This study aims to test the hypothesis that zandelisib in combination with rituximab has better clinical activity and risk/benefit profile compared to standard 2nd line immunochemotherapy (R-CHOP/R-B) in subjects with relapsed FL or MZL. Primary…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's unspecified histology
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
PFS as determined by the IRRC
Secondary outcome
• Efficacy: ORR and CRR as determined by the IRRC
• OS
• PRO - time to deterioration in the 9-item DRS-P subset of FlymSI-18
• PRO-change from baseline in EQ-5D total score at specified study visits
• Treatment-emergent AEs, serious AEs, and laboratory abnormalities
Background summary
Indolent B-cell lymphomas (NHLs), which include follicular lymphoma (FL) and
marginal zona lymphoma (MZL), generally have a good prognosis and median
survival rates longer than 10 years, but are not curable with current available
therapeutic options, especially for those with advanced stages at diagnosis.
While FL and MZL respond initially to therapy, their natural history is
characterized by remissions and relapses. Although most relapses can be
generally treated with success, the quality and duration of remissions
decreases over time. Finally, these lymphomas evolve into refractory disease or
undergo transformation into an aggressive histologic type with poor prognosis.
Therapeutic options for previously untreated FL and MZL include single agent
anti-CD20 immunotherapy (most commonly with rituximab (Rituxan®, MabThera®, or
biosimilar, [R]); in this protocol, henceforth, R refers to rituximab, i.e.,
Rituxan, MabThera, or biosimilar); to anti-CD20-based immunochemotherapy (most
commonly the combination of R with cyclophosphamide, hydroxydoxorubicin,
vincristine and prednisone (CHOP) designated as R-CHOP or the alkylating agent
bendamustine (B) designated as R-B. Other chemotherapy regimens are also
acceptable in combination with an anti-CD20 antibody as well as the combination
of R and lenalidomide (Revlimid® [L]) (R-L).
For patients with relapsed disease, a similar immunochemotherapy approach,
utilizing a chemotherapy regimen not previously administered, can be used. The
combinations of R-B showed high rates of objective response of >=90%, and median
progression-free survival (PFS) of 23-24 months. Combination of R and
chemotherapy for relapsed disease is associated with a PFS of about 18 months.
Response outcome varies based on duration of prior response, disease-and
patient related factors. However, the disease will inevitably relapse.
Therefore, active agents with different mechanisms of action than cytotoxic
chemotherapy are needed for patients with relapsed disease. Furthermore, since
the median age of patients with FL and MZL at relapse is >60 years, new
treatment options must be well-tolerated and avoid the toxicities typically
reported with chemotherapy.
Phosphoinositide 3 kinase (PI3K) inhibitors, a novel class of drugs for B-cell
malignancies, have proven to be active in patients with FL and MZL, but the
benefit of therapy is often limited by class-associated toxicities potentially
related to immune dysfunction, including effects on regulatory T-cells. These
toxicities are often delayed and cumulative in nature, and include diarrhea and
colitis, stomatitis, hepatitis (elevation of transaminases), infectious and
non-infectious pneumonitis.
Zandelisib (code name ME-401), is an orally bioavailable PI3Kδ inhibitor with
optimal pharmacologic properties and high potency, with a plasma half-life (t*)
of approximately 28 hours supporting once-daily dosing. In an ongoing Phase 1b
study (ME-401-002), zandelisib has been evaluated in a continuous daily dosing
schedule (CS) and an intermittent schedule (IS), with zandelisib given daily
for 2 initial cycles followed by 1 week on, 3 weeks off therapy in every
subsequent 28-day cycle. Preliminary data indicate that both treatment
schedules were associated with a high and comparable response rate in subjects
with indolent B-cell malignancies, while the IS led to a significant reduction
in Grade (Gr) 3 class-related adverse events (AE) compared to CS. The incidence
of these AEs with the IS and the CS, respectively, were: colitis/diarrhea (5%
and 23%), rash/skin reaction (0% and 8%), stomatitis (0% and 3%), AST/ALT
elevation (2% and 8%), pneumonia/infectious pneumonitis (2% and 10.0%). With IS
dosing, these Gr 3 AEs were not reported beyond Cycle 3, when zandelisib is
administered for 1 week per cycle, whereas there is a continued increase in the
cumulative risk of Gr 3 AEs in the CS group.
In 36 subjects with FL in the IS group, the overall response rate (ORR) was 83%
(76% in monotherapy group, 89% in zandelisib in combination with rituximab),
and the median duration of response was not reached with a median follow-up of
13.2 months (15.4 months for monotherapy and 12.8 months in combination with
rituximab). The ORR in 9 subjects with CLL/SLL was 89% (100% monotherapy and
83% combination therapy with rituximab) and 100% in 4 subjects with MZL (all
enrolled in the rituximab combination group). Therapy on IS proved to be well
tolerated, with few subjects experiencing Gr 3 class-related AEs. Those who had
treatment interruptions were successfully re-challenged with zandelisib
therapy.
To date, over 150 subjects have been treated with zandelisib as a single agent
or in combination with other agents. Zandelisib monotherapy is being evaluated
in a global Phase 2 study in subjects with FL who have received 2 prior lines
of therapy. IS dosing is being evaluated in all clinical studies with
zandelisib.
Study objective
This study aims to test the hypothesis that zandelisib in combination with
rituximab has better clinical activity and risk/benefit profile compared to
standard 2nd line immunochemotherapy (R-CHOP/R-B) in subjects with relapsed FL
or MZL.
Primary Objective
• To demonstrate that zandelisib in combination with R is superior to standard
immunochemotherapy in prolonging PFS as determined by the Independent Response
Review Committee (IRRC) in previously treated subjects with follicular and
marginal zone lymphoma
Secondary objectives
• Time to next anti-lymphoma treatment (TTNT)
• PFS on next anti-lymphoma treatment (PFS2)
• To compare zandelisib + R to standard immunochemotherapy by ORR and complete
response rate (CRR) as determined by the IRRC
• To compare zandelisib + R to standard immunochemotherapy by overall survival
(OS)
• To evaluate Patient Reported Outcome (PRO) assessment with:
o FlymSI-18
o PRO with EuroQol 5 Dimension 3 Level (EQ-5D-3L)
• To evaluate the safety and tolerability of zandelisib in combination with R
Exploratory objectives
To evaluate
• Efficacy:
o PFS, CRR and ORR, as determined by the Investigator
o ORR at week 24 by the Investigator and by the IRRC
o DOR by the Investigator and by the IRRC
o Time to progression (TTP) by the Investigator and by the IRRC
• To characterize the relationship between zandelisib exposure in plasma with
efficacy and safety
Study design
This is an open label, randomized, two-arm Phase 3 study in subjects with
relapsed or refractory FL and MZL to evaluate efficacy and safety of zandelisib
in combination with rituximab in comparison to standard immunochemotherapy (R-B
or R-CHOP). Subjects must have relapsed after at least one previous line of
systemic immunochemotherapy. Previous treatments must have included an
anti-CD20 monoclonal antibody (mAb) with chemotherapy such as B, CHOP, CVP,
FND, or similar regimens, or an anti-CD20 mAb with L.
Subjects who meet the eligibility criteria will be randomly assigned in a 1:1
ratio to one of the treatment arms:
• Arm 1: R plus zandelisib
• Arm 2: R plus chemotherapy (CHOP or B)
Subjects will be stratified based on following criteria:
• Prior treatment regimen: anti-CD20 mAb in combination with non bendamustine
chemotherapy regimen or R-L vs. anti-CD20 mAb in combination with B
• Number of prior therapies: 1 vs. >1
• NHL histology: FL vs. MZL
• Duration of treatment-free interval from the last lymphoma-directed therapy:
<=24 months vs. >24 months
Study treatments will be administered as detailed above. Treatment will be
discontinued at any time in case of disease progression or unacceptable
toxicity. Before treatment discontinuation due to any reason, including disease
progression, the Investigator must review the reasons with the Sponsor*s
medical monitor or designee.
Primary analysis will be based on assessment of efficacy by an IRRC. Subject
management will be based on disease response assessment according to
investigators.
During the study, continuing review of safety data by the sponsor and an
independent Data Monitoring Committee (DMC) will be performed. An independent
DMC will regularly review safety and efficacy data from all subjects to assess
benefit/risk profile of zandelisib-rituximab therapy. The DMC will meet at
least once every 3 months, with the first data review meeting occurring when
approximately 60 subjects (~30 in each arm) have completed at least 1 cycle of
treatment or 6 months after the first subject is dosed, whichever occurs first.
Details of this review will be outlined in a separate DMC charter document.
The study is composed of the following periods:
• Screening
• Treatment
• Follow-up (efficacy follow-up until disease progression, safety follow-up,
and survival follow-up)
Intervention
Study Treatments
Zandelisib:
Administered in a 28-day cycle.
Zandelisib capsule should be taken once a day on dosing days at approximately
the same time in the morning on an empty stomach on the following schedule:
60 mg daily for the first two cycles of therapy (56 days) followed by:
60 mg for the first 7 days followed by 21 days off treatment in every
subsequent 28 day cycle, defined as the IS.
Rituximab:
R is administered by intravenous infusion according to institutional standards
• R 375 mg/m2 body surface on Day (D)1, D8, D15, and D22 of Cycle (C)1 and then
on D1 of C3, C4, C5, and C6 for a total of 8 doses in 6 cycles
Dosing of immunochemotherapy (C1-C6):
R-B will be administered in a 28-day cycle as follows:
• R intravenously (IV) 375 mg/m2 body surface on D1
• B IV 90 mg/m2 body surface on D1 and D2
R-CHOP will be administered in a 21-day cycle as follows:
• R IV 375 mg/m2 body surface on D1
• Cyclophosphamide IV 750 mg/m2 body surface on D1
• Doxorubicin IV 50 mg/m2 body surface on D1
• Vincristine IV 1.4 mg/m2 body surface (maximum dose 2 mg) on D1
• Prednisone 100 mg daily orally (PO) from D1 to D5
The chemotherapy regimen administered in the study must be different from the
one used as prior line of therapy.
• Subjects who received B with anti-CD20 antibody (R or obinutuzumab [O]) as a
prior line of therapy will be allocated to R CHOP if randomized to the R
chemotherapy treatment group
• Subjects who received CHOP or another chemotherapy regimen, (e.g.,
cyclophosphamide, vincristine, prednisone (CVP), fludarabine, + mitoxantrone +
dexamethasone, [FND]), with anti-CD 20 antibody (R or O) or R-L previously,
will be allocated to R-B if randomized to the R-chemotherapy group.
Study burden and risks
Participants may experience the side effects and discomforts as described below
and in Appendix. D of the Patient Information Form
- There may be some discomfort from the measurements during the study.
- Taking part in the study will cost the participant extra time.
- The participant will need to come to the hospital more often
- The participant will have to comply with the study agreements.
- The participant will have to follow strict rules about taking medicines.
- The questionnaires can be confrontational
- The participant will be exposed to 83-133 mSv of radiation in the first
year, 33-63 mSv in the second year and 22-42 mSv for each year
onwards. If MUGA scan will be used, the participant will be exposed to
an additional 7-8 mSv radiation dose
The following side effects of the study drug are common (in 10% or more):
(Applicable for participants in Group 1 only)
• Diarrhea (loose stools) and colitis (inflammation of the colon).
• Abdominal pain (stomach pain) and constipation.
• Decreased appetite.
• Gastroesophageal reflux disease (heartburn, acid reflux).
• Nasal congestion, wet cough, upper respiratory tract infection.
• Rash and skin reactions.
• Nausea.
• Fatigue (tiredness).
• Cough.
• Oedema peripheral (swelling of legs).
• Stomatitis (inflammation of the mouth and lips).
• Hepatitis (iInflammation of the liver) as reflected by increased liver
enzymes in laboratory measurements.
• Pneumonitis (iInflammation of the lungs) and pneumonia (inflammation of the
lungs caused by an infection).
• Neutropenia (a rReduction of certain white blood cells circulating around the
body).
• Blood creatinine increased (dDecreased kidney function).
• Thrombocytopenia (a reduction of bloodplatelets/thrombocytes [components of
blood that react to bleeding from blood vessel injury by clumping together and
forming a blood clot] circulating around the body).
• Pyrexia (raised Raised temperature, fever).
For participants in group 1, treatment may include a more effective, safer and
less toxic option compared to standard treatment but also participants in group
1 may not get any direct benefit at all
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Listed location countries
Age
Inclusion criteria
1. Male or female subjects >=18 years of age, >=19 years in Korea, or >=20 years
for subjects in Japan and Taiwan, at time of signing informed consent
2. Histologically confirmed diagnosis of CD20 positive iNHL with histological
subtype limited to:
a. FL Gr 1, Gr 2, or Gr 3a
b. MZL (splenic, nodal, or extra-nodal)
[Histopathological report confirming diagnosis must be available during
screening procedures]
3. Subjects with relapsed or refractory disease who received >=1 prior lines of
therapy that must have included an anti-CD20 antibody in combination with
cytotoxic chemotherapy or L, with or without subsequent maintenance therapy. [A
line of therapy is defined as following: a minimum of 2 consecutive cycles of
immunochemotherapy or R-L, at least 4 doses of anti-CD20 mAb (R) single agent
therapy a minimum of 2 consecutive cycles of therapy with an investigational
agent. Maintenance therapy given after an induction treatment (e.g., R
maintenance) is considered as the same line of therapy]. [Please seeExclusion
Criteria #2 for further clarification]. Relapsed or refractory disease defined
as:
• Relapsed disease: disease progression after a response (complete response
[CR] or partial response [PR]) lasting >=6 months
• Refractory disease: no response to therapy (no CR or PR) or response lasting
<6 months
4. Subjects must have at least one bi-dimensionally measurable nodal lesion
with the longest diameter > 1.5 cm and/or an extranodal lesion >1.0 cm in the
longest diameter (that has not been previously irradiated) according to the
Lugano Classification
5. Adequate hematologic parameters at screening unless abnormal values are due
to disease per Investigator assessment:
• Absolute neutrophil count (ANC) >=1.0 × 109/L (>=1,000/mm3)
• Platelet count >=75.0 × 109/L (>=75,000/mm3)
• Hemoglobin >=9 g/dL
6. Adequate renal and hepatic function per local laboratory reference range at
screening as follows:
• Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <=1.5 × upper
limit of normal (ULN)
• Total bilirubin <=2.0 × ULN or <=3 × ULN for subjects with Gilbert-Meulengracht
syndrome
• Estimated glomerular filtration rate (eGFR) >50 mL/min using the
Cockcroft-Gault equation (Appendix 2)
7. QT-interval corrected according to Fridericia*s formula (QTcF) <=450 msec;
subjects with QTc >450 msec but <480 msec may be enrolled provided the
QTc prolongation is due to a right bundle branch block (RBBB), left bundle
branch block (LBBB), or pacemaker and is confirmed stable by a cardiologist.
8. Left ventricular ejection fraction (LVEF) >=45% as measured by echocardiogram
(ECHO) or multi-gated acquisition scan. [If LVEF <45% by ECHO, a repeat
measurement can be conducted within the screening period.]
9. Subjects must have completed any prior systemic anti-cancer treatment >=4
weeks (or >=5 times the half-life [t*] of used therapeutics [including
investigational therapy], whichever is longer) or radiation therapy >=2 weeks
before study D1, and >=3 months before study D1 for high dose therapy with stem
cell transplantation, radioimmunotherapy, and CAR T-cell therapy.
10. Eastern Cooperative Oncology Group (ECOG) performance status 0-1
11. Life expectancy of at least 3 months
12. All AEs and laboratory toxicities related to prior therapy must resolve to
Gr <=1 prior to the start of the study therapy (unless otherwise specified in
eligibility criteria)
13. For females of childbearing potential, a negative serum human chorionic
gonadotropin pregnancy test within 28 days of study D1 and negative result
(urine or serum) on study D1
14. Subjects must agree to use appropriate contraception methods during the
clinical study (Appendix 3)
15. Subject is willing and able to comply with all scheduled visits, treatment
plans, laboratory tests, and other study procedures
Exclusion criteria
1. Histologically confirmed diagnosis of FL Gr 3b or transformed disease
• For subjects with clinical signs of rapid disease progression (e.g., marked
B-symptoms), and laboratory or radiographic indication (e.g., high lactate
dehydrogenase level or standardized uptake value by PET), a fresh biopsy is
recommended to rule out transformed disease
2. Subjects who received both R/O-B and R/O-CHOP (or other
anthracycline-containing regimen) as previous lines of therapy, and those who
received only single agent anti-CD20 mAb therapy as prior line of treatment
3. Prior therapy with PI3K inhibitors
4. Ongoing or history of drug-induced pneumonitis
5. Known lymphomatous involvement of the central nervous system
6. Seropositive for or active viral infection with hepatitis B virus:
• HBsAg positive
• HBsAg negative, anti-HBs positive and/or anti-HBc positive and detectable
viral DNA by PCR
[Note: Subjects who are HBsAg negative and viral DNA PCR negative are eligible.
These subjects should receive prophylactic therapy for hepatitis as per
institutional standards.]
7. Known seropositive for, or active infection with hepatitis C virus.
• Subjects with positive hepatitis C virus (HCV) antibodies are eligible with
negative PCR test for HCV
8. Known seropositive for, or active and uncontrolled infection with human
immunodeficiency virus (HIV), or with acquired immunodeficiency syndrome
(AIDS), or currently taking medications for HIV that are contraindicated for
concomitant use in this study
9. Known seropositive for, or active infection with human T-cell leukemia virus
type 1
10. Any uncontrolled clinically significant illness including, but not limited
to, active infections requiring systemic antimicrobial therapy, hypertension,
angina, arrhythmias or other uncontrolled cardiovascular condition, pulmonary
disease, autoimmune dysfunction and urinary infection or flow obstruction.
11. Hypersensitivity or other clinically significant reaction to the study drug
or its inactive ingredients or other therapy used in the study
12. Major surgical procedure within 4 weeks prior to study D1 (minor surgical
procedures, e.g., lymph node biopsy, performed within 1 day or with an
overnight stay are allowed)
13. Previous or concurrent cancer that is distinct in primary site or histology
from indolent B cell NHL within 3 years before start of study treatment except
for curatively treated cervical cancer in situ, non-melanoma skin cancer, and
superficial bladder tumors (Ta [non-invasive tumor], Tis [carcinoma in situ],
and T1 [tumor invades lamina propria]), and asymptomatic localized prostate
cancer with no requirement for systemic therapy or requiring only hormonal
therapy and with normal prostate-specific antigen values within >=12 months
prior to randomization
14. History of clinically significant cardiovascular abnormalities such as
congestive heart failure (New York Heart Association (NYHA) classification >= II
[NYHA 1994]), myocardial infarction within 6 months of study entry.
15. History of clinically significant gastrointestinal (GI) conditions,
particularly:
• Known GI condition that would interfere with swallowing or the oral
absorption or tolerance of study drug
• Pre-existing malabsorption syndrome or other clinical situation that would
affect oral absorption
16. Females who are pregnant; females who plan to breastfeed during study
treatment through 90 days after ending treatment
17. Substance abuse, medical, psychological or social conditions that may
interfere with the subject*s participation in the study or evaluation of the
study results.
18. Any illness or medical conditions that are unstable or could jeopardize the
safety of the subjects and their compliance in the study. Inability to
understand and sign informed consent form.
19. Received a live virus vaccination within 28 days of first dose of study
drug, (e.g., yellow fever vaccination)
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 | EUCTR2020-004199-16-NL |
| ClinicalTrials.gov | NCT04745832 |
| CCMO | NL76898.075.21 |