| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Diffuse Large B-Cell Lymphoma (DLBCL) |
| Diffúz, nagy B - sejtes lymfhoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| Diffuse Large B-Cell Lymphoma (DLBCL) |
| Diffúz, nagy B - sejtes lymfhoma |
|
| 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 | 10012818 |
| E.1.2 | Term | Diffuse large B-cell lymphoma |
| 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 compare the overall response rate (ORR) of JHL1101 in combination with CHOP and rituximab (MabThera) in combination with CHOP after 6 cycles of treatment in patients with previously untreated DLBCL. |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the safety of the two treatment groups among the patients with DLBCL.
2. To compare the complete response rate (CR) after 6 cycles of treatment, 1-year progression-free survival rate, 1-year event-free survival rate, and 1-year overall survival rate of the two groups.
3. To compare the immunogenicity of JHL1101 and rituximab (MabThera) in patients with DLBCL
4. To analyze the population pharmacokinetic characteristics of JHL1101 and rituximab (MabThera) in patients with DLBCL and the pharmacokinetic characteristics of patients who experienced infusionrelated reactions.
5. To analyze the pharmacodynamics of B-cell depletion in the two treatment groups among the patients with DLBCL. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Previously untreated patients histopathologically or cytologically diagnosed with CD20-positive DLBCL;
2. Aged ≥ 18 years and and ≤ 70 years of any gender;
3. International Prognostic Index (IPI) for Lymphoma score of 0 - 2 points;
4. Informed consent form has been signed before any specific study procedure is performed;
5. At least one measurable lesion. Intranoal lesions are defined as: the long diameter is ≥ 1.5 cm and the short diameter is ≥ 1.0 cm; for extranodal lesions, the long diameter should be ≥ 1.0 cm;
6. Eastern Cooperative Oncology Group (ECOG) performance status score of 0 - 2;
7. The left ventricular ejection fraction (LVEF) measured by echocardiography is ≥ 50%;
8. The patients have sufficient organ function, including:
• Absolute neutrophil count ≥ 1.5 x 10exp9/L; hemoglobin ≥ 80 g/L, platelet counts ≥ 75 x 10exp9/L;
• Total bilirubin level ≤ 1.5 × upper limit of normal (ULN), aspartate aminotransferase (AST), alanine aminotransferase (ALT) ≤ 2.5 × ULN;
• Serum creatinine level ≤ 1.5 × ULN;
• Prothrombin time (PT) or activated partial thromboplastin time (APTT) or international normalized ratio (INR) ≤ 1.5 × ULN in the absence of anticoagulant therapy;
9. Men and women of childbearing age who have not undergone sterilization surgery must agree to practice effective contraception during the treatment period and within 12 months after the last administration of the study drug;
*Women of childbearing potential willing to use an highly effective method of contraception,including.
i. oral birth control medications.
ii. placement of an intrauterine device with or without hormones.
iii. vasectomized male partner who is the sole partner for this patient.
*Male patients must be using 2 acceptable methods of contraception one of which must be a physical barrier method, (eg, spermicidal gel plus condom; condom plus partner is sterilized at least 6 months prior).
10. Have an expected survival of at least 6 months as judged by the investigator. |
|
| E.4 | Principal exclusion criteria |
1. Participated in other interventional clinical trials within three months prior to enrollment. Patients participating in non-interventional trials are eligible to participate in this study;
2. Have received blood transfusion, erythropoietin (EPO), granulocyte colony-stimulating factor (G-CSF) or granulocyte-macrophage colonystimulating factor (GM-CSF) for treatment within 14 days before
enrollment;
3. Patients who are or plan to be immunized with live virus vaccine within 28 days (or within 5 half-lives of the drug) before enrollment;
4. Patients who underwent or plan to undergo major surgery within 28 days before enrollment, or patients whose surgical wounds have not healed;
5. Patients who are receiving continuous corticosteroid treatment, with > 30 mg/day prednisone or equivalent dose of corticosteroids for ≥ 10 days of continuous treatment;
6. Have a history of gastrointestinal perforation and/or fistula within 6 months before enrollment;
7. Known to be allergic to monoclonal antibody (mAb) therapy or rituximab,or patients with known sensitivity or allergy to murine products;
8. Patients who have contraindications to any component of the CHOP regimen;
9. Have previously received treatment for DLBCL, including: chemotherapy, immunotherapy, local radiotherapy for lymphoma, surgical treatment (except for tumor or pathologic biopsy and surgical
resection not for lymphoma), and any monoclonal antibody therapy within 3 months prior to enrollment;
10. Have previously received cytotoxic drugs or anti-CD20 monoclonal antibody therapy for other diseases (such as rheumatoid arthritis);
11. Have a history of other malignancies that may affect study protocol compliance or result analysis (patients with a history of cured cutaneous basal cell carcinoma or squamous cell carcinoma, or cutaneous
melanoma or cervical carcinoma in situ can be enrolled if no evidence of relapse at least over past 3 years);
12. Also suffering from severe non-malignant diseases that can affect study protocol compliance, such as severe cardiovascular diseases (e.g., New York Heart Association Class III or IV heart disease, myocardial
infarction or unstable arrhythmia or unstable angina that occurred within the last 6 months), uncontrolled diabetes and hypertension, peripheral nervous system or central nervous system diseases;
13. Known to have uncontrollable active infectious diseases or any major infection events (other than neoplastic fever) requiring intravenous antibiotic treatment or hospitalization within four weeks prior to
enrollment;
14. Subjects known to be positive for human immunodeficiency virus (HIV) antibody;
15. Positive for hepatitis C virus (HCV) antigen or antibody;
16. Patients with HBs Ag(+), and his/her HBV-DNA level is > 10exp3 copies;
17. The investigator believes the subject is unsuitable for enrollment. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Primary efficacy endpoint: Overall response rate (ORR) after 6 cycles treatment, which is the percentage
of CR + PR. The evaluation is according to the International Working Group’s Lugano criteria (based on 5-
point scale). |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Secondary efficacy endpoint:
1. Complete response rate (CR) after 6 cycles treatment: the complete response rate.
2. 1-year progression-free survival (PFS) rate: the proportion of subjects who did not experience disease
progression or death from any cause one year after randomization.
3. 1-year event free survival (EFS) rate: the proportion of subjects who did not experience disease
progression or who stop receiving treatment for any reasons (such as disease progression, toxicity,
patient’s willingness, initiation of new treatment in the absence of clear progression, or death) one
year after randomization.
4. 1-year overall survival (OS) rate: the proportion of subjects who did not die from any cause one year
after randomization.
Safety:
Safety and tolerability will be evaluated using the following key safety parameters:
1. Incidence of all adverse events (AEs), treatment-emergent adverse events (TEAEs), adverse events of
special interest, and serious adverse events (SAEs) of J-CHOP as compared to R-CHOP, and their severity and correlation with the investigational drug.
2. Changes in vital signs, physical examination findings, and laboratory results before, during, and after
study treatment.
ADA Analysis:
Perform immunogenicity testing on all subjects: Serum samples that are positive for anti-drug antibodies
(ADAs) after drug administration will be tested continuously for the presence of neutralizing antibodies (NAbs).
The time points for collection of immunogenicity blood samples are: within one hour before the administration of monoclonal antibody on Day 1 of Cycle 1, 2 and Cycle 3, D21 ± 3 days of Cycle 6 (or the date of early withdrawal from the study), 12 weeks ± 3 days after the last drug administration, and 1 year after randomization.
4 mL of venous blood will be collected each time.
Population PK Analysis
Population pharmacokinetics: PK samples will be collected from all patients. During Cycle 1, samples will
be collected predose and one hour post infusion on Day 1. Additional samples will be collected on Days 2, 4, 8, and 22. The sample on Day 22 will be obtained just prior to the start of the Cycle 2 infusion. In Cycle 3 and Cycle 6, samples will be collected predose and 1 hour post-infusion. For subjects who experienced grade 2 and above infusion-related reactions, PK samples must be collected: upon the occurrence of infusion-related reaction and upon relief of infusion-related reactions. 4 mL of venous blood will be collected each time.
Pharmacodynamics Analysis
PD blood samples of CD19+ B-cell count in peripheral blood will be performed in all patients at baseline
(predose of Day1) , one hour post infusion of Day 1, predose of Cycle 2 infusion, D21 ± 3 days of Cycle 6 and 1-year after randomization (or the date of early withdrawal from the study), 4 mL of venous blood will be collected each time.
Subgroup Analysis
Subgroup analysis will be conducted on efficacy, safety and PK/ADA between Race (Chinese population,
European population, and patients from other countries) and ECOG (0,1,2). |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. Complete CR after 6 cycles treatment
2. 1-year PFS rate: one year after randomization.
3. 1-year EFS rate: one year after randomization.
4. 1-year OS rate: one year after randomization.
Safety: during and after study treatment.
ADA Analysis: Day 1 of Cycle 1, 2 and Cycle 3, D21 ± 3 days of Cycle 6, 12 weeks ± 3 days after the last drug administration, and 1 year after randomization.
Population PK: During Cycle 1, samples will be collected on Day 1. Additional samples will be collected on Days 2, 4, 8, and 22. In Cycle 3 and 6, samples will be collected predose and 1 hour post-infusion.
PD blood samples will be performed in all patients at baseline, Day 1, predose of Cycle 2 infusion, D21 ± 3 days of Cycle 6 and 1-year after randomization
|
|
| 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 | No |
| 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) | 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 | No |
| 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 | 91 |
| 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 |
| Belarus |
| Bulgaria |
| China |
| Croatia |
| Czech Republic |
| Germany |
| Hungary |
| India |
| Israel |
| Philippines |
| Poland |
| Romania |
| Serbia |
| Singapore |
| Slovakia |
| Thailand |
| Turkey |
| Ukraine |
| United Kingdom |
|
| 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
|
|
| 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 | 3 |
| 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 |
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