Primary objectives1. To assess the safety of Tam added to Ven. Venetoclax will be dosed at 800 mg once daily. After 2 days of venetoclax, tamoxifen will be orally administrated in a ramp-up phase (2 days 10mg, 2 days 20mg, to a final dose of 40 once…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Descriptive analyses of safety and toxicity (using SAE grade 3 and 4 listing)
of tamoxifen and venetoclax
Secondary outcome
• To assess the effectivity of the combination Tam and Ven as measured by the
day + 28 and +90 response as measured by FDG PET CT scan.
• To assess the duration of response (DOR)
• To assess the progression free survival (PFS) after 3 months (after the first
dose of TAM)
• To assess the overall survival (OS) after 3 months
Background summary
This trial aims to asses safety of tamoxifen added to venetoclax in patients
with Diffuse Large B-cell Lymphoma (DLBCL) who have no other treatment options.
The rationale for tamoxifen (Tam) and venetoclax (Ven) is based on pre-clinical
and clinical data; 1) Single agent therapy of the selective estrogen receptor
modulator Tam has been shown to be safe and might be effective in patients with
B-cell lymphomas; 2) Studies from the Dutch cancer registry demonstrated that
women with breast cancer (BC) who were treated with Tam had a significant lower
incidence of DLBCL compared to women with breast cancer who were not treated
with tamoxifen; 3) The BCL-2 inhibitor Ven is modestly effective as a single
agent (overall response rate 18%, dose: 800-1200mg) and in combination with
chemotherapy in patients with DLBCL (dose venetoclax 800mg); 4) Research in our
own lab showed that in malignant and normal lymphocytes, the estrogen receptor
beta (ER) is expressed in the mitochondria of these cells. Ligation of ER* with
tamoxifen results in BAD-independent (BCL-2 protein response) apoptosis.
Subsequently, pre-clinical data in DLBCL cell lines demonstrated a synergistic
cell killing effect of the combination Tam and Ven; 5) The combination of Tam
(40 mg) and Ven (800 mg) was studied in patients with estrogen receptor alfa
(ER) positive BC. This combination was effective and safe, with one important
side-effect, a marked lymphopenia (but no other cytopenias), confirming that
B-lymphocytes are a targeted by the combination of Tam and Ven.
Study objective
Primary objectives
1. To assess the safety of Tam added to Ven. Venetoclax will be dosed at 800 mg
once daily. After 2 days of venetoclax, tamoxifen will be orally administrated
in a ramp-up phase (2 days 10mg, 2 days 20mg, to a final dose of 40 once daily,
see study scheme)
Secondary objectives
1. To assess efficacy of Tam added to Ven. An FDG PET / CT scan will be
performed at day +28 and +90 of treatment.
2. To assess the duration of response (DOR)
3. To assess the progression free survival (PFS)
4. To assess the overall survival (OS)
Study design
This is a prospective, explorative feasibility trial.
Intervention
Patients in this study are treated with oral Ven (800 mg once daily) and oral
Tam (starting with a ramp-up phase; 2 days 10mg, 2 days 20mg, and 40mg once
daily). These doses are the approved doses for treatment of breast cancer (Tam)
and the advised dose for the treatment of B-cell Non-Hodgkin Lymphoma (NHL)
Study burden and risks
The benefit of this study is to explore an oral treatment regimen in patients
who have no other (curative) treatment options.
The burden and risks associated with participation mainly involves potential
toxicity associated with the study drugs, e.g. tumor lysis syndrome. To that
end patients will be hospitalized and monitored for at least 24 hrs after the
first dose of venetoclax and after the addition of tamoxifen.
Hanzeplein 1
Groningen 9713GZ
NL
Hanzeplein 1
Groningen 9713GZ
NL
Listed location countries
Age
Inclusion criteria
• Patients of 18 years and older and under the age of 70 with a diagnosis of
Diffuse Large B-cell lymphoma (according WHO 2016) and refractory after 2 lines
of therapy for patients ineligible for CAR T-cell therapy and after CAR T-cell
therapy (hence after 3rd line of therapy). Patients with relapsed/refractory
DLBCL older than 70 years after at least 1 line of conventional chemotherapy or
after CAR T-cell therapy.
• Written informed consent.
• No known allergy to Ven or Tam.
Exclusion criteria
• Eastern Cooperative Oncology Group (ECOG) performance status >2
• Absolute neutrophil count (ANC) <1,000/µL
• Platelet count <50,000/µL
• Absolute lymphocyte count <100/µL
• Primary and secondary CNS lymphoma
• Active systemic fungal, viral or bacterial infection
• CrCl <30 mL/min calculated according to the modified formula of Cockcroft and
Gault or by direct urine collection
• Pregnant or breast-feeding woman
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 |
|---|---|
| EudraCT | EUCTR2020-005515-51-NL |
| CCMO | NL76026.042.21 |
| Other | NL9075 |