Primary Objective: Safety Run-in Period:To evaluate the occurrence of tumor lysis syndrome (TLS) and doselimiting toxicities (DLTs) with the concurrent administration of ibrutinib and venetoclax.Randomization Phase:To evaluate whether the…
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Brief title
Condition
- Lymphomas non-Hodgkin's B-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Randomization Phase:
To evaluate whether the combination of ibrutinib and venetoclax will result in
prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed
or refractory MCL.
Treatment-naive Open-label Arm Primary Endpoint
The primary efficacy endpoint of the treatment-naive open-label arm is the
complete response (CR) rate based on the best overall response according to the
Revised Response Criteria for Malignant Lymphoma
(Cheson 2014) - every 3 months for the first year starting with week 13; every
4 months during the second and third years, and every 6 months thereafter until
PD
Secondary outcome
Secondary Objective:
Safety Run-in Period: To evaluate response (partial and complete response),
progression-free survival (PFS), duration of response (DOR), and overall
survival (OS).
Randomization Phase:
• To evaluate whether the combination of ibrutinib and venetoclax will increase
the complete response (CR) rate, the overall response rate (ORR), the minimal
residual disease (MRD) negative remission rate in subjects who were MRD
positive at screening and achieve CR, OS, DOR, and time-to-next treatment
(TTNT) compared to ibrutinib and placebo.
• To evaluate the frequency, severity, and relatedness of adverse events (AEs);
frequency, severity and management of TLS; AEs requiring dose reductions and/or
discontinuation of study drug, or leading to death.
• To determine the pharmacokinetics (PK) of ibrutinib and venetoclax.
• To evaluate whether the combination of ibrutinib and venetoclax will improve
quality of life using a Health-related quality of life questionnaire (FACT-Lym)
compared to ibrutinib and placebo.
Treatment-Naive Open-Label Arm Secondary Endpoints
•Overall response rate (ORR), defined as CR or PR according to the Revised
Response Criteria for Malignant Lymphoma (Cheson 2014) - every 3 months for the
first year starting with week 13; every 4 months during the second and third
years, and every 6 months thereafter until PD
•Duration of Response (DOR), defined for subjects who achieve an overall
response as the time from the first occurrence of response (CR or PR) to
disease progression or death, whichever occurs first - every 3 months for the
first year starting with week 13; every 4 months during the second and third
years, and every 6 months thereafter until PD
•Duration of CR, defined for subjects who achieve CR as the time from the first
occurrence of CR to disease progression or death, whichever occurs first -
every 3 months for the first year starting with week 13; every 4 months during
the second and third years, and every 6 months thereafter until PD
•MRD-negative remission rate in subjects who achieve CR. MRD-negative remission
is defined the same as described in Section 10.2.3 of the Protocol - every 3
months for the first year starting with week 13; every 4 months during the
second and third years, and every 6 months thereafter until PD
•PFS, defined as the time from the date of the first dose of study treatment to
the date of disease progression using the Revised Response Criteria for
Malignant Lymphoma (Cheson 2014), or death from any cause, whichever occurs
first - every 3 months for the first year starting with week 13; every 4 months
during the second and third years, and every 6 months thereafter until PD
•OS, defined as the time from the date of the first dose of study treatment to
death from any cause - after progression every 12 weeks until death
•TTNT, defined as the duration from the date of the first dose of study
treatment to the start date of any anti-lymphoma treatment subsequent to study
treatment - after progression every 12 weeks until death
Background summary
Mantle cell lymphoma (MCL) accounts for about 6-9% of all non-Hodgkin lymphoma
(NHL) cases in the Western world. The annual incidence of MCL has increased
during recent decades to 1-2/100,000. MCL occurs more frequently in older
adults. Most patients with MCL are men (median age: 65 years) who present with
advanced stage disease (ie, Stage III or IV). Though the clinical course of MCL
may be somewhat indolent at diagnosis, the course invariably becomes aggressive
over time. Unlike other NHLs, MCL is considered incurable with standard
therapies and is associated with a poor prognosis and a relatively short median
overall survival.
Current initial therapy for the treatment of MCL includes cyclophosphamide,
doxorubicin, vincristine, and prednisone (CHOP) or hyperfractionated
cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with
methotrexate and cytarabine (Hyper-CVAD), often in combination with rituximab
(R-CHOP or R-Hyper CVAD). In recent years, treatment with bendamustine and
rituximab has gained increasing use following studies showing that this
combination significantly prolongs PFS, while maintaining a favorable safety
profile among patients with previously untreated MCL.
In cases of early relapses or in patients with refractory disease, newer
targeted approaches should be strongly considered. Three non-cytotoxic drugs,
ibrutinib, bortezomib and lenalidomide, are FDA approved for previously treated
patients with MCL in the US. In the European Union, approved treatment in the
relapsed and refractory MCL setting was limited to temsirolimus until the
approval of ibrutinib in 2014. Based on registration trials, the ORR for these
drugs are 68% (21% CR) with ibrutinib, 33% (8% CR) with bortezomib, 28% (8% CR)
with lenalidomide, and 22% (2% CR) with temsirolimus.
These drugs are being combined with rituximab and incorporated into standard
therapeutic and maintenance regimens showing some improved efficacy. Despite
the fact that results from ibrutinib showed marked improvement over
temsirolimus, the median PFS of approximately 14 months underscores the need to
improve further on the dismal outcome for relapsed MCL patients, with a median
PFS of 13.9, 6.5, 4 and
4.8 months, respectively.
Based on the preliminary data showing a CR rate of 70% with an acceptable
safety profile observed in an ongoing study of ibrutinib and venetoclax in
patients with relapsed or refractory MCL (Tam 2016) coupled with the durability
of responses observed with ibrutinib monotherapy and venetoclax monotherapy in
patients with relapsed or refractory MCL who achieved CR observed with each
(Rule 2016, Gerecitano 2015), the combination of ibrutinib and venetoclax is
expected to induce deep and durable responses in patients with
relapsed/refractory MCL.
In treatment-naive MCL, the standard of care for patients that
are >=65 years of age and transplant-ineligible is BR or a variety of other
options based on fitness
level. The reported overall response rates with different therapeutic
approaches for treatment naive
MCL patients with varying fitness levels vary from 75 - 94%, the corresponding
CR rates vary from 35 - 72% and for BR, one of the most commonly used therapies
used in the transplant-ineligible and less fit treatment-naive MCL population,
are
approximately around 50%. Patients with a TP53 mutation are chemo-insensitive
and therefore have limited treatment
options.
Based on recent encouraging results in a study of ibrutinib and venetoclax
including 24 patients, with a median age of 68 years (CR rate of 71% overall
and CR rate of 50% in patients with a TP53 mutation), among which 1
treatment-naive MCL patient with a TP53 mutation who responded (Tam2018), it is
of interest to explore the combination of ibrutinib and venetoclax
in treatment-naive MCL in patients that are >=65 years of age and
transplant-ineligible and in
patients with a TP53 mutation.
Study objective
Primary Objective:
Safety Run-in Period:
To evaluate the occurrence of tumor lysis syndrome (TLS) and doselimiting
toxicities (DLTs) with the concurrent administration of ibrutinib and
venetoclax.
Randomization Phase:
To evaluate whether the combination of ibrutinib and venetoclax will result in
prolongation of PFS compared to ibrutinib and placebo in subjects with relapsed
or refractory MCL.
Treatment-naive Open-label Arm:
To evaluate the complete response (CR) rate with the combination of ibrutinib
and venetoclax in subjects with treatment-naive MCL
Study design
This Phase 3 multinational, randomized, double-blind study is designed to
compare the efficacy and safety of the combination of ibrutinib and venetoclax
vs. ibrutinib and placebo in subjects with MCL.
A separate open-label arm is designed to explore the efficacy and safety of the
combination of
ibrutinib and venetoclax in subjects with treatment-naive MCL. Approximately 50
subjects >=65 years and approximately 25 subjects less than 65 years of age with
a TP53 mutation will be enrolled.
Intervention
Ibrutinib
• 560 mg of ibrutinib dosed orally once daily. Ibrutinib may be supplied either
as 560 mg tablet (1 tablet dosed once daily) or as 140 mg capsules (4 capsules
dosed once daily)
Venetoclax
• Orally once daily venetoclax at a target dose of 400 mg (4 X 100 mg).
Placebo (only in Safety Run-in and Randomization Phase)
• Oral once daily matching placebo for venetoclax at a target dose of 400 mg (4
X 100 mg).
Ibrutinib 560 mg (4 x 140-mg capsules) is administered orally once daily. The
ibrutinib capsules are to be taken with venetoclax(/placebo tablets) at
approximately the same time each day with a meal and water.
In order to assess tumor lysis syndrome (TLS) and dose limiting toxicity (DLT),
6 patients will initially be treated with ibrutinib at 560 mg daily and
venetoclax starting at 20 mg and gradually ramped up to a target dose of 400 mg
once daily over a 5-week period.
Study burden and risks
Several in vitro studies have shown ibrutinib and venetoclax to be an active
combination. In one study, MCL cell lines and leukemic patient cells were
exposed to ibrutinib, venetoclax and the combination for 72 hours. The
combination substantially increased induction of apoptosis compared to each
agent alone (combo: 23%, ibrutinib: 3.8%, venetoclax: 3.0%).
A separate study using MCL cell lines confirmed the synergistic effect of
ibrutinib and
venetoclax on proliferation inhibition and apoptosis through perturbation of
the BTK, AKT and
BCL2 pathways providing further mechanistic rationale for co-targeting of these
two oncogenic pathways.
Supportive in vivo data is derived from a CCMCL1/NSG mouse model where the
ibrutinib and
venetoclax combination was tested. The combination produced apoptosis of MCL
tumor cells, which was associated with a down-regulation of SOX11 and PAX5.
Simultaneous downregulation of MCL1 via ibrutinib and targeting of BCL2 was
hypothesized to contribute to the in vitro synergism and in vivo activity
observed in this report.
With respect to venetoclax monotherapy activity, in clinical trial M12-175,
venetoclax was tested in 28 subjects with relapsed/refractory MCL at target
doses of 200 to 1200 mg. The ORR was found to be 75% with a CR rate of 21%
(Gerecitano 2015). Based on these data and prior
ibrutinib studies, the ongoing AIM Trial (ABT-199 and ibrutinib in MCL) is
evaluating the combination of ibrutinib at 560 mg and venetoclax at a target
dose of 400 mg in subjects with relapsed and refractory MCL. This study is
using a 4-week venetoclax ramp-up after 4 weeks of
ibrutinib monotherapy. Twenty-one subjects have completed response assessments
at the
primary endpoint landmark of 16 weeks; 10 subjects achieved confirmed CR
(including MRD
clearance), 4 subjects achieved unconfirmed CR, and 4 subjects achieved PR (Tam
2017). These results display a high initial response rate for the ibrutinib and
venetoclax combination.
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Age
Inclusion criteria
For SRI and Randomization Phase
Disease-Related
• Pathologically confirmed MCL (in tumor tissue), with documentation of either
overexpression of cyclin D1 in association with other relevant markers (eg,
CD19, CD20, PAX5, CD5) or evidence of t(11;14) as assessed by cytogenetics,
fluorescent in situ hybridization (FISH), or polymerase chain reaction (PCR).
• At least 1 measurable site of disease on cross-sectional imaging that is >=2.0
cm in the longest diameter and measurable in 2 perpendicular dimensions per CT
• At least 1, but no more than 5, prior treatment regimens for MCL including at
least 1 prior rituximab/anti-CD20 containing regimen
• Failure to achieve at least partial response (PR) with, or documented disease
progression after, the most recent treatment regimen
• Subjects must have adequate fresh or paraffin embedded tissue., Laboratory
• Adequate hematologic function
• Adequate hepatic and renal function, Demographic
• Men and women >= 18 years of age
• Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <=2.
For Treatment-naive Open-label Arm:
1. Pathologically confirmed treatment-naive MCL (tumor tissue), with
documentation of either
overexpression of cyclin D1 in association with other relevant markers (eg,
CD19, CD20,
PAX5, CD5) or evidence of t(11;14), as assessed by cytogenetics, fluorescent in
situ
hybridization (FISH), or polymerase chain reaction (PCR)
• A report from the local laboratory is acceptable if available; however, it
must be reviewed
and approved by the central pathology laboratory to verify the above criteria
prior to
enrollment
• If the report from the local laboratory is not available, a tumor block or
slides must be sent
to the central pathology laboratory for confirmation of the MCL diagnosis prior
to
enrollment.
2. Men and women >=18 years of age, with a TP53 mutation
3. At least 1 measurable site of disease that is >=2.0 cm in the longest
diameter and measurable in
2 perpendicular dimensions per CT
4. Subjects must have adequate fresh or paraffin-embedded tissue
5. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of <= 2
6. Adequate hematologic function independent of transfusion and growth factor
support for at
least 7 days prior to first dose, with the exception of pegylated G-CSF
(pegfilgrastim) and
darbepoeitin which require at least 14 days prior to the first dose defined as:
• Absolute neutrophil count (ANC) >1000 cells/mm3 (1.0 x 109/L)
• Platelet count >50,000 cells/mm3 (50 x 109/L)
• Hemoglobin >8.0 g/dL
7. Adequate hepatic and renal function defined as:
• Serum aspartate transaminase (AST) or alanine transaminase (ALT) <=3.0 x upper
limit of
normal (ULN)
• Estimated Creatinine Clearance (CrCl) >=30 mL/min (Cockcroft-Gault)
• Bilirubin <=1.5 x ULN (unless bilirubin rise is due to Gilbert*s syndrome or
of non-hepatic
origin)
8. Prothrombin time (PT) or International normal ratio (INR) <1.5 x upper limit
of normal
(ULN) and PTT (activated partial thromboplastin time [aPTT]) <1.5 x ULN (unless
abnormalities are unrelated to coagulopathy or bleeding disorder). When treated
with warfarin
or other vitamin K antagonists, then INR <=3.0
9. Male and female subjects of reproductive potential who agree to use both a
highly effectivemethod of birth control (eg, implants, injectables, combined
oral contraceptives, some
intrauterine devices [IUDs], complete abstinence5, or sterilized partner) and a
barrier method
(eg, condoms, cervical ring, sponge, etc) during the period of therapy and for
90 days after the
last dose of study drug
Exclusion criteria
For SRI and Randomization Phase
Disease-Related
• History or current evidence of central nervous system lymphoma Concurrent
Conditions
• Concurrent enrollment in another therapeutic investigational study or prior
therapy with ibrutinib or other BTK inhibitors
• Prior treatment with venetoclax or other BCL2 inhibitors
• Anticancer therapy including chemotherapy, radiotherapy, small molecule and
investigational agents <=21 days prior to receiving the first dose of study drug
• Treatment with any of the following within 7 days prior to the first, dose of
study drug:
• moderate or strong cytochrome P450 3A (CYP3A) inhibitors
• moderate or strong CYP3A inducers
For Treatment-naive Open-label Arm:
1. Blastoid variant of MCL
2. History or current evidence of central nervous system lymphoma
3. Concurrent enrollment in another therapeutic investigational study or prior
therapy, including
ibrutinib or other BTK inhibitors
4. Prior treatment with venetoclax or other BCL2 inhibitors
5. History of other malignancies, except:
• Malignancy treated with curative intent and with no known active disease
present for
>=3 years before the first dose of study drug and felt to be at low risk for
recurrence by
treating physician
• Adequately treated non-melanoma skin cancer or lentigo maligna without
evidence of
disease.
• Adequately treated carcinoma in situ without evidence of disease.
6. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose
of study drug
7. Clinically significant infection requiring IV systemic treatment that was
completed <=14 days
before the first dose of study drug
8. Any uncontrolled active systemic infection
9. Known bleeding disorders (eg, von Willebrand*s disease or hemophilia)
10. History of stroke or intracranial hemorrhage within 6 months prior to
enrollment
11. Known history of human immunodeficiency virus (HIV) or active with
hepatitis C virus
(HCV) or hepatitis B virus (HBV). Subjects who are positive for hepatitis B
core antibody, or
hepatitis C antibody must have a negative polymerase chain reaction (PCR)
result before
enrollment. Those who are hepatitis B surface antigen (HBsAg) or PCR positive
will be
excluded.
12. Major surgery within 4 weeks of the first dose of study drug.
13. Any life-threatening illness, medical condition, or organ system
dysfunction that, in the
investigator*s opinion, could compromise the subject*s safety or put the study
outcomes at
undue risk
14. Currently active, clinically significant cardiovascular disease, such as
uncontrolled
arrhythmia or Class 3 or 4 congestive heart failure as defined by the New York
Heart
Association Functional Classification; or a history of myocardial infarction,
unstable angina, or
acute coronary syndrome within 6 months prior to randomization
15. Unable to swallow capsules or tablets, or malabsorption syndrome, disease
significantly
affecting gastrointestinal function, or resection of the stomach or small
bowel, symptomatic
inflammatory bowel disease or ulcerative colitis, or partial or complete bowel
obstruction
16. Treatment with any of the following within 7 days prior to the first dose
of study drug:
• Moderate or strong cytochrome P450 3A (CYP3A) inhibitors
• Moderate or strong CYP3A inducers
17. Administration or consumption of any of the following within 3 days prior
to the first dose
of study drug:
• grapefruit or grapefruit products
• Seville oranges (including marmalade containing Seville oranges)
• star fruit
18. Known allergy to xanthine oxidase inhibitors and/or rasburicase for
subjects with known
risk factors (as defined by high tumor burden and/or diminished renal function,
as detailed in
*Study Design* section above) for TLS
19. Subjects with chronic liver disease with hepatic impairment Child-Pugh
class B or C
20. Female subject who is pregnant, breastfeeding or is considering becoming
pregnant during
the study or for approximately 90 days after the last dose of study drug
21. Male subject who is considering fathering a child or donating sperm during
the study or for
approximately 90 days after the last dose of study drug
22. Unwilling or unable to participate in all required study evaluations and
procedures
23. Unable to understand the purpose and risks of the study and to provide a
signed and dated
informed consent form (ICF) and authorization to use protected health
information
(in accordance with national and local subject privacy regulations)
24. Known hypersensitivity to the active ingredient or other components of one
or more study
Drugs
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 | EUCTR2017-000129-12-NL |
| ClinicalTrials.gov | NCT03112174 |
| CCMO | NL63543.078.17 |