This study has been transitioned to CTIS with ID 2024-512390-27-00 check the CTIS register for the current data. The primary objectives of this trial are:• Part 1 (dose escalation): To evaluate the safety of BYON4228 alone and in combinationwith…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's unspecified histology
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary endpoints
The primary endpoint for Part 1 of the trial is:
• Incidence of dose limiting toxicity (DLT), or
• Optimal biological dose (OBD).
The primary endpoint for Part 2 of the study is:
• Objective response rate (ORR).
Optimal biological dose (OBD) is defined as the dose level where no DLTs were
experienced, providing maximal target engagement over the full dosing interval
(28 days for the 4-weekly cohorts, 14 days for the 2-weekly cohorts) an
acceptable benefit/risk profile for all evaluable patients in the dose-cohort.
Objective response rate (ORR) is defined as the percentage of patients with a
best overall tumor response of complete response (CR) or partial response (PR)
according to the Lugano classification.
Secondary outcome
Safety endpoints
The endpoints related to safety include:
• Incidence and severity of (serious) AEs;
• Changes in vital signs and weight;
• Changes in ECOG performance status;
• Changes in laboratory parameters;
• Percentage of patients with confirmed anti-BYON4228 and anti-rituximab
antibodies;
• Number of patients with dose modifications due to AEs.
Efficacy endpoints
Preliminary efficacy will be assessed by:
• ORR (Part 1);
• Clinical benefit rate (CBR);
• Number of patients with CR, PR, stable disease (SD) and progressive disease
(PD);
• Best percent change in target lesion measurements;
• Time to response;
• Duration of response (DOR);
• Progression-free survival (PFS);
• Overall survival (OS).
Clinical benefit rate (CBR) is defined as the percentage of patients with CR,
PR, SD or non-CR/non-PD (SD or non-CR/non-PD for 6 or more months).
Time to response (TTR) is defined as the time from first day of IMP treatment
to first observation of CR or PR.
Duration of response (DOR) is defined as the duration from first observation of
response (CR or PR) to the time of disease progression or death from any cause.
Progression-free survival (PFS) is defined as the time from first day of IMP
treatment to disease progression or death from any cause.
All above described responses will be calculated using the Lugano
classification first and subsequently using the LYRIC criteria.
Overall survival (OS) is defined as the time from first day of IMP treatment to
death from any cause.
14.2.3. Pharmacokinetic endpoints
PK endpoints will include standard parameters such as Cmax, tmax, area under
the curve (AUC), Cmin (trough-levels), terminal half-life (t*), volume of
distribution, and drug clearance.
14.2.4. Other endpoints
The exploratory pharmacodynamic and predictive biomarker endpoints will
include, but are not limited to:
• SIRPα receptor occupancy (RO) on peripheral blood monocytes over time;
• Tumor DNA/RNA whole exome sequencing;
• Blood transcriptional profiling (RNA sequencing);
• Proteolytic serum fragments;
• Histamine.
Background summary
BYON4228 is a monoclonal antibody, a type of protein designed to recognize and
attach to a specific target substance in the body. BYON4228 attaches to a
target protein called SIRPα, which is present on immune cells. Normally, SIRPα
binds to a protein CD47 present on NHL tumour cells. Binding results in a
*don*t-eat-me-signal* which prevents the immune system from attacking the tumor
cell. BYON4228 treatment aims to block the binding between the immune cell and
the tumor cell. As a result, the *don*t-eat-me-signal* is suppressed which may
enhance the tumor cell killing activity of other therapeutic anticancer
treatments like rituximab.
Study objective
This study has been transitioned to CTIS with ID 2024-512390-27-00 check the CTIS register for the current data.
The primary objectives of this trial are:
• Part 1 (dose escalation): To evaluate the safety of BYON4228 alone and in
combination
with rituximab to determine the maximum tolerated dose (MTD), or optimal
biological dose
(OBD) if the MTD is not reached, and recommended combination dose regimen for
expansion (RDE);
• Part 2 (expansion): To evaluate the objective tumor response rate (ORR) of
the combined
BYON4228/rituximab dose regimen.
The secondary objectives of this trial are to evaluate the BYON4228/rituximab
combination
with respect to:
• Safety (Part 2);
• Pharmacokinetics (PK);
• Immunogenicity;
• Preliminary efficacy
Other exploratory objectives of this trial (Part 1 and 2) are to evaluate:
• Pharmacodynamic (PD) and predictive biomarkers.
Study design
This is the first-in-human study with BYON4228, a humanized monoclonal antibody
(mAb) directed against SIRPα.
This study includes a dose escalation part (Part 1) in which the MTD or OBD and
RDE will be determined, and an expansion part (Part 2) to evaluate efficacy and
safety in specific patient cohorts. Eligible patients with CD20 positive B-cell
NHL will participate. The trial will investigate administration of BYON4228 as
single agent and in combination with rituximab.
Intervention
BYON4228 will be given by intravenous infusion. Different doses of BYON4228
will be given to different patients. The first patient will receive the lowest
dose 7 mg and will be escalated for the following patients as presented in
Table 2 (page 6 of the protocol). The maximum dose of BYON4228 will be 1500 mg.
The patient will continue with the same dose that they started with, so the
dose will not be increased for them.
In this study patients will receive BYON4428 alone in the first cycle (four
weeks) and the combination of BYON4228 + Rituximab from cycles 2 to 7.
Rituximab will be given to the patient for what is standard for treating NHL,
this will be the same dose for all patients for a total of 6 treatment cycles.
Thereafter, from cycle 8 onwards, the patient will continue treatment with
BYON4228 alone.
In this study there are 2 possible schedules for the administration of
BYON4228, once every 4 weeks or once every 2 weeks
Study burden and risks
For the study, the patient needs to visit the hospital approximately 7 times
during the first cycle of 4 weeks, followed by approximately 5 times in the
second cycle, and 1 or 2 times per cycle thereafter, depending on which
schedule the patient is in. Patients who are eligible will be treated until
disease progression or unacceptable toxicity.
A follow-up visit is planned 30 days after the treatment discontinuation visit.
Patients will subsequently be contacted every 3 months to collect survival data.
The following procedures will take place during the hospital visits:
- Physical exam, Vital signs, demographics, medical history, weight
- Blood and urine tests
- ECOG performance status
- ECG
- Pregnancy tests in women of childbearing potential
-PET-CT/MRI scan
- Buccal swab
-infusion of study drugs. For the first two infusions the patient will need to
stay overnight in the hospital.
-A tumor biopsy sample will be required at screening in case no recent archival
material is available.
Microweg 22
Nijmegen 6545 CM
NL
Microweg 22
Nijmegen 6545 CM
NL
Listed location countries
Age
Inclusion criteria
1. Male or female, age >= 18 years at the time of signing informed consent; 2.
Patient with: a. Part 1 only: (Aggressive or indolent) B-cell NHL expressing
CD20 by immunohistochemistry (IHC) or flow cytometry, R/R to at least 2 prior
lines of therapy or autologous CAR-T cell therapy; b. Part 2 cohort A only:
Histologically confirmed aggressive B cell NHL (e.g., DLBCL, MCL) expressing
CD20 by IHC or flow cytometry, R/R to frontline therapy, or second line salvage
regimens or autologous hematopoietic cell transplantation, or autologous CAR-T
therapy; c. Part 2 cohort B only: Histologically confirmed indolent B-cell NHL
(e.g., marginal zone, follicular lymphoma (Grade 1-3a) expressing CD20 by IHC
or flow cytometry, R/R to at least 2 prior lines of therapy; For both parts:
autologous hematopoietic stem cell transplantation (HSCT) and autologous CAR-T
cell therapy (if more than 3 months prior to start IMP), and allogeneic HSCT
(if more than 6 months prior to start IMP) are allowed as prior lines. 3.
Eastern Cooperative Oncology Group (ECOG) performance status <= 1; 4. For Part 2
only: Disease that is measurable or assessable for response per Lugano
Classification for lymphomas; 5. Laboratory measurements, blood counts (Growth
Factor (GF) support and blood transfusions are not allowed within 2 weeks prior
to this assessment): a. Hemoglobin >= 8.5 g/dL (> 5.28 mmol/L); b. Absolute
neutrophil count (ANC) >= 1.0 × 109/mL; c. Platelet counts >= 50 × 109/mL; If
bone marrow involvement: >= 25 × 109/mL;
6. Laboratory measurements, hepatic function: a. Aspartate aminotransferase
(AST)/alanine aminotransferase (ALT) < 5 × upper limit of normal (ULN); b.
Total bilirubin <= 1.5 × ULN or 3.0 × ULN and primarily unconjugated if patient
has a documented history of Gilbert*s syndrome or a genetic equivalent; 7.
Laboratory measurements, renal function: Serum creatinine <= 1.5 × ULN or
calculated glomerular filtration rate (GFR) >30 mL/min/1.73 m2 (calculated with
CKD-EPI formula); 8. Females of childbearing potential must be willing to use a
highly effective method of contraception during the study and for 12 months
after the last dose of rituximab or for 6 months after the last dose of
BYON4228, whichever takes longer; 9. Part 1: Willing to consent to 1
pre-treatment tumor biopsy. If a recent (<= 2 months) archival tumor biopsy
sample is available prior to signing the ICF and the patient did not have
anticancer treatment (including steroids) since the biopsy was performed, this
could be used as the pre-treatment tumor biopsy; 10. Part 2: Willing to consent
to 1 pre-treatment and 1 on-treatment tumor biopsy. If a recent (<= 2 months)
archival tumor biopsy sample is available prior to signing the ICF and the
patient did not have anticancer treatment (including steroids) since the biopsy
was performed, this could be used as the pre-treatment tumor biopsy.
Exclusion criteria
1. Having been treated with:
a. CD47 or SIRPα targeting agents at any time;
b. Other anticancer therapy including investigational agents within 2
weeks prior to start of BYON4228 treatment or within 4 times the
elimination half-life (up to a maximum of 4 weeks) whichever is longer.
Note: treatment with hormonal therapy with LHRH agonists for localized prostate
cancer, and treatment with bisphosphonates and RANKL inhibitors are not
criteria for exclusion;
c. Radiotherapy within 1 week prior to start of BYON4228;
d. Autologous HSCT or CAR-T cell therapy within 3 months prior to start IMP, or
allogeneic HSCT within 6 months prior to start IMP.
In addition, the patient must have sufficiently recovered from any
treatment-related toxicities or CTCAE Grade <= 1 or baseline, except for
toxicities not considered a safety risk for the patient at the investigator's
discretion;
2. Any contraindication to rituximab treatment;
3. History of hypersensitivity or allergic reaction to any of the excipients of
BYON4228 or rituximab which led to permanent discontinuation of the treatment;
4. Currently diagnosed or suspected CNS involvement;
5. Burkitt's lymphoma;
6. Known active or chronic (DNA or RNA positive) hepatitis B, C or E
infection or human immunodeficiency virus (HIV);
7. Red blood cell (RBC) transfusion dependence, defined as requiring
more than 2 units of RBC transfusions during the 4-week period prior to
screening;
8. Patients with active graft versus host disease (GVHD) or ongoing
immunosuppression for GVHD;
9. History of autoimmune hemolytic anemia or autoimmune
thrombocytopenia that in the investigator's opinion is likely to
jeopardize patient safety;
10. History of autoimmune disorders (including but not limited to:
Crohn's disease, rheumatoid arthritis, scleroderma, systemic lupus
erythematosus, Grave's disease) or other conditions that compromise or impair
the immune system (except for hypogammaglobulinemia) and that in the
investigator's opinion is likely to jeopardize patient safety;
11. Second malignancy, other than the one treated in this trial, in the
last 3 years before signing ICF. Except, if appropriately treated: basal
cell or localized squamous skin carcinomas, localized prostate cancer or
localized cervical cancer. Any other indolent malignancy may be allowed upon
discussion with the medical monitor;
12. History (within 6 months prior to start of BYON4228 treatment) or
presence of clinically significant cardiovascular disease such as unstable
angina, congestive heart failure, myocardial infarction, uncontrolled
hypertension, or cardiac arrhythmia requiring medication. Presence of atrial
fibrilation may be allowed upon discussion with the medical monitor;
13. Severe active infection or other severe uncontrolled systemic disease
(e.g., advanced renal disease, pulmonary, uncontrolled diabetes mellitus,
severely immunocompromised state, or metabolic disease) at screening;
14. Major surgery within 4 weeks prior to start of BYON4228 treatment;
15. Pregnancy or active breastfeeding;
16. Other condition that in the investigator's opinion is likely to
jeopardize patient safety or interfere with the patient's ability to comply
with trial requirements.
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EU-CTR | CTIS2024-512390-27-00 |
| EudraCT | EUCTR2022-002018-18-NL |
| CCMO | NL82832.091.22 |