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. Relapsed/ refractory Hematologic Malignancies
Conditions
Interventions
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.
Sponsors
Mundipharma Research Limited
Eligibility
Age
18 Years to 99 Years
Inclusion criteria
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 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) = 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,
Exclusion criteria
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 outcomes
Primary
| Measure | Time frame |
|---|---|
| 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 | — |
Secondary
| Measure | Time frame |
|---|---|
| 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. | — |
Countries
Netherlands
Outcome results
None listed