(Ph I) Relapsed or refractory Hodgkin (HL) and Non Hodgkin lymphoma (NHL) in patients in the absence, unable ot who have been refused to undergo alternative salvage regimens. (Ph II) Relapsed or refractory Peripheral T-cell lymphomas (PTCL) in patients who have received at least one prior systemic therapy. MedDRA version: 14.1 Level: HLGT Classification code 10025319 Term: Lymphomas Hodgkin's disease System Organ Class: 10005329 - Blood and lymphatic system disorders MedDRA version: 14.1 Le
Conditions
Interventions
Product Code: PHA-739358
Pharmaceutical Form: Concentrate for solution for infusion
INN or Proposed INN: DANUSERTIB HYDROCHLORIDE
CAS Number: 827318-97-8
Other descriptive name: PHA-739358
Concentrati
Sponsors
Fondazione IRCCS Istituto Nazionale Tumori
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: (Ph I) -Histologically or cytologically confirmed lymphoid malignancy as per WHO Classification (Hodgkin lymphoma or non-Hodgkin lymphoma, for which standard curative or palliative measures do not exist, are no longer effective or have been refused by the patient). (Ph II) -Patients with histologically or cytologically confirmed relapsed or refractory Peripheral T-cell lymphomas as per WHO Classification, who have received at least one prior systemic therapy (not just steroids or local radiation), ineligible and/or unwilling to undergo second line high-dose chemotherapy with either autologous or allogeneic stem cell transplantation (according to local guidelines or physician’s choice). (Ph I)/(Ph II) - Signed and dated IEC-approved Informed Consent. - Presence of measurable disease in two dimensions and > 20 mm is acceptable (or 15 mm if 5 mm slices are used, as in spiral computed tomography [CT] scans); lesions that are considered intrinsically non-measurable including bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal masses that are not confirmed and followed by imaging techniques, cystic lesions, lesions that are situated in a previously irradiated area will be considered only assessable. - Age = 18 years with ECOG performance status = 2. - Life expectancy =12 weeks. - Resolution of all acute toxic effects (excluding alopecia) of any prior anticancer therapy to NCI CTC (Version 4.03) Grade = 1 or to the baseline laboratory values. - Baseline laboratory values: Absolute Neutrophils Count (ANC) = 1,500/mm3 (= 1.5 x 10^9/L); Platelets = 100,000/mm3 (=100 x 10^9/L); Hemoglobin > 9.0 g/dL; Serum Creatinine = 1.5 x ULN or Creatinine Clearance calculated by Cockcroft and Gault’s formula > 60 mL/min; Total Serum Bilirubin = 1.5 x ULN; Liver Transaminases (AST/ALT) = 3 x ULN (if liver metastasis are present = 5 x ULN); Alkaline Phosphatase (ALP) = 2.5 x ULN or = 5 x ULN if liver and/or bone metastasis are present; Amylase and lipase within the ULN. Electrolyte: Serum Potassium = 3.8 mmol/L; Serum Magnesium = 1.8 mmol/L; LVEF (by MUGA) above the LLN; QTc = 480 milliseconds; Pregnancy Test negative within 7 days of starting treatment if female with child bearing potential. - For males and females of child producing potential, agreement upon use of effective contraceptive methods prior to study entry, for study participation duration and for 90 days after discontinuation of study treatment. Are the trial subjects under 18? no Number of subjects for this age range: F.1.2 Adults (18-64 years) yes F.1.2.1 Number of subjects for this age range 26 F.1.3 Elderly (>=65 years) no F.1.3.1 Number of subjects for this age range 13
Exclusion criteria
Exclusion criteria: (Ph II) Patients at first treatment failure (partial response, progression, relapse following first line chemotherapy) who are eligible for and willing to undergo high dose salvage therapy with autologous or allogeneic stem cells rescue. (Ph I) / (Ph II) - Current enrollment in another therapeutic clinical trial - History of allergic reactions attributed to compounds of similar chemical composition to the study drugs. - Patients with known central nervous system or meningeal involvement. - Major surgery, other than diagnostic surgery, within 4 weeks prior to treatment start. - Patients who have had chemotherapy or radiotherapy within 4 weeks (6 weeks for nitrosoureas or mitomycin C) prior to treatment start or those who have not recovered from adverse events due to agents administered more than 4 weeks earlier. Prior radiation therapy must not have been to more than 25% of the bone marrow (whole pelvic radiation is considered to be over 25%). - History of prolonged QTc interval or additional risk factors for torsade de pointes (e.g., heart failure, hypokalemia, family history of long QT syndrome). - Known history of sustained ventricular tachycardia (VT), ventricular fibrillation (VF), Torsade de Pointes, or cardiac arrest unless currently addressed with an automatic implantable cardioverter defibrillator (AICD). - Any cardiac arrhythmia requiring an anti-arrhythmic medication (excluding stable doses of beta-blockers). - Use of concomitant medications that increase or possibly increase the risk to prolong the QTc interval and/or induce torsades de pointes, ventricular arrhythmia. - Hypertrophic cardiomegaly or restrictive cardiomyopathy from prior treatments or other causes. -Other significant ECG abnormalities including 2nd degree atrio-ventricular (AV) block type II, 3rd degree AV block, or bradycardia (ventricular rate less than 50 beats/min). -Symptomatic coronary artery disease (CAD), e.g., angina Canadian Class II-IV or suspected cardiac ischemia (i.e., ST depression depression of =2 mm, measured from isoelectric line to the ST segment). In any patient in whom there is doubt, the patient should have a stress imaging study and, if abnormal, angiography to define whether or not CAD is present. - Congestive heart failure (CHF) that meets New York Heart Association (NYHA) Class II to IV definitions. - Uncontrolled hypertension (i.e., blood pressure of =160/95 mmHg). Patients who have a history of hypertension controlled by medication must be on a stable dose (for at least one month). - Any of the following in the past 6 months: myocardial infarction, unstable angina, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack, pulmonary embolism, deep vein thrombosis. - Prior allogeneic stem cell transplant patients will be allowed to enroll if they are past day +100 of transplant, have no active graft-versus-host-disease, are not on any immunosuppressants, and have been off immunosuppressants for at least 4 weeks. - Prior autologous stem cell transplant patients will be allowed to enter this study if they are past their day +100 of transplant. - Prior use of valproic acid or any other histone deacetylase (HDAC) inhibitor for lymphoma treatment, including romidepsin. - Known active infections (bacterial, fungal, viral), particularly active viral infection with human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV). Patients who are serop
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: (Ph I) To determine the maximum tolerated dose/recommended phase two dose (MTD/RP2D) and the associated dose-limiting toxicities (DLTs) observed during the first cycle of treatment with romidepsin in combination with danusertib in patients with relapsed or refractory Hodgkin and Non-Hodgkin Lymphoma. (Ph II) To evaluate antitumor activity of romidepsin in combination with danusertib in patients with relapsed or refractory Peripheral T-Cell Lymphomas who have received at least one prior systemic therapy. ;Secondary Objective: (Ph I) •To define the safety profile of the combination. •To monitor blood level of romidepsin and danusertib at the end of infusion. •To document any antitumor activity of the combination. (Ph II) •To further evaluate the efficacy of the combination. •To characterize the safety profile of the combination. ;Primary end point(s): (Ph I) MTD/RP2D and First cycle DLTs (Ph II) Objective Response Rate (ORR) (complete and partial response) as per Cheson’s Criteria ;Timepoint(s) of evaluation of this end point: (Ph I) Up to definition of RP2D (Ph II) All study period | — |
Secondary
| Measure | Time frame |
|---|---|
| Secondary end point(s): (Ph I) 1) Overall safety profile characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.03), timing of adverse events and laboratory abnormalities. 2) Romidepsin and danusertib maximal plasma concentration (Cmax). 3) Objective tumor response defined by Cheson’s Criteria. (Ph II) 1) Time to Response (TTR), Duration of Response (DoR), Time to Progression (TTP), Overall Survival (OS). 2) Overall safety profile characterized by type, frequency, severity (graded using the National Cancer Institute Common Terminology Criteria for Adverse Events [NCI CTCAE] Version 4.03), timing of adverse events and laboratory abnormalities. ;Timepoint(s) of evaluation of this end point: (Ph I) 1) All cycles from enrollment to 28 days after last treatment 2) Cycle 1 only 3) All study period (Ph II) 1) Up to two years after the end of treatment visit 2) All cycles from enrollment to 28 days after last treatment | — |
Countries
Italy
Contacts
Public ContactAlessandro Massimo Gianni
Fondazione IRCCS Istituto Nazionale Tumori
Outcome results
None listed