A phase 3, multicenter, randomized, double-blind, placebo-controlled trial comparing the efficacy and safety of tafasitamab plus lenalidomide in addition to R-CHOP versus R CHOP in previously untreated, high-intermediate and high-risk patients with newly-diagnosed diffuse large B-cell lymphoma (DLBCL) [frontMIND]
- Trial ID
- 2022-500237-92-00
- Protocol
- MOR208C310
- Sponsor
- Incyte Corp.
Trial statistics
Diseases & Conditions
Objectives
The primary objective of this phase 3, multicenter, randomized, double-blind, placebo-controlled trial is to compare the **efficacy** of tafasitamab plus lenalidomide in addition to R-CHOP versus tafasitamab placebo, lenalidomide placebo, and R-CHOP in patients with newly-diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma (DLBCL). This comparison is clinically relevant as it aims to determine whether the addition of tafasitamab and lenalidomide to the standard R-CHOP regimen can improve treatment outcomes in this patient population, potentially offering a more effective therapeutic option.
Secondary objectives include:
- Comparing the efficacy (additional parameters) and safety of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
- Comparing the efficacy of tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP in DLBCL subtypes of cell of origin (COO) and in subtypes: DLBCL NOS versus high-grade B-cell lymphoma (HGBL) versus other.
- Comparing the incidence of central nervous system relapse in patients receiving tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
- Assessing patient-reported outcomes in patients receiving tafasitamab plus lenalidomide in addition to R-CHOP versus R-CHOP.
- Assessing the pharmacokinetic profile and potential immunogenicity of tafasitamab.
Participants
The clinical trial involves a total of **507 participants** diagnosed with **newly-diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma (DLBCL)**. The study population includes both male and female adults aged 18 to 80 years. Participants are required to have a local biopsy-proven, CD20-positive DLBCL, and must be appropriate candidates for R-CHOP therapy. The trial population was selected based on specific laboratory criteria and the ability to comply with study-related procedures. Participants must have an Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2, and a left ventricular ejection fraction of at least 50%. Lifestyle considerations include the ability to receive adequate prophylaxis for thromboembolic events, and females of childbearing potential must adhere to strict pregnancy prevention measures. The trial includes a vulnerable population, and the selection process ensures that participants are able to understand and comply with the study requirements.
Plans and Procedures
The clinical trial is a **randomized**, **double-blind**, placebo-controlled study designed to evaluate the efficacy and safety of **tafasitamab** plus **lenalidomide** in addition to R-CHOP compared to R-CHOP alone in patients with newly-diagnosed high-intermediate and high-risk diffuse large B-cell lymphoma (DLBCL). The trial is expected to run from May 25, 2021, to August 21, 2026. Participants will be randomly assigned to receive either the investigational treatment or the control treatment, ensuring that neither the participants nor the investigators know which treatment is being administered, thus maintaining the double-blind nature of the study.
The trial will include several study visits, beginning with a screening visit to determine eligibility based on specific inclusion criteria, such as age, laboratory values, and medical history. Following successful screening, participants will be enrolled and randomized into one of the study arms. The treatment phase will involve regular follow-up visits to monitor the participants' health, assess the efficacy of the treatment, and record any adverse events. These visits will occur at predetermined intervals throughout the treatment period, which may last up to 132 days, depending on the specific treatment regimen assigned.
The end-of-study visit will occur after the completion of the treatment phase, where final assessments will be conducted to evaluate the primary endpoint of progression-free survival (PFS) and secondary endpoints such as overall survival (OS) and event-free survival (EFS). Participants' involvement in the study is expected to last until the end-of-study visit, with the possibility of early termination if they experience significant adverse events, withdraw consent, or if the investigator deems it necessary for their safety.
Throughout the trial, participants will be closely monitored for any treatment-emergent adverse events (TEAEs), and their health-related quality of life will be assessed using standardized instruments. The study aims to provide valuable data on the potential benefits and risks of adding tafasitamab and lenalidomide to the standard R-CHOP regimen in this patient population.
Treatment
The clinical trial involves the administration of several experimental and non-experimental treatments. **Doxorubicin hydrochloride** is administered as an intravenous solution with a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 50 mg/m², with a total maximum dose of 300 mg/m² over a treatment period of 119 days. This medication is a chemical substance used in the trial as part of the R-CHOP regimen.
**Betamethasone sodium phosphate** is provided in an oral form coded as PHF00059MIG. The maximum daily dose is 100 mg, with a total maximum dose of 3000 mg over 124 days. This chemical substance is used as an auxiliary treatment in the study.
**Rituximab** is administered intravenously with a pharmaceutical form coded as PHF00230MIG. The maximum daily dose is 375 mg/m², with a total maximum dose of 2250 mg/m² over 119 days. Rituximab is a protein-based substance included in the R-CHOP regimen.
**Sodium chloride** is used as a solution for intravenous infusion with a concentration of 0.9% weight/volume. It serves as a non-experimental treatment, providing a standard infusion medium over a maximum treatment period of 132 days.
**Lenalidomide** is administered orally in hard capsule form. The maximum daily dose is 25 mg, with a total maximum dose of 1500 mg over 127 days. This chemical substance is part of the experimental treatment in combination with tafasitamab.
**Prednisolone** is provided in an oral form coded as PHF00245MIG. The maximum daily dose is 100 mg, with a total maximum dose of 3000 mg over 124 days. It is used as an auxiliary treatment in the trial.
**Tafasitamab** is administered intravenously as a powder for concentrate for solution for infusion. The maximum daily dose is 14.4 mg/kg, with a total maximum dose of 259.2 mg/kg over 132 days. Tafasitamab is a protein-based monoclonal antibody used as an experimental treatment in the study.
**Cyclophosphamide** is administered intravenously with a pharmaceutical form coded as PHF00231MIG. The maximum daily dose is 750 mg/m², with a total maximum dose of 4500 mg/m² over 119 days. This chemical substance is part of the R-CHOP regimen.
**Vinorelbine** is administered intravenously with a pharmaceutical form coded as PHF00007MIG. The maximum daily dose is 1.4 mg/m², with a total maximum dose of 8.4 mg/m² over 119 days. This chemical substance is used as an auxiliary treatment in the trial.
Placebos for lenalidomide are included in the study to maintain the double-blind design. These placebos are provided in various dosages (10 mg, 15 mg, and 25 mg) and are used to compare the efficacy of the active treatment against a non-active control.
Efficacy
The efficacy of the clinical trial will be assessed using several primary and secondary endpoints. The primary endpoint is **Progression-Free Survival (PFS)**, defined as the time from the date of randomization until disease progression or death from any cause, as assessed by the investigator. Disease progression will be determined based on the Lugano Response Criteria for Malignant Lymphoma.
Secondary endpoints include Event-Free Survival (EFS), Overall Survival (OS), and the metabolic, positron emission tomography (PET)-negative complete response (CR) rate at the end of treatment (EOT), as assessed by both the investigator and the Blinded Independent Review Committee (BIRC). Additional secondary endpoints involve the Overall Response Rate (ORR) at EOT, Time to Next Anti-Lymphoma Treatment (TTNT), Duration of CR, and various survival rates at three years, including EFS, PFS, and OS. The incidence and severity of treatment-emergent adverse events (TEAEs) will also be monitored from the first dose of study medication until the 90th day after the last dose.
Further assessments will include the PFS and EFS by cell of origin (COO) subtype and locally determined histological subtype, as well as the metabolic, PET-negative CR rate at EOT by these subtypes. The two-year rate of relapse with central nervous system (CNS) involvement will be evaluated, along with health-related quality of life (HRQoL) using standardized instruments such as the EORTC QLQ-C30 and FACT-Lym. Serum concentration of tafasitamab at specific time points and the incidence of anti-tafasitamab antibody formation will also be measured.
Inclusion and Exclusion Criteria
Inclusion Criteria
- Signed written informed consent form (ICF).
- Adult subjects aged 18 (or legal age per local regulations) to 80 years of age inclusive.
- Previously untreated patients with local biopsy-proven, CD20-positive DLBCL, including one of the following diagnoses by 2016 World Health Organization (WHO) classification of lymphoid neoplasms are eligible: • DLBCL, NOS including GCB type, ABC type • T-cell rich large BCL • Epstein-Barr virus-positive DLBCL, NOS • Anaplastic lymphoma kinase (ALK)-positive large BCL • Human herpes virus-8 (HHV8)-positive DLBCL, NOS • 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). Please note: Patients must be appropriate candidates for R-CHOP. If an investigator deems a patient with a known double- or triple-hit lymphoma (HGBL) should be treated more aggressively (e.g. dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab [DA-EPOCH-R] or cyclophosphamide, vincristine, doxorubicin and dexamethasone (CVAD) followed by methotrexate and cytarabine [Hyper CVAD]), this patient would not be considered eligible for this study • HGBL-NOS • DLBCL coexistent with either FL of any grade, gastric mucosa-associated lymphoid tissue (MALT) lymphoma or non-gastric MALT lymphoma • FL Grade 3b
- Availability of archival or freshly collected tumor tissue sent for retrospective central pathology review. Please note: Neither receipt of tumor samples nor central review of diagnosis is necessary prior to study enrollment.
- Up to six (6) of the largest target nodes, nodal masses, or other lymphomatous lesions that are measurable in two (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. At baseline, a measurable node must be greater than 15 mm in longest diameter (LDi). Measurable extranodal disease may be included in the six (6) representative, measured lesions. At baseline, measurable extranodal lesions should be greater than 10 mm LDi. All other lesions (including nodal, extranodal, and assessable disease) should be followed as nonmeasured disease as non-target lesions (e.g. cutaneous, GI, spleen, liver, kidneys, pleural or pericardial effusions, ascites, bone, bone marrow). Patients with ONLY bone lesions should be excluded. At least one (1) measurable lesion must be confirmed to be PET-positive (Deauville score of 4 or 5) at the time of randomization by local assessment.
- Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2.
- IPI status of 3 to 5 (for patients > 60 years of age) or aaIPI 2 to 3 (for patients ≤ 60 years of age).
- Diagnosis to treatment interval, defined as the time between the date of DLBCL diagnosis (date of the first biopsy specimen containing B-cell lymphoma according to the local pathology report) and the start of treatment (cycle 1 study day 1 (C1D1)) ≤ 28 days.
- Left ventricular ejection fraction ≥ 50% as assessed by local echocardiography or cardiac multi-gated acquisition (MUGA) scan.
- Patient must have the following local laboratory criteria at screening: a. Absolute neutrophil count (ANC) ≥ 1.5 x 10^9/L (unless secondary to bone marrow involvement by DLBCL) b. Platelet count ≥ 75 x 10^9/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 (ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP) ≤ 3 × ULN, or ≤ 5 × ULN in cases of documented liver involvement e. Serum creatinine clearance must be ≥ 30 mL/minute either measured or calculated using a standard Cockcroft and Gault formula (Cockroft and Gault, 1976)
- 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 325 mg per os, orally (PO) daily (81 to 325 mg PO daily in the US) or low molecular weight heparin (e.g. enoxaparin 40 mg (4,000 IU) once daily by subcutaneous (SC) injection). This is due to increased risk of thrombosis in patients treated with lenalidomide without prophylaxis. Patients unable or unwilling to take any prophylaxis are not eligible 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 and in writing acknowledge to adhere to them
- 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 three (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. Additionally, 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 four (4) weeks prior to start of study drugs, during the study treatment and for three (3) months after the last dose of study drug, or, for R-CHOP, according to the local guidelines, whichever is longer.
- 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 three (3) months after the last dose of study drug, or according to the local guidelines for R-CHOP, whichever is longer
Exclusion Criteria
- 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.
- History of radiation therapy to ≥ 25% of the bone marrow for other diseases.
- 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 two (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.
- 4a) Patients with 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
- 4b) Patients with 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 was 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
- 4c) Patients with Seropositive (local test during screening) for, or history of active viral infection with human immunodeficiency virus (HIV)
- 4d) Patients with 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
- 4e) Patients with positive results for the human T-lymphotropic 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)
- 4f) Patients with known CNS lymphoma involvement
- 4g) Patients with 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
- 4h) Patients with history or evidence of rare hereditary problems of galactose intolerance, Lapp lactase deficiency or glucose-galactose malabsorption
- 4i) Patients with vaccination with live vaccine within 21 days prior to study randomization
- 4j) Patients with 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
- 4k) Patients with any systemic anti-lymphoma and/or investigational therapy prior to the start of C1D1, except for permitted pre-phase treatment
- 4l) Patients with contraindication to any of the individual components of R-CHOP, including prior receipt of anthracyclines
- 4m) Patients with pregnancy or lactation
- 4n) Patients with 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
Trial Status by Country
| Country | Status | Start of Recruitment | Planned Patients |
|---|---|---|---|
 Austria | Not Recruiting | 25 May 2021 | 29 |
 Czechia | Not Recruiting | 25 May 2021 | 52 |
 France | Not Recruiting | 25 May 2021 | 45 |
 Germany | Not Recruiting | 25 May 2021 | 83 |
 Hungary | Not Recruiting | 25 May 2021 | 22 |
 Ireland | Not Recruiting | 25 May 2021 | 4 |
 Italy | Not Recruiting | 25 May 2021 | 77 |
 Poland | Not Recruiting | 25 May 2021 | 5 |
 Romania | Not Recruiting | 25 May 2021 | 17 |
 Slovakia | Not Recruiting | 25 May 2021 | 5 |
Sites & Investigators
Research sites
Investigators
Investigational Products
Details about the medicinal products being studied in this clinical trial.
| Product Name | Role in Trial | Formulation | Administration | Max Daily Dose | Treatment Duration | EU MP Number |
|---|---|---|---|---|---|---|
MINJUVI 200 mg powder for concentrate for solution for infusion | Test | POWDER FOR CONCENTRATE FOR SOLUTION FOR INFUSION | INTRAVENOUS USE | 14.4 | 132 | PRD9171980 |
Placebo for lenalidomide 15mg | Placebo | N/A | — | — | — | N/A |
Placebo for lenalidomide 10mg | Placebo | N/A | — | — | — | N/A |
Placebo for lenalidomide 25mg | Placebo | N/A | — | — | — | N/A |
VINCRISTINE | Other | PHF00007MIG | INTRAVENOUS USE | 1.4 | 119 | SCP1137788 |
LENALIDOMIDE | Test | — | ORAL USE | 25 | 127 | SUB25389 |
CYCLOPHOSPHAMIDE | Other | PHF00231MIG | INTRAVENOUS USE | 750 | 119 | SCP130444 |
LENALIDOMIDE | Test | — | ORAL USE | 25 | 127 | SUB25389 |
DOXORUBICIN | Other | PHF00231MIG | INTRAVENOUS USE | 50 | 119 | SCP138158 |
PREDNISONE | Other | PHF00245MIG | ORAL USE | 100 | 124 | SCP131338 |