML)
Conditions
Interventions
Product Name: LAVA-051
Product Code: [LAVA-051]
Pharmaceutical Form: Concentrate for solution for infusion
Current Sponsor code: LAVA-051
Concentration unit: mg/ml milligram(s)/millilitre
Concentratio
Sponsors
LAVA Therapeutics NV
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: 1. Patient must be 18 years of age inclusive or above, at the time of signing the informed consent 2. Confirmed tumor cell CD1d positivity/expression 3. Patients with documented diagnosis of CLL, MM, or AML who have failed to respond to or who have relapsed after prior therapy and are not amenable to standard treatments or for whom no standard treatments are available. Patients may have undergone prior cell therapy CLL/ SL) patients: -Proven disease by the presence of CD5+CD19+CD23+ clonal B cells in blood, bone marrow and/or lymph nodes. -Patients should meet criteria for requiring therapy (the most recent iwCLL guidelines (39)) and must have measurable disease (measurable lesion > 1.5 cm diameter in at least one dimension) and/or lymphocytosis -Patients must have failed at least one line of targeted therapy (ibrutinib or venetoclax or similar) and not be amenable to- or for whom no further standard treatment is available -Patients with Richter’s transformation can be included in Part 1 of the trial but not in Part 2 of the trial MM patients: -Documented diagnosis of MM and measurable disease -Documented progression or refractory multiple myeloma as per the IMWG uniform response criteria following =3 prior regimens that include at least one immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 monoclonal antibody in any order. AML patients: -Patients with relapsed/refractory AML -Patients with relapsed/refractory AML after at least one prior AML therapy. 4. Males or non-pregnant, non-breastfeeding females who are: a. Surgically sterile b. Female of childbearing potential with a negative pregnancy test prior to first dosing and compliant with a highly effective contraceptive regimen from signing of the ICF through 90 days after the last IMP administration. Abstinence is not considered an adequate contraceptive regimen. c. Female, postmenopausal defined as continuous amenorrhea for at least 12 consecutive months without an alternative medical cause and a serum follicle-stimulating hormone (FSH) measurement of > 40 IU/L). d. Male, compliant with an effective contraceptive regimen (i.e., use of male condom with female partner and assuring use of an additional highly effective contraceptive method with a failure rate of 40 mL/min/1.73m2), hepatic function [(total bilirubin = 2 times upper limit of normal (ULN), unless in patients with known Gilbert’s syndrome who must have total bilirubin = 3 times ULN; AST and ALT = 3.0 times ULN] and hematological function (neutrophils = 1 x109/L; platelet count = 75x109/L, unless due to bone marrow tumor infiltration, in which case it must be = 50x109/L) 8. Capable of giving signed and dated informed consent prior to initiation of any trial-related procedure that is not conside
Exclusion criteria
Exclusion criteria: 1. Prior allogeneic bone marrow transplant as long as the patient still has active acute or chronic graft versus host disease requiring >10 mg prednisone or equivalent corticosteroids. 2. Concomitant malignancies except carcinoma in situ, basal or squamous cell skin carcinoma. Patients who had no evidence of disease from another primary cancer for 2 or more years are allowed to participate in the trial. Localized non-metastatic prostate cancer, not requiring systemic treatment, and for which no local treatment is planned, is allowed. 3. Uncontrolled or severe intercurrent medical condition. 4. Known uncontrolled central nervous system involvement. 5. Patient has any active-, uncontrolled-, or suspected infection. 6. A significant history of renal, neurologic, psychiatric, pulmonary, endocrinologic, metabolic, immunologic, cardiovascular, or hepatic disease that in the opinion of the investigator would adversely affect his/her participating in this trial. 7. Unstable cardiovascular function defined as: (a) symptomatic ischemia, or (b) uncontrolled clinically significant conduction abnormalities (i.e., ventricular tachycardia on antiarrhythmic agents are excluded; 1st degree atrioventricular block or asymptomatic left anterior fascicular block/right bundle branch block (left anterior fascicular block /right bundle branch block) will not be excluded), or (c) congestive heart failure New York Heart Association Class = 3, or (d) myocardial infarction within 3 months. 8. Previous treatment with radiotherapy, immunotherapy, or chemotherapy in the 2 weeks prior to initial IMP administration. 9. Previous treatment with biological therapy or with an investigational product in the 4 weeks prior to initial IMP administration. 10. Previous treatment with an aminobisphosphonate IV (e.g., ibandronate, pamidronate, zoledronate etc) within 4 weeks prior to initial IMP. 11. Previous treatment of any systemic immunosuppressant within 2 weeks prior to initial IMP administration, with the exception of systemic corticosteroid use up to oral dose of 10 mg prednisolone daily (or equivalent for other steroids). 12. Previous treatment with live or live attenuated vaccines within 2 weeks prior to initial IMP administration. Other (new) types of vaccines need to be evaluated as to their mode of action. 13. Known non-CLL/MM/AML related pre-existing clinically relevant immunodeficiency disorders. 14. Positive serological testing for Human Immunodeficiency Virus (HIV) antibody, hepatitis B surface antigen [HBsAg] and hepatitis B core antibody (anti-HBc) negative, and hepatitis C virus antibody. Patients who are positive for anti-HBc or hepatitis C antibody may be included if they have a negative PCR within 6 weeks prior to initial IMP administration. Those who are PCR positive will be excluded. 15. Known allergies, hypersensitivity, or intolerance to the excipients of the IMP. 16. Major surgery within 4 weeks of initial IMP administration or planned surgery during the time the patient is expected to participate in the trial. 17. Known ongoing drug and alcohol abuse in the opinion of the investigator.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: Part 1 Dose Escalation • To investigate the safety and tolerability of LAVA-051 in patients with relapsed/refractory CLL, MM, or AML with positive tumor cell expression for CD1d. • To determine the recommended Phase 2a dose (RP2D) of LAVA-051 in patients with relapsed/refractory CLL, MM or AML with positive tumor cell expression for CD1d. Part 2 Proof of Concept (PoC) • To evaluate the antitumor activity of LAVA-051 at the respective RP2D in separate cohorts with relapsed/refractory CLL, MM or AML with positive tumor cell expression for CD1d. • To investigate the safety and tolerability of LAVA-051 in these respective expansion cohorts.;Secondary Objective: Part 1 Dose Escalation • To explore the antitumor activity of LAVA-051. Part 1 Dose Escalation and Part 2 PoC • To evaluate the pharmacokinetics of LAVA-051. • To evaluate the pharmacodynamics of LAVA-051. • To evaluate the immunogenicity of LAVA-051.;Primary end point(s): Part 1 Dose Escalation • Frequency and severity of Adverse Events using the Common Terminology Criteria and grading for Adverse Events (CTCAE version 5.0) and American Society for Transplantation and Cellular Therapy (ASTCT) grading for CRS. • Frequency and type of dose-limiting toxicity (DLT). Part 2 PoC • Antitumor Response: o For CLL patients: Response according to the most recent International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guideline (Appendix 6, Section 13.6.1). o For MM patients: Response according to the most recent International Myeloma Working Group (IMWG) criteria (Appendix 6, Section 13.6.3). o For AML patients: Response according to the most recent European LeukemiaNet (ELN) criteria (Appendix 6, Section 13.6.4). • Frequency and severity, including CTCAE and ASTCT grading, of AEs.;Timepoint(s) of evaluation of this end point: Part 1 AEs are monitored continuously from ICF signature until the FU visit. DLT is defined as an AE and is occurring during Cycle 1 (28 days). Part 2 Anti-tumor response will | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): Part 1 Dose Escalation • For CLL patients: Response according to the most recent iwCLL guideline • For MM patients: Response according to the most recent IMWG criteria • For AML patients: Response according to the most recent most recent ELN criteria criteria Part 1 Dose Escalation and Part 2 PoC • Pharmacokinetic parameters. • Pharmacodynamic markers (binding of LAVA-051 to V¿9Vd2-T cells and CD1d positive tumor cells, frequency and activation status of V¿9Vd2-T cells and iNKT cells, induction of activation of V¿9Vd2-T cells ex vivo and general immune monitoring) and serum cytokines (IL-1ß, IL-2, IL-6, IL-8, TNF-a, IFN-¿) and CD1d and CD277 expression on tumor cells. • Presence or development of anti-LAVA-051 antibodies.;Timepoint(s) of evaluation of this end point: PK collection: SCR, C1D1 at predose, C1D1 1h after SoI, EoI, 15min after EoI, 30min after EoI, 1h, 1,5h, 2h, 3h, 4h, 6h, 8h and 12h after EoI, 24h, 36h, 48h, 72h and 96h after SoI; C1D2-D4-D6 at predose and EoI; C1D3 predose, EoI, 24h and 48h after SOI; C2D1 predose, EoI, 1h, 2h and 4h after EoI, 24h and 48h after SoI; C3-6D1 predose and EoI; EoT PD collection: SCR, C1D1 predose, 2h after EoI, 24h, 48h, 72h and 96h after SoI; C1D2-D4-D6 predose; C1D3 predose, 24h and 48h after SoI; C2D1 predose, 24h and 48h after SoI; C3-6D1 predose; EoT Lava antibodies collection: SCR, C1D1, C1D4, C2-6D1 and EoT. | — |
Countries
Italy, Netherlands, Spain
Contacts
Public ContactProject Manager
CATO SMS
Outcome results
None listed