A Phase 1 and 2a open-label study to evaluate the safety, tolerability, pharmacokinetics, pharmacodynamics, immunogenicity and antitumor activity of LAVA-051 in patients with relapsed or refractory chronic lymphocytic leukemia, multiple myeloma or acute myeloid leukemia
- Conditions
- leukemiamyeloma10024324
- Registration Number
- NL-OMON51940
- Lead Sponsor
- AVA Therapeutics BV
- Brief Summary
Not available
- Detailed Description
Not available
Recruitment & Eligibility
- Status
- Recruiting
- Sex
- Not specified
- Target Recruitment
- 20
1. Patient must be 18 years of age inclusive or above, at the time of signing
the informed consent.
2. 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.
2.1. CLL/ Small Lymphocytic Lymphoma (SLL) patients:
2.1.1. Proven disease by the presence of CD5+CD19+CD23+ clonal B cells in
blood, bone marrow and/or lymph nodes.
2.1.2. 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.
2.1.3. Patients must have received at least 2 prior lines of therapy and 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.
2.2. MM patients:
2.2.1. Documented diagnosis of MM and measurable disease (see Appendix 6,
Section 13.6.2; measurable disease is defined as serum monoclonal paraprotein
(M-protein) >= 5 g/L or urine M-protein >= 200 mg/24 hours or abnormal free light
chain (FLC) ratio with involved FLC > 100 mg/L or proven plasmacytoma by
biopsy*).
2.2.2. Documented progression or refractory multiple myeloma as per the IMWG
uniform response criteria (see Appendix 6, Section 13.6.3) following >=3 prior
regimens that include at least one immunomodulatory drug, a proteasome
inhibitor, and an anti-CD38 monoclonal antibody in any order.
* If plasmacytoma is the only measurable parameter, the patient is not allowed
to be included in the trial, because of difficult response evaluation.
2.3. AML patients:
2.3.1. Patients with relapsed/refractory AML (defined using World Health
Organization [WHO] 2016 criteria, WHO classification definition of >= 20%
blasts) of any type with the exception of acute promyelocytic leukemia (APL;
AML M3). [Patients with a myelomonocytic or monocytic lineage (M4, M5) are most
likely to be positive for the CD1d expression].
2.3.2. Patients with relapsed/refractory AML (defined as hematologic
relaps,molecular relaps, or primary refractory disease as per ELN 2017
quidelines)
3. Males or non-pregnant, non-breastfeeding females who are:
a. Surgically sterile (hysterectomy, bilateral oophorectomy or bilateral
salpingectomy, vasectomy).
b. 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 (IUD),
intrauterine hormone-releasing systems; refer to Appendix 4. Section 13.4 for
more details) from signing of the informed consent form (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
1. Prior allogeneic bone marrow transplant if 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 patients'
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 will not be excluded), or (c) congestive heart failure New
York Heart Association Class >= 3, or (d) myocardial infarction within 3 months
or (e) QTc>480 msec using Fredericia's QT formula.
8. Previous treatment with radiotherapy, immunotherapy, investigational product
or chemotherapy in the 2 weeks prior to initial IMP administration.
9. Previous treatment with an aminobisphosphonate IV (e.g., ibandronate,
pamidronate, zoledronate etc) within 4 weeks prior to initial IMP.
10. 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).
11. 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.
12.Previous autologous haematopoietic stem cell transplantation (HSCT) or
treatment with Chimeric Antigen Receptor (CAR) T-cell therapy within 6 months
prior to initial IMP administration.
13. Known non-CLL/MM/AML related pre-existing clinically relevant
immunodeficiency disorders.
14. Patients with Richter*s transformation are excluded.
15. 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.
16. Known allergies, hypersensitivity, or intolerance to the excipients of the
IMP.
17. Major surgery within 4 weeks of initial IMP administration or planned
surgery during the time the patient is expected to participate in the trial.
18. Known ongoing drug and alcohol abuse in the opinion of the investigator.
Study & Design
- Study Type
- Interventional
- Study Design
- Not specified
- Primary Outcome Measures
Name Time Method <p>Part 1 Dose Escalation<br /><br>• Frequency and severity of AEs using the CTCAE version 5.0 and ASTCT grading<br /><br>for CRS.<br /><br>• Frequency and type of DLT.<br /><br>Part 2 Dose Expansion<br /><br>• Frequency and severity applying CTCAE and ASTCT grading of AEs at the<br /><br>respective RP2D.</p><br>
- Secondary Outcome Measures
Name Time Method <p>Part 1 Dose Escalation and Part 2 Dose Expansion<br /><br>• Antitumor Response :<br /><br>o For CLL patients: Response according to the most recent International<br /><br>Workshop on Chronic Lymphocytic Leukemia (iwCLL) guideline.<br /><br>o For MM patients: Response according to the most recent International Myeloma<br /><br>Working Group (IMWG) criteria.<br /><br>o For AML patients: Response according to the most recent European LeukemiaNet<br /><br>(ELN) criteria.<br /><br>• Pharmacokinetic parameters.<br /><br>• Presence or development of anti-LAVA-051 antibodies.</p><br>