| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| RELAPSED OR REFRACTORY DIFFUSE LARGE B-CELL LYMPHOMA |
|
| E.1.1.1 | Medical condition in easily understood language |
A type of cancer of blood cells called lymphocytes. Refractory means it
did not respond to chemotherapy treatment, relapsed means it has come back after chemotherapy treatment. |
|
| 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 | 10012821 |
| E.1.2 | Term | Diffuse large B-cell lymphoma recurrent |
| 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 | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Stage 1
• To select adequate (e.g., p-value <0.15 in favor of lenalidomide) subtype(s) for Stage 2. Germinal center B-cell (GCB), non-GCB, both subtypes, or neither subtype will be selected based on the overall response rate (ORR) in the individual subtype to lenalidomide monotherapy versus single agent of Investigator’s choice.
Stage 2
• To compare the progression free survival (PFS) of lenalidomide monotherapy versus single agent of Investigator’s choice in the subtype(s) selected in Stage 1.
|
|
| E.2.2 | Secondary objectives of the trial |
Evaluate concordance between IHC assays for stratification of GCB and non-GCB to gene expression profiles
Investigate potential predictive biomarkers of clinical response or resistance to lenalidomide
Investigate mechanistic biology parameters
Determine efficacy using the 2007 Revised Response Criteria for Malignant Lymphoma with FDG-PET (Cheson 2007)
For full secondary objectives, please see protocol. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1.Histologically proven DLBCL following WHO subcategories a.NOS(common morphologic variants,rare morphologic variants,molecular subgroups,and IHC subgroups[CD5+,GCB,non-GCB])
b.Tcell/histiocyte rich
c.EBV+of the elderly
d.Associated with chronic inflammation
e.Submission of an FFPE tumor block or appropriately stained slides from a fresh biopsy is required.If fresh specimen cannot be obtained without putting the patient at unjustifiable risk,then slides prepared from the
archival specimen supporting a prior DLBCL diagnosis may be submitted to fulfill this inclusion criterion with medical monitor approval
2.Can wait for subtype results from central pathology prior to randomization.In the event that the patient requires immediate treatment and the sample cannot be submitted to and evaluated by central pathology prior to start of treatment,medical monitor approval for enrollment is required;in this case submission of an appropriate sample(either fresh biopsy acquired prior to Cycle 1 Day 1 or archival sample) is absolutely required and the sample should be submitted no later than 4 weeks post Cycle 1 Day
3.Relapsed/refractory to
a.One combination chemotherapy regimen containing rituximab and an anthracycline or equivalent if anthracycline is contracindicated;and
b.At least one additional treatment with either a combination chemotherapy regimen (which must include at least one
of:ifosphamide,gemcitabine,etoposide or a platinum agent and rituximab if not previously used) or conditioning regimen containing an alkylating agent followed by autologous or allogenieic SCT.If a patient is documented as ineligible for both the additional combination chemotherapy and SCT at the time of
inclusion in the study,they are exempted from requirement 3b
c.For patients who have relapsed or progressed after achieving a response(defined as CR or PR),documented,Investigator-assessed
relapse or progression after the last treatment is required
d.For patients refractory to their last treatment(defined as not having achieved a CR or PR prior to enrollment by
Investigatorassessment),documented progression will not be required
e.For patients whom the physician considers ineligible for SCT at the time of enrollment because of one or more of the following reasons,documentation of SCT ineligibility is required
•Age>65years
•Comorbidity for patients<65years(any condition including laboratory abnormalities or clinical symptoms such as e.g. cardiac insufficiency and severe pulmonary diseases that places the patient at an unacceptable
risk if he/she undergoes transplant)
•Patient declines transplant
•Physician considers that patient's disease cannot be adequately treated
by autologous transplantation.Possible reasons: active disease following
salvage therapy or insufficient CD34 cell collection
f.For patients whom the physician considers ineligible for second line
combination chemotherapy at the time of enrollment because of one or
more of the following reasons,documentation of the ineligibility is
required
•Poor performance status
•Major organ dysfunction or significant medical condition that places the
patients at unacceptable risk
•Patient refuses multi-agent chemotherapy
4.Must have measurable disease on cross sectional imaging by CT/MRI
that is at least 2cm longest diameter and measurable in two
perpendicular dimensions.(CT is to be performed with contrast unless it
is medically contraindicated)
6.Life expectancy>3months
7.Must understand and voluntarily sign an ICF
8.Must be≥18years of age at the time of signing the ICF
9.Must be able to adhere to the study visit schedule and other protocol
requirements
10.FCBP must
a.Have a negative medically supervised pregnancy test prior starting
study therapy.She must agree to pregnancy testing during the study,and
after end of study therapy.This applies even if the patient practices
complete and continued sexual abstinence
b.Either commit to continued abstinence from heterosexual
intercourse(which must be reviewed on a monthly basis)or agree to
use,and be able to comply with,effective contraception without
interruption,28 days prior to starting study drug,during the study
therapy (including dose interruptions),and for 28 days after
discontinuation of study therapy
11.Male patients must
a.Agree to use a condom during sexual contact with a FCBP,even if they
have had a vasectomy,throughout study drug therapy,during any dose
interruption and for28days after discontinuation of study therapy
b.Agree to not donate semen during study drug therapy and for 28days
after discontinuation of study drug therapy
12.All patients must
a.Understand that the study drug could have a potential teratogenic risk
b.Agree to abstain from donating blood while taking study drug therapy
and for 28 days after discontinuation of study drug therapy
c.Agree not to share study medication
d.Agree to be counseled about pregnancy precautions and risks of fetal
exposure
|
|
| E.4 | Principal exclusion criteria |
1.Diagnosis of lymphoma histologies other than diffuse large B-cell lymphoma.Patients with history of low-grade
B-cell NHL;evidence of concurrent,follicular lymphoma;or history of known transformed large-cell NHL
2.Prior history of malignancies, other than diffuse large B-cell lymphoma, unless the patient has been free of the
disease for≥5years.Exceptions to the≥5year time limit include history of the following
Basal cell carcinoma of the skin
Squamous cell carcinoma of the skin
Carcinoma in situ of the cervix
Carcinoma in situ of the breast
Incidental histological finding of prostate cancer (TNM stage of T1a or T1b)
3.Prior use of lenalidomide
4.Patients in whom autologous or allogeneic SCT or combination chemotherapy is considered appropriate at the
time of inclusion in the study
5.Prior allogeneic SCT with persistent donor hematopoiesis
6.Known seropositive for or history of, active viral infection with human HIV
7. Seropositive for or active viral infection with HBV
HBsAg positive
HBsAg negative,anti-HBs positive and/or anti-HBc positive and detectable viral DNA
•Patients who are HBsAg negative and viral DNA negative are eligible
•Patients who had HBV but have received an antiviral treatment and show no detectable viral DNA for 6 months
are eligible
•Patients who are seropositive because of HBV vaccination are eligible
8.Known seropositive for or active viral infection with HCV
9.Neuropathy Grade 4
10.The following WHO subcategories of DLBCL
a.Active CNS lymphoma with the exception of those patients whose CNS lymphoma has been treated with
chemotherapy, radiotherapy or surgery, have remained asymptomatic for 12 weeks(3 months)and demonstrate
no CNS lymphoma as shown by lumbar puncture,CT/brain MRI are eligible.Patients with a history of CNS
involvement or CNS symptoms will be required to have negative cerebrospinal fluid cytology examination and a
head CT during the Screening Phase(known and active CNS or leptomeningeal involvement)
b.Primary cutaneous,leg type
c.Primary mediastinal(thymic)
d.Lymphomatoid granulomatosis
e.ALK-positive cases
f.Plasmablastic lymphoma
g.Large B cell lymphoma arising in HHV8 associated multicentric Castleman disease
h.Primary effusion lymphoma
i.Intravascular large B cell
j.Unclassifiable cases with features intermediate between DLBCL and Burkitt
k.Unclassifiable cases with features intermediate between DLBCL and classical Hodgkin’s lymphoma
11.Patients who are at a high risk for a thromboembolic event and are not willing to take VTE0 prophylaxis
12.Any of the following laboratory abnormalities
a.Absolute neutrophil count<1,500cells/mm3(1.5x109/L)unless secondary to bone marrow involvement by
lymphoma as demonstrated by recent bone marrow aspiration and bone marrow biopsy
b.Platelet count<50,000/mm3(50x 09/L)unless secondary to bone marrow involvement by lymphoma as
demonstrated by recent bone marrow aspiration and bone marrow biopsy
c.Serum aspartate transaminase(AST/SGOT)or alanine transaminase(ALT/SGPT)> 3.0x upper limit of
normal(ULN),except in patients with documented liver involvement by lymphoma
d.Serum bilirubin>1. xULNexcept in cases of Gilbert’s Syndrome and documented liver involvement by
lymphoma
e.Calculated creatinine clearance (Cockcroft-Gault formula) of<3 mL/min
13.Chemotherapy, radiotherapy, investigational anticancer therapy or major surgery within28days of Day1dosing
a.Patients with rapidly progressing disease who have recovered from all prior treatment related toxicities may be
able to start Day 1 dosing in less than 28 days from their prior treatment upon approval by the sponsor
b.Patients who received SCT must recover from all acute toxicity and be transfusion independent
14.Uncontrolled intercurrent illness including, but not limited to
a.Ongoing or active infection requiring parenteral antibiotics
b.Uncontrolled diabetes mellitus as defined by the Investigator
c.Chronic symptomatic congestive heart failure (Class III or IV of the New York Heart Association Classification
for Heart Disease)
d.Unstable angina pectoris, angioplasty, stenting, or myocardial infarctions within6months
e.Clinically significant cardiac arrhythmia that is symptomatic or requires treatment, or asymptomatic sustained
ventricular tachycardia. Patients with controlled atrialfibrillation that is asymptomatic are eligible
15.Any serious medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient
from signing the informed consent form
16.Pregnant or lactating females
17.Any condition, including the presence of laboratory abnormalities, which places the patient at unacceptable
risk if he/she were to participate in the study, or which confounds the ability to interpret data from the study |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Stage 1: Overall response rate (CR+CRu+PR) to select adequate subtypes for Stage 2 testing
Stage 2: Progression-free survival based on 1999 IWRC |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Stage 1: Treatment effect on best response will be evaluated after all 50 patients in a particular biomarker -defined subtype complete four cycle of treatment or have discontinued prior to four cycles of treatment
Stage 2: 1 year from 122 pts. enrolled |
|
| E.5.2 | Secondary end point(s) |
Stage 2, key ranked:
1. Complete response (CR+CRu) rate
2. Overall Response rate (CR+CRu+PR)
3. Duration of response (CR+CRu+PR)
4. Overall survival (OS)
Stage 2, unranked:
- Duration of complete response (CR+CRu)
- Overall response rate for patients with a duration of response lasting ≥ 16 weeks
- Time to progression (TTP)
- Safety
- Health-related Quality of Life by using EORTC QLQ-C30 and EQ-5D |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Complete response (CR+CRu) rate: 1 Year from 122 pts. enrolled
2. Overall Response rate (CR+CRu+PR): 1 Year from 122 pts. enrolled
3. Duration of response (CR+CRu+PR): 1 Year from 122 pts. enrolled
4. Overall survival (OS): at the time of PFS analysis and the end of follow-up phase
- Duration of complete response (CR+CRu): 1 Year from 122 pts.
enrolled
- Overall response rate for patients with a duration of response lasting ≥ 16 weeks: 1 Year from 122 pts. enrolled |
|
| 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 | No |
| 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 |
| Quality of life questionnaires EORTC QLQ-C30 and EQ-5D |
|
| 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) | 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 | Yes |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | Yes |
| E.8.1.7.1 | Other trial design description |
| Investigator's choice: Gemcitabine / Rituximab / Etoposide / Oxaliplatin |
|
| 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 | Yes |
| E.8.2.3.1 | Comparator description |
| Investigator's choice: Gemcitabine / Rituximab / Etoposide / Oxaliplatin |
|
| E.8.2.4 | Number of treatment arms in the trial | 5 |
| 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 | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 26 |
| 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 |
| Austria |
| Czech Republic |
| France |
| Italy |
| Spain |
| Sweden |
| United Kingdom |
|
| 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
|
| Treatment phase will continue until disease progression or until subsequent antilymphoma therapy. Then, follow-up phase will start and it will continue until 70% of the patients in Stage 2 have died, are lost to follow-up, or four years from the last patient randomized, whichever occurs first, at which time the study will be terminated. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 5 |
| 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 | 5 |
| 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
