Oral Panobinostat Adult Patients DLBCL Relapsed/Refractory Stem Cell Transfusion (ASCT) or Not Eligible for ASCT
Condition: Diffuse Large B-cell Lymphoma
MeSH terms: Lymphoma; Lymphoma, B-Cell; Lymphoma, Large B-Cell, Diffuse
Intervention: Panobinostat
Intervention description: 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.
Intervention MeSH terms: Panobinostat
Phase: Phase 2
Study type: Interventional
Primary purpose: Treatment
Intervention model: Single Group Assignment
Masking: None (Open Label)
Enrollment: 35.0
Sex: All
Minimum age: 18 Years
Healthy volunteers: No
Keywords: Diffuse Large B-cell Lymphoma (DLBCL); Panobinostat; Patients with relapsed/refractory DLBCL.

Summary:

      Treatment of adult patients with Diffuse Large B-cell Lymphoma (DLBCL), relapsed or
      refractory to previous CHOP-R (or CHOP-R like regimen) front line therapy, relapsed or
      refractory to second or subsequent salvage therapies which included high dose therapy with
      autologous stem cell support (ASCT).

      Treatment of adult patients with DLBCL relapsed or refractory to front line therapy with
      CHOP-R (or CHOP-R like regimen) or subsequent treatments, who are not consider eligible for
      ASCT consolidation because of age, co-morbidities, impossibility to perform ASCT.

      The trial is conducted according to the optimal two-stage design of Simon with alpha 0.05 and
      beta 0.10, considering the following two hypotheses: first a response rate (RR) less than 10%
      is of no further interest; and second, an RR 30% is clinically meaningful. In the initial
      stage, 18 patients have to enter onto the study. If less than 3 responses (</=2 in 18) will
      be observed, the trial would be terminated. Otherwise, accrual will continue to a total of a
      maximum of 35 patients. At the end of the trial, if 6 or fewer responses will occur among the
      35 patients (</= 6 in 35), it will be concluded that the regimen is not worthy of further
      investigations for that group of patients.

      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).
    

Eligibility criteria:

        Inclusion Criteria:

          1. Patient age is ≥ 18 years

          2. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2

          3. Patient has a history of DLBCL according to the WHO classification

          4. 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

          5. 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

          6. 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

          7. 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

          8. 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

          9. Clinically euthyroid. Note: Patients are permitted to receive thyroid hormone
             supplements to treat underlying hypothyroidism

         10. Written informed consent was obtained from the patient prior to any study-specific
             screening procedures

         11. Patient has the ability to swallow capsules or tablets

         12. Practice acceptable birth control.

        Exclusion Criteria:

          1. Patient has a history of prior treatment with a DAC inhibitors including panobinostat

          2. Patient will need valproic acid for any medical condition during the study or within 5
             days prior to the first panobinostat treatment

          3. 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

          4. Patient has been treated with any other anti lymphoma therapy within 3 weeks of start
             of study treatment

          5. Patient is using any anti-cancer therapy concomitantly

          6. Patient has been treated with > 5 prior systemic lines of treatment

          7. Patient has received prior radiation therapy ≤ 4 weeks or limited field radiotherapy ≤
             2 weeks prior to start of study treatment

          8. 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

          9. 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

         10. Patient has a history of CNS involvement with lymphoma

         11. 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)

         12. Patient has any other clinically significant heart disease (e.g., uncontrolled
             hypertension)

         13. 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)

         14. Patient has unresolved diarrhoea ≥ grade 2

         15. 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

         16. Patient has a known history of HIV seropositivity

         17. 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 +

         18. 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)

         19. 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

         20. 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

         21. 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

         22. 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