E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Advanced stage follicular lymphoma. |
|
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 | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016910 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage IV |
E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
E.1.2 Medical condition or disease under investigation |
E.1.2 | Version | 20.0 |
E.1.2 | Level | PT |
E.1.2 | Classification code | 10016909 |
E.1.2 | Term | Follicle centre lymphoma, follicular grade I, II, III stage III |
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 |
To demonstrate comparability of the overall response rate in patients with previously untreated, advanced stage follicular lymphoma who receive GP2013-CVP combination treatment to patients who receive MabThera®-CVP treatment. ORR will be determined during the combination treatment period using Modified Response Criteria for Malignant Lymphoma |
|
E.2.2 | Secondary objectives of the trial |
Other efficacy
• To evaluate CR rate at the end of combination treatment period;
• To evaluate PR rate at the end of combination treatment period;
• To evaluate PFS, which is defined as time from date of randomization
to date of first documented progression of disease, or death due to any
cause;
• To evaluate OS, which is defined as: time from date of randomization
to date of death due to any cause.
Safety
• To describe safety of GP2013-CVP in comparison to MabThera®-CVP;
• To evaluate the incidence of ADA formation against GP2013 and
MabThera®.
Pharmacokinetics/Pharmacodynamics
• To evaluate the pharmacokinetics of GP2013 and MabThera®. To
evaluate peripheral CD19+ Bcell count as a pharmacodynamic marker
following treatment with GP2013-CVP and MabThera®- CVP.
|
|
E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
Patients eligible for inclusion in this study have to meet all of the
following criteria:
1. Patient with previously untreated advanced stage, CD20-positive FL:
a. Ann Arbor classification stage III/IV;
b. WHO histologic grade 1, 2 or 3a, as confirmed by central
pathological testing; and
c. Require therapy for FL as per local guidelines or in the opinion of
the treating physician.
2. Patient age ≥ 18 years.
3. Patient with at least one measurable lesion (accurately measurable in
at least 2 perpendicular dimensions);
a. at least 1 measurable nodal lesion > 20 mm in the long axis; OR
b. at least 1 measurable extranodal lesion with both long and short
axes ≥ 10 mm.
4. Patient with ECOG performance status 0, 1 or 2.
5. Patient with adequate cardiac function defined as cardiac ejection
fraction ≥ 45% as measured by ECHO or MUGA, without clinically
significant abnormalities.
6. Patient with the following laboratory values obtained during
Screening (up to 28 days before randomization):
a. hemoglobin ≥ 10g/dL (unless abnormalities are due to
histologically proven bone marrow involvement by lymphoma);
b. absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (unless
abnormalities are due to histologically proven bone marrow involvement
by lymphoma);
c. platelet count ≥ 100 x 10^9/L (unless abnormalities are due to
histologically proven bone marrow involvement by lymphoma);
d. total bilirubin < 1.5 x ULN (upper limit of normal) (if Gilbert-
Meulengracht syndrome is present, up to 2.0 x ULN is allowed);
e. transaminases < 2.5 x ULN;
f. serum creatinine level < 2 x ULN or calculated creatinine clearance
> 50 mL/min;
g. negative serologic or virologic markers for active or latent hepatitis
B and hepatitis C infections.
7. Sexually active males who accept to use a condom during intercourse
while taking the drug and for 12 months after stopping treatment as
they should not father a child in this period. A condom is required to be
used also by vasectomised men (as well as during intercourse with a
male partner) in order to prevent delivery of the drug via seminal fluid.
8. a) Women of child-bearing potential, defined as all women
physiologically capable of becoming pregnant, including women whose
career, lifestyle, or sexual orientation precludes intercourse with a male
partner and women whose partner have been sterilized by vasectomy or
other means, who accept to use a highly effective method of birth
control while taking study drug and for 12 months after stopping
treatment.
OR
b) Women who are considered post-menopausal and not of child bearing
potential i.e. if they have had 6 months of natural (spontaneous)
amenorrhea with an appropriate clinical profile (e.g. age appropriate,
history of vasomotor symptoms) or have had surgical bilateral
oophorectomy (with or without hysterectomy) or tubal ligation at least
six weeks ago (in the case of oophorectomy alone, only when the
reproductive status of the woman has been confirmed by follow up
hormone level assessment).
9. Patient has signed and dated informed consent documents according
to local guidelines. |
|
E.4 | Principal exclusion criteria |
Patients eligible for this study must not meet any of the following
criteria:
1. Patient with Grade 3b (aggressive) FL or any histology other than FL
grade 1, 2 or 3a.
2. Patient with histological evidence of transformation to high grade or
diffuse large B-cell lymphoma.
3. Patient who has previously received any prior therapy for lymphoma,
e.g. cytostatic or cytotoxic agents, antibodies, anti-lymphoma
vaccination, experimental treatments and radiotherapy, except who received involved field radiation 4 weeks prior to Cycle 1 Day 1, of up to two lesions that will not be used to evaluate disease progression.
4. Evidence of significant leukemic disease defined as >10 x 109 /L
circulating CD20+ lymphoma cells.
5. Patient with clinical evidence of central nervous system (CNS)
involvement by lymphoma or any evidence of spinal cord compression by lymphoma.
6. Patient with evidence of any uncontrolled, acute or chronic active infection (viral, bacterial, including tuberculosis or fungal).
7. Patient receiving chronic (>3 months), high dose (> 20 mg of
prednisone or > approximately 3 mg of dexamethasone per day orequivalent doses of other steroid medications) of systemic
corticosteroids.
8. Patient with any malignancy within 5 years prior to date of
randomization, with the exception of adequately treated in situ
carcinoma of the cervix uteri, basal or squamous cell carcinoma or
nonmelanomatous skin cancer.
9. Patient with a known hypersensitivity to any of the study treatment
ingredients e.g. to recombinant human antibodies.
10. Patient with concurrent serious illnesses, uncontrolled medical
conditions, or other medical history including clinically relevant
abnormal laboratory results, which in the investigator's opinion would
be interfere with a patient's participation in the study, or with the
interpretation of study results:
a. uncontrolled neurological disease (e.g. recurrent seizures despite
existing anticonvulsant therapy);
b. neuropathy ≥ grade 1, neuromuscular disease;
c. severe disturbance of liver function;
d. severe constipation;
e. cystitis or other ongoing infections;
f. disturbance of micturition;
g. severe chronic obstructive pulmonary disease with clinically
manifest hypoxemia;
h. uncontrolled hypertension (defined as systolic BP > 160 mm Hg or
diastolic > 100 mm Hg);
i. history of stroke or cerebral ischemia (within 6 months prior to
screening);
j. history of myocardial infarction or other clinically significant
myocardial disease (within 6 months prior to screening) or unstable
angina (≥ NYHA Grade II);
k. known infection with HIV or any other severe immunecompromised
state according to patient history (if required by local
regulations or clinical practice guidelines, patient may be tested during
the screening period to confirm HIV status);
l. evidence of ongoing drug or alcohol abuse within the last 6 months
before screening;
m . active tuberculosis. Patients with evidence of latent tuberculosis
as per results of the tuberculosis screening test and further follow-up
may enter the study after evaluation by an appropriate specialist and
after sufficient treatment has been initiated according to local medical
practice.
11. Patient has had major surgery, open biopsy or trauma within 4
weeks prior to date of screening (lymph node biopsy is not regarded as
major surgery), or expects the need for major surgery during the course
of study treatment.
12. Female patient who is nursing (lactating/breast-feeding), pregnant
or planning a pregnancy within 12 months after the last infusion of study
drug; where pregnancy is defined as the state of a female after
conception and until the termination of gestation, confirmed by a
positive hCG laboratory test (> 5 mIU/mL).
13. Patient has received therapy with any other investigational medicinal
product within the last 30 days or 5 times the half-life, whichever is
longer, prior to screening.
14. Patient plans to receive live vaccines during the study or has
received live vaccines 4 weeks prior to date of screening. Examples of
live vaccines include intranasal influenza, measles, mumps, rubella, oral
polio, BCG, yellow fever, varicella, and TY21a typhoid vaccines.
15. Patient is using growth factors or transfusions to meet study
eligibility requirements during Screening period. (The use of growth
factors and transfusions during screening is permissible, if there is
suspicion of bone marrow involvement by lymphoma and patient is
deemed not to be growth factor-dependent or transfusion-dependent) |
|
E.5 End points |
E.5.1 | Primary end point(s) |
Overall response rate at the end of combination treatment period using modified response criteria for lymphoma. Overall response rate is defined as the proportion of patients whose best overall disease response is either complete response or partial response at the end of the combination treatment period based on independent central radiology review. |
|
E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
E.5.2 | Secondary end point(s) |
Other efficacy
* Complete response during the combination treatment period
* Partial response during the combination treatment period
* Progressive free survival (from date of randomization to date of first
documented progression of disease, or death due to any cause) with up
to 3 years of follow-up post randomization
* Overall survival (from date of randomization to date of death due to
any cause) with up to 3 years of follow-up post randomization
Safety:
* Incidence, severity, type and relationship of AEs to the study
treatments
* Percentage of patients with immunogenicity (ADA formation)
Pharmacokinetics/Pharmacodynamics:
* Pharmacokinetic variables (Cmax, Cmin) at Cycle 4, Day 1
* CD19+ B-cell count (AUEC0-21 days)
Exploratory:
* Pharmacokinetic variables (Cmax, Cmin) |
|
E.5.2.1 | Timepoint(s) of evaluation of this end point |
Other efficacy
* CR: after 6 months and at the end of maintenance
* PR: after 6 months and at the end of maintenance
* PFS: end of 3-year follow-up period
* OS: at the end of maintenance
Safety:after 6 months and at the end of maintenance
Pharmacokinetics/Pharmacodynamics: after 6 months and at the end of maintenance
Exploratory: after 6 months and at the end of maintenance |
|
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 | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | Yes |
E.6.13.1 | Other scope of the trial description |
|
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | Information not present in EudraCT |
E.7.1.2 | Bioequivalence study | Information not present in EudraCT |
E.7.1.3 | Other | Information not present in EudraCT |
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 | Yes |
E.8.1.7.1 | Other trial design description |
Due to implementation of USM, all the subjects assigned to GP2013 were shifted to MabThera (blinded) |
|
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 | 2 |
E.8.5 | The trial involves multiple Member States | Yes |
E.8.5.1 | Number of sites anticipated in the EEA | 98 |
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 |
Austria |
Brazil |
Bulgaria |
Colombia |
France |
Germany |
Hungary |
India |
Ireland |
Israel |
Italy |
Japan |
Malaysia |
Netherlands |
New Zealand |
Peru |
Poland |
Portugal |
Romania |
Russian Federation |
South Africa |
Spain |
Ukraine |
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
|
|
E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | 3 |
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 | 4 |
E.8.9.2 | In all countries concerned by the trial months | 6 |