The primary objective of the Phase I portion of the study is the following:* To estimate the maximum tolerated dosing schedule for venetoclax given in combination with R-CHOP or G-CHOP to patients with B-cell NHL, either previously untreated or…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Safety outcome measures:
* Incidence and nature of combination DLTs
Pharmacokinetic and Pharmacodynamic Outcome Measures
From the plasma concentration*time profile of venetoclax following
administration:
* Total exposure (area under the concentration*time curve [AUC])
* Time to maximum observed plasma concentration (Tmax)
* Cmax of plasma
* Minimum concentration under steady-state conditions with a dosing interval
(Cmin) of
plasma
From the concentration-time profiles of rituximab, obinutuzumab and CHOP
components:
* Cmax of serum
* Cmin of serum
Activity outcome measures:
* CR, as defined by PET/CT scan as well as bone marrow examination when
applicable
* CR as defined by CT scan and bone marrow examination, when applicable
* OR, defined as a PR or CR
* Duration of response (DOR), defined as the first occurrence of a documented
response until the time of relapse or death from any cause
* PFS, defined as the time from date of first dose of study drug to the first
occurrence of progression, relapse, or death while in the study, where death
while in the study is defined as death from any cause within 12 weeks of the
last tumor assessment
* Progression-free survival at 12 months
* Relative dose intensity
* OS, defined as the time from date of first dose of study drug until the date
of death from any cause. For patients who have not died, survival data will be
censored at the date of last contact.
Secondary outcome
Safety outcome measures:
* Incidence, nature, and severity of adverse events and serious adverse events
graded according to NCI CTCAE v 4.0. AEs of special interest include Grade 4
neutropenic fever, Grade * 3 IRRs to rituximab or obinutuzumab, and Grade * 4
TLS
* Change in clinical laboratory results (including hematology, chemistry, and
urinalysis) and vital signs
* Maintenance of relative dose intensity of CHOP chemotherapy
Pharmacokinetic and Pharmacodynamic Outcome Measures
PK parameters such as clearance (CL), volume of distribution (V), and half-life
(T1/2) may also be calculated as data allow
Exploratory Assessments
The following correlative biology measures will be assessed:
* Bcl-2 high (Bcl-2 positive) as defined by immunohistochemistry
* Bcl-2 copy number gain by FISH and translocation t(14;18) by FISH
* Expression of transcripts for Bcl-2 family members, other apoptotic genes and
genes associated with the ABC or GCB subtypes of DLBCL
* Subgroups relevant to DLBCL biology, including CD79b, Myd88, CARD11, and
TNFAIP3; epigenetic markers; and MYC/BCL2 double hit
Background summary
Non-Hodgkin*s lymphoma (NHL) is the most common hematologic malignancy in
adults. The majority of NHL (also known as malignant lymphoma) are of B cell
origin, and are characterized by the expression of a membrane antigen, CD20,
that is important in cell cycle initiation and differentiation. NHL can be
divided into aggressive and indolent NHL. The clinical course of indolent NHL
is characterized by remission and relapse. Although there is no agreed-upon
standard therapy for indolent NHL, R-CHOP is a common regimen, with a high
response rates and long remission duration in many patients, particularly those
patients with follicular lymphoma (FL). Patients with advance stage disease are
not considered curable with conventional treatment and ultimately die from
recurrent disease or treatment-related toxicity. Therefore, there is a need for
the development of new treatments, that could improve both response and
survival rates of patients with indolent NHL.
Diffuse large B-cell lymphoma (DLBCL) is the most common subtype of NHL,
comprising approximately 30% of all NHL cases. Approximately 75% of patients
with DLBCL who are treated with current standard therapy (R-CHOP) achieve a
complete remission, and 50%*60% of patients is cured of their disease with this
treatment. DLBCL is a molecularly heterogeneous disease, with different
molecular subtypes having been identified through gene expression profiling.
Bcl-2 is an anti-apoptotic molecule over expressed in many hematologic
malignancies, including many DLBCLs. Bcl-2 protein inhibits death of lymphoma
cells in response to chemotherapy and other anti-neoplastic agents, including
rituximab (R). Overexpression of Bcl-2 has been shown to be associated with
inferior outcomes in DLBCL with standard treatment. The frequent overexpression
of Bcl-2 combined with its contribution to therapy resistance makes Bcl-2
inhibition an attractive therapeutic target in DLBCL.
venetoclax is a highly selective, orally available small molecule Bcl-2 family
protein inhibitor that
binds with high affinity to Bcl-2 and with lower affinity to other Bcl-2 family
proteins.
Obinutuzumab is a humanized and glycoengineered monoclonal antibody, derived by
humanization of the parental B-Ly1 mouse antibody and subsequent
glycoengineering leading to the following characteristics
* High-affinity binding to CD20
* Type II binding to the CD20 epitope
* Compared with rituximab, increased antibody-dependent cell-mediated
cytotoxicity (ADCC)
* Compared with rituximab, increased direct cell death induction
Obinutuzumab is currently being compared with rituximab in combination with
CHOP chemotherapy in a randomized trial in DLBCL (Study BO21005). If
obinutuzumab proves to be superior to rituximab, standard of care would change
to G-CHOP.
Therefore, the combination of venetoclax with both R-CHOP and G-CHOP will be
examined in this study.
This study will explore the safety of the combination of venetoclax and R-CHOP
or G-CHOP in patients with B cell NHL who are felt to be appropriate candidates
for R-CHOP therapy during initial dose-finding cohorts and will further explore
safety and efficacy in Phase II cohorts of previously untreated DLBCL in order
to identify appropriate populations for evaluation in a Phase III setting.
Study objective
The primary objective of the Phase I portion of the study is the following:
* To estimate the maximum tolerated dosing schedule for venetoclax given in
combination with R-CHOP or G-CHOP to patients with B-cell NHL, either
previously untreated or relapsed/refractory after a maximum of one prior therapy
The primary objectives of the Phase II portion of the study are the following:
* To assess the safety and tolerability of the combination of venetoclax and
R-CHOP or G-CHOP administered to patients with previously untreated DLBCL
* To make a preliminary assessment of efficacy as measured by CR rate
determined by PET/CT scan, of the combination of venetoclax and R-CHOP
administered to patients with previously untreated DLBCL, co expressing both
Bcl-2 and c-Myc proteins
Study design
This is a Phase Ib/II, multicenter, open-label, dose-finding study of
venetoclax administered orally in combination with rituximab or obinutuzumab
and standard doses of CHOP in patients with NHL. Two parallel treatment arms
will explore doses of venetoclax ranging from 200 to 800 mg in combination with
R-CHOP and G-CHOP. Patients will be treated for a total of eight cycles (6
cycles of CHOP and 8 cycles of venetoclax and rituximab or obinutuzumab). Each
cycle will consist of 21 days.
Intervention
Phase Ib: Dose finding
Each study arm (R-CHOP or G-CHOP) will have up to 4 dose-finding cohorts
exploring venetoclax doses ranging from 200 to 800 mg. Patients will be
allocated to a study arm in an alternating fashion, starting with Arm A, Cohort
1, followed by Arm B, Cohort 1, Arm A, Cohort 2, etc.
TLS is a known risk following initiation of chemotherapy and anti-CD20 therapy
in DLBCL. It is possible that, with the combination of venetoclax and
chemoimmunotherapy, an increased rate and severity of TLS could occur. In order
to mitigate the risk for TLS, venetoclax will be initiated on Day 4 of Cycle 1.
Cycle 1
Patients in the R-CHOP arm will receive the first rituximab infusion (375
mg/m2), administered per package insert (along with standard premedications) on
Day 1 (Cycle 1 Day 1)
Patients in the G-CHOP arm will receive their first obinutuzumab infusion (1000
mg) on Day 1 (Cycle 1 Day 1) along with standard premedication. During Cycle 1,
obinutuzumab will also be administered on Days 8 and 15.
Following rituximab or obinutuzumab infusion, patients will receive CHOP
chemotherapy as per standard administration procedures, along with standard
premedications.
Oral dosing of venetoclax will start on Day 4 of the first cycle (Cycle 1 Day
4). Patients will be monitored for signs of acute TLS for at least 8 hours
after the first venetoclax dose. Oral dosing of venetoclax will continue on a
daily basis through Cycle 8 Day 21.
Cycle 2-6
Patients will continue to receive an oral daily dose of venetoclax. On Day 1 of
each cycle, venetoclax will be administered prior to any infusions. Rituximab
or obinutuzumab will be administered on Day 1 along with CHOP as per standard
administration guidelines. venetoclax will continue on a daily basis for all
cycles.
Cycles 7-8
Patients will continue receiving an oral daily dose of venetoclax. On Day 1 of
Cycles 7 and 8, venetoclax will be administered prior to infusion of rituximab
or obinutuzumab.
On days that predose PK sampling is required, venetoclax dosing will occur in
the clinic to facilitate PK sampling.
Patients should be premedicated with antihistamines and acetaminophen
(corticosteroids if necessary) and anti-emetics and IV hydration per
institutional policy and standard of practice.
Phase II:
The Phase II portion of the study will consist of one cohort for each study arm
using the established dosing schedule identified during the dose-finding stage.
Patients will be assigned to Arm A (venetoclax + R-CHOP) or Arm B (venetoclax +
G-CHOP) through randomization. The Phase II portion will only enroll patients
with previously untreated DLBCL.
Study burden and risks
venetoclax
Treatment with venetoclax in cancer patients has been associated with nausea,
decreases in lymphocytes and neutrophils (two different types of white blood
cells), decreases in red blood cells (anemia), infections and tumor lysis
syndrome (TLS).
Obinutuzumab
The side effects of obinutuzumab appear generally similar to those with
rituximab. During or after treatment administration patients may develop fever,
chills and shivering or other infusion-related effects. Preexisting heart
conditions such as angina pectoris or congestive heart failure may get worse.
The frequency of such reactions decreases with subsequent infusions. Because
of the possibility of a reaction like this, patients will be monitored closely
during each infusion and for a time afterward. Other side effects such as TLS,
allergic reactions, infections or abnormal laboratory tests can occur.
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Listed location countries
Age
Inclusion criteria
General Inclusion Criteria:
- Patients, age ><= 18 years
- At least one bi-dimensionally measurable lesion defined as >1.5 cm in its longest dimension
- Ability and willingness to comply with the study protocol procedures
- Confirmed availability of archival or freshly biopsied tumor tissue prior to study enrollment
- ECOG performance status of 0, 1, or 2
- Adequate hematologic function
- For female patients of childbearing potential and male patients with female partners of childbearing potential, agreement to use highly effective forms of contraception ;Dose Escalation Portion of the Study:
- Patients must have histologically confirmed B-cell non-Hodgin's Lymphoma (NHL)
- Patients must have never received previous R-CHOP treatment
- Any relapsed/refractory patients that are enrolled during the dose escalation should have received only a single previous treatment regimen;Expansion Portion of the Study:
- Patients must have previously-untreated diffuse large, B-cell lymphoma
- International prognostic index (IPI) score must be 2-5
Exclusion criteria
General Exclusion Criteria:
- Contraindication to receive any of the individual components of CHOP, rituximab or obinutuzumab
- Primary CNS lymphoma
- Vaccination with live vaccines within 28 days prior to randomization
- History of other malignancy that could affect compliance with the protocol or interpretation of results
- Evidence of significant, concomitant disease or illness
- Use of CYP3A inhibitors or inducers within 7 days of the first dose of venetoclax
- Requires use of Warfarin
- Recent major surgery
- Women must not be pregnant or breastfeeding;Dose Escalation Portion of the Study:
- Prior anthracycline therapy
- Chemotherapy or other investigational therapy within 5 half-lives of a biologic agent with a minimum of 28 days prior to the start of Cycle 1
- histologically confirmed mantle cell lymphoma (MCL) or small lymphocytic lymphoma (SLL);Expansion Portion of the Study:
- Patients with transformed lymphoma
- Prior therapy for non-hodgkin's lymphoma (NHL)
- Current Grade > 1 peripheral neuropathy
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 | EUCTR2013-003749-40-NL |
| ClinicalTrials.gov | NCT02055820 |
| CCMO | NL48557.029.14 |