Diffuse Large B Cell Lymphoma, High-grade B-cell Lymphoma
Conditions
Keywords
DLBCL, HGBL
Brief summary
This is an open label, multi-centre, phase Ib/II, parallel arm study evaluating the safety and tolerability of glofitamab in addition to backbone chemotherapy consisting of R-CHOP or polatuzumab vedotin-RCHP for younger patients with higher-risk Diffuse Large B-cell Lymphoma or High Grade B-Cell Lymphoma.
Interventions
DRUGRituximab
Rituximab 375 mg/m\^2 administered by IV infusion on Day 1 of every 21-day cycle
DRUGCyclophosphamide
Cyclophosphamide 750mg/m\^2 administered by IV infusion on Day 1 of every 21-day cycle
DRUGDoxorubicin
Doxorubicin 50mg/m\^2 administered by IV infusion on Day 1 of every 21-day cycle
DRUGVincristine
Vincristine 1.4mg/m\^2 administered by IV infusion on Day 1 of every 21-day cycle
DRUGPrednisolone
Prednisolone 100mg orally on Days 1-5 of every 21-day cycle
DRUGGlofitamab
Glofitamab will be administered by IV infusion as per the schedule specified in the respective arm
DRUGPolatuzumab vedotin
Polatuzumab 1.8mg/kg administered by IV infusion on Day 1 of every 21-day cycle
Sponsors
Hoffmann-La Roche
Peter MacCallum Cancer Centre, Australia
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to 65 Years
Healthy volunteers
No
Inclusion criteria
1. Age ≥18yo and ≤65yo at the time of signing consent 2. Have a histologically confirmed diagnosis of one of the following, according to the 2016 WHO classification: 1. DLBCL, NOS or DLBCL arising as a result of transformation of an indolent lymphoma 2. HGBL, NOS 3. HGBL with rearrangements of MYC and BCL2 and/or BCL6 3. For DLBCL, and HGBL, NOS meets one of the following risk criteria: a. NCCN-IPI of ≥4 or IPI ≥3 (appendix 1 and 3) 4. Considered fit for 6 cycles of full dose R-CHOP chemotherapy, as per the Investigator 5. ECOG performance status (appendix 5) of: 1. 0-2 inclusive or 3 if directly attributable to lymphoma for patients entering the trial prior to cycle 1 of R-CHOP 2. 0-1 inclusive for patients entering the trial at cycle 2 6. Patients must be treatment-naïve or have received a maximum of one cycle of full-dose R-CHOP chemotherapy (with or without a steroid pre-phase) 7. Able to provide an archival pre-treatment biopsy. 8. Have measurable disease on a pre-chemotherapy PET/CT, defined as at least one bi-dimensionally measurable nodal lesion of \>1.5cm in longest dimension, or at least one bi-dimensionally measurable extranodal lesion of \>1.0cm in longest dimension 9. Life expectancy (in the opinion of the Investigator) of ≥ 18 weeks 10. Adequate haematological function 11. Adequate renal function 12. Adequate hepatic function 13. Negative serologic or PCR test results for active acute or chronic HBV infection. 14. Non-haematological AEs from prior anti-cancer therapy must have resolved to Grade ≤1 (with the exception of alopecia and inclusion criteria 10-12) 15. Negative test results for HCV and HIV.
Exclusion criteria
1. Inability to comply with protocol mandated hospitalisations and restrictions 2. Prior systemic treatment of an underlying indolent lymphoma with an anthracycline-containing regimen 3. Richter's syndrome 4. Patients with known CNS involvement by lymphoma 5. With the exception of rituximab, any prior treatment with systemic immunotherapeutic agents, including, but not limited to, radio-immuno-conjugates, antibody-drug conjugates, immune/cytokines, and monoclonal antibodies within 4 weeks or five half-lives of the drug, whichever is shorter, before the first dose of study drug 6. With the exception of CHOP used as a first cycle of lymphoma treatment, any chemotherapeutic agent, or treatment with any other investigational agent within 4 weeks prior to study treatment 7. Prior solid organ transplantation 8. Prior autologous or allogeneic stem cell transplantation 9. A history of treatment-emergent immune related AEs associated with prior immunotherapeutic agents 10. Current or past history of CNS disease, such as stroke, epilepsy, CNS vasculitis, or neurodegenerative disease 1. Note: patients with a history of stroke who have not experienced a stroke or transient ischaemic attack in the past 2 years are allowed 2. Note: patients with a history of epilepsy who have not experienced a seizure in the past 2 years are allowed, so long as continuation of any ongoing established pharmacologic treatment is not contraindicated 11. Past history of confirmed progressive multifocal leukoencephalopathy 12. Past history of chronic active EBV or HLH 13. Major surgery or significant traumatic injury \<28 days prior to study treatment or anticipation of the need for major surgery during study treatment 14. Significant cardiovascular disease, defined as: 1. A left ventricular ejection fraction (as determined by nuclear gated blood pool scan or echocardiogram) \<50% 2. Myocardial infarction or unstable angina within the past 6 months 3. Unstable arrhythmia 4. Any other cardiac illness that, in the opinion of the Investigator or CPI, makes the patient unsuitable for anthracycline containing therapy 15. Significant pulmonary disease, including but not limited to clinically significant obstructive pulmonary disease or history of bronchospasm 16. Current grade \>1 peripheral neuropathy by clinical examination or demyelinating form of Charcot-Marie-Tooth disease 17. Known clinically significant liver disease, including active viral or other hepatitis, current alcohol abuse, or cirrhosis 18. Administration of a live, attenuated vaccine within 4 weeks before study treatment note: influenza vaccination should be given during influenza season only. Patients must not receive live, attenuated influenza vaccine at any time during the study treatment period 19. History of other active malignancy within 5 years prior to registration, with the exception of: 1. FL or MZL, previously untreated, or treated with no more than one line of therapy which must not have contained an anthracycline 2. Basal or squamous cell carcinoma or Stage 1 melanoma of the skin or in situ carcinoma of the cervix 3. Prior malignancy treated with a curative intent that has remained in remission without treatment for ≥2 years prior to registration 20. Patients with known active bacterial, viral, fungal, mycobacterial, parasitic, or other infection (excluding fungal infections of the nail beds) at registration a. Note: Patients with latent tuberculosis are excluded 21. Other significant life-threatening illness or medical condition which, in the Investigator's opinion, could compromise the patient's safety, interfere with absorption or metabolism of study drug, affect compliance with the protocol or interpretation of results, or put the study outcomes at undue risk 22. Major contraindication to any of the individual components of the chemotherapy backbone (R, C, H, O, Polatuzumab vedotin, prednisolone) 23. Patients who are pregnant or breastfeeding Other protocol-defined inclusion and
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| To evaluate the Relative Dose Intensity (RDI) of the chemotherapy backbone | From start of study treatment till the end of study treatment, assessed up to approximately 12 months |
| To evaluate the rates of early chemotherapy discontinuation | From start of study treatment till the end of study treatment, assessed up to approximately 12 months |
| To assess safety of the combination of glofitamab and R-CHOP or pola-RCHP according to number of participants with treatment-related adverse events | From start of treatment till the end of study, assessed up to approximately 60 months |
Secondary
| Measure | Time frame |
|---|---|
| To describe progression free survival (PFS) | From first dose of chemotherapy induction to first date of objectively documented progressive disease or date of death of any cause, whichever occurs first, assessed up to approximately 60 months |
| Overall survival (OS) as defined as the time from first dose of chemotherapy induction to the date of death from any cause | From first dose of chemotherapy induction to the date of death from any cause, assessed up to approximately 60 months |
| To describe the duration of response (DoR) measured in the subset of patients who achieved CR or PR | Time from the first documented disease response to the date of progressive disease or death, whichever occurs first, assessed up to approximately 60 months |
| To estimate the proportion of patients achieving a complete response (CR) after cycles 2, 4 and at end of induction treatment (6 cycles) of the novel combination therapy according to Lugano 2014 criteria | Up to approximately 6 months (each cycle is 21 days) |
| To estimate overall response rate (ORR) | Up to approximately 6 months (each cycle is 21 days) |
Other
| Measure | Time frame |
|---|---|
| Correlation between circulating tumour DNA detection and response (CR and ORR) | From start of treatment till end of study assessed up to 60 months |
| Comparison of efficacy (rates of CR, ORR, DOR, PFS and OS) between the two study arms | From start of treatment till end of study assessed up to 60 months |
Countries
Australia
Outcome results
None listed