None listed
Conditions
Brief summary
The primary purpose of this study is to evaluate if treatment with epcoritamab plus pirtobrutinib will improve outcomes for patients than standard of care R-(mini)-CHOP in patients with previously untreated Richter transformation. Who is it for? Patients over 18 with confirmed CLL and diagnosis of Diffuse Large B-cell Lymphoma (DLBCL)-type Richter's transformation (RT) who have not received prior treatment for RT. Study details This is a randomized, open-label, phase-III study. Arm A consists of patients that will receive standard of care (SOC) R- CHOP or R-(mini)-CHOP. R-CHOP regimen consists of cyclophosphamide, doxorubicin, vincristine, rituximab, and prednisolone. Given in 6 cycles, with each cycle being 21 days. Arm B consists of patients that will receive epcoritamab plus pirtobrutinib. Given in 12 cycles (each cycle is 21 days). Additional treatments will be stem cell transplant and radiation if deemed necessary by treating physician. There will be a cross-over option. If the standard treatment doesn't work, patients can switch to the other treatment arm. To monitor treatment response and safety, several diagnostic tests will be performed, including Positron Emission Tomography (PET)-Computed Tomography (CT) scans, bone marrow biopsies, electrocardiograms (ECG), and laboratory evaluations. These tests help assess disease progression, organ function, and potential adverse effects. It is hoped this research will determine if epcoritamab and pirtobrutinib can improve outcomes for patients previously untreated for RT.
Interventions
The investigational product is epcoritimab and pirtobrutinib being compared to conventional Standard of Care (SOC) R-CHOP or R-mini-CHOP.
Arm A: SOC Chemoimmunotherapy (Control arm)
Pre-phase (optional. at the discretion of the treating physician)
4 days Dexamethasone 12-16 mg per oral (po) or intravenous (iv) or prednisolone equivalent (75mg po)
6 cycles, each with a duration of 21 days.
Cycle 1-6
Day 1: Cyclophosphamide 750 mg/m2 iv
Doxorubicin 50 mg/m2 iv
Vincristine 1.4 mg/m2 (max 2 mg) i
The investigational product is epcoritimab and pirtobrutinib being compared to conventional Standard of Care (SOC) R-CHOP or R-mini-CHOP. Arm A: SOC Chemoimmunotherapy (Control arm) Pre-phase (optional. at the discretion of the treating physician) 4 days Dexamethasone 12-16 mg per oral (po) or intravenous (iv) or prednisolone equivalent (75mg po) 6 cycles, each with a duration of 21 days. Cycle 1-6 Day 1: Cyclophosphamide 750 mg/m2 iv Doxorubicin 50 mg/m2 iv Vincristine 1.4 mg/m2 (max 2 mg) iv Rituximab 375 mg/m2 iv or subcutaneous (sc) Day 1-5: Prednisolone 100 mg po If R-CHOP-ineligible, considering age and comorbidities, R-mini-CHOP is administered: Cycle 1-6 Day 1: Cyclophosphamide 400 mg/m2 iv Doxorubicin 25 mg/m2 iv Vincristine 1 mg iv Rituximab 375 mg/m2 iv or sc Day 1-5: Prednisolone 40 mg/m2 po Consolidation treatment Consolidation with allogeneic stem cell transplantation is permitted at any time according to the investigator’s discretion. Irradiation treatment Irradiation of positron emission tomography (PET)-positive lesions or initially bulky lesion of 7.5 cm or greater at the end of therapy will be offered according to local standard practices. Cross-over Patients with relapse or progressive disease (PD) on or after R-CHOP or R-mini-CHOP may undergo a cross-over to Arm B to receive pirtobrutinib plus epcoritamab, if clinically feasible. Cross over must be approved by central review of PD staging results by the German CLL Study Group (GCLLSG) study office and central PET review. Arm B: Targeted therapy (Interventional arm) 12 cycles, each with a duration of 21 days Cycle 1 Day 1-21: Pirtobrutinib 200 mg po, once a day Day 1: Epcoritamab 0.16 mg sc Day 8: Epcoritamab 0.8 mg sc Day 15: Epcoritamab 48 mg sc Cycle 2-4 Day 1-21: Pirtobrutinib 200 mg po, once a day Day 1, 8, 15: Epcoritamab 48 mg sc Cycle 5-6 Day 1-21: Pirtobrutinib 200 mg po, once a day Day 1: Epcoritamab 48 mg sc Cycle 7- 12: Day 1-28: Pirtobrutinib 200 mg po, once a day Day 1: Epcoritamab 48 mg sc For patients with complete response (CR), partial response (PR) or stable disease (SD) after 12 cycles (=end of treatment (EOT)), maintenance treatment with pirtobrutinib 200 mg once a day until unacceptable toxicity, disease progression or allogeneic stem cell transplantation will be offered. All treatment will be administered by the study team. Drug accountability will be performed by the administering institutions to assess compliance. Drug accountability is assessed through a combination of medical records, dispensing documentation, and physical review of returned medication packaging.
Sponsors
Australasian Leukaemia and Lymphoma Group
Study design
Allocation
Randomised controlled trial
Primary purpose
Treatment
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Confirmed diagnosis of chronic lymphocytic leukaemia (CLL) or small lymphocytic lymphoma (SLL) according to International Workshop of Chronic Lymphocytic Leukaemia (iwCLL) criteria. 2. Confirmed histopathological diagnosis of Diffuse large B-Cell Lymphoma (DLBCL)-type Richter’s Transformation (RT) according to World Health Organisation (WHO) classification. 3. Previously untreated RT (prior CLL treatment or pre-phase treatment of RT with corticosteroids is allowed) 4. Patients are required to have the below mentioned washout periods prior to planned Cycle 1 Day 1 (C1D1). In addition, prior treatment-related adverse events (AEs) must have recovered to Grade less than or equal to 1 with the exception of alopecia and lymphopenia. - Targeted agents, investigational agents, therapeutic monoclonal antibodies or cytotoxic chemotherapy: 5 half-lives or 2 weeks, whichever is shorter. - Broad field radiation (greater than or equal to 30% of the bone marrow or whole brain radiotherapy) must be completed 14 days prior to study enrollment. - Palliative limited field radiation must be completed 7 days prior to study enrollment. 5. Creatinine clearance greater than or equal to 40ml/min calculated according to the modified formula of Cockcroft and Gault or directly measured with 24 hour urine collection or an equivalent method. 6. Adequate liver function as indicated by a total bilirubin less than or equal to 1.5 x Aspartate aminotransferase (AST)/ Alanine aminotransferase (ALT) less than or equal to 3.0 x the institutional Upper limit of normal (ULN) value, unless directly attributable to the patient’s CLL/RT or to Gilbert’s Syndrome, in which case a max. total bilirubin less than or equal to 3 x and AST/ALT less than or equal to 5 x the institutional ULN value are required. 7. Neutrophil count greater than or equal to 1.0 G/l (Granulocyte colony stimulating factor (G-CSF) administration allowed), Hemoglobin (Hb) greater than or equal to 8 g/dl/ 4.96mmol/L (except for patients with bone marrow involvement due to CLL or RT in which the Hb must be greater than or equal to 6.0G/dl/ 3.72 mmol/L), platelet count greater than or equal to 50 G/l (except for patients with bone marrow involvement due to CLL or RT in which the platelet count must be greater than or equal to 30,000). 8. Adequate coagulation, defined as activated partial thromboplastin time (aPTT) or partial thromboplastintime (PTT) and prothrombin (PT) or (international normalised ratio (INR) not greater than 1.5 x ULN. 9. Negative testing for: hepatitis B (Hepatitis B surface antigen (HBsAg) negative and anti-Hepatitis B core antigen (HBc) negative; patients positive for anti-HBc may be included if polymerase chain reaction (PCR) for Hepatitis B virus (HBV) deoxyribonucleic acid (DNA) is negative, treated with appropriate antiviral therapy and HBV-DNA PCR is performed every two months until 12 months after last dose of study treatment); hepatitis-C (patients with positive for hepatitis C on serologic testing can be enrolled if hepatitis C ribonucleic acid (RNA) is negative); negative human immunodeficiency virus (HIV) test within 6 weeks prior to registration 10. Age at least 18 years 11. Eastern Cooperative Oncology Group (ECOG) performance status 0-2, 12. Life expectancy greater than or equal to 3 months 13. Willingness of women of reproductive potential and their partners to observe highly effective birth control methods for the duration of treatment and for 1 month following the last dose of study treatment 14. Ability and willingness to provide written informed consent and to adhere to the study visit schedule and other protocol requirements
Exclusion criteria
1. Patients with prior Richter’s Transformation (RT)-directed therapy, including corticosteroids given for greater than 10 days with a daily dose above 50mg prednisolone or equivalent for more than 10 days. 2. Patients with previous Chronic Lymphocytic Leukemia (CLL) progression on non-covalent Bruton’s Tyrosine Kinase (BTK) inhibitors or CD20 targeting T-cell engaging antibodies. 3. Patients with Richter transformation to Hodgkin’s lymphoma or patients with other types of lymphoma. 4. Allogenic stem cell transplantation or Chimeric Antigen Receptor (CAR)-T cell therapy within the last 100 days as well as: • Active graft versus host disease (GVHD); • Cytopenia from incomplete blood cell count recovery post-transplant not matching inclusion criterion 7; • Need for anti-cytokine therapy for toxicity from CAR-T therapy; residual symptoms of neurotoxicity greater than Grade 1 from CAR-T therapy; • Ongoing immunosuppressive therapy (greater than 20 mg prednisone or equivalent daily). 5. Patients with known central nervous system (CNS) involvement of RT. 6. Patients with confirmed progressive multifocal leukoencephalopathy (PML). 7. Decompensated auto-immune cytopenia (defined as ongoing drop in haemoglobin [Autoimmune hemolytic anemia (AIHA)] or in platelets [Idiopathic thrombocytopenic purpura (ITP)] in spite of prednisolone and/or intravenous immunoglobulins treatment). 8. Increased risk of bleeding, due to: o History of severe bleeding disorder such as hemophilia A, hemophilia B, von Willebrand disease, or history of spontaneous bleeding requiring blood transfusion or other medical intervention o Anticoagulant therapy with warfarin or other vitamin K antagonists (anticoagulation with a direct oral drug or thrombin inhibitor or heparin is permitted) o History of major stroke or intracranial hemorrhage within 6 months before first dose of study drug 9. Requiring supplemental oxygen 10. Significant cardiovascular disease defined as: • unstable angina or acute coronary syndrome within the past 2 months prior to randomization • history of myocardial infarction within 3 months prior to randomization or • documented left ventricular ejection fraction (LVEF) by any method of less than or equal to 40% in the 12 months prior to randomization • greater than or equal to Grade 3 New York Heart Association (NYHA) functional classification system of heart failure • Uncontrolled or symptomatic arrhythmias • Prolongation of the QT interval corrected for heart rate (QTcF) greater than 470 msec. QTcF is calculated using Fridericia’s Formula (QTcF): QTcF = QT/(RR0.33). • Correction of suspected drug-induced QTcF prolongation can be attempted at the investigator’s discretion and only if clinically safe to do so with either discontinuation of the of-fending drug or switch to another drug not known to be associated with QTcF prolongation. • Correction for underlying bundle branch block (BBB) allowed. 11. Unable to swallow capsules or disease significantly affecting gastrointestinal function such as malabsorption syndrome, re-section of the stomach or small bowel, bariatric surgery procedures, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction 12. Non-curatively treated malignancies other than the disease under the study (unless the malignant disease is in a stable remission [e.g. prostate cancer with standard deviation (SD) under antihormonal therapy] and life expectancy greater than 2 years) 13. Active infection (e.g. persisting fever related to infection and not RT or persisting positive blood cultures) currently requiring systemic treatment 14. In case of suspicion for Cytomegalovirus (CMV) infection, CMV testing (CMV polymerase charin reaction (PCR) in Serum) should be done. Unknown or negative status are eligible. 15. Any comorbidity or organ system impairment rated with a cumulative illness rating scale (CIRS) score of 4, excluding the eyes/ears/nose/throat/larynx organ system , or any other life-threatening illness, medical condition or organ system dysfunction that – in the investigator´s opinion could comprise the patient’s safety or interfere with the absorption or metabolism of the study drugs (i.e. swallow study drug) 16. Requirement of therapy with strong cytochrome P (CYP)3A4 inhibitors/ inducers 17. Known active infection with human immunodeficiency virus (HIV), or serologic status reflecting active hepatitis B or C infection and not meeting the inclusion criteria from 9., which says: Negative serological testing for hepatitis B (Hepatitis B surface antigen (HbsAg) negative and anti-Hepatitis B core antigen (HBc) negative); patients positive for anti-HBc may be included if PCR for HBV deoxyribonucleic acid (DNA) is negative treated with appropriate antiviral therapy and HBV-DNA PCR is performed every two months until 12 months after last dose of study treatment; and for hepatitis C (anti-hepatitis C virus (HCV)-ab negative; in case of positive HCV antibody test, negative HCV-PCR is required). 18. Major surgery within 4 weeks of the first dose of study drug. 19. Use of investigational agents, e.g. monoclonal antibodies or other experimental drugs within clinical trials, which might interfere with the study drug within 28 days (or 5 times the half-life of the compound, whichever is shorter) prior to registration; bridging for CLL, e.g. with covalent bruton tyrosine kinase (BTK) inhibitors or B-cell lymphoma (BCL)2 inhibitors may be used, if the abovementioned criteria for a time interval of 5 times half-life before day1 cycle1 within the study protocol is maintained; bridging for RT is recommended with steroids. 20. Known hypersensitivity to pirtobrutinib or epcoritamab or any of the ingredients. 21. Pregnant women and nursing mothers or planning to become pregnant during the study or within 1 months of the last dose of study treatment. 22. Fertile men or women of childbearing potential unless: a. surgically sterile or greater than or equal to 2 years after the onset of menopause, or b. willing to use two methods of reliable contraception including one highly effective contraceptive method (Pearl Index less than 1) and one additional effective (barrier) method during study treatment and for 12 months after the end of study treatment. 23. Vaccination with a live vaccine less than 28 days prior to registration for study screening 24. Legal incapacity 25. Prisoners or subjects who are institutionalized by regulatory or court order 26. Persons who are in dependence to the sponsor or an investigator
Outcome results
None listed