Intervention: Panobinostat
Trial phase: Phase 2
ATC code: L01XH03 | L01XX42
SMILES: Cc1[nH]c2ccccc2c1CCNCc1ccc(/C=C/C(=O)NO)cc1
Sex: All
Age groups: Adult | Older Adult
Healthy volunteers: No
Participants at risk: 35
Group description: The treatment is divided in three phases: induction phase (course 1 to 6), consolidation phase (courses 7 to 12), maintenance phase (from course 13 until the end of therapy for any reason). The duration of a treatment course will be 28 days. The first dose of panobinostat in course 1 defines day 1 of the treatment cycle, and each cycle thereafter will begin 28 days later.

Treatment:

Panobinostat: Induction Phase: Patients will receive panobinostat for 6 courses (1 course = 28 days). Consolidation phase (courses 7-12). Maintenance phase (course 13-end of therapy).

Panobinostat should be taken p.o. at the dose of 40 mg/day 3-times every week (QW) as part of a 4 week treatment cycle. The dose of panobinostat may be modified: the 1st dose adjustment consists in the modification of drug administration from 3 times every week (QW) to 3 times every other week (QOW). Levels lower than 30 mg 3 times QOW is not permitted.
Eligibility criteria:
Inclusion Criteria:

Patient age is ≥ 18 years
Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
Patient has a history of DLBCL according to the WHO classification
Patient has progressive disease after receiving at least CHOP-R or CHOP-R like first line regimen, standard second line therapy (DHAP, ESHAP, ICE or similar salvage regimens) inclusive ASCT
Patient has progressive disease after receiving at least CHOP-R or CHOP-R like first line regimen and is not considered eligible for intensive salvage therapy including ASCT because of age, co-morbidities, impossibility to perform ASCT
Patient undergoes at baseline new lymphnode or other pathologic tissue biopsy for confirmation of diagnosis and biologic studies; bone marrow biopsy is not adequate for this purpose and should be performed only for staging. Patients with primary refractoriness, not eligible for intensive salvage therapy including ASCT, who performed a previous biopsy with stored frozen material 6 months or less before enrolment into the study do not have to repeat a new biopsy
Patient has at least one site of measurable nodal disease at baseline ≥ 2.0 cm in the longest transverse diameter as determined by CT scan (MRI is allowed only if CT scan can not be performed). Note: Patients with bone marrow involvement are eligible, but this criteria alone should not be used for disease measurement

Patient has the following laboratory values (labs may be repeated, if needed, to obtain acceptable values before screen fail):

Absolute neutrophil count (ANC) ≥ 1.5 x 109/L [SI units 1.5 x 109/L]
Platelet count ≥ 100 x 109/L
Serum potassium, magnesium, phosphorus, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits (WNL) for the institution
Serum creatinine ≤ 1.5 x ULN
Serum bilirubin ≤ 1.5 x ULN (or ≤ 3.0 x ULN, if patient has Gilbert syndrome)
AST/SGOT and/or ALT/SGPT ≤ 2.5 x upper limit of normal (ULN) or ≤ 5.0 x ULN if the transaminase elevation is due to disease involvement
Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone supplements to treat underlying hypothyroidism
Written informed consent was obtained from the patient prior to any study-specific screening procedures
Patient has the ability to swallow capsules or tablets
Practice acceptable birth control.

Exclusion Criteria:

Patient has a history of prior treatment with a DAC inhibitors including panobinostat
Patient will need valproic acid for any medical condition during the study or within 5 days prior to the first panobinostat treatment
Patient has been treated with monoclonal antibody therapy (e.g., rituximab or anti CD-30 antibody, etc.) within 4 weeks of start of study treatment
Patient has been treated with any other anti lymphoma therapy within 3 weeks of start of study treatment
Patient is using any anti-cancer therapy concomitantly
Patient has been treated with > 5 prior systemic lines of treatment
Patient has received prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤ 2 weeks prior to start of study treatment
Patient treated with allogeneic hematopoietic stem cell transplant with active progressive cGVHD; patient has received DLI ≤ 6 weeks prior to start of study treatment; patient is planned to receive DLI
Patient has a history of another malignancy ≤ 3 years before study entry, with the exception of non-melanoma skin cancer and carcinoma in situ of uterine cervix
Patient has a history of CNS involvement with lymphoma

Patient has impaired cardiac function including any of the following:

Complete left bundle branch block or use of a permanent cardiac pacemaker, congenital long QT syndrome, history or presence of ventricular tachyarrhythmias, clinically significant resting bradycardia (<50 beats per minute), QTcF > 450 msec on screening ECG, or right bundle branch block + left anterior hemiblock (bifascicular block)
Presence of unstable atrial fibrillation (ventricular heart rate >100 bpm). Patients with stable atrial fibrillation are allowed in the study provided they do not meet the other cardiac exclusion criteria
Previous history angina pectoris or acute MI within 6 months
Congestive heart failure (New York Heart Association functional classification III-IV)
Patient has any other clinically significant heart disease (e.g., uncontrolled hypertension)
Patient has an impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of panobinostat (e.g., ulcerative disease, uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, obstruction, or stomach and/or small bowel resection)
Patient has unresolved diarrhoea ≥ grade 2
Patient has any other concurrent severe and/or uncontrolled medical condition(s) (e.g., uncontrolled diabetes mellitus, active or uncontrolled infection, chronic obstructive or chronic restrictive pulmonary disease including dyspnoea at rest from any cause) that could cause unacceptable safety risks or compromise compliance with the protocol
Patient has a known history of HIV seropositivity

Patient has active HBV hepatitis. The following categories of patients HBV positive but with non evidence of active hepatitis may be considered for the study and treated with panobinostat (see also Section 8.12 of the study protocol):

patient is HBsAg + with HBV DNA < 2000 UI/ml (inactive carriers); HBV DNA > 2000 UI/ml is criteria of exclusion
patient is HBsAg - HBsAb +
patient is HBsAg - but HBcAb +
Patients with HCV active hepatitis are excluded from the study. Patient with no evidence of active hepatitis and/or advanced chronic liver disease according to liver biopsy or fibro-scan evaluation may be included into the study (see also Section 8.12 of the study protocol)
Patient is using medications that have a relative risk of prolonging the QT interval or of inducing "Torsade de Pointes", where such treatment cannot be discontinued or switched to a different medication prior to starting study drug
Women who are pregnant or breast feeding or women of childbearing potential (WOCBP) not willing to use a double method of contraception during the study and 3 months after the end of treatment. One of these methods of contraception must be a barrier method. WOCBP are defined as sexually mature women who have not undergone a hysterectomy or who have not been naturally postmenopausal for at least 12 consecutive months or had menses any time in the preceding 12 consecutive months. WOCBP must have a negative serum pregnancy test at baseline
Male patient whose sexual partner(s) are WOCBP who are not willing to use a double method of contraception, one of which includes a condom, during the study and for 3 months after the end of treatment
Patient does not have before entering into the study a new lymphnode or other pathologic tissue biopsy for confirmation of diagnosis and biologic studies; bone marrow biopsy is not adequate for this purpose and should be performed only for staging