Clinical Trials Register

Summary
EudraCT Number:	2020-004583-26
Sponsor's Protocol Code Number:	LV2020-001
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2021-01-18
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

Netherlands - Competent Authority

A.2

EudraCT number

2020-004583-26

A.3

Full title of the trial

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

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A dose escalation trial to assess the safety and tolerability of multiple doses of the LAVA-051 antibody in patients with chronic lymphocytic leukemia, multiple myeloma or acute myeloid leukemia

A.3.2

Name or abbreviated title of the trial where available

LAVA

A.4.1

Sponsor's protocol code number

LV2020-001

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	LAVA Therapeutics N.V.
B.1.3.4	Country	Netherlands
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	LAVA Therapeutics N.V.
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	LAVA Therapeutics N.V.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	520 Walnut Street, suite 1150
B.5.3.2	Town/ city	Philadelphia
B.5.3.3	Post code	PA 1910
B.5.3.4	Country	United States
B.5.4	Telephone number	+18003116892
B.5.6	E-mail	clinicaltrials@lavatherapeutics.com

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	LAVA-051
D.3.2	Product code	LAVA-051
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	LAVA-051
D.3.9.3	Other descriptive name	LAVA-051
D.3.10	Strength
D.3.10.1	Concentration unit	mg/ml milligram(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	1
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	Yes
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Relapsed/refractory chronic lymphocytic leukemia (CLL), multiple myeloma (MM), or acute myeloid leukemia (AML)

E.1.1.1

Medical condition in easily understood language

Patients with chronic lymphocytic leukemia, multiple myeloma or acute myeloid leukemia

E.1.1.2

Therapeutic area

Diseases [C] - Blood and lymphatic diseases [C15]

MedDRA Classification

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Part 1 Dose Escalation
• To investigate the safety and tolerability of LAVA-051 in patients with relapsed/refractory CLL, MM, or AML
• To determine the recommended Phase 2a dose (RP2D) of LAVA-051 in patients with relapsed/refractory CLL, MM or AML
Part 2 Dose Expansion
• To confirm the safety and tolerability of LAVA-051 in diseases specific dose expansion cohorts.

E.2.2

Secondary objectives of the trial

Part 1 Dose Escalation and Part 2 Dose Expansion
• To explore the preliminary antitumor activity of LAVA-051.
• To evaluate the pharmacokinetics of LAVA-051.
• To evaluate the immunogenicity of LAVA-051.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

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] most recent classification) 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 relapse, molecular relapse, or primary refractory disease as per most recent ELN guidelines).
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 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 following from signing of the ICF through 90 days after the last IMP administration; refer to Appendix 4, Section 13.4 for more details) from signing of the ICF through 90 days after the last IMP administration). Abstinence is not considered an adequate contraceptive regimen.
e. Male, refraining from donating sperm following from signing of the ICF through 90 days after the last IMP administration.
4. Predicted life-expectancy of ≥ 3 months
5. Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1
6. Adequate renal function (creatinine clearance ≥ 50 mL/min), hepatic function [(total bilirubin ≤ 1.5 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, unless this is considered due to bone marrow tumor infiltration; platelet count ≥ 75x109/L, unless due to bone marrow tumor infiltration, in which case it must be ≥ 50x109/L)
7. 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. This also means that (according to French Public Health Code article L 1121-6, L 1121-8 & L 1126-6) patients should not be (1) deprived of liberty, (2) placed under legal protection or unable to express their consent, (3) hospitalized without consent.

E.4

Principal exclusion criteria

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 the patients' participation 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 correction formula.
8. Previous treatment with radiotherapy, targeted therapy, investigational product, or chemotherapy in the 2 weeks (or 4 weeks for previous T-cell directed immunotherapy if requested by specific regulatory authorities) 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.
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 or IL-2.
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.

E.5 End points

E.5.1

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 DLT.
Part 2 Dose Expansion
• Frequency and severity, applying CTCAE and ASTCT grading, of AEs at the respective P2D.

E.5.1.1

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 take place: 1) CLL: screening, Peripheral blood at predose of C1-6D1, CT-scan of neck/chest/abdomen in the C3-4th wk, Peripheral Blood MRD at predose of C4D1, BM biopsy in case of suspected remission based on CT analysis and blood evaluation and EoT. 2) MM: screening, Blood/24-h urine at predose of C1-6D1, BM biopsy in C3-4th wk and for confirmation of CR or at disease progression, CT-scan as clinically indicated to document progression and in the C3-4th wk, PE at predose of C1-6D1, and EoT. 3) AML: screening, Peripheral blood at predose of C1-6D1, BM biopsy in the C3-4th wk, MRD of C4D1 and EoT

E.5.2

Secondary end point(s)

Part 1 Dose Escalation and Part 2 Dose Expansion
• Antitumor Response:
o For CLL patients: Response according to the most recent International Workshop on Chronic Lymphocytic Leukemia (iwCLL) guideline.
o For MM patients: Response according to the most recent International Myeloma Working Group (IMWG) criteria.
o For AML patients: Response according to the most recent most recent European LeukemiaNet (ELN) criteria criteria.
• Pharmacokinetic parameters.
• Presence or development of anti-LAVA-051 antibodies

E.5.2.1

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

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolerability, immunogenicity, antitumor activity

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

Dose escalation and dose expansion study

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

United States

France

Netherlands

Spain

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

The trial completion is defined as LPLV. For patients still on treatment beyond their maximum planned treatment duration follow up in the trial will end at the date of database lock of Part 2.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

F.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

114

F.5

Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)

At the request of the treating physician and in consultation with the sponsor, continued access to IMP might be offered beyond the planned treatment duration of 24 weeks for individual patients with ongoing disease control provided that there is availability of IMP allocated to this trial

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2021-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2022-03-08

P. End of Trial
P.	End of Trial Status	Completed
P.	Date of the global end of the trial	2023-09-06

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