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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
10/11/2024
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
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
Secondary ID [1] 312826 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Acute myeloid leukaemia (AML) 334932 0
Refractory/Relapsed (R/R) acute myeloid leukaemia (AML) 334933 0
Intermediate risk myelodysplastic syndrome (MDS) 335181 0
High risk myelodysplastic syndrome (MDS) 335182 0
Extremely high risk myelodysplastic syndrome (MDS) 335183 0
Condition category
Condition code
Cancer 331471 331471 0 0
Leukaemia - Acute leukaemia
Blood 331669 331669 0 0
Haematological diseases

Intervention/exposure
Study type
Interventional
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.
Intervention code [1] 329372 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 339210 0
Frequency of Adverse events (AEs)
Timepoint [1] 339210 0
Will be collected during the entire treatment period and for up to 4 months after.
Primary outcome [2] 339211 0
Severity of Adverse events (AEs)
Timepoint [2] 339211 0
Will be collected during the entire treatment period and for up to 4 months after.
Primary outcome [3] 339458 0
Frequency of Dose-limiting-toxicity (DLT)
Timepoint [3] 339458 0
First 35 days of treatment
Secondary outcome [1] 439088 0
Type of Dose-limiting-toxicity (DLT)
This is an additional primary outcome
Timepoint [1] 439088 0
First 35 days of treatment
Secondary outcome [2] 439089 0
Rates of remission
Timepoint [2] 439089 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [3] 439090 0
Duration of remission
Timepoint [3] 439090 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [4] 439091 0
Rate of relapse
Timepoint [4] 439091 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [5] 439092 0
Time to relapse
Timepoint [5] 439092 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [6] 439093 0
Overall Survival rate
Timepoint [6] 439093 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [7] 439094 0
Percent change in blast count
Timepoint [7] 439094 0
Up to 12 months from the start of treatment
Secondary outcome [8] 439096 0
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.
Timepoint [8] 439096 0
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.
Secondary outcome [9] 439097 0
Incidence of anti-LAVA-1266 antibodies.
Timepoint [9] 439097 0
Within 14 days of the decision to stop LAVA-1266 treatment which may occur anytime up to 12 months from the start of treatment
Secondary outcome [10] 440057 0
Prevalence of anti-LAVA-1266 antibodies.
Timepoint [10] 440057 0
Within 14 days of the decision to stop LAVA-1266 treatment which may occur anytime up to 12 months from the start of treatment
Secondary outcome [11] 440058 0
Measurable residual disease (MRD) Clearance
Timepoint [11] 440058 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [12] 440059 0
Length of remission
Timepoint [12] 440059 0
Will be collected during the entire treatment period and for up to 4 months after.
Secondary outcome [13] 440060 0
Rate of Haematopoietic stem cell transplant (HSCT)
Timepoint [13] 440060 0
Will be collected during the entire treatment period and for up to 4 months after.

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.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
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).

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 1
Type of endpoint/s
Safety
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
30/11/2024
Actual
Date of last participant enrolment
Anticipated
31/01/2026
Actual
Date of last data collection
Anticipated
31/05/2027
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC

Funding & Sponsors
Funding source category [1] 317264 0
Commercial sector/Industry
Name [1] 317264 0
LAVA Therapeutics (Australia) Pty Ltd
Country [1] 317264 0
Australia
Primary sponsor type
Commercial sector/Industry
Name
LAVA Therapeutics N.V.
Address
Country
Netherlands
Secondary sponsor category [1] 319542 0
Commercial sector/Industry
Name [1] 319542 0
Worldwide Clinical Trials Pty Ltd
Address [1] 319542 0
Country [1] 319542 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 316004 0
Alfred Hospital Ethics Committee
Ethics committee address [1] 316004 0
Ethics committee country [1] 316004 0
Australia
Date submitted for ethics approval [1] 316004 0
16/07/2024
Approval date [1] 316004 0
20/09/2024
Ethics approval number [1] 316004 0

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 136470 0
Dr Shaun Fleming
Address 136470 0
Board Name: Alfred Hospital Ethics Committee Board Affiliation: Alfred Health Address: 55 Commercial Rd, Melbourne, VIC 3004, Australia
Country 136470 0
Australia
Phone 136470 0
+61 3 9076 3619
Fax 136470 0
Email 136470 0
S.Fleming2@alfred.org.au
Contact person for public queries
Name 136471 0
Kim Paulsen
Address 136471 0
LAVA Therapeutics N.V., 520 Walnut Street, Suite 1150 Philadelphia, PA 19106
Country 136471 0
United States of America
Phone 136471 0
+1 609 284 0363
Fax 136471 0
Email 136471 0
Lava1266studies@lavatherapeutics.com
Contact person for scientific queries
Name 136472 0
Kim Paulsen
Address 136472 0
LAVA Therapeutics N.V., 520 Walnut Street, Suite 1150 Philadelphia, PA 19106
Country 136472 0
United States of America
Phone 136472 0
+1 609 284 0363
Fax 136472 0
Email 136472 0
Lava1266studies@lavatherapeutics.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


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.