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Trial registered on ANZCTR
Registration number
ACTRN12624001214527
Ethics application status
Approved
Date submitted
11/09/2024
Date registered
3/10/2024
Date last updated
13/10/2024
Date data sharing statement initially provided
3/10/2024
Type of registration
Prospectively registered
Titles & IDs
Public title
A clinical trial to assess the safety, distribution, effects on certain immune cells and anti-leukaemia effects of LAVA-1266 in patients with acute myeloid leukaemia or certain types of myelodysplastic syndrome
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Scientific title
A Phase 1 open-label trial to evaluate the safety, tolerability, PK, PD, immunogenicity, and preliminary antitumor activity of LAVA-1266, a CD123-targeting bispecific gamma delta-T cell engager, in patients with CD123 positive R/R AML and intermediate risk, high risk, or extremely high risk MDS
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Secondary ID [1]
312826
0
None
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Universal Trial Number (UTN)
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Trial acronym
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Linked study record
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Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML)
334932
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Refractory/Relapsed (R/R) acute myeloid leukaemia (AML)
334933
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Intermediate risk myelodysplastic syndrome (MDS)
335181
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High risk myelodysplastic syndrome (MDS)
335182
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Extremely high risk myelodysplastic syndrome (MDS)
335183
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Condition category
Condition code
Cancer
331471
331471
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0
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Leukaemia - Acute leukaemia
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Blood
331669
331669
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0
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Haematological diseases
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Intervention/exposure
Study type
Interventional
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Description of intervention(s) / exposure
This trial is an open-label, multi-center, Phase 1 first-in-human trial to investigate the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), immunogenicity, and preliminary anti-tumor activity of LAVA-1266 in patients with CD123 positive R/R AML and intermediate risk, high risk, or extremely high risk MDS.
The starting dose: The starting target dose for LAVA-1266 will be 100 micrograms. The starting dose for subsequent cohorts will be determined based on review of the safety and available PK data by the dose escalation committee (DEC).
The dose escalation regimen, duration and frequency of treatments:
LAVA-1266 will be administered every 2 weeks as a target dose. The dose escalation regimen will be determined based on review of the safety and available PK data by the DEC. LAVA-1266 will be given as a target dose every two weeks.
The duration of infusion for LAVA -1266 ranges from 30 minutes to 2 hours depending on which dose in the regimen is being administered.
Dose cohorts and dosing regimen:
Eligible patients will receive sequentially higher target doses of LAVA-1266 in escalating dose cohorts and will continue receiving LAVA-1266 until disease progression, unacceptable toxicity, or withdrawal of consent or other study discontinuation criterion is met.
Duration of Patient Participation:
Screening phase: within 28 days before initial IMP.
Treatment phase: planned treatment duration for approximately 49 weeks.
Post-treatment phase: A follow-up phase of 120 days after the last dose of investigational medicinal product (IMP) for each patient with an end of treatment (EoT) visit within 14 days of the decision to stop LAVA-1266 treatment.
LAVA-1266 will be administered via intravenous infusion.
The database which includes the protocol specified visit schedule will be verified against the patient electronic medical record. As the study treatment is administered intravenously and only during doctor visits, adherence to the required visit schedule will be used as a surrogate for adherence to the study treatment.
In this study, different dose levels (amounts of drug given to a patient) of LAVA-1266 will be given to participants to determine the most appropriate dose level that can safely be given to patients. The study starts with a very low dose level which increases with each participant or set of participants if it is safe to do so.
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Intervention code [1]
329372
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Treatment: Drugs
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Comparator / control treatment
No control group
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Control group
Uncontrolled
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Outcomes
Primary outcome [1]
339210
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Frequency of Adverse events (AEs)
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Assessment method [1]
339210
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Frequency of Adverse events (AEs) using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) grading for Cytokine Release Syndrome (CRS).
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Timepoint [1]
339210
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Will be collected during the entire treatment period and for up to 4 months after.
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Primary outcome [2]
339211
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Severity of Adverse events (AEs)
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Assessment method [2]
339211
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Frequency and severity of Adverse events (AEs) using the Common Terminology Criteria for Adverse Events (CTCAE) version 5.0 and American Society for Transplantation and Cellular Therapy (ASTCT) grading for Cytokine Release Syndrome (CRS).
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Timepoint [2]
339211
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Will be collected during the entire treatment period and for up to 4 months after.
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Primary outcome [3]
339458
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Frequency of Dose-limiting-toxicity (DLT)
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Assessment method [3]
339458
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Mode of assessment includes medical history, physical examination, vital signs, full blood counts, serum chemistry labs including liver function tests, bone marrow assessments when clinically indicated and any additional labs or tests performed by the treating physician during the assessment of the DLT.
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Timepoint [3]
339458
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First 35 days of treatment
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Secondary outcome [1]
439088
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Type of Dose-limiting-toxicity (DLT)
This is an additional primary outcome
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Assessment method [1]
439088
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Mode of assessment includes medical history, physical examination, vital signs, full blood counts, serum chemistry labs including liver function tests, bone marrow assessments when clinically indicated and any additional labs or tests performed by the treating physician during the assessment of the DLT.
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Timepoint [1]
439088
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First 35 days of treatment
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Secondary outcome [2]
439089
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Rates of remission
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Assessment method [2]
439089
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*Rates and duration of remission according to European Leukemia Net (ELN) 2022 criteria.
*Rates and duration of remission according to International Working Group (IWG) 2023 Response Criteria for Higher-Risk MDS
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Timepoint [2]
439089
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Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [3]
439090
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Duration of remission
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Assessment method [3]
439090
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*Rates and duration of remission according to European Leukemia Net (ELN) 2022 criteria.
*Rates and duration of remission according to International Working Group (IWG) 2023 Response Criteria for Higher-Risk MDS
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Timepoint [3]
439090
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Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [4]
439091
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Rate of relapse
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Assessment method [4]
439091
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Tools such as the patient electronic medical record, the electronic clinical study database, safety reporting forms, and follow up visits will be utilized to collect data on the rate to relapse. Tests such as bone marrow aspirate and biopsy results, full blood counts, and physical exam and vital signs when available or clinically indicated will be utilized to assess rate to relapse.
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Timepoint [4]
439091
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Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [5]
439092
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Time to relapse
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Assessment method [5]
439092
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Tools such as the patient electronic medical record, the electronic clinical study database, safety reporting forms, and follow up visits will be utilized to collect data on the time to relapse. Tests such as bone marrow aspirate and biopsy results, full blood counts, and physical exam and vital signs when available or clinically indicated will be utilized to assess time to relapse.
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Timepoint [5]
439092
0
Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [6]
439093
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Overall Survival rate
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Assessment method [6]
439093
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Overall Survival rate at 6 months and 1 year from the first IMP administration to death from any cause
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Timepoint [6]
439093
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Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [7]
439094
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Percent change in blast count
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Assessment method [7]
439094
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Tools such as the patient electronic medical record, the electronic clinical study database, safety reporting forms, and follow up visits will be utilized to collect data on the percent change in blast count. Tests such as the full blood counts, bone marrow aspirate and biopsy results including assessments using flow cytometry, cytogenetics, FISH, and genetic testing will be utilized to assess percent change in blast count.
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Timepoint [7]
439094
0
Up to 12 months from the start of treatment
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Secondary outcome [8]
439096
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PK of LAVA-1266: Blood samples will be used to measure LAVA-1266 levels in the peripheral blood, through PK assessments to evaluate the following parameters:
tmax : The time after dosing at which the maximum concentration was observed.
Cmax : The maximum concentration observed.
Ctrough: Observed concentration just before the beginning of the dosing interval.
AUCtau : The area under the concentration versus time curve over a dosing interval.
t1/2 : The apparent elimination half-life, determined by linear regression of at least
three data points on the terminal phase of the log (Concentration) vs time plot.
CL : Total body clearance.
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Assessment method [8]
439096
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Peripheral blood sample
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Timepoint [8]
439096
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At Priming Doses 1 and 2 samples will be collected prior to infusion, at the end of infusion and 4 hours after. At Cycle 1 Target Dose 1, samples will be collected prior to infusion, at the end of infusion and at 2, 4, 8, 24, 48, 96 and 168 hours after. At Cycle 1 Target Dose 2, samples will be collected prior to infusion and at the end of the infusion. At Cycles 2 and 6 Day 1, samples will be collected prior to the infusion, at the end of the infusion and at 2, 4, 24 and 96 hours after. At Cycles 2 and 6 Day 15, samples will be collected prior to infusion and at the end of the infusion. At Cycles 3-5 and 7- 12, samples will be collected prior to and at the end of each infusion.
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Secondary outcome [9]
439097
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Incidence of anti-LAVA-1266 antibodies.
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Assessment method [9]
439097
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Electrochemiluminescence immunoassay (ECLIA) of peripheral blood sample
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Timepoint [9]
439097
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Within 14 days of the decision to stop LAVA-1266 treatment which may occur anytime up to 12 months from the start of treatment
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Secondary outcome [10]
440057
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Prevalence of anti-LAVA-1266 antibodies.
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Assessment method [10]
440057
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Electrochemiluminescence immunoassay (ECLIA) of peripheral blood sample
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Timepoint [10]
440057
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Within 14 days of the decision to stop LAVA-1266 treatment which may occur anytime up to 12 months from the start of treatment
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Secondary outcome [11]
440058
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Measurable residual disease (MRD) Clearance
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Assessment method [11]
440058
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MRD clearance (for patients with AML). MRD clearance by molecular biology assessment and/or flow cytometry will be assessed in bone marrow and/or blood (from patients achieving a complete remission (CR), complete remission with incomplete haematological recovery (CRi), complete remission with partial haematologic recovery (CRh) or Morphologic Leukemia Free state (MLFS)
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Timepoint [11]
440058
0
Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [12]
440059
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Length of remission
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Assessment method [12]
440059
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Tools such as the patient electronic medical record, the electronic clinical study database, safety reporting forms, and follow up visits will be utilized to collect data on refractory disease, relapse or death due to any cause. Tests such as the bone marrow aspirate and biopsy results, full blood counts, and physical exam and vital signs when available or clinically indicated will be utilized to assess relapse, refractory disease, or death due to any cause.
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Timepoint [12]
440059
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Will be collected during the entire treatment period and for up to 4 months after.
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Secondary outcome [13]
440060
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Rate of Haematopoietic stem cell transplant (HSCT)
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Assessment method [13]
440060
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Number of patients transferred for HSCT with a best response of Partial Remission (PR) or better. Tools such as the patient electronic medical record, the electronic clinical study database, and follow up visits will be utilized to collect data on the number of patients transferred for HSCT with a best response of PR or better. Tests such as the bone marrow aspirate and biopsy results, full blood counts, and physical exam and vital signs when available or clinically indicated will be utilized to assess the number of patients transferred for HSCT with a best response of PR or better
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Timepoint [13]
440060
0
Will be collected during the entire treatment period and for up to 4 months after.
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Eligibility
Key inclusion criteria
Patients are eligible to be included in the study only if all of the following criteria apply:
1. Patient must be 18 years of age or above at the time of signing the informed consent.
2. Patients with documented diagnosis of AML or MDS; (defined using the most recent International Consensus Classification (ICC) guidelines).
3. AML:
*Patients with relapsed/refractory AML (defined as relapsed disease or refractory disease as per the most recent ELN guidelines).
*Patients may have extramedullary disease (Note: a response monitoring plan must be developed a priori for subjects with extramedullary disease)
4. MDS
*Patients with MDS should have morphologically confirmed diagnosis with marrow blasts > 5%.
5. Prior lines of therapy;
*MDS: Patients with MDS must have progressed after prior therapy with at least 4 cycles of at least one prior hypomethylating agent.
*AML: Patients must be relapsed from or refractory to one or more prior lines of therapy which can include induction chemotherapy, stem cell transplant (including those who have received donor lymphocyte infusions), salvage chemotherapy and/or venetoclax-based regimens
6. Patients must have CD123-positive AML or MDS as confirmed by local flow cytometry (or immunohistochemistry).
7. Patients who are not amenable to further standard treatment or for whom no standard treatments are available as per investigator judgement.
8. Males or non-pregnant, non-breastfeeding females who fulfil any of the following criteria:
*Surgically sterile (hysterectomy, bilateral oophorectomy or bilateral salpingectomy, vasectomy)
*Female of childbearing potential with a negative pregnancy test prior to first dosing and compliant with a highly effective contraceptive regimen (i.e., pregnancy rate of < 1% per year: oral contraceptives, intrauterine device, intrauterine hormone-releasing systems) from signing of the informed consent form (ICF) through 90 days after the last IMP administration. Abstinence is not considered an adequate contraceptive regimen.
*Female, postmenopausal defined as continuous amenorrhea for at least 12 consecutive months without an alternative medical cause and/or a serum follicle-stimulating hormone measurement of > 40 IU/L.
*Male participants with female partners must be 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 < 1% per year when having sexual intercourse with a woman of childbearing potential who is not currently pregnant) from signing of the ICF through 90 days after the last IMP administration).
*Male, refraining from donating sperm following from signing of the ICF through 90 days after the last IMP administration.
9. Predicted life-expectancy of greater than or equal to 3 months.
10. Eastern Cooperative Oncology Group performance status of 0-2.
11. Adequate Organ Function, defined as:
*Estimated glomerular filtration rate per local laboratory greater than or equal to 60 mL/min/1.73 m-squared
*Total bilirubin < 1.5 times upper limit of normal (ULN), unless in patients with known Gilbert’s syndrome who must have total bilirubin less than or equal to 3 times ULN (Patient with leukaemic organ involvement as assessed by the study investigator, Serum direct bilirubin less than or equal to 5.0 x ULN), and
*Aspartate aminotransferase and alanine aminotransferase less than or equal to 3.0 times ULN or < 5 times ULN if leukaemic liver involvement.
12. Patients should be at least 14 days or 5 half-lives (whichever is longer) from having received prior therapy and have resolved adverse reactions to prior therapy to no more than Grade 1, except for alopecia or peripheral neuropathy.
13. Capable of giving signed and dated informed consent prior to initiation of any trial-related procedure that is not considered Standard of Care which includes compliance with the requirements and restrictions listed in the ICF and in the protocol.
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Minimum age
18
Years
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Maximum age
No limit
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Sex
Both males and females
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Can healthy volunteers participate?
No
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Key exclusion criteria
AML and MDS patients are excluded from the trial if any of the following criteria apply:
1. Has a white blood cell count > 20,000/micro L. NOTE: Hydroxyurea is permitted for the duration of the first cycle and should be stopped greater than or equal to 24 hours before starting the second cycle of treatment in this trial.
2. Patients with absolute lymphocyte count in peripheral blood of less than 50% of the lower limit of normal.
3. Prior treatment with an anti-CD123-directed agent.
4. Patients with acute promyelocytic leukaemia (APL; AML M3).
5. 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.
6. Uncontrolled or severe intercurrent medical condition as per investigator judgment.
7. Known central nervous system involvement.
8. Patient has any active infection or uncontrollable infection requiring systemic treatment (except for mild-low genitourinary system infection and upper respiratory tract infection)
9. 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 the patient’s participation in this trial.
10. Unstable cardiovascular function defined as:
(a) symptomatic ischaemia, or
(b) uncontrolled clinically significant conduction abnormalities (i.e., patients with ventricular tachycardia on antiarrhythmic agents are excluded; patients with first 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 greater than or equal to 3, or
(d) myocardial infarction within 3 months, or
(e) QTc > 480 msec using Fredericia’s QT correction formula, or
(f) serum albumin is < 3.2 g/dL.
11. Known non-AML or MDS related pre-existing clinically relevant immunodeficiency disorders.
12. Positive serological testing for human immunodeficiency virus antibody, hepatitis B surface antigen, 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 Polymerase chain reaction (PCR) within 6 weeks prior to initial IMP administration. Those who are PCR positive will be excluded.
13. Major surgery within 4 weeks of initial IMP administration or planned surgery during the time the patient is expected to participate in the trial.
14. HSCT within 60 days of study entry. No acute or chronic graft-versus-host disease (GVHD) or ongoing treatment for acute or chronic GVHD at the time of potential study entry. If patients discontinued calcineurin inhibitors (CNI) previously, they should be off the CNI for at least 4 weeks to be eligible.
15. Treatment with radiotherapy, immunotherapy, investigational product, or chemotherapy in the 2 weeks prior to initial IMP administration (with the exception of hydroxyurea which must be stopped at least 24 hours prior to the second cycle of IMP administration).
16. Treatment with an amino bisphosphonate (e.g., ibandronate, pamidronate, zoledronate etc.) within 12 months prior to initial IMP.
17. 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).
18. Treatment with live or live attenuated vaccines within 2 weeks prior to initial IMP administration. Other (new) types of vaccines need to be discussed with the Sponsor as to their mode of action and potential interaction with LAVA-1266.
19. Known allergies, hypersensitivity, or intolerance to the excipients of the IMP.
20. Known ongoing drug and alcohol abuse in the opinion of the investigator.
21. Patient for which any drug-related toxicity adverse effects of any prior cancer therapy have not resolved to Grade 1 or less according CTCAE version 5.0 or to baseline severity level (except for alopecia or peripheral neuropathy).
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Study design
Purpose of the study
Treatment
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Allocation to intervention
Non-randomised trial
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Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
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Methods used to generate the sequence in which subjects will be randomised (sequence generation)
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Masking / blinding
Open (masking not used)
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Who is / are masked / blinded?
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Intervention assignment
Single group
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Other design features
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Phase
Phase 1
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Type of endpoint/s
Safety
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Statistical methods / analysis
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Recruitment
Recruitment status
Not yet recruiting
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Date of first participant enrolment
Anticipated
31/10/2024
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Actual
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Date of last participant enrolment
Anticipated
31/01/2026
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Actual
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Date of last data collection
Anticipated
31/05/2027
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Actual
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Sample size
Target
50
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Accrual to date
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Final
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Recruitment in Australia
Recruitment state(s)
VIC
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Funding & Sponsors
Funding source category [1]
317264
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Commercial sector/Industry
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Name [1]
317264
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LAVA Therapeutics (Australia) Pty Ltd
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Address [1]
317264
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Country [1]
317264
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Australia
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Primary sponsor type
Commercial sector/Industry
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Name
LAVA Therapeutics N.V.
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Address
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Country
Netherlands
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Secondary sponsor category [1]
319542
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Commercial sector/Industry
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Name [1]
319542
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Worldwide Clinical Trials Pty Ltd
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Address [1]
319542
0
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Country [1]
319542
0
Australia
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Ethics approval
Ethics application status
Approved
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Ethics committee name [1]
316004
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Alfred Hospital Ethics Committee
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Ethics committee address [1]
316004
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https://www.alfredhealth.org.au/research/ethics-research-governance
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Ethics committee country [1]
316004
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Australia
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Date submitted for ethics approval [1]
316004
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16/07/2024
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Approval date [1]
316004
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20/09/2024
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Ethics approval number [1]
316004
0
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Summary
Brief summary
This study is a first in human (FIH) clinical trial evaluating a drug called LAVA-1266 in patients with myelodysplastic syndrome (MDS) and relapsed/refractory acute myeloid leukaemia (R/R AML). Who is it for? You may be eligible for this study if you are an adult who has a confirmed diagnosis of CD123 positive R/R AML or intermediate risk, high risk, or extremely high risk MDS. Study details Participants will undergo a 1-month screening period and then receive every 2 weeks (or bi- weekly) intravenous infusions of escalating doses of LAVA-1266 for up to 12 months, or until disease progression, unacceptable toxicity, or withdrawal of consent or other study discontinuation criterion is met. Participants will be asked to provide data on side effects as well as blood and bone marrow samples for outcome assessment. It is hoped that findings from this study help researchers develop a new treatment option for patients with AML and MDS.
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Trial website
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Trial related presentations / publications
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Public notes
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Contacts
Principal investigator
Name
136470
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Dr Shaun Fleming
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Address
136470
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Board Name: Alfred Hospital Ethics Committee Board Affiliation: Alfred Health Address: 55 Commercial Rd, Melbourne, VIC 3004, Australia
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Country
136470
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Australia
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Phone
136470
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+61 3 9076 3619
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Fax
136470
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Email
136470
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[email protected]
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Contact person for public queries
Name
136471
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Kim Paulsen
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Address
136471
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LAVA Therapeutics N.V., 520 Walnut Street, Suite 1150 Philadelphia, PA 19106
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Country
136471
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United States of America
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Phone
136471
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+1 609 284 0363
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Fax
136471
0
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Email
136471
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[email protected]
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Contact person for scientific queries
Name
136472
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Kim Paulsen
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Address
136472
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LAVA Therapeutics N.V., 520 Walnut Street, Suite 1150 Philadelphia, PA 19106
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Country
136472
0
United States of America
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Phone
136472
0
+1 609 284 0363
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Fax
136472
0
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Email
136472
0
[email protected]
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Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
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No/undecided IPD sharing reason/comment
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What supporting documents are/will be available?
No Supporting Document Provided
Results publications and other study-related documents
Documents added manually
No documents have been uploaded by study researchers.
Documents added automatically
No additional documents have been identified.
Download to PDF