| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| CD20-positive primary and transformed diffuse large B cell lymphoma (DLBCL) and grade 3 follicular lymphoma (FL). |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| 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 | 16.1 |
| E.1.2 | Level | HLT |
| E.1.2 | Classification code | 10029592 |
| E.1.2 | Term | Non-Hodgkin's lymphomas NEC |
| E.1.2 | System Organ Class | 100000004851 |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| To determine objective response rate (ORR) (complete remission [CR] + partial remission [PR]) per modified [the International Working Group (IWG) Revised Response Criteria for Malignant Lymphomas (2007)]. |
|
| E.2.2 | Secondary objectives of the trial |
To evaluate the following:
• Safety and tolerability of YM155 given in combination with rituximab.
• CR Rate.
• PR Rate.
• Time to response.
• Duration of response.
• Clinical benefit rate (CBR).
• Progression-free survival (PFS).
• Overall survival (OS). |
|
| 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 |
The pharmacogenomic sub-study is included in the main protocol.
Study objectives are to comprehensively analyze:
• Suspected disease-related genes such as oncogenes, survivin and vascular
endothelial growth factor (VEGF)
• Genes potentially involved in drug excretion and/or metabolism such as the
organic anion/cation transporters (OAT, OCT)
• Genes of relevance to toxicity/safety issues, to be identified in a
precautionary / retrospective setting |
|
| E.3 | Principal inclusion criteria |
A subject is eligible for the study if all of the following apply:
1. Institutional Review Board (IRB)-/Independent Ethics Committee (IEC)-approved
written Informed Consent and privacy language as per national regulations (e.g.,
HIPAA Authorization for U.S. sites) must be obtained from the subject prior to
any study-related procedures (including withdrawal of prohibited medication, if
applicable).
2. Male or female subject aged 18 years or older.
3. Any stage, histologically confirmed CD20-positive primary or transformed DLBCL or
grade 3 FL.
4. Ineligible for or have previously received an ASCT.
5. Subject must have relapsed or transformed from a low grade NHL to a DLBCL and have documented at least a PR that was maintained for 3 months prior to progression; following receipt of last dose of systemic chemotherapy or ASCT.
6. At least one prior chemotherapy regimen.
o Prior regimen must have contained anthracycline (unless contraindicated).
o Any planned maintenance therapy should be considered as part of the
previous treatment regimen.
o Any preparative treatment (salvage chemotherapy, high-dose
chemotherapy, radiation therapy, etc.) should be included with the ASCT
as one treatment regimen.
7. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 at the
Baseline Visit.
8. Life expectancy greater than 12 weeks at the Baseline Visit based on Investigator's judgement.
9. At least one measurable lesion ≥ 1.5 cm in the longest diameter (LDi) OR > 1.0 - ≤ 1.5 cm in LDi and > 1.0 cm in the shortest diameter (SDi) as assessed via diagnostic computed tomography (CT) or FDG PET scans.
10. Subject with a previous history of non-CD20+ B cell NHL malignancy is eligible only if the subject meets the following:
o Previous history of a non-invasive carcinoma if in the opinion of the investigator the subject has had potentially curative treatment prior to enrollment.
o For all other malignancies, the subject has undergone potentially curative therapy and has been considered disease free for at least 5 years.
11. Female subject must be either:
• Of non-child bearing potential
• post-menopausal (defined as at least 1 year without any mensus) prior to Screening, or
• documented surgically sterile or status post hysterectomy (at least 1 month prior to Screening), or
• If of childbearing potential,
• must have a negative serum or urine pregnancy test at Screening
• must use two forms of birth control* (at least one of which must be a barrier method) starting at Screening and throughout the study period and for 28 days after final study drug administration.
12. Male subject and their female spouse/partners of childbearing potential must be using highly effective contraception consisting of two forms of birth control* (one of which must be a barrier method) starting at Screening and continue throughout the study period and for 28 days after final study drug administration.
13. Female subject must not be breastfeeding at Screening or during the study period and for 28 days after final study drug administration.
14. Female subject must not donate ova starting at Screening and throughout the study period and for 28 days after final study drug administration.
15. Male subject must not donate sperm starting at Screening and throughout the study period and for at least 28 days after final study drug administration.
16. Subject agrees not to participate in another interventional study while on treatment.
*Note: Acceptable forms of birth control include established use of oral, injected or implanted hormonal methods of contraception, placement of an intrauterine device (IUD) or intrauterine system (IUS), or barrier methods of contraception including a condom or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository.
|
|
| E.4 | Principal exclusion criteria |
A subject will be excluded from participation if any of the following apply:
1. Use of systemic steroids within 5 days of the Baseline Visit.
o A subject receiving steroids at the time of the Baseline Visit is eligible as
long as the subject is receiving a biologic dose or has been on a stable,
non-biologic dose for at least 4 weeks prior to the first dose of YM155 and
plans on continuing to receive the stable, non-biologic dose during study
participation.
o Systemic steroid use within 5 days of the Baseline Visit for the purposes
of pre-medication prior to study regimen treatment is allowed.
2. Prior allogeneic stem cell transplant (SCT).
3. Inadequate marrow, hepatic and/or renal function at the Baseline Visit defined as:
o Serum creatinine ≥ 1.5 x upper limit of normal (ULN) or calculated serum
creatinine clearance < 60 mL/min.
o Absolute neutrophil count (ANC) ≤ 1000/mm3.
o Platelet ≤ 75,000/mm3.
o Alanine transaminase (ALT) and Aspartate transaminase (AST)
≥ 2.5 x ULN or ≥ 5 x ULN if secondary to liver metastases.
4. Central nervous system (CNS) or leptomeningeal involvement by lymphoma as
determined by the Investigator through physical examination and medical history
review at the Baseline Visit.
5. The subject has significant and/or uncontrolled cardiac, renal, hepatic, or other
systemic disorders or significant psychological conditions at the Baseline Visit that
in the Investigator’s judgment would jeopardize subject enrollment or compliance
with the study procedures.
6. The subject has known human immunodeficiency virus (HIV), hepatitis B surface
antigen, or hepatitis C antibody.
7. The subject has been previously treated with YM155.
8. The subject has received other investigational therapy or procedures within 21
days prior to the first study drug administration. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| The primary endpoint for this study is the objective response rate (ORR). The ORR is defined as the proportion of subjects with confirmed CR or confirmed PR assessed by the investigator. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
The ORR will be calculated along with the corresponding exact two-sided 90% confidence interval (CI). For the full analysis, the study will be considered successful if there are at least 10 responders out of 34 PPS subjects.
Subgroup analyses of ORR will be conducted on each level of the following baseline variables:
Age (< 60-, >= 60)
Race (White, Black, Asian, Other)
Gender (Male, Female)
ECOG performance status (0, 1)
NHL sub-type (primary DLBCL, transformed DLBCL and grade 3 follicular lymphoma)
Lymphoma Prognostic Index (low, intermediate, and high) |
|
| E.5.2 | Secondary end point(s) |
To evaluate the following:
• Safety and tolerability of YM155 given in combination with
rituximab
• Complete Remission Rate (CR)
• Partial Remission Rate (PR)
• Time to response
• Duration of response
• Clinical benefit rate (CBR)
• Progression-free survival (PFS)
• Overall survival (OS) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Safety:Assessed by physical examination,vitals,laboratory assessments,ECG,standard safety evaluations,recording of adverse events+assessment for toxicity.CR:Proportion of subjects with confirmed CR.PR:Proportion of subjects with confirmed PR.Time to Response:Time from 1st dose of study drug until 1st documentation of response(CR or PR).Duration of response:Time from 1st documentation of response(CR or PR) until objective tumor progression.CBR:Proportion of subjects with confirmed CR,confirmed PR and SD.PFS:Time from 1st dose of study drug until objective tumor progression or death.OS:Time from 1st dose of study drug until death.Follow-up survival will continue until subject death for no more than 1 year following EOT. |
|
| 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 | 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 |
| Potential efficacy biomarkers |
|
| 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) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| 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.8.2.4 | 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 | 6 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 20 |
| 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 | Yes |
| 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 |
|
| 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
|
| The end of trial for all participating countries is defined as the date of the Last Subject’s Last Visit or date of Last Follow-up contact, whichever is later. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 6 |
| E.8.9.1 | In the Member State concerned months | |
| E.8.9.1 | In the Member State concerned days | 13 |
| E.8.9.2 | In all countries concerned by the trial years | 6 |
| E.8.9.2 | In all countries concerned by the trial days | 13 |
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