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
• Evaluate CR rate during the combination treatment period;
• Evaluate PR rate during the combination treatment period;
• 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, with up to 3 years of follow up post randomization;
• Evaluate OS, which is defined as: time from date of randomization to date of death due to any cause, with up to 3 years of follow up post randomization.
Safety
• Describe safety of GP2013-CVP in comparison to MabThera® either asngle agent or in combination with CVP;
• Evaluate the incidence of immunogenicity (ADA formation) against GP2013 and MabThera®
PK/PD
• Evaluate the pharmacokinetics of GP2013 and MabThera®.
• 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; and
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 2D-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 ULNor calculated creatinine clearance › 50 mL/min;
g. negative serology 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, radiotherapy, antibodies, anti-lymphoma vaccination, experimental treatments), 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 doses (> 20 mg of prednisone or > approximately 3 mg of dexamethasone per day; or equivalent 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 likely to 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 (dyspnea > grade 1);
h. uncontrolled hypertension (definied as systolic BP > 160 mm Hg or diastolic > 100 mm Hg);
i. history of stroke or cerebral ischemia (within 6 months prior to randomization);
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 immune-compromised 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 result of the tuberculosis screening test and futher 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 lympoma 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 the 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 adverse event and laboratory test abnormalities
* Percentage of patients with immunogenicity (ADA formation) PK/PD:
* 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
PK/PD: 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 | 7 |
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 | 5 |
E.8.9.1 | In the Member State concerned months | 9 |
E.8.9.1 | In the Member State concerned days | 19 |
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 |