Diffuse Large B-cell Lymphoma
Conditions
Keywords
Diffuse Large B-cell Lymphoma (DLBCL), Panobinostat, Patients with relapsed/refractory DLBCL.
Brief 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).
Detailed description
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
Interventions
DRUGPanobinostat
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.
Sponsors
Fondazione Italiana Linfomi - ETS
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Overall Response Rate (ORR) at the End of the Induction Phase | 6 months | ORR is defined as the proportion of patients achieving a Complete Response (CR) or Partial Response (PR) according to the Cheson 1999 response criteria |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Complete Response (CR) Rate | 6 months | Proportion of CR at the end of the induction phase according to the Cheson 1999 response criteria |
| Time to Response (TTR) | 36 months | TTR is defined as the time from enrolment to Overall Response |
| Progression Free Survival (PFS) | 36 months | PFS is defined as the time from enrolment to disease progression or relapse or death from any cause |
| Overall Survival (OS) | 36 months | OS is defined as the time from enrolment to death from any case |
Countries
Italy
Participant flow
Recruitment details
Date of first enrolment: 14th June 2011 Date of last completed: 3rd April 2017 All patients (35) were enrolled in Italy.
Participants by arm
| Arm | Count |
|---|---|
| Panobinosat 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 should be taken p.o. at the dose of 40 mg/day three-times every week (QW), as part of a 4 week (28 days) treatment cycle. 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. | 35 |
| Total | 35 |
Baseline characteristics
| Characteristic | Panobinosat |
|---|---|
| Age, Continuous | 73 years |
| Region of Enrollment Italy | 35 participants |
| Sex: Female, Male Female | 14 Participants |
| Sex: Female, Male Male | 21 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | 29 / 35 |
| other Total, other adverse events | 8 / 35 |
| serious Total, serious adverse events | 12 / 35 |
Outcome results
Primary
Overall Response Rate (ORR) at the End of the Induction Phase
ORR is defined as the proportion of patients achieving a Complete Response (CR) or Partial Response (PR) according to the Cheson 1999 response criteria
Time frame: 6 months
Population: 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.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panobinosat | Overall Response Rate (ORR) at the End of the Induction Phase | 17.1 percentage of participants |
Secondary
Complete Response (CR) Rate
Proportion of CR at the end of the induction phase according to the Cheson 1999 response criteria
Time frame: 6 months
Population: 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
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Panobinosat | Complete Response (CR) Rate | 11.4 percentage of participants |
Secondary
Overall Survival (OS)
OS is defined as the time from enrolment to death from any case
Time frame: 36 months
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinosat | Overall Survival (OS) | 7.6 months |
Secondary
Progression Free Survival (PFS)
PFS is defined as the time from enrolment to disease progression or relapse or death from any cause
Time frame: 36 months
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinosat | Progression Free Survival (PFS) | 2.4 months |
Secondary
Time to Response (TTR)
TTR is defined as the time from enrolment to Overall Response
Time frame: 36 months
Population: 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
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Panobinosat | Time to Response (TTR) | 2.6 months |