| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| High-risk Diffuse Large B-cell Lymphoma (DLBCL ) |
| Linfoma Difuso de Grandes Células B. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Lymph node cancer |
| Tumor ganglios linfaticos |
|
| 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 | 15.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10012819 |
| E.1.2 | Term | Diffuse large B-cell lymphomas |
| E.1.2 | System Organ Class | 100000004851 |
|
| 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 compare maintenance therapy with enzastaurin versus placebo, in terms of the overall disease-free survival (DFS) time in patients with DLBCL in first remission with high risk of relapse (initial IPI score ≥3) following R-CHOP using a 14- or 21-day cycle |
| Comparação da taxa de sobrevivência livre de doença entre os dois braços em estudo. |
|
| E.2.2 | Secondary objectives of the trial |
To compare time-to-event efficacy variables
including rate of disease free survival at 2 years, event free survival between treatment arms, rate of event free survival at 2 years, overall survival time.
To compare adverse events between treatment arms.
To compare health-related quality of life using the FACT-Lym.
To assess health status using the EQ-5D scale.
To perform exploratory assessments of biomarkers relevant to enzastaurin and disease state and their correlation to clinical outcome.
To characterize the pharmacokinetics (PK) of enzastaurin and its metabolites using a sparse sampling strategy.
|
Comparação dos dois braços de estudo relativamente a:
•Taxa de sobrevivência livre de doença aos dois anos.
•Taxa de sobrevivência livre de morbilidade.
•Taxa de sobrevivência livre de morbilidade aos dois anos.
•Tempo de sobrevivência.
•Efeitos Adversos.
•Qualidade de vida relacionada com a saúde, recorrendo ao inquérito FACT – Lym.
•Estado de saúde utilizando o inquérito: Escala EQ-5D.
•Biomarcadores relevantes para a Enzastaurina e para o estadio da doença e a sua correlação com os resultados clínicos.
•Características farmacocinéticas da Enzastaurina e dos seus metabolitos.
|
|
| E.2.3 | Trial contains a sub-study | Yes |
| E.2.3.1 | Full title, date and version of each sub-study and their related objectives |
1) PK addendum, version 1.0 dated 17 Jan 2007: collection of additional PK samples in order to provide additional data for an exposure-response analysis
2) ECG addendum, version 2.2 dated 27 Oct 2009: collection of extra ECGs to determine if long-term use of enzastaurin (>12 months) is associated with any general cardiac issues (as measured by changes in ECGs).
|
1)análise farmacocinética addendum, versao 1.0 de 17 Jan 2007: colheita adicional de amostras para análise farmacocinética de modo a obter dados adicionais para uma analise exposiçao-resposta
2)ECG addendum, versao 2.2 de 27 Out 2009: realizaçao de extra ECGs para determinar se a longo prazo o uso de enzastaurin (>12 meses) esta associado a questoes cardiacas (avaliadas por alteraçoes nos ECGs).
|
|
| E.3 | Principal inclusion criteria |
Patients may be included in the study only if they meet all of the following criteria:
[1] have had a histologically confirmed diagnosis of DLBCL by the World Health Organization classification (Harris et al. 1999) at the time of original diagnosis. Pathology must be reviewed and confirmed prior to enrollment at the investigational site where the patient is entered. Patients may be entered and randomized based on local pathology; however, an independent centralized pathology review will be performed on all enrolled patients (see Protocol Section 6.4.1). Commonly accepted histological variants of DLBCL, such as immunoblastic lymphoma, primary mediastinal B-cell lymphoma, and T-cell rich B-cell lymphoma are allowed.
[2] if any gallium scan was performed, the most recent gallium scan must be negative. However, gallium scans are not a required study procedure.
[3] if any PET scan was performed, the most recent PET scan must be negative, as judged by local radiologist and/or physician (an independent centralized radiology review will also be performed on these patients). Exceptions may be made (after consultation with the Lilly clinical research physician) for patients with PET-positive lesions in which a subsequent confirmation procedure (for instance, biopsy) reveals the lesion is not due to DLBCL. However, PET scans are not a required study procedure. (See Protocol Section 6.1.1 for more information.)
[4] have completed six to eight 21-day cycles of R-CHOP, or six to eight 14-day cycles of R-CHOP as first-line therapy for DLBCL. (Refer to Section 5.5 for recommended regimens.) Patient must have achieved a CR or CRu (and have not subsequently progressed) according to International Workshop criteria (Cheson et al. 1999), or must be PET scan negative (according to Juweid et al. 2007), as judged by local radiologist and/or physician (an independent centralized radiology review will also be performed on these patients). Exceptions may be made (after consultation with the Lilly clinical research physician) for patients with PET-positive lesions in which a subsequent confirmation procedure (for instance, biopsy) reveals the lesion is not due to DLBCL.
[5] have an IPI score 3 at time of original diagnosis (refer to Protocol Attachment 4).
[6] have had Stage 3 or 4 disease, or have had Stage 2 with bulky disease (defined as 10 cm), at time of original diagnosis.
[7] have given informed consent.
[8] have an estimated life expectancy of at least 12 weeks.
[9] have a performance status of 0, 1, or 2 on the Eastern Cooperative Oncology Group (ECOG) scale (see Protocol Attachment 7; Oken et al. 1982).
[10] exhibit patient compliance and geographic proximity that allow for adequate follow-up.
[11] have adequate organ function as follows:
• Hepatic: total bilirubin 1.5 times upper limit of normal (ULN); alanine transaminase (ALT) and aspartate transaminase (AST) 2.5 times ULN
• Renal: serum creatinine <1.5 times ULN
• Adequate bone marrow reserve: platelets 50 x 109/L, absolute neutrophil count (ANC) 1.0 x 109/L, hemoglobin 8 g/dL.
[12] male and female patients with reproductive potential must use an approved contraceptive method, if appropriate (for example, intrauterine device [IUD], birth control pills, or barrier device) during and for 3 months after discontinuation of study treatment. Women with childbearing potential must have a negative serum pregnancy test within 7 days prior to study enrollment.
[13] are at least 18 years of age.
[14] patients must receive on-study therapy no later than 90 days either from their last cycle (Day 1) of induction therapy or from the last day of consolidation radiotherapy.
|
1. Diagnostico histológico de Linfoma Difuso de Gra ndes Células B confirmado, ao momento do diagnóstico original, de acordo com os critérios da OMS. Variantes comuns de Linfoma Difuso de Grandes Células B, serão incluiveis, como por exemplo: Linfoma Mediastinico Primário de Células B, Linfoma Imunoblástico, Linfoma de Células B Rico emCélulas T.
2. Conclusão de 6 a 8 ciclos de 21 dias de tratamento R-CHOP ou 6 ciclos de 14 dias de RCHOP, como terapia de primeira linha condutora à remissão comp leta ou à remissão completa não confirmada. No caso de ser utilizado como meio de diagnóstico o ex ame PET, o doente deverá apresentar um resultado negativo segundo os critérios descritos por Juweidet et Al. 2007. São considerados incluiveis doentes com resultado positivo no exame PET se os resultados dos exames de confirmação subsequentes, por exemplo biopsia, revelarem que a(s) lesão(ões) detectada(s) não é (são) devida(s) ao Linfoma Difuso de Grandes Células B.
3. Inicio da terapia de estudo no período máximo de 90 dias após o primeiro dia do ultimo ciclo da terapia de primeira linha.
4. Score IPI, no momento do diagnóstico inicial igual ou superior a 3.
5. Estadio 3 ou 4 no momento do diagnostico inicial, ou estadio 2, no caso de doença volumosa – definindo doença volumosa pela presença de massas tumorais superiores a 10cm.
6. Assinatura do formulário de consentimento esclarecido. Atestando o carácter voluntário da sua participação no estudo e a sua compreensão dos procedimentos, objectivos, direitos e responsabilidades.
7. Esperança de vida estimada, de pelo menos 12 semanas, após o momento da inclusão.
8. Performance status ECOG de 0,1 ou 2.
9. Assegurar a adesão ao tratamento do estudo.
10. Idade mínima de 18 anos.
11. Doentes – Homens ou Mulheres – em idade fértil, deverão utilizar um método contraceptivo
aprovado, durante a sua permanência no estudo e durante os 3 meses seguintes à sua descontinuação do estudo. Mulheres em idade fértil deverão realizar um teste de gravidez de resultado negativo, nos sete dias anteriores à sua inclusão no estudo.
12. Funções orgânicas adequadas, de acordo com os seguintes parâmetros:
• Hepáticas: Total de Bilirubinas até 1,5 vezes superior ao limite superior do intervalo normal dos valores referência.
• Valores de ALT e de AST até 2,5 vezes ao limite superior do intervalo normal dos valores referência.
• Renais: Valores de Creatinina Sérica inferiores a 1,5 vezes ao limite superior do intervalo normal dos valores referência.
• Medula Óssea: Plaquetas – 50X109/L; Neutrófilos – 1 .0X109/L; Hemoglobina – 8g/dL.
|
|
| E.4 | Principal exclusion criteria |
Patients will be excluded from the study if they meet any of the following criteria:
[15] have received treatment within the last 30 days with a drug that has not received regulatory approval for any indication at the time of study entry
[16] receive concurrent administration of any other systemic anticancer therapy. Also, any systemic anti-cancer agent (for example, methotrexate or etoposide, and including investigational agents) initiated for treatment of DLBCL in combination with R-CHOP is not allowed. Patients who had been receiving chronic therapy such as hormonal therapy (for example, tamoxifen), low-dose (7.5 mg/week) methotrexate, or corticosteroids prior to the diagnosis and treatment of DLBCL, may continue to receive these therapies while on study, after agreement with the Lilly clinical research physician; however, initiation of these medications while the patient is on study is not allowed. Intrathecal prophylaxis is allowed.
[17] have received radiation therapy to more than one targeted lesion (local residual disease) for treatment of lymphoma or have not recovered from the acute effects of radiation therapy prior to study entry.
[18] are pregnant or breastfeeding.
[19] have central nervous system (CNS) metastases (unless the patient has completed successful local therapy for CNS metastases and has been off of corticosteroids for at least 4 weeks before starting study therapy). In the absence of a clinical suspicion of brain metastases, no screening computed tomography (CT) or magnetic resonance imaging (MRI) scan before enrollment is required.
[20] have serious concomitant disorder, including active bacterial, fungal, or viral infection, incompatible with the study (at the discretion of the investigator).
[21] are known to be HIV positive.
[22] have a second primary malignancy (except adequately treated non-melanomatous skin cancer, or other cancer that is considered cured by surgical resection or radiation). Patients who had another malignancy in the past, but have been disease-free for more than 5 years, are eligible.
[23] have a serious cardiac condition, such as myocardial infarction within 6 months, angina, or heart disease, as defined by the New York Heart Association Class III or IV (see Attachment 5). It is recommended that patients with a prolonged QT interval corrected for heart rate (QTc) > 450/470 msec (males/females) at baseline on electrocardiogram (ECG), and patients who have a congenital long QT syndrome in their own or family medical history should be excluded, at the investigator’s discretion. It is recommended that QTc be calculated using Fridericia correction formula (QTcF; see Attachment 10). A patient may still be entered on study with prolonged QT-interval only after discussion and agreement between the principal investigator and the Lilly clinical research physician.
[24] are unable to swallow tablets.
[25] requires use of carbamazepine, phenobarbital, or phenytoin (refer to Section 5.7).
[26] prior stem cell or bone marrow transplantation.
[27] a prior clinical history of an indolent lymphoma. |
1.Tratamento com um medicamento não aprovado, nos 30 dias anteriores à sua inclusão no estudo.
2.Administração concomitante de qualquer medicamento de quimioterapia, de imunoterapia ou medicamento experimental. São consideradas as excepções: doentes que estejam em tratamento com
terapias crónicas, como por exemplo terapia hormona l (i.e. Tamoxifeno), metotrexate em baixa dose (7,5 mg/semana) ou corticoides, iniciadas anteriormente ao momento do diagnóstico e tratamento do Linfoma
Difuso de Grandes Células B, poderão continuar a receber a terapia referida durante o estudo, após acordo do médico da Lilly; O início destas terapias após o início do medicamento de estudo não é
permitido.
3. Radioterapia para mais de que uma lesão, para tratamento do linfoma, ou sem ter ocorrido
recuperação total dos efeitos tóxico agudos da radioterapia.
4.Gravidez e/ou em período de aleitamento.
5.Metástases cerebrais.
6.Comorbidade grave.
7.Doentes VIH positivos.
8.Doença cardíaca grave.
9.Incapacidade para deglutir comprimidos.
10.Necessite de utilizar, Carbamazapina, Fenobarbital ou Fenytoino.
11.Outra neoplasia primária.
12.Histórico de transplante de células estaminais ou de medula.
13.Historial clínico de Linfoma indolente.
14.Terapêutica com outro agente anti-cancerigeno (por exemplo metotrexato ou etoposido ou agentes em investigação) concomitante com o R-CHOP para o tratamento do LDGCB.
15.Observância de um prolongamento do intervalo QT no ECG de Baseline. História familiar de sindroma de prolongamento do intervalo QT, prevalece neste caso a opinião do investigador. Um doente com estas condições poderá ser incluído no estudo, após discussão entre o investigador e os médicos da Lilly responsáveis pelo estudo.
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall Disease Free survival is the primary efficacy endpoint. Overall DFS time is defined as the time from the date of study enrollment to the first date of objectively determined disease recurrence or death from any cause. For patients not known to have died as of the data cut-off date and who do not have objectively determined disease recurrence, overall
DFS will be censored at the date of the last objectively determined disease-free assessment. For patients who receive subsequent anticancer therapy (after discontinuation from the study therapy) prior to objectively determined disease recurrence, overall DFS will be censored at the date of the latest objectively-determined disease-free
assessment prior to the initiation of subsequent therapy
|
| A sobrevivência livre de doença é o primeiro endpoint de eficácia. (SLD) é definida como o tempo desde a data de inclusao do estudo até á primeira data de recidiva da doença ou morte por qualquer causa. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| Last Patient Entered Treatment + 3 years (LPET+3 years) |
| Ultimo doente em tratamento + 3 anos (LPET+3 anos) |
|
| E.5.2 | Secondary end point(s) |
| Patients will continue to be followed for DFS for up to 5 years after LPET (LPET+5 years) |
| Doentes continuarao a ser seguidos para SLD até 5 years após LPET (LPET+5 anos) |
|
| 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 | Yes |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Patient reported outcomes- Quality of Life |
| Resultados - Qualidade de Vida |
|
| 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 | No |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | Yes |
| E.8.1.5 | Parallel group | Yes |
| 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 | Yes |
| 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 | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 67 |
| 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 |
| Belgium |
| Brazil |
| Canada |
| China |
| Czech Republic |
| Denmark |
| Finland |
| France |
| Germany |
| Greece |
| Hungary |
| India |
| Italy |
| Japan |
| Korea, Republic of |
| Mexico |
| Poland |
| Portugal |
| Spain |
| Sweden |
| Taiwan |
| United Kingdom |
| United States |
|
| 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
|
| The end of study will occur when a total of 366 deaths have been observed. |
| O fim do estudo ocorre quando se observarem um total de 366 mortes. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
Print
