| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| patients with classical HL, who achieved a complete response following HDT and AHSCT |
|
| E.1.1.1 | Medical condition in easily understood language |
Patients with classical Hodgkin's Lymphoma, who achieved a complete
response following high dose chemotherapy and autologous
hematopoietic stem cell transplant |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 14.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10020206 |
| E.1.2 | Term | Hodgkin's disease |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To characterize the safety and tolerability of oral panobinostat in patients with HL after achieving a complete response following AHSCT with HDT.
|
|
| E.2.2 | Secondary objectives of the trial |
Exploratory:
• To evaluate disease progression and survival on study
• To explore the relationship of PK-PD (safety and efficacy) in patients with HL following AHSCT as feasible |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient age is ≥ 18 years
2. Patient has a history of histologically confirmed classical HL (i.e. Nodular sclerosing (NSHL), Mixed-cellularity (MCHL), Lymphocyte-rich (LRHL), Lymphocyte depleted (LDHL))
3. Patient has achieved a complete response by CT/MRI scan between 6 and 12 weeks from the day of their first autologous peripheral blood/bone marrow stem cell transfusion (AHSCT) following HDT.
Complete response is defined as:
Normalization of all nodes and lesions compared to pre-transplant scan performed prior to salvage therapy for relapse. Any residual abnormal masses (>1,5 cm) on the post transplant CT/MRI must be metabolically inactive on a PET scan.
Note: If the first AHSCT was a tandem transplant, the 6-12 week window will be from the date of the second transfusion.
4. Patient has at least one of the following factors that places them at risk for relapse:
• Primary refractory disease (including relapse in ≤ 3 months of completion of 1st line treatment)
• First relapse >3 but <12 months from last dose of 1st line treatment
• Multiple relapses (prior to transplant)
• Stage III/IV disease (at relapse, prior to transplant)
• Hemoglobin <10.5 gm/dL (at relapse, prior to transplant)
5. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of ≤ 2
6. Patient has the following laboratory values within 3 weeks prior to starting study drug (labs may be repeated, if needed, to obtain acceptable values before failure at screening is concluded)
• Absolute neutrophil count (ANC) ≥ 1.5 x 109 /L
• Platelet count ≥ 100 x 109 /L
• AST/SGOT and ALT/SGPT ≤ 2.5 x ULN
• Serum total bilirubin ≤ 1.5 ULN
• Serum creatinine ≤ 1.5 x ULN
• Serum potassium, magnesium, sodium, total calcium (corrected for serum albumin) or ionized calcium within normal limits
Note: Potassium, magnesium, and/or sodium supplements (but not platelet or RBC transfusions) may be given to correct values that are < lower limit of normal (LLN). Post-correction values must not be deemed to be a clinically significant abnormality prior to patients being dosed.
7. Patient has the ability to swallow capsules
8. Sexually active patient (men and women of child bearing potential {WOCBP}) agrees to use double barrier method of contraception during the course of the study treatment period (13 cycles) and for 3 months after completing study treatment. 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.
9. Patient has signed informed consent prior to any screening procedures |
|
| E.4 | Principal exclusion criteria |
1. Patient has been treated with allogeneic transplant
2. Patient has received any anti-lymphoma therapy after AHSCT including
but not limited to:
• chemotherapy prior to start of study
• biologic immunotherapy including monoclonal antibodies or
experimental therapy prior to start of study
• radiation therapy
3. Patient has not recovered from reversible toxicity due to any prior
therapies (e.g. returned to baseline or Grade ≤1) except for
hematological laboratory parameters
Note: Patient does not meet this criteria if the toxicity is stable and
irreversible, and there is no evidence that panobinostat causes a similar
toxicity
4. Patient has received prior treatment with DAC inhibitors including
panobinostat
5. Patient has received an investigational agent of any kind within 28 days
of randomization
6. Patient taking any anti-cancer therapy concomitantly
7. Patient needs valproic acid within 5 days prior to first administration of
panobinostat/ study treatment
8. Patients with evidence of another malignancy not in remission or history
of such a malignancy within the last 3 years (except for treated basal or
squamous cell carcinoma, or in situ cancer of the cervix).
9. Patient has undergone major surgery ≤ 2 weeks prior to starting study
drug or who have not recovered from side effects of such therapy to <
grade 1 CTCAE or baseline
10. Patient has impaired cardiac function, including any one of the following:
• Left ventricular ejection fraction (LVEF) < the lower limit of
institutional norm, as determined by echocardiogram (ECHO) or
multiple uptake gated acquisition scan (MUGA)
• Obligate use of a permanent cardiac pacemaker
• Congenital long QT syndrome
• History or presence of ventricular tachy-arrhythmias
• Resting bradycardia defined as < 50 beats per minute
• QTcF > 480 msec on screening ECG
• Complete left bundle branch block, bifasicular block
• Any clinically significant ST segment and/or T-wave abnormalities
• Presence of unstable atrial fibrillation (ventricular response rate >
100 bpm). Patients with stable atrial fibrillation are allowed in the
study provided they do not meet the other cardiac exclusion criteria.
• Myocardial infarction or unstable angina pectoris ≤ 6 months prior to
starting study drug
• Congestive heart failure (New York Heart Association class III-IV)
• Other clinically significant heart disease and vascular disease (e.g.
uncontrolled hypertension)
11. Patient is taking medications with relative risk of prolonging the QT
interval or inducing torsade de pointes, if such treatment cannot be
discontinued or switched to a different medication prior to starting study
drug
12. Patient has impairment of gastrointestinal (GI) function or GI disease that
may significantly alter the absorption of panobinostat, such as:
• ulcerative disease
• uncontrolled nausea
• vomiting
• diarrhea CTCAE grade ≥ 2 (despite antidiarrheal medications)
• malabsorption syndrome
• obstruction
• stomach and/or small bowel resection
13. Patient has any other concurrent severe and/or uncontrolled medical
conditions that could cause unacceptable safety risks or compromise compliance with the protocol such as:
• uncontrolled diabetes
• active or uncontrolled infection
• chronic obstructive or chronic restrictive pulmonary disease
including dyspnea at rest from any cause
• uncontrolled thyroid dysfunction
• recent, acute or active bleeding
14. Patient has a known history of human immunodeficiency virus (HIV)
seropositivity or history of active/treated hepatitis B or C (a test for
screening is not required)
15. Women who are pregnant or breast feeding |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary safety endpoint:
• AEs as determined by Common Terminology Criteria for Adverse Events (CTCAE) version 3 and SAEs
• Electrocardiogram (ECG) parameters (for randomized phase only)
• Laboratory parameters |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Exploratory endpoints:
• OS Disease progression and survival on study
• Pharmacokinetic parameter: Cmax Cmin as feasible
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 74 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Belgium |
| Brazil |
| France |
| Germany |
| Israel |
| Italy |
| Netherlands |
| New Zealand |
| Poland |
| Russian Federation |
| Singapore |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 2 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 18 |
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