| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Newly-diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma (DLBCL). |
|
| E.1.1.1 | Medical condition in easily understood language |
| Recently diagnosed cancer of the blood system. |
|
| 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 | 21.0 |
| 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.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10012820 |
| E.1.2 | Term | Diffuse large B-cell lymphoma NOS |
| 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 efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus tafasitamab placebo, lenalidomide placebo and R-CHOP (henceforth referred to as R-CHOP in the context of the control arm). |
|
| E.2.2 | Secondary objectives of the trial |
1. To compare the efficacy (additional parameters) of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
2. To compare the safety of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
3. To compare the efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP in DLBCL subtypes of COO
4. To compare the efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP in DLBCL subtypes: DLBCL NOS versus HGBL versus other.
5. To compare the incidence of central nervous system relapse in patients receiving tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
6. To assess patient-reported outcomes in patients receiving tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
7. To assess the pharmacokinetic profile of tafasitamab.
8. To assess the potential immunogenicity of tafasitamab.
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Signed written informed consent form (ICF).
2. Adult subjects aged 18 (or legal age per local regulations) to 80 years of age inclusive.
3. Previously untreated patients with local biopsy-proven, CD20-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization classification of lymphoid neoplasms are eligible:
a. DLBCL, NOS including GCB type, ABC type
b. T-cell rich large BCL
c. Epstein-Barr virus-positive DLBCL, NOS
d. Anaplastic lymphoma kinase-positive large BCL
e. Human herpes virus-8-positive DLBCL, NOS
f. High-grade BCL with MYC and B-cell lymphoma 2 (BCL2) and/or B-cell lymphoma 6 (BCL6) rearrangements (double-hit or triple-hit lymphoma).
g. HGBL-NOS
h. DLBCL coexistent with either FL of any grade, gastric mucosa-associated lymphoid tissue (MALT) lymphoma or non-gastric MALT lymphoma
i. FL grade 3b
4. Availability of archival or freshly collected tumor tissue sent for retrospective central pathology review.
5. Up to 6 of the largest target nodes, nodal masses, or other lymphomatous lesions that are measurable in 2 diameters should be identified by local assessment from different body regions representative of the patient’s overall disease burden and include mediastinal and retroperitoneal disease, if involved.
6. ECOG performance status of 0,1 or 2.
7. IPI status of 3 to 5 (for patients > 60 years of age) or aaIPI 2 to 3 (for patients ≤60 years of age).
8. Diagnosis to treatment interval, defined as the time between the date of DLBCL diagnosis (date of the first biopsy specimen containing lymphoma according to the local pathology report) and the start of treatment (C1D1) ≤28 days.
9. Left ventricular ejection fraction ≥50% as assessed by local echocardiography or cardiac multi-gated acquisition (MUGA) scan
10. Patient must have the following local laboratory criteria at screening:
a. Absolute neutrophil count ≥1.5x109/L (unless secondary to bone marrow involvement by DLBCL)
b. Platelet count ≥75x109/L (unless secondary to bone marrow involvement by DLBCL)
c. Total serum bilirubin <1.5× upper limit of normal (ULN) unless secondary to Gilbert’s Syndrome or documented liver involvement by lymphoma. Patients with Gilbert’s Syndrome or documented liver involvement by lymphoma may be included if their total bilirubin is ≤5×ULN
d. Alanine aminotransferase, aspartate aminotransferase and alkaline phosphatase ≤3×ULN, or ≤5×ULN in cases of documented liver involvement
e. Serum creatinine clearance must be ≥30mL/minute either measured or calculated using a standard Cockcroft and Gault formula (Cockroft and Gault, 1976)
11. In the opinion of investigator, the patient must:
a. Be able and willing to receive adequate prophylaxis and/or therapy for thromboembolic events, e.g.aspirin 75 to 325mg PO daily (81 to 325mg PO daily in the US) or low molecular weight heparin (e.g.enoxaparin 40mg ([4,000IU)] once daily by subcutaneous injection).
b. Be able to understand, give written informed consent, and comply with all study-related procedures, medication use, and evaluations
c. Not have a history of noncompliance in relation to medical regimens nor be considered potentially unreliable and/or uncooperative
d. Be able to understand the reason for complying with the special conditions of the pregnancy prevention risk management plan and in writing acknowledge to adhere to them
12.Due to the teratogenic potential of lenalidomide, females of childbearing potential (FCBP) must:
a. Not be pregnant as confirmed by a negative serum pregnancy test at screening and a medically supervised urine pregnancy test prior to starting study therapy
b. Refrain from breast feeding and donating oocytes during the course of study and for 3 months after the last dose of study drug or according to local guidelines for R-CHOP, whichever is longer
c. Agree to ongoing pregnancy testing during the course of the study, and after study therapy has ended. Agree to pregnancy testing and counseling if a patient misses her period or if there is any abnormality in her menstrual bleeding. This applies even if the patient applies complete sexual abstinence
d. Commit to continued abstinence from heterosexual intercourse if it is in accordance with her lifestyle (which must be reviewed on a monthly basis) or agree to use and be able to comply with the use of highly effective contraception without interruption at least 4 weeks prior to start of study drugs, during the study treatment and for 3 months after the last dose of study drug, or, for R-CHOP, according to the local guidelines, whichever is longer
13. Male participants must:
a. Use an effective barrier method of contraception without interruption if the patient is sexually active with a FCBP. Male participants should refrain from donating sperm during the study participation and for 3 months after the last dose of study drug, or according to the local guidelines for R-CHOP, whichever is longer |
|
| E.4 | Principal exclusion criteria |
1. Any other histological type of lymphoma according to WHO 2016 classification of lymphoid neoplasms, e.g., primary mediastinal (thymic) large B-cell lymphoma, Burkitt’s lymphoma, BCL, unclassifiable, with features intermediate between DLBCL and classical Hodgkin lymphoma (grey-zone lymphoma); primary effusion lymphoma; primary cutaneous DLBCL, leg type; primary DLBCL of the CNS; DLBCL arising from CLL or indolent lymphoma.
2. History of radiation therapy to ≥ 25% of the bone marrow for other diseases.
3. History of prior non-hematologic malignancy except for the following:
a. Malignancy treated with curative intent and with no evidence of active disease present for more than 2 years before screening
b. Adequately treated lentigo maligna melanoma without current evidence of disease or adequately controlled non-melanomatous skin cancer
c. Adequately treated carcinoma in situ without current evidence of disease
4. Patients with:
a. Positive local test result during screening for hepatitis C (hepatitis C virus [HCV] antibody serology testing) and a positive test for HCV RNA. Patients with positive serology must have been tested locally for HCV RNA and are eligible, in case of negative HCV RNA test results
b. Positive local test result during screening for chronic hepatitis B virus (HBV) infection (defined by hepatitis B surface antigen [HBsAg] positivity). Patients with occult or prior HBV infection (defined as negative HBsAg and positive total hepatitis B core antibody [HBcAb]) may be included if HBV DNA is undetectable (local test result), provided that they are willing to undergo ongoing DNA testing. Patients who have protective titers of hepatitis B surface antibody (HBsAb) after vaccination or prior but cured hepatitis B are eligible
c. Seropositive (local test result during screening) for, or history of active viral infection with human immunodeficiency virus (HIV)
d. Known active systemic bacterial, viral, fungal, or other infection at screening, including patients with suspected active or latent tuberculosis (as confirmed by a positive interferon-gamma release assay). Antiviral or antibacterial prophylaxis may be administered as per institutional guidelines.
e. Positive results for the human T-lymphotrophic 1 virus (HTLV-1). HTLV testing during screening is required for patients at sites in endemic countries (Japan and Melanesia and countries in the Caribbean basin, South America, Central America, and sub-Saharan Africa)
f. Known CNS lymphoma involvement
g. History or evidence of clinically significant cardiovascular, CNS and/or other systemic disease that in the investigator’s opinion would preclude participation in the study or compromise the patient’s ability to give informed consent
h. History or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
i. Vaccination with live vaccine within 21 days prior to study randomization
j. Major surgery within up to 21 days prior to signing the informed consent form (ICF), unless the patient is recovered at the time of signing the ICF
k. Any systemic anti-lymphoma and/or investigational therapy prior to the start of C1D1, except for permitted pre-phase treatment
l. Contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines
m. Pregnancy or lactation
n. History of hypersensitivity to any component of R-CHOP, to lenalidomide, to compounds of similar biological or chemical composition to tafasitamab, IMiDs® and/or the excipients contained in the study drug formulations |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| Progression-free survival (PFS) is defined as the time from date of randomization until Progressive Disease or death from any cause. In this trial the primary endpoint is PFS as assessed by the investigator. Disease progression will be determined based on the Lugano Response Criteria for Malignant Lymphoma. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| E.5.2 | Secondary end point(s) |
Key secondary
1. Event-free survival (EFS) as assessed by the investigator
2. Overall survival (OS)
Secondary
3. Metabolic, PET-negative complete response (CR) rate at end of treatment (EOT) as assessed by the BIRC
4. Metabolic, PET-negative CR rate at EOT as assessed by the investigator
5. ORR at EOT as assessed by the investigator
6. Time to next anti-lymphoma treatment (TTNT)
7. Duration of CR as assessed by the investigator
8. EFS rate at three (3) years as assessed by the investigator
9. PFS rate at three (3) years as assessed by the investigator
10. OS rate at three (3) years
11. Incidence and severity of treatment emergent adverse events (TEAEs) from the first dose of study medication until the 90th day (inclusive) after last dose of study medication.
12. PFS as assessed by the investigator by COO subtype
13. Investigator-assessed EFS by COO subtype
14. OS by COO subtype
15. Metabolic, PET-negative CR rate at EOT as assessed by the BIRC by COO subtype
16. Metabolic, PET-negative CR rate at EOT as assessed by the investigator by COO subtype
17. PFS as assessed by the investigator by locally determined histological subtype
18. Investigator assessed EFS by locally determined histological subtype
19. OS by locally determined histological subtype
20. Metabolic, PET-negative CR rate at EOT as assessed by the BIRC by locally determined histological subtype
21. Metabolic, PET-negative CR rate at EOT as assessed by the investigator by locally determined histological subtype
22. Two (2)-year rate of relapse with CNS involvement, as assessed by the investigator
23. Health-related quality of life (HRQoL), using the European Organisation for the Research and Treatment of Cancer (EORTC) QLQ-C30 and Functional Assessment of Cancer Therapy for Patients with Lymphoma (FACT-Lym) standardized instruments.
24. Serum concentration of tafasitamab at specific time points (trough and maximum plasma concentration (Cmax) levels).
25. Incidence of anti-tafasitamab antibody formation, titer determination of confirmed positive samples. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Key secondary:
1) event driven, primary analysis (PA) at 274 PFS events
2) event driven, PA at 274 PFS events
Secondary:
3) end of treatment (EOT)
4/5) EOT
6/7) event driven, PA at 274 PFS events
8/9/10) 3 yrs after randomization
11) 30 days after D21 of the last treatment cycle
12/13/14) event driven, PA at 274 PFS events
15/16) EOT
17/18) event driven, PA at 274 PFS events
19) event driven, PA analysis at 274 PFS events
20/21) EOT
22) 2 yrs after randomization
23) event driven, PA at 274 PFS events
24/25) during the study |
|
| 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 | Yes |
| 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 |
| Immunogenicity, Biomarker |
|
| 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 | 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 | Yes |
| 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 | 146 |
| 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 |
| Canada |
| Colombia |
| Hong Kong |
| Israel |
| Japan |
| Korea, Republic of |
| Malaysia |
| New Zealand |
| Philippines |
| Taiwan |
| Thailand |
| United States |
| Russian Federation |
| Turkey |
| Ukraine |
| Serbia |
| Austria |
| Czechia |
| France |
| Germany |
| Hungary |
| Ireland |
| Italy |
| Poland |
| Romania |
| Slovakia |
| Spain |
| 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
|
| The end of the study will occur after the last patient has completed a minimum of 3 years of follow up post treatment (this is expected to occur approximately 5 years after the first patient is enrolled). |
|
| 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 |
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