The primary objective of this study is to evaluate the efficacy of venetoclax monotherapy in subjects with relapsed or refractory chronic lymphocytic leukemia (CLL).
ID
Source
Brief title
Condition
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary efficacy endpoint will be measured by complete remission rate (CR +
CRi) of the subjects who have not been previously treated with BCRi therapy as
assessed by the investigator.
Secondary outcome
Key secondary efficacy endpoints:
Overall response rate, duration of response, time to progression,
progression-free survival, overall survival, complete remission rate in B-cel
receptor inhibitor treated subjects.
Background summary
Chronic lymphocytic leukemia is a lymphoproliferative disorder, characterized
by progressive accumulation of B cells in peripheral blood, bone marrow, and
secondary lymphoid organs. It is the most common form of leukemia in adults in
the Western World, accounting for approximately 30% of all leukemias. The
approximate 5-year survival rate for patients with CLL is 73%. Standard
chemotherapeutic options for CLL cause significant immune suppression, are not
well-tolerated by the elderly population and have not consistently offered
survival advantage. With the notable exception of allogeneic stem cell
transplantation, CLL is currently an incurable disease, despite good initial
responses to chemo immunotherapy.
Despite some improvement in disease outcomes in relapsed/refractory CLL
subjects, including those who have received novel agents, significant
toxicities remain a concern, complete disease responses are uncommon, and
relapse is virtually inevitable.
Current treatment recommendations for patients carrying TP53 aberrations and
those who have failed or are intolerant to a BCRi include participation in
investigative clinical trials proceeding to allogeneic hematopoietic stem cell
transplantation. Globally, access to allogeneic stem cell transplant and/or
clinical trials is limited, and treatment options for relapsed disease tend to
have increased toxicity and reduced antitumor activity. This group continues to
represent a significant unmet medical need.
Venetoclax, also known as ABT-199, is a novel, orally available, small molecule
Bcl-2 family protein inhibitor that binds with high affinity to Bcl-2.
Selective inhibition by venetoclax disrupts Bcl-2 signaling and rapidly induces
multiple hallmarks of apoptotic cell death in Bcl-2-dependent human tumor cell
lines, independent of p53 activity.
There is data that shows substantial efficacy of venetoclax monotherapy in the
treatment of relapsed/refractory CLL characterized by 17p deletions. Venetoclax
is expected to be as active in subject selected for TP53 mutations as these
subject populations overlap and the oncogenic effect of both genetic defects
occurs via p53 abrogation. In addition, there is limited data in the BCRi
failure CLL population for subjects that subsequently receive venetoclax.
Clinical safety data indicate that the adverse effects of venetoclax
administered with appropriate measures are manageable and as expected from a
treatment targeting hematologic cells including in patients with 17p, TP53
mutation or BCRi failure patients.
This study will further investigate the efficacy of venetoclax monotheraphy in
subject with relapsed/ refractory CLL.
Study objective
The primary objective of this study is to evaluate the efficacy of venetoclax
monotherapy in subjects with relapsed or refractory chronic lymphocytic
leukemia (CLL).
Study design
An Open-Label, Single Arm, Phase 3b, Multi-Center Study.
Intervention
Subjects receive venetoclax orally once daily. During the 5 week dose titration
the initial dose of venetoclax 20 mg QD will be escalated every week until the
maximum dose of 400 mg QD is reached (week 1: 20 mg, week 2: 50 mg, week 3: 100
mg, week 4: 200 mg, week 5: 400 mg). In this period subjects will visit the
site on days 1 and 2 of every week. From week 8 on subjects will visit every 4
weeks until week 48. Thereafter, subjects will visit once every 12 weeks up to
the final visit in week 108.
Study burden and risks
The subjects participating in the study will have a higher burden because of
participation in the trial. This burden consists of extra visits to the site,
two times a CT scan, additional blood draws besides the standard safety labs.
Next to this, the subjects will complete 3 questionnaires (EQ-5D-5L, FACT-Leu
en FACIT-F) during 11 visits and the subjects will be asked to keep a
medication diary. While being treated with venetoclax subjects are not allowed
to consume any grapefruit or Sevilla oranges or starfruit. Also the products
related to these fruits (including marmalade which contains Sevilla oranges)
are not allowed.
Subjects will daily take venetoclax orally. Possible adverse events include:
nausea, vomiting, diarrhea, constipation, feeling tired, decreases in
lymphocytes and neutrophils (two different types of white blood cells),
decreases in red blood cells, tumor lysis syndrome (TLS) and infections. Some
common infections were pneumonia (infection of the lungs) and infections of the
nose and throat and urinary organs.
Before the start of treatment subjects will be classified based on the risk to
develop TLS. When necessary due to a high risk to develop TLS subjects can be
hospitalized during the dose titration phase for observation (1 or 2 days).
The current data of venetoclax and the lack of a curative treatment alternative
reflect an acceptable rationale and risk for treating adult patients with
relapsed or refractory CLL with venetoclax in the context of a clinical trial.
Wegalaan 9
Hoofddorp 2132JD
NL
Wegalaan 9
Hoofddorp 2132JD
NL
Listed location countries
Age
Inclusion criteria
1. Age >= 18 years., 2. Eastern Cooperative Oncology Group (ECOG) performance
score of <= 2., 3. Subject has relapsed/refractory disease (received at least
one line of prior therapy). , 4. Diagnosis of CLL that meets published 2008
Modified International Workshop on CLL National Cancer Institute - Working
Group (IWCLL NCI-WG) Guidelines and:
• has an indication for treatment according to the 2008 Modified IWCLL NCI-WG
Guidelines
• has clinically measurable disease (lymphocytosis > 5 × 10^9/L and/or palpable
and measurable nodes by physical exam and/or organomegaly assessed by physical
exam)
• subjects with or without the 17p deletion or TP53 mutation are eligible
• subjects who have received prior B-cell receptor inhibitor therapy are also
eligible (up to 60 subjects total will be enrolled in the study), 5. Adequate
bone marrow function as follows:
• platelets >= 25,000/mm^3 without any of the following:
o transfusion support within 14 days of Screening
o evidence of mucosal bleeding
o known history of bleeding episode within 3 months of Screening
• hemoglobin >= 8.0 g/dL
Exclusion criteria
1. Subject has developed Richter's transformation or Prolymphocytic leukemia
(PLL), 2. Subject has previously received venetoclax., 3. History of active
malignancies other than CLL within the past 2 years prior to first dose of
venetoclax, with the exception of:
• adequately treated in situ carcinoma of the cervix uteri
• adequately treated basal cell carcinoma or localized squamous cell carcinoma
of the skin
• previous malignancy confined and surgically resected (or treated with other
modalities) with curative intent., 4. Active and uncontrolled autoimmune
cytopenias (within 2 weeks prior to Screening), including autoimmune hemolytic
anemia (AIHA) or idiopathic thrombocytopenic purpura (ITP), despite low dose
corticosteroids., 5. Prior allogeneic stem cell transplant.
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 | EUCTR2015-003667-11-NL |
| ClinicalTrials.gov | NCT02756611 |
| CCMO | NL56737.018.16 |