Main objective:1. To estimate the Overall Response Rate (ORR) and the clinical benefit rate in selected cohorts of patients with hematologic malignancies,separately for each cohort2. To evaluate the safety of the selected dose regimes in an expanded…
ID
Source
Brief title
Condition
- Other condition
- Lymphomas Hodgkin's disease
Synonym
Health condition
relapsed or refractory lymphoid malignancy, relapsed/refractory multiple myeloma, relapsed/refractory Hodgkins lymphoma, relapsed/refractory peripheral T-cell lymphoma, relapsed/refractory cutaneous T-cell lymphoma, subtypes mycosis fungoides and Sézary syndrome, relapsed/refractory T-cell Prolymphocytic leukemia. Note: Recruitment to the CTCL and T-PLL cohorts was halted on 01 March 2021.
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
This stage of the trial (Stage 2) is designed to determine the objective
response rate (ORR) (complete response [CR] plus partial response
[PR]) and the clinical benefit (CR plus PR plus Stable Disease) separately for
each cohort, and to evaluate the safety of the selected
tinostamustine doses in the lymphoma subtypes and myeloma cohorts.
Six cohorts will be opened:
• Expansion cohort 1: relapsed/refractory MM. Recruitment of patients to this
cohort was halted on 10 December 2021.
• Expansion cohort 2/2A: relapsed/refractory HL.
• Expansion cohort 3: relapsed/refractory PTCL. Recruitment to this cohort was
halted on 01 March 2021.
• Expansion cohort 4: relapsed/refractory CTCL, subtypes mycosis
fungoides (MF) and Sézary syndrome (SS).
• Expansion cohort 5: relapsed/refractory T-PLL. Recruitment to this cohort was
halted on 01 March 2021.
SAFETY ASSESMENT
Patients will be monitored for safety, toxicity, and efficacy on an ongoing
basis. All relevant patient data will be reviewed, including patient clinical
status, laboratory values, radiographic scans and adverse events (AEs). The
DSMC will provide safety assessments in course of the trial. A first
meeting is planned after 20 patients have completed their treatment (up to 6
cycles). The Safety physician or designated physician will inform the committee
of important new safety information and facilitate the assessment. The Medical
Monitor will inform the committee of treatments' responses or disease
progression rates. The roles and responsibilities of the DSMC are outlined in
the DSMC Charter.
STOPPING RULES
Stopping rules apply for patients who experience QTc prolongations >500 ms that
are not transient or occur in more than 1 cycle.
If the QTcF value on the electrocardiogram (ECG) machine printout is >500 ms or
represents an increase > 60 ms from baseline, 2 additional
ECGs are to be performed approximately 1 minute apart. If the average QTcF of
the 3 ECGs is >500 ms or increased > 60 ms from baseline, the
tinostamustine infusion must be stopped. The patient should stay in the unit
until the QTcF has decreased to <=500 ms or is <=60 ms relative to
baseline. In addition, the patient is to be continuously observed for syncope
or other clinically relevant cardiac events. A thorough evaluation of ECGs and
QTc prolongations, including expedited central review by an independent
assessor, will be performed. The decision will then be made by the Investigator
in consultation with the Medical Monitor, whether tinostamustine treatment is
to continue, be postponed, or be stopped.
Secondary outcome
1. To evaluate time to Objective Response (OR) and duration of response (DR).
2. To evaluate the safety of the selected doses in an expanded population of
patients with MM and the selected lymphoma subtypes
3. To determine the progression free survival (PFS) time for patients who
received the Recommended Phase 2 Dose (RP2D).
4. To determine the overall survival (OS) time for patients who received the
RP2D.
5. To further establish the PK profiles of tinostamustine.
6. To perform a concentration corrected QT (QTc) analysis.
Background summary
The ability to fuse discrete small molecules with different types of
pharmacologic activity has created remarkable opportunities in drug discovery
and development. Bendamustine itself is a fusion molecule of the nitrogen
mustard mechlroethamine and a purine analog based on fludarabine that exhibits
unique activity where cancer cells have become resistant to conventional
alkylating agents. In fact, randomized clinical studies have established that
the combination of rituximab and bendamustine exhibits less toxicity and
greater efficacy of a conventional five drug R-CHOP based regimen. This concept
opens the prospect that other rational fusion molecules could exhibit activity
even greater than that seen in the parent
molecule. EDO-S101 is a unique new chemical entity that rationally fuses a
molecule of vorinostat, an HDAC inhibitor, to the bendamustine backbone.
Preclinical studies have unequivocally demonstrated that EDO-S101 exhibits
activity greater than that seen with traditional Bendamustine. This clinical
trial will represent the first in human experience with this novel first in
class drug.
Study objective
Main objective:
1. To estimate the Overall Response Rate (ORR) and the clinical benefit rate in
selected cohorts of patients with hematologic malignancies,
separately for each cohort
2. To evaluate the safety of the selected dose regimes in an expanded
population of patients with Multiple Myeloma (MM) and the selected
lymphoma and leukemia subtypes for which there are no standard therapies
available
Secondary objectives:
1. To evaluate time to Objective Response (OR) and duration of response (DR).
2. To evaluate the safety of the selected doses in an expanded population of
patients with MM and the selected lymphoma subtypes
3. To determine the progression free survival (PFS) time for patients who
received the Recommended Phase 2 Dose (RP2D).
4. To determine the overall survival (OS) time for patients who received the
RP2D.
5. To further establish the PK profiles of tinostamustine.
6. To perform a concentration corrected QT (QTc) analysis.
Study design
The study is designed as a two stage Phase 1 trial. Stage 1 of the study is
designed to determine the MTD, the optimal infusion time and identify the RP2D
(recommended phase 2 dose). Stage 2 of the study is designed to evaluate the
safety and efficacy of the selected doses in expansion cohorts of selected
hematologic malignancies. Phase 1 of the trial has been completed.
Intervention
100mg/m² of Tinostamustine on D1 of 21d cycle for lymphoma/T-PLL patients and
60mg/m² on D1/D15 of 28d cycle for MM patients.
Study burden and risks
Participants may or may not benefit from the study drug. Other patients with
relapsed/refractory hematologic malignancies have the potential to benefit from
the development of a possible new treatment. Information collected during the
study may increase what doctors know about EDO-S101. As part of the study, the
subject will receive EDO-S101 and some tests at no cost.
Disadvantages of participation in the study may be:
- possible side effects of EDO-S101;
- possible adverse effects/discomforts of the evaluations in the study.
Please refer to section E9. "What risks does participation involve for human
subjects" for a detailed overview of the risks associated with the study drug
and study procedures
Participation in the study also means:
- additional time;
- additional or longer hospital stays;
- additional tests;
- instructions the subject needs to follow
Cambridge Science Park , Milton Road -
Cambridge CB4 OAB
GB
Cambridge Science Park , Milton Road -
Cambridge CB4 OAB
GB
Listed location countries
Age
Inclusion criteria
1. Patient willing and able to sign an informed consent.
2. Patients age >=18 years at signing the informed consent.
3. Life expectancy > 3 months.
4. Diagnosis of relapsed or refractory lymphoid malignancy for which there are
no available therapies.
5. Eastern Cooperative Oncology Group (ECOG) performance status <=2.
6. Absolute neutrophil count (ANC) (polymorphonuclear [PMN] cells plus
bands) >1,000 / µL.
7. Platelets >= 100,000 / µL.Platelet transfusions within the 14 days before Day
1 of Cycle 1 is prohibited.
8. Aspartate aminotransferase (AST)/alanine aminotransferase (ALT) <= 2.5 x ULN.
9. Total bilirubin <2.0 mg/dL unless elevated due to known Gilbert's syndrome.
10. Renal function: estimated creatinine clearance by Cockroft-Gault
formula >= 45 mL/min.
11. Serum potassium and magnesium at least at the lowest limit of normal (LLN)
range, before every IMP administration; if it is below LNN, supplementation is
permissible.
12. Female study participants of childbearing potential, and their
partners, and male study participants who intend to be sexually active with a
woman of childbearing potential, must be willing to use at least TWO
highly effective forms of contraception. For female study participants,
this should start from the time of study enrollment and continue
throughout tinostamustine administration and for at least six months
after the last administration of IMP to be eligible to participate. For male
subjects who intend to be sexually active with a women of childbearing
potential they must use a condom during treatment and for at least 90
days after the last administration of IMP. Female study participants
should be willing to have a pregnancy test performed at screening, <= 1
day prior to day 1 of each IMP administration and at study treatment
discontinuation. Vasectomized males are considered fertile; therefore,
vasectomized partners and patients must be willing to use a secondary
method of effective birth control. Sexual abstinence is considered a
highly effective method only if defined as refraining from heterosexual
intercourse during the entire period of risk associated with the study
treatment. The reliability of sexual abstinence needs to be evaluated in
relation to the duration of the clinical trial and the preferred and usual
lifestyle of the patient.
Apart from the above general inclusion criteria, there are some criteria that
are specific for each cohort, see details in the protocol.
Exclusion criteria
1. Patients with any central nervous system (CNS) involvement.
2. Patient who had a hematologic malignancy that has transformed.
3. Patients who have relapsed within 100 days of stem cell infusion following an
autologous or allogeneic bone marrow transplant.
4. Patients with QTc interval (Fridericia*s formula) > 450 msec.
5. Patients who are on treatment with drugs known to prolong the
QT/QTc interval. Refer to CredibleMeds list of drugs with known risk of
Torsade de pointes (TdP): http://crediblemeds.org
6. Any serious medical condition that interferes with adherence to
study procedures.
7. Patients with a history of an other malignancy diagnosed within
three (3) years prior to study enrollment excluding basal cell carcinoma
of the skin, squamous cell carcinoma of the skin, or in situ cervical
cancer that has undergone potentially curative therapy.
8. Pregnant or breast feeding females.
9. New York Heart Association (NYHA) stage III/IV congestive heart
failure. The following arrhythmias: atrial fibrillation/flutter with poor rate
control, documented sustained ventricular tachycardia (defined as >30 seconds
or requiring cardioversion before 30 seconds have elapsed) or Torsades de
Pointes.
10. active infections, or other significant co-morbidities [e.g. active
central nervous system metastases and/or carcinomatous meningitis,
active infection requiring systemic therapy, history of human
immunodeficiency virus (HIV) infection, or active Hepatitis B or Hepatitis
C].
11. Use of other anti cancer therapies and investigational agents within 28
days prior to the first dose of tinostamustine. After 28 days, patients may be
enrolled if they have recovered form any related toxicities >= Grade 1 (except
alopecia).
12. Steroid treatment within seven days prior to trial treatment. Patients that
require intermittent use of bronchodilators, topical steroids or local
steroid injections will not be excluded from the trial. Patients who have
been stabilized to 10 mg orally (PO) once daily (QD) or less seven days
prior to tinostamustine administration are allowed.
13. Patients on Valproic Acid for any indication (epilepsy, mood disorder)
must be excluded from the trial.
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 | EUCTR2015-002697-20-NL |
| ClinicalTrials.gov | NCT02576496 |
| CCMO | NL67414.029.19 |