Main info

Identificatie:

HO168-DLBCL

Sponsor:

HOVON

Working group party:

Lymphoma

Stadium:

1st lijn

Echelon:

Level D

Included patients:

0

(of 276)

Active sites:

0

(of 60)

61 sites are pending

Title:

Epcoritamab in Addition to R-Mini-CHOP Compared to R-Mini-CHOP in Elderly
Frail or Unfit Patients with Diffuse Large B-cell Lymphoma

Timeline

Details

Phase:

Prospective randomized Phase II study

Monitoring Type:

HOVON Monitoring Visit

Objectives:

Primary objective

*The primary objective of this study is to evaluate whether the addition of epcoritamab to 6 cycles of standard R-mini-CHOP followed by 2 cycles of epcoritamab can improve efficacy compared with 6 cycles of R-mini-CHOP alone followed by 2 cycles of rituximab in elderly, frail, or unfit participants with newly diagnosed DLBCL as measured by CR at or after the end of treatment according to Lugano 2014 criteria and Progression Free Survival (PFS) from the date of randomization to disease progression or death, whichever occurs first.

Secondary objectives

• The secondary objectives are to evaluate whether epcoritamab + R-mini-CHOP followed by 2 cycles of epcoritamab compared to R-mini-CHOP alone followed by 2 cycles of rituximab improve clinical outcomes.

Eligibility

Inclusion Criteria:

To be eligible to participate in this study, a patient must meet all the following criteria:

Consent

• Patients must voluntarily sign and date an informed consent, approved by an IEC/IRB, prior to the initiation of any screening or study-specific procedures. Patients should be legally capable of giving informed consent.

Demographic and Laboratory Assessments

• Adult individuals, at least 70 years old with a life expectancy of ≥ 12 months:

- Age ≥ 80 years old
OR
- Age ≥ 70 years and patient is considered unfit or frail by any of the following criteria:
- ADL score < 5 defined by the Katz-score (appendix O) [28] AND/OR
- iADL score < 6 defined by Lawton Score (appendix O) [29] AND/OR
- ≥ 9 moderate (grade = II) comorbidities defined by the CIRS-G AND/OR severe (grade ≥ III) comorbidities defined by the CIRS-G.

• Laboratory values meeting the following criteria within the screening period prior to the first dose of study drug:

- Absolute Neutrophil Count (ANC) ≥ 1.0 × 109/L. (antibacterial prophylaxis per institutional standard practice should be considered for patients with ANC < 1.0 × 109/L).
- Hemoglobin ≥ 8.0 g/dL (≥ 5.0 mmol/L) without prior transfusion 2 weeks prior to registration.
- Platelet count ≥ 75 × 109/L, or ≥ 50 × 109/L in the presence of bone marrow involvement or splenomegaly.
- Serum aspartate aminotransferase and serum alanine aminotransferase ≤ 3.0 × Upper Limit of Normal (ULN) unless due to hepatic involvement of disease or non-hepatic origin. For patients with hepatic involvement of disease, serum aspartate aminotransferase and serum alanine aminotransferase ≤ 5.0 × ULN.
- Total bilirubin level ≤ 1.5 × ULN, unless the bilirubin rise is due to Gilbert's syndrome or lymphoma hepatobiliary involvement. Patients with Gilbert's syndrome must have a direct bilirubin of < 2 × ULN. Patients with hepatobiliary involvement must have a total bilirubin of < 5 × ULN and without a percutaneous biliary drain.
- Estimated creatinine clearance (as calculated by the Cockcroft-Gault formula, modified as needed for factors such as body weight, see appendix K) or estimated glomerular filtration rate (as calculated by the Modification of Diet in Renal Disease equation) ≥ 40 mL/min.
- International normalized ratio (or prothrombin time) and activated partial thromboplastin time ≤ 1.5 × ULN, unless receiving anticoagulation.
- Are willing and able to comply with procedures required in this protocol.
- Are able to tolerate SC injections.
- Have available adequate fresh or paraffin-embedded tumor biopsy material at Screening.

Disease/Condition Activity

• Newly diagnosed, histologically confirmed

- CD20+ DLBCL NOS,
- CD20+ Follicular large B-cell lymphoma (FLBL, previously follicular lymphoma Grade 3B), transformed follicular lymphoma
- CD20+ DLBCL/high grade B-cell lymphoma (HGBL) with MYC and BCL2 rearrangements at representative tumor biopsy based on the pathology report, with a WHO 2022 classification [1]
Note: The local pathology report must be available at Screening to support CD20+ and eligible histology.

• Patient must have an ECOG performance status score of 0-2 prior to initiating treatment. Patients with an ECOG status of 3 may be allowed if Grade 3 status is related to lymphoma.
• Ann Arbor Stage I(E) bulky disease (>10 cm), stage II – IV
• Patient has measurable disease defined as

- ≥ 1 measurable nodal lesion (long axis > 1.5 cm) or
- ≥ 1 measurable extra-nodal lesion (long axis >1.0 cm) on CT or MRI
AND
- At least one positive lesion on 18F-FDG PET scan.

Exclusion Criteria:

A patient who meets any of the following criteria cannot be included in this study:

Patient History

• Patient has history of prior systemic anti-lymphoma therapy for DLBCL (including any definitive radiotherapy with curative intent) other than a) corticosteroids with or without vincristine during pre-phase treatment or b) non-curative intent palliative radiotherapy with the stipulation that radiated lesions cannot be selected as target lesion for response assessment.
• Subject with histologically transformed FL, who has previously been treated with > 1 lines of therapy for FL and had an anthracycline-containing regimen or a CD3‑CD20 bispecific antibody.
• Patient has history of primary mediastinal lymphoma, or mediastinal or pericardial radiation.
• Patient has a primary CNS tumor or known CNS involvement at Screening.
• Patient has history of severe allergic or anaphylactic reactions to anti-CD20 mAb therapy or known allergy or intolerance to any component or excipient of epcoritamab (e.g., sorbitol) or the CHOP (cyclophosphamide, doxorubicin, vincristine, prednisolone) regimen.
• Patient has known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of nail beds). No new IV therapy or intravenous antibiotics may be initiated for infection within 2 weeks prior to first dose of study drug.
• Patient has an active hepatitis B virus or Hepatitis C virus infection. * Patients who are positive for hepatitis B core antibody, hepatitis B surface antigen, or hepatitis C antibody must have a negative PCR result before enrollment. Those who are PCR positive are excluded from participation in the study.
• Patient has known history of HIV infection. Note: HIV testing does not need to be conducted at screening unless it is required per local guidelines or institutional standards.
• Patient has active tuberculosis (TB) or history of completed treatment for active TB within the past 12 months.

Note: IGRA testing must be performed if active or latent TB is suspected (e.g., clinical signs and symptoms of TB, contact history, or if the patient lives in or has traveled to or lived in the WHO high TB burden countries). For patients with positive IGRA, active pulmonary TB must be excluded with clinical evaluation and radiologic imaging. Patients with positive IGRA and no evidence of active disease may be enrolled after treatment for latent TB infection (recommend isoniazid monotherapy for a total of 6 months) has been initiated.

• Patient has an active (symptomatic) CMV disease. If preemptive or prophylactic antiviral treatment is initiated, lab inclusion criteria #3 would have to be met on C1D1. Note: Foscarnet use within 7 days prior to C1D1 or during C1 and C2 is prohibited.
• Patient has known active SARS-CoV-2 infection. If a patient has signs/symptoms suggestive of SARS-CoV-2 infection, the patient must have a negative molecular (e.g., PCR) test or 2 negative antigen test results at least 24 hours apart. Note: SARS-CoV-2 diagnostic tests should be applied following local requirements/recommendations.
• Patients who do not meet SARS-CoV-2 infection eligibility criteria must be screen-failed and may only rescreen if the following have been met:

At least 10 days since first positive test result have passed in asymptomatic patients or at least 10 days since the onset of symptoms for symptomatic patients.

• Patient had major surgery within 4 weeks prior to randomization.
• Patient has clinically significant cardiovascular disease, including:

Myocardial infarction or stroke within 6 months prior to enrollment.
OR
The following conditions within 3 months prior to enrollment: unstable or uncontrolled disease/condition related to or affecting cardiac function (e.g., unstable angina, congestive heart failure, New York Heart Association Class III-IV, defibrillator implanted), uncontrolled cardiac arrhythmia
OR
Screening 12-lead ECG showing a baseline QTcF > 470 msec (male) or > 480 msec (female)
OR
Other clinically significant ECG abnormalities within 6 months prior to enrollment unless deemed stable and appropriately treated.

• Left ventricular ejection fraction is <45% by multi-gated acquisition or transthoracic echocardiography within 12 weeks before registration.
• Patient has clinically significant liver disease, including hepatitis, current alcohol abuse, or cirrhosis.
• Patient has clinical signs of severe pulmonary dysfunction defined as breathlessness at rest (defined as COPD gold classification IV) unless clearly related to DLBCL.
• Patient has history of Progressive Multifocal Leukoencephalopathy.
• Patient has history of other prior malignancies, except:

- Malignancy treated with curative intent and with no known active disease present for ≥ 3 years before the first dose of study drug and felt to be at low risk for recurrence by treating physician.
- Adequately treated non-melanoma skin cancer or lentigo malignant without evidence of disease.
- Adequately treated carcinoma in situ without evidence of disease.
- Localized prostate cancer, post-radical prostatectomy or with non-rising prostate-specific antigen levels < 0.1 ng/mL.

• Patient has neuropathy Grade > 1 or demyelinating form of Charcot-Marie-Tooth Disease.
• Patient has current autoimmune disease requiring immunosuppressive therapy except for up to 10 mg prednisolone daily or equivalent.
• Patient has life-threatening illness, medical condition, or organ system dysfunction that, in the Investigator's opinion, could compromise the patient's safety, compliance with the protocol, interpretation of the study results, or put the study outcomes at undue risk.
• Patient has current seizure disorder requiring therapy within the past 12 months. Patients with history of seizure disorder must have complete CNS workup.

Concomitant Medications

• Patient has medication known to decrease T-cell numbers or activity or other concurrent immunosuppressive medication except for up to 20 mg prednisolone daily or equivalent, unless for disease control during screening (refer to paragraph 9.10.2.)
• Patient has been treated with any investigational drug within 30 days or 5 half-lives of the drug (whichever is longer) prior to the first dose of study treatment or is currently taking an investigational drug or is participating in another interventional study until participant is in the survival follow-up phase.
• Patient has received any live vaccine within 28 days prior to the first dose of study drug, or is expected to need any live vaccination during study treatment including at least 3 months following the last dose of study treatment. COVID-19 non-replicating adenoviral vaccines are permitted with a minimum period of 3 days between the vaccine and a dose of study drug.

Contraception

• Male patient who is considering fathering a child or donating sperm during the study or for 12 months after the last dose of study drug. Note: Male participant who is sexually active with female partner(s) of childbearing potential, must agree, from the time of ICF through 12 months after the last dose of study drug, to practice the protocol-specified contraception.

Participating Sites

= Active hospitals

= Inactive hospitals