| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Chronic lymphocytic leukemia (CLL). |
| Leucemia linfocitica cronica (LLC). |
|
| E.1.1.1 | Medical condition in easily understood language |
| CLL is a type of cancer in which the bone marrow makes too many lymphocytes. Lymphocytes are a type of white blood cell. |
| CLL è un tipo di tumore in cui il midollo osseo produce troppi linfociti. I linfociti sono un tipo di globuli bianchi. |
|
| 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 | 14.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10008976 |
| E.1.2 | Term | Chronic lymphocytic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 demonstrate superiority in progression-free survival of dinaciclib compared to ofatumumab in CLL subjects with del 17 p, or in the overall CLL population (those with del17p and those without del17p), who are refractory to either fludarabine or chemoimmunotherpy. |
| Dimostrare la superiorità nella sopravvivenza libera da progressione (PFS, progression-free survival) di dinaciclib rispetto ad ofatumumab, nei pazienti con LLC con delezione di 17p (del 17p) o nella popolazione complessiva di pazienti con LLC (sia con del 17p che senza del 17p), refrattaria sia al trattamento con fludarabina che alla chemio-immunoterapia. |
|
| E.2.2 | Secondary objectives of the trial |
| To demonstrate superiority in overall response rate (ORR = CR + PR) of dinaciclib compared to ofatumumab in CLL subjects with del17p, or in the overall CLL population (those with del17p and those without del17p), who are refractory to either fludarabine or chemoimmunotherpy. To demonstrate superiority in overall survival of dinaciclib compared to ofatumumab in CLL subjects with del17p, or in the overall CLL population (those with del17p and those without del17p), who are refractory to either fludarabine or chemoimmunotherpy. |
| Dimostrare la superiorità nel tasso di risposta complessivo (overall response rate, ORR = CR + PR) di dinaciclib rispetto ad ofatumumab nei pazienti con LLC con del 17p o nella popolazione complessiva di pazienti con LLC (sia con del 17p che senza del 17p), refrattaria sia al trattamento con fludarabina che alla chemio-immunoterapia. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
| 1. 18 years of age or older, or either sex, and of any race 2. Confirmed diagnosis of CLL, as defined by iwCLL criteria. 3. Have fludarabine or chemoimmunotherapy refractory disease defined as follows • Fludarabine refractory defined as failing to respond to or relapsed within 6 months of completing fludarabine or another purine analog (e.g. pentostatin) alone or in combination regimens or • Chemoimmunotherapy refractory defined as failing to respond to chemoimmunotherapy or relapsed within 24 months of completing therapy with a combination of chemotherapy plus an anti-CD20 monoclonal antibody. 4. Eastern Cooperative Oncology Group (ECOG) Performance status 0, 1, or 2 5. Adequate laboratory parameters to include: • Creatinine ≤ 2.0 mg/dL • Bilirubin ≤ 1.5 x ULN (unless secondary to Gilbert's) • AST and ALT ≤ 2 x ULN, or if CLL involvement of the liver ≤ 5 x ULN • White blood cell count < 150 x 109/L 6. Women who are sexually active, including both female subjects and the female sexual partners of male subjects, of child-bearing potential must agree to use a medically accepted method of contraception prior to enrollment, while receiving protocol-specified medication, and for 6 months after stoppingdinaciclib or 12 months after stopping ofatumumab. Note: Subjects who fulfill all the inclusion criteria are eligible for this trial but the protocol will require subjects with an increased risk of developing TLS on study treatment, defined as any one of the following • White blood cell count > 50 x 109/L • Bulky disease (any lymph node >5 cm by physical exam or CT scan) • Splenomegaly (defined as spleen >18 cm by CT scan) to be treated with a short term steroid based regimen prior to randomization. |
• LLC confermata, come definita dai criteri iwCLL
• Malattia refrattaria alla fludarabina o alla chemio-immunoterapia, definita come segue:
• Refrattaria alla fludarabina definita come non rispondente alla fludarabina oppure recidivante entro 6 mesi dal completamento del trattamento con fludarabina o altro analogo purinico (ad es. pentostatina) da solo o in regimi combinati
o
• Refrattaria a chemio-immunoterapia definita come non rispondente alla chemio-immunoterapia oppure recidivante entro 24 mesi dal completamento della terapia con una combinazione di chemioterapia più un anticorpo monoclonale anti-CD20 |
|
| E.4 | Principal exclusion criteria |
| 1. Symptomatic brain metastases or primary central nervous system malignancy. 2. Treatment with a CYP3A4 inhibitor or inducer within 1 week prior to randomization, or any chemotherapy or biologic therapy within 4 weeks prior to randomization. 3. Grade 2 or higher non-hematological toxicities from prior therapy. However, Grade 1 and Grade 2 persistent treatment-related neurotoxicity will be allowed. 4. Presence of any serious or uncontrolled infection at Screening (defined as infection requiring hospital admission and/or parenteral antibiotics). 5. Known human immunodeficiency virus (HIV) infection or a known HIV-related malignancy. 6. Subjects with clinically active hepatitis B or C defined as disease that requires therapy 7. Allergy/sensitivity to study drug or its excipients. 8. Subjects who test positive for G6PD deficiency 9. Women who are breast-feeding, pregnant, or intend to become pregnant. 10. Prior allogeneic bone marrow transplant (auto HSCT is allowed if fully recovered). 11. Subjects with Richter's transformation. 12. Subjects with indeterminate deletion 17p status. 13. Prior malignancy, except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer or other cancer from which the subject is considered by his or her physician to have a 2 year survival expectation. 14. Any clinically significant condition or situation, other than the condition being studied that, in the opinion or the investigator, would interfere with the study evaluations or optimal participation in the study. 15. Any investigational drugs within 4 weeks prior to the start of treatment. 16. Concurrently receiving treatment in any other clinical study. 17. Previously treated with dinaciclib, ofatumumab or other CDK inhibitors. 18. Active autoimmune anemia or thrombocytopenia unless stable, defined as being responsive to corticosteroids or other standard therapy. |
• Metastasi cerebrali sintomatiche o tumore primario al sistema nervoso centrale
• Precedente trapianto di midollo osseo
• Trattamento precedente con dinaciclib, ofatumumab o altri inibitori della chinasi ciclina-dipendente (CDK, cyclin-dependent kinase),
• Anemia autoimmune attiva o trombocitopenia, tranne se stabili, definite come responsive ai corticosteroidi o altra terapia standard |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary efficacy endpoint is progression-free survival (PFS) which is defined as the time from the date of randomization until the first date of documented disease progression or date of death due to any reason, whichever occurs earlier. PFS is determined per the 2008 International Workshop on CLL criteria in the intent to treat (ITT) population. The intent to treat (ITT) population will serve as the primary population for the analysis of efficacy data in this study. The ITT population consists of all randomized subjects. Subjects will be included in the treatment group to which they are randomized for the analysis of efficacy data using the ITT population. |
| L'endpoint primario di efficacia è la sopravvivenza libera da progressione (PFS), che è definita come il tempo dalla data di randomizzazione fino alla prima data di progressione della malattia documentata o la data di morte per qualsiasi motivo, se precedente. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Progression free survival is defined as the time from the date of randomization until the first date of documented disease progression or date of death due to any reason, whichever occurs earlier. |
| Sopravvivenza libera da progressione è definita come il tempo dalla data di randomizzazione fino alla prima data di progressione della malattia documentata o la data di morte per qualsiasi motivo, se precedente. |
|
| E.5.2 | Secondary end point(s) |
| The secondary efficacy endpoints are overall response rate (ORR = CR + PR) and overall survival (OS). Subjects will be assessed using the 2008 International Workshop on CLL criteria for response. Overall survival (OS) is defined as the time from randomization to death due to any cause. Subjects without documented death at the time of analysis will be censored at the date last known to be alive. |
| Gli endpoint secondari di efficacia sono il tasso di risposta globale (ORR = CR + PR) e la sopravvivenza globale (OS). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Overall survival is defined as the time from randomization to death due to any cause. Response is assessed every 12 weeks for the first 18 months, then every 24 weeks until disease progression is documented. |
| La sopravvivenza globale è definita come il tempo trascorso dalla randomizzazione alla morte per qualsiasi causa. La risposta viene valutata ogni 12 settimane per i primi 18 mesi, poi ogni 24 settimane fino alla progressione documentata della malattia. |
|
| 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 | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | Yes |
| E.6.11 | Pharmacogenomic | Yes |
| E.6.12 | Pharmacoeconomic | Yes |
| 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 | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 4 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 60 |
| 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 |
| Argentina |
| Australia |
| Brazil |
| Colombia |
| Croatia |
| India |
| Israel |
| New Zealand |
| Peru |
| Puerto Rico |
| Venezuela, Bolivarian Republic of |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
| Trial will end when the last patient ends participation in the trial. |
| Lo studio termina quando l'ultimo paziente finisce la partecipazione alla sperimentazione. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 0 |
| E.8.9.1 | In the Member State concerned months | 38 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 0 |
| E.8.9.2 | In all countries concerned by the trial months | 38 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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