Oral Panobinostat Adult Patients DLBCL Relapsed/Refractory Stem Cell Transfusion (ASCT) or Not Eligible for ASCT

A Phase II Study of Oral Panobinostat in Adult Patients With Diffuse Large B-cell Lymphoma Relapsed/Refractory After High-dose Chemotherapy With Autologous Stem Cell Transfusion (ASCT) or Not Eligible for ASCT

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).

Overview Of Study Design This is a prospective, multicenter phase II trial designed to evaluate the safety and activity of the panobinostat in patients with relapsed/refractory diffuse large B-cell lymphoma (DLBCL). Study design 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). Study duration This study is expected to start in February 2011. The last patient is expected to be enrolled at the end of January 2013. Considering a possible treatment duration of 24 months, this trial is due to be completed by January 2015.

Objectives:

Primary objective 1. To explore the antitumor activity of panobinostat in term of overall response (OR) at the end of the induction phase (i.e. month 6 from the beginning of panobinostat) Secondary objectives

1. To explore the antitumor activity of panobinostat in terms of Complete Response (CR)
2. To assess the time to response (TTR)
3. To evaluate Progression Free Survival (PFS)
4. To assess the safety and tolerability of panobinostat
5. To evaluate the Overall Survival (OS) Exploratory objectives

1. To study the impact of pharmacogenetics in predicting the response to panobinostat 2. To study the impact of immunohistochemical patterns and patient's specific gene expression and response to panobinostat 3. To assess the correlation between "telomeric asset" and response to panobinostat

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