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
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
LAVA Therapeutics N.V.
50 participants
Dec 30, 2024
Interventional
Conditions
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.
Eligibility
Inclusion Criteria27
- Patients are eligible to be included in the study only if all of the following criteria apply:
- Patient must be 18 years of age or above at the time of signing the informed consent.
- Patients with documented diagnosis of AML or MDS; (defined using the most recent International Consensus Classification (ICC) guidelines).
- 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)
- MDS
- Patients with MDS should have morphologically confirmed diagnosis with marrow blasts > 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
- Patients must have CD123-positive AML or MDS as confirmed by local flow cytometry (or immunohistochemistry).
- Patients who are not amenable to further standard treatment or for whom no standard treatments are available as per investigator judgement.
- 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.
- Predicted life-expectancy of greater than or equal to 3 months.
- Eastern Cooperative Oncology Group performance status of 0-2.
- 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.
- 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.
- 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.
Exclusion Criteria28
- AML and MDS patients are excluded from the trial if any of the following criteria apply:
- 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.
- Patients with absolute lymphocyte count in peripheral blood of less than 50% of the lower limit of normal.
- Prior treatment with an anti-CD123-directed agent.
- Patients with acute promyelocytic leukaemia (APL; AML M3).
- 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.
- Uncontrolled or severe intercurrent medical condition as per investigator judgment.
- Known central nervous system involvement.
- Patient has any active infection or uncontrollable infection requiring systemic treatment (except for mild-low genitourinary system infection and upper respiratory tract infection)
- 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.
- 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.
- Known non-AML or MDS related pre-existing clinically relevant immunodeficiency disorders.
- 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.
- Major surgery within 4 weeks of initial IMP administration or planned surgery during the time the patient is expected to participate in the trial.
- 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.
- 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).
- Treatment with an amino bisphosphonate (e.g., ibandronate, pamidronate, zoledronate etc.) within 12 months prior to initial IMP.
- 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).
- 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.
- Known allergies, hypersensitivity, or intolerance to the excipients of the IMP.
- Known ongoing drug and alcohol abuse in the opinion of the investigator.
- 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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Interventions
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.
Locations(4)
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ACTRN12624001214527