Primary ObjectiveThe primary objective is to determine if maintenance treatment with resminostat increases progression free survival (PFS) compared to placebo in patients with advanced stage (Stage IIB IVB) MF or SS that have achieved disease…
ID
Source
Brief title
Condition
- Lymphomas non-Hodgkin's T-cell
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Efficacy
All efficacy assessments will be done according to 2011 ISCL, the United States
Cutaneous Lymphoma Consortium (USCLC), and the Cutaneous Lymphoma Task Force of
the EORTC consensus statement of clinical endpoints and response criteria in MF
and SS.
Primary Endpoint
- PFS
PFS is defined as the time from date of randomisation to first date that
criteria for PD have been met according to the global response score or death
due to any cause in the absence of documented PD.
Secondary outcome
Key Secondary Endpoint
- TTSW (pruritus)
Secondary Endpoints
- TTP
- TTNT
- PFS2
- PFS3
- ORR (CR, PR)
- DOR
- OS
- HrQoL
o VAS (itching)
o FACT-G
o Skindex-29
- PK analysis (peripheral blood)
Safety Endpoints
- AEs
- vital signs (body weight, heart rate, systolic blood pressure [SBP],
diastolic blood pressure [DBP])
- 12-lead ECGs
- safety laboratory data (haematology, clinical chemistry)
Exploratory Endpoints
• Biomarkers
o descriptive analysis of changes in gene or protein expression related to
resminostat*s MoA
o exploratory analysis of potential biomarkers of response to resminostat
treatment
o exploratory analysis of potential prognostic biomarkers
• Other
o descriptive analysis of changes in requirement of anti itching treatment
o exploratory analysis of change of VAS itching score (e.g., as area under
the curve [AUC] per time period between treatment Arms)
o evaluation of efficacy of blinding using a survey including patients and
investigators
Background summary
(Below information is an extract from section 7 of the protocol. Please refer
to the protocol for full information)
Primary CTCLs (cutaneous T-cell lymphomas) represent a heterogeneous group of
extranodal Non Hodgkin*s lymphomas (NHL) that arise from malignant clonal
transformation of skin homing and/or skin residing T-cells. CTCLs primarily
affect the skin, but may ultimately involve lymph nodes, blood and visceral
organs. The most common subtype of CTCL is mycosis fungoides (MF), accounting
for ~60% of primary CTCL; Sézary Syndrome (SS), an erythrodermic and leukemic
CTCL variant, occurs less frequently (~5% of primary CTCL)
CTCL is responsive to current treatment modalities even in advanced stage
disease. However the duration of response (DOR) is generally relatively short
and declines as the severity of the disease increases. None of the existing
therapies applied in patients with CTCL are curative. Therefore, the key
therapeutic challenge that remains is to make remissions more durable, thus
halting disease progression, improving quality of life and prolonging
progression free (PFS) and overall survival (OS). However, only few formal
studies of maintenance therapy have been conducted in MF/SS and there is little
evidence currently available to guide practice. There remains a high unmet
medical need to develop new agents to maintain long-term remissions and
stabilisation of disease without overlapping toxicity with currently available
treatment modalities, particularly in patients with advanced stage CTCL.
Histone deacetylases (HDACs) are enzymes that catalyse the removal of acetyl
groups from histones, which results in changes of chromatin structures and gene
transcription activity. In addition, HDACs can also regulate gene expression in
an indirect fashion. HDACs are known to play a central role in the regulation
of several cellular properties linked with the development and progression of
cancer. Indeed, inhibition of HDACs is associated with anti proliferative and
anti tumour activity.
Resminostat inhibits the enzymatic activity of various Class I, IIb and IV HDAC
enzymes, including pronounced inhibition of HDAC6. Inhibition of HDACs
enzymatic activity by resminostat leads to changes in acetylation status of
histone and non-histone proteins, resulting in transcriptional activation as
well as repression of genes mediating pleiotropic effects such as pathway
modulation, cell growth arrest, differentiation and apoptosis.
Study objective
Primary Objective
The primary objective is to determine if maintenance treatment with resminostat
increases progression free survival (PFS) compared to placebo in patients with
advanced stage (Stage IIB IVB) MF or SS that have achieved disease control
(complete response [CR], partial response [PR] or stable disease [SD]) with
previous systemic therapy.
Secondary Objectives
Key Secondary Objective
• To determine if maintenance treatment with resminostat increases time to
symptom (pruritus) worsening (TTSW) compared to placebo.
Secondary Objectives
• Compare time to progression (TTP) in patients when treated with resminostat
vs placebo
• Compare time to next treatment (TTNT) in patients when treated with
resminostat vs placebo
• Assess the effect of maintenance treatment with resminostat by means of PFS
of subsequent treatments (PFS2, PFS3)
• Compare overall response rate (ORR, including CR, PR) in patients when
treated with resminostat vs placebo
• Assess the ORR (including CR, PR) in patients who opted for rollover to
resminostat
• Compare duration of response (DOR) in patients when treated with resminostat
vs placebo
• Compare overall survival (OS) in patients when treated with resminostat vs
placebo
• Assess the safety and tolerability of resminostat
• Compare changes in health related quality of life (HrQoL) parameters in
patients when treated with resminostat vs placebo
• Assess the pharmacokinetics (PK) of resminostat and metabolites.
Exploratory Objectives
• Analysis of protein- and ribonucleic acid- (RNA) biomarkers in peripheral
blood and skin lesion biopsies
o Immuno-histochemistry (IHC)- based expression analysis of mode of action
(MoA) related target proteins (e.g., histone deacetylase [HDAC] isoforms and
RAD23B) as biomarkers of response to treatment
o changes in expression of circulating cytokines and chemokines related to
immune oncology and cutaneous T-cell lymphoma (CTCL) disease (e.g., interleukin
[IL] 22, IL 31, CCL17, vascular endothelial growth factor [VEGF]) in serum
o changes in expression of genes (e.g., related to HDAC-inhibition, immune
oncology, and CTCL disease) in peripheral blood cells and skin lesion biopsies
• Evaluation of efficacy of blinding
• Changes in requirement of anti itching treatment.
• Change of VAS itching score (e.g., as area under the curve [AUC] per time
period between treatment Arms)
Study design
This is a multicentre, double blind, randomised, placebo-controlled,
prospective, efficacy trial. Patients will be randomised in a 1:1 ratio to oral
treatment with resminostat or matching placebo. Patients will administer trial
treatment on Days 1 - 5 of each cycle until disease progression or unacceptable
toxicity. All Cycles are 14 days.
Patients who discontinued treatment for any reason other than progression will
remain blinded and, after an End of Study (EOS) Visit, move to Survival FU.
Patients who discontinue treatment due to progression will be unblinded and
appropriate treatment or follow-up (FU) will be determined. Unblinded patients
found to have been treated in Arm A (resminostat) will undergo the EOS Visit,
then move to Survival FU. Unblinded patients found to have been treated in Arm
B (placebo) will have the option of rolling over to resminostat treatment or
may undergo EOS assessments and move to Survival FU.
Patients who rollover to resminostat will continue treatment per trial schedule
(600 mg orally once a day on Days 1 - 5 of 14 day treatment cycles) and undergo
safety and efficacy assessments according to the trial schedule, starting with
Day 1, Cycle 1. Treatment of rollover patients may continue as long as they
derive benefit from the treatment in the opinion of the investigator or until
unacceptable toxicity. At that time, rollover patients will again undergo EOT
assessments, EOS assessments and move to Survival FU.
It is planned that 150 patients will be enrolled, for a total of 75 patients in
each treatment Arm.
Intervention
Resminostat (4SC 201) 600mg (3x200 mg film coated tablet) or matching placebo
tablet.
Study burden and risks
Non-clinical and clinical data collected on the HDACi resminostat indicate a
positive benefit-risk ratio for use of resminostat in patients with advanced
cancers or haematological malignancies. Resminostat has the potential to
address an unmet medical need in patients with advanced stage MF/SS to maintain
long term remissions and improve quality of life at an acceptable safety
profile and without compromising the immune function needed to limit life
threatening infectious complications in CTCL.
Please refer to section 10.2.1 of the study protocol for a detailed assessment.
Fraunhoferstr. 22
Planegg-Martinsried 82152
DE
Fraunhoferstr. 22
Planegg-Martinsried 82152
DE
Listed location countries
Age
Inclusion criteria
1.Patients with histologically confirmed MF (Stage IIB-IVB) or SS in an ongoing
CR, PR or SD after at least one prior systemic therapy according to local
standards (including but not limited to α-interferon, bexarotene,
extracorporeal photopheresis, chemotherapy) or total skin electron beam
irradiation
- the most recent systemic therapy must have been completed as planned or
stopped due to unacceptable toxicity 2-12 weeks prior to randomisation, i.e.
patients should not be
withdrawn from a treatment from which they derive benefit
2.Male or female >= 18 years
3.Written informed consent obtained prior to any trial specific procedure
4.Eastern Cooperative Oncology Group (ECOG) status score 0-2
5.Adequate haematological, hepatic and renal function, as demonstrated by:
a)haemoglobin >= 9.0 g/dl (International System [SI] of Units: 5.6 mmol/L)
b)absolute neutrophil count >= 1,000/mm3
c)platelets >= 75 × 109/L
d)alanine aminotransferase and aspartate amino-transferase <= 2 times upper
limit of normal
e)total bilirubin <= 2 mg/dL (SI units: 34.2 µmol/L) (unless known Gilbert
syndrome)
f)serum creatinine <= 1.5 mg/dL (SI units: 132 µmol/L)
g)prothrombin time International Normalised Ratio <= 2.3
6.Women of childbearing potential (not post-menopausal for 1 year and not
surgically sterile) and males with partners of childbearing potential must be
sexually abstinent (i.e. refraining
from heterosexual intercourse) or must use a highly effectivecontraception (at
least one of the following: combined (oral, intravaginal or transdermal) or
progestegen-only
(oral, injectable or implantable) hormonal contraceptives, intrauterine
device,intrauterine hormone-releasing system, bilateral tubal occlusion,
vasectomy of the partner from the time of screening to 30 days (female
patients) or 3 months (male patients) after the last dose of trial treatment
7.Adequate recovery from precedent non-haematological toxicities, excluding
alopecia, to <= National Cancer Institute (NCI) Common Terminology Criteria for
Adverse Events (CTCAE) Grade 1
8.Able to comply with all the requirements of the protocol
Exclusion criteria
1.Patients with PD
2.Known central nervous system involvement
3.History and current cardiovascular complications, including unstable angina
pectoris, uncontrolled hypertension, congestive heart failure (New York Heart
Association [NYHA] Class III or IV) related to primary cardiac disease, a
condition requiring anti arrhythmic therapy, ischemic or severe valvular heart
disease, or a myocardial infarction within 6 months prior to randomisation
4.Baseline corrected QT (QTc) interval > 500 milliseconds [NOTE: QTcF is
relevant]
5.History of additional risk factors for Torsade de Pointes (e.g., heart
failure, hypokalaemia, family history of Long QT Syndrome)
6.Use of concomitant medications that are known to prolong the QT/QTc interval
7.Concurrent use of any other specific anti tumour therapy including psoralen
photo chemotherapy (PUVA), chemotherapy, immunotherapy, hormonal therapy,
radiation therapy, or experimental medications
8.Previous or concurrent cancer that is distinct in primary site or histology
from CTCL, except curatively treated squamous-cell carcinoma of the skin stage
0-1 and curatively treated malignant melanoma stage 0-1A with a low risk of
recurrence/metastasis as per assessment of the investigator, cervical carcinoma
in situ, treated basal cell carcinoma, superficial bladder tumours (Ta, Tis and
T1); any cancer curatively treated > 3 years prior to randomisation will be
allowed
9.Current evidence of any uncontrolled clinically significant internal,
psychiatric or neurologic disease
10.Altered mental status precluding understanding of the informed consent
process and/or completion of the necessary trial procedures
11.Pregnant or breast feeding women
12.History of allergic reactions attributed to compounds of similar chemical or
biological composition to the trial drugs
13.Active alcohol and/or drug abuse
14.Any other acute or chronic condition that, in the investigator*s opinion,
would limit the patient*s ability to complete or participate in this trial
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
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 | EUCTR2016-000807-99-NL |
| CCMO | NL57945.058.16 |