Valemetostat tosylate may modify epigenetic changes, which plays an important role in the pathogenesis of PTCL. In the ongoing open-label Phase 1 study (DS3201-A-J101, 25 Dec 2019 data cut-off), valemetostat tosylate monotherapy demonstrated…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's T-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Primary Study Objective:
• To estimate the objective response rate (ORR) with valemetostat tosylate
monotherapy treatment in R/R PTCL, including R/R ATL.
Secondary outcome
Secondary Study Objectives:
• To evaluate the duration of response (DoR)
• To assess the CR rate
• To evaluate the duration of CR (DoCR)
• To assess the PR rate
• To assess the safety and tolerability of valemetostat tosylate monotherapy
Background summary
For patients with R/R PTCL, the therapeutic options are currently limited.
Accelerated approval was granted for belinostat, romidepsin, and pralatrexate
for R/R PTCL in the US, which demonstrated 25.8%, 26.2%, and 27% of objective
response rate (ORR), respectively. No
drug is approved for R/R PTCL in the European Union (EU). Forodesine, a purine
nucleoside phosphorylase inhibitor, was approved in Japan, with 22.5% of ORR.
Brentuximab vedotin, an antibody-drug conjugate against CD30, showed 86% of ORR
in ALCL, and is the only drug with full approval for R/R PTCL in the US.
However, in the US and EU, its indication is limited to ALCL in which CD30 is
universally expressed. Although conventional chemotherapy can be used for
patients with R/R PTCL, the durability of response is quite short; bendamustine
monotherapy resulted in a median duration of response (DoR) of 3.5 months.
Patients who are able to achieve a good response (typically CR) can undergo an
allogeneic hematopoietic cell transplantation (HCT) for potential cure, but
the modality is limited due to the lack of adequate donor and patients*
comorbidities. Thus, there remains a compelling unmet need for improved salvage
therapy for patients with R/R PTCL.
For refractory or relapsed ATL, no therapy clearly demonstrated survival
benefits. Outside Japan, no drug has been approved for relapsed or refractory
ATL. Thus, a high unmet need exists for relapsed or refractory ATL patients.
Recent evidence suggests that PTCL, including ATL, can be driven by epigenetic
dysregulation. EZH1 and EZH2, catalytic subunits of the polycomb repressive
complex 2, specifically methylate H3K27.Hypertrimethylation of H3K27 is
considered to silence tumor suppressor genes and has been associated with
lymphoma progression, including PTCL and ATL. Valemetostat tosylate may modify
epigenetic changes, which plays an important role in the pathogenesis of PTCL.
Study objective
Valemetostat tosylate may modify epigenetic changes, which plays an important
role in the pathogenesis of PTCL. In the ongoing open-label Phase 1 study
(DS3201-A-J101, 25 Dec 2019 data cut-off), valemetostat tosylate monotherapy
demonstrated approximately 62% ORR (34% CR rate) from 21 evaluable R/R PTCL
subjects and approximately 50% ORR (20% CR rate) from 10 evaluable R/R ATL
subjects. This Phase 2 study will further characterize the safety and clinical
activity of valemetostat tosylate and provide an estimate of the clinical
benefit as measured by ORR in subjects with R/R PTCL and R/R ATL.
The primary objective is to evaluate the clinical benefit of valemetostat
tosylate monotherapy, by evaluating the objective response rate, as measured by
blinded independent central review (BICR) in relapsed/refractory peripheral
T-cell lymphoma, including relapsed/refractory ATL participants.
Study design
This global, multicenter, open-label, single-arm, 2-cohort, phase 2 study was
designed to evaluate the efficacy and safety of valemetostat tosylate
monotherapy.The 2 cohorts are:
• Cohort 1: R/R PTCL
• Cohort 2: R/R ATL
Approximately 176 subjects will be enrolled (128 subjects with R/R PTCL and 48
subjects with R/R ATL).
The interventional phase of the study will be divided into 3 periods:
Screening, Treatment, and Follow-up (which
includes the Long-Term Follow-up [LTFU]). The Screening Period will be
approximately up to 28 days. Subjects
will be enrolled once considered eligible and will then enter the Treatment
Period. Subjects will undergo disease
assessment by radiographic images at regularly scheduled intervals.
The Follow-up Period begins after the End of Treatment (EOT) Visit, which
should occur within 7 days after the last dose of valemetostat tosylate or at
the time the decision is made to discontinue valemetostat tosylate (if this is
more than 7 days after the last dose of valemetostat tosylate), unless there is
a medical condition that prevents subjects from completing the visit within
this time, or permanent discontinuation of study drug at any time. In addition,
after the EOT visit, a 30-day Safety Follow-up Visit will occur, 30 days (± 7
days) after the last dose of valemetostat tosylate. Subsequently, LTFU visits
will occur every 3 months. The Survival Follow-up Period is at least 3 years
after the first dose of the study drug in the last subject. However, the
sponsor may stop the study at any time. The primary completion date for Cohort
1 is at least 10 months after the first dose of the last subject enrolled into
Cohort 1 has occurred. This date is used as the cut-off date for the primary
analysis for Cohort 1 in this study. The primary completion date for Cohort 2
is the date at least 10 months after the first dose of the last subject
enrolled into Cohort 2. This date is used as the cut-off date for the primary
analysis for Cohort 2 in this study. All subjects who are still on treatment or
who discontinued study drug at the primary completion date will continue to
follow the study schedule of events (Table 1.1) until the overall End of Study
(EOS) is reached, or the subject is lost to follow up, or the subject withdraws
consent or until death. Overall EOS will occur when the last subject*s last
visit has occurred and is defined as the completion of survival follow-up of at
least 3 years after the first dose of the last subject either from Cohort 1 or
Cohort 2, whichever occurs later. The subject*s EOS is defined as the date of
his/her last study visit/contact.
Intervention
DS-3201b (valemetostat tosylate) tablets 50 mg are white, round-shaped,
film-coated tablets, each of which contains
50 mg of DS-3201a as the free form of valemetostat tosylate. DS-3201b
(valemetostat tosylate) tablets 100 mg are grayish-red, oblong-shaped,
film-coated tablets, each of which contains 100 mg of DS-3201a as the free form
of valemetostat tosylate.
DS-3201b (valemetostat tosylate) will be administered at a dose of 200 mg once
daily.
Subjects are instructed to orally take valemetostat tosylate under fasting
conditions (to be taken at least 1 hour
before or at least 2 hours after a meal).
Study burden and risks
In general, study participants can experience physical or psychological
discomfort through examination tests and examination
procedures. In addition, subjects can experience side effects from the study
medication.
The study load consists of:
- Visits to the research location
- Physical examination
- Measuring vital functions and weight
- ECOG and Karnofsky performance status
- ECG
- Blood and urine collection
- Pregnancy test
- CT/MRI
- FDG/PET scan
- Assessment of skin lesions
- Oral mucosa smear
- Upper gastrointestinal endoscopy and possibly colonoscopy
- Bone marrow and tumor biopsy
- Receive study medication
- Beoordeling van huid-laesies
- Mondslijmvlies uitstrijkje
- Bovenste gastro-intestinale endoscopie en eventuele colonscopie
Mount Airy Road 211
Basking Ridge (New Jersey) 07920
US
Mount Airy Road 211
Basking Ridge (New Jersey) 07920
US
Listed location countries
Age
Inclusion criteria
1. Sign and date the ICF, prior to the start of any study-specific
qualification procedures.
2. Subjects >=18 years of age or the minimum legal adult age (whichever is
greater) at the time the ICF is signed.
3. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0, 1,
or 2
4. Cohort 1 (R/R PTCL): Should be pathologically confirmed by the local
pathologist/investigators; local histological diagnosis will be used for
eligibility determination, but histology will be centrally reviewed following
study entry. Subjects with the following subtypes of PTCL are eligible,
according to 2016 World Health Organization classification prior to the
initiation of study drug. Any T-cell lymphoid malignancies not listed below are
excluded. Below is the complete list of eligible subtypes:
- Enteropathy-associated T-cell lymphoma
- Monomorphic epitheliotropic intestinal T-cell lymphoma
- Hepatosplenic T-cell lymphoma
- Primary cutaneous γδ T-cell lymphoma
- Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T-cell lymphoma
- PTCL, not otherwise specified
- Angioimmunoblastic T-cell lymphoma
- Follicular T-cell lymphoma
- Nodal PTCL with TFH phenotype
- Anaplastic large cell lymphoma, ALK positive
- Anaplastic large cell lymphoma, ALK negative
5. Cohort 2 (R/R ATL): (acute, lymphoma, or unfavorable chronic type) with
positive anti-human T-cell leukemia
virus type 1 (anti-HTLV-1) antibody. R/R ATL should be pathologically or
hematocytologically confirmed by the local pathologist/investigators. The
positivity of anti-HTLV-1 antibody will be locally confirmed.
6. Must have at least 1 of the following lesions which are measurable in 2
perpendicular dimensions on CT (or MRI) based on local radiological read:
- Longest diameter (LDi) >=2.0 cm for a nodal lesion
- LDi >1.0 cm for an extranodal lesion
For Cohort 2 (ATL), subjects who had disease only in peripheral blood or/and
skin lesions are eligible, as defined below.
o An abnormal lymphocyte count (actual number) is >=1.0 × 10^9 /L and the
abnormal lymphocyte-to-leucocyte ratio is >=5%.
o Skin lesion(s) measured by modified severity weighted assessment tool (mSWAT)
score.
7. Documented failure to achieve CR (or uncertified CR [CRu] for ATL) from
prior systemic lymphoma therapy, or relapsed disease (after CR or CRu for ATL),
or progressive disease (after PR or stable disease).
8. Must have at least 1 prior line of systemic therapy for PTCL or ATL.
- Subjects must also be considered as HCT-ineligible during Screening due to
disease status (active disease), comorbidities, or other factors; in case of
other factors, the eligibility should be discussed with the study medical
monitor, and the reason must be clearly documented.
- In Cohort 1, subjects with ALCL must have prior brentuximab vedotin treatment.
Please refer to the protocol for the full list of inclusion criteria.
Exclusion criteria
1. Diagnosis of mycosis fungoides, Sézary syndrome, and primary cutaneous ALCL
and systemic dissemination of primary cutaneous ALCL
2. Diagnosis of precursor T-cell lymphoblastic leukemia and lymphoma (T-cell
acute lymphoblastic leukemia and T-cell lymphoblastic leukemia), T-cell
prolymphocytic leukemia, or T-cell large granular lymphocytic leukemia
3. Prior malignancy active within the previous 2 years except for locally
curable cancer that is currently considered as cured, such as cutaneous basal
or squamous cell carcinoma, superficial bladder cancer, or cervical carcinoma
in situ, or an incidental histological finding of prostate cancer
4. Presence of active central nervous system (CNS) involvement of lymphoma
5. History of autologous HCT within 60 days prior to first dose of study drug
6. History of allogeneic HCT within 90 days prior to the first dose of study
drug
7. Clinically significant graft-versus-host disease (GVHD) or GVHD requiring
initiation of systemic treatment or systemic treatment escalation
8. Inadequate washout period from prior lymphoma-directed therapy before
enrollment, defined as follows:
- Prior systemic therapy (eg, chemotherapy, immunomodulatory therapy, or
monoclonal antibody therapy) within 3 weeks prior to the first dose of study
drug
- Had curative radiation therapy or major surgery within 4 weeks or palliative
radiation therapy within 2 weeks prior to the first dose of study drug
9. Uncontrolled or significant cardiovascular disease, including the following:
- Evidence of prolongation of QT/QTc (eg, repeated episodes of QT corrected for
heart rate using Fridericia*s method [QTcF] >450 ms) (average of triplicate
determinations)
- Diagnosed or suspected long QT syndrome, or known family history of long QT
syndrome
- History of clinically relevant ventricular arrhythmias, such as ventricular
tachycardia, ventricular fibrillation, or Torsade de Pointes
- Uncontrolled arrhythmia (subjects with asymptomatic, controllable atrial
fibrillation may be enrolled), or asymptomatic persistent ventricular
tachycardia
- Subject has clinically relevant bradycardia of <50 bpm unless the subject
has a pacemaker
- History of second- or third-degree heart block. Candidates with a history of
heart block may be eligible if they currently have pacemakers, and have no
history of fainting or clinically relevant arrhythmia with pacemakers, within 6
months prior to Screening
- Myocardial infarction within 6 months prior to Screening
- Angioplasty or stent graft implantation within 6 months prior to Screening
- Uncontrolled angina pectoris within 6 months prior to Screening
- New York Heart Association (NYHA) Class 3 or 4 congestive heart failure
- Coronary/peripheral artery bypass graft within 6 months prior to Screening
- Uncontrolled hypertension (resting systolic blood pressure >180 mmHg or
diastolic blood pressure >110 mmHg)
- Complete left or right bundle branch block
10. History of treatment with other EZH inhibitors
11. Current use of moderate or strong cytochrome P450 (CYP)3A inducers (Table
10.4)
12. Systemic treatment with corticosteroids (>10 mg daily prednisone
equivalents). Note: Short-course systemic corticosteroids (eg,
prevention/treatment for transfusion reaction) or use for a non-cancer
indication (eg, adrenal replacement) is permissible.
Please refer to the protocol for the full list of exclusion criteria.
Design
Recruitment
Medical products/devices used
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
metc-ldd@lumc.nl
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 | EUCTR2020-004954-31-NL |
| ClinicalTrials.gov | NCT04703192 |
| CCMO | NL76530.058.21 |