Arm in the randomised trial. CHOP-R chemoimmunotherapy will continue for up to 6 cycles (each cycle is 21 days), and will be given according to the following schedule:
Rituximab, 375 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Cyclophosphamide, 750 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Doxorubicin, 50 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Vincristine, 1.4 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Prednisolone, 40 mg/m2, PO, OD, 6 cycles, days of cycle: 1-5

Arm in the randomised trial. CHOP-R chemoimmunotherapy will continue for up to 6 cycles (each cycle is 21 days), and will be given according to the following schedule:
Rituximab, 375 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Cyclophosphamide, 750 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Doxorubicin, 50 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Vincristine, 1.4 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Prednisolone, 40 mg/m2, PO, OD, 6 cycles, days of cycle: 1-5
Acalabrutinib 100 mg, PO, BD will be taken on days 6-21, of each cycle - up to cycle 6. Acalabrutinib treatment will be continuous thereafter until disease progression toxicity, patient choice or death.

Registration arm in platform study. Patients registered to Cohort 1 will receive 100 mg acalabrutinib monotherapy, twice daily, continuously from day 1 until disease progression, toxicity, patient choice or death.

Registration arm in platform study. CHOP-R chemoimmunotherapy will continue for up to 6 cycles (each cycle is 21 days), and will be given according to the following schedule:
Rituximab, 375 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Cyclophosphamide, 750 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Doxorubicin, 50 mg/m2, IV bolus, OD, 6 cycles, days of cycle: 1 Vincristine, 1.4 mg/m2, IV infusion, OD, 6 cycles, days of cycle: 1 Prednisolone, 40 mg/m2, PO, OD, 6 cycles, days of cycle: 1-5
Acalabrutinib 100 mg, PO, BD will be taken on days 6-21, of each cycle - up to cycle 6. Acalabrutinib treatment will be continuous thereafter until disease progression toxicity, patient choice or death.

Richter Syndrome

Acalabrutinib

Cyclophosphamide

Doxorubicin

Vincristine

Prednisolone

Rituximab

A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter's Syndrome

A Phase II, Randomised Study of CHOP-R in Combination With Acalabrutinib Compared to CHOP-R in Patients With Newly Diagnosed Richter's Syndrome and a Platform for Initial Investigations Into Activity of Novel Treatments in Relapsed/Refractory and Newly Diagnosed Richter's Syndrome.

Progression free survival (PFS) defined as the time from randomisation to the date of progression or death from any cause. Progression will be defined by the modified Cheson criteria (Appendix 1). Patients who are alive and progression free at the time of analysis will be censored at date last seen. Any participants who withdraw or are lost to follow-up will also be censored at date last seen.

Overall response after 24 weeks of treatment based on the modified Cheson criteria (Appendix 1). Complete response (CR) and partial response (PR) are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 6 month assessment or do not have the 6 month assessment will be considered non responders.

Overall response after 6 cycles of treatment, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.

Defined as time from date of randomisation (for randomised trial) or registration (to the relevant cohort for single-arm cohorts) to date of death from any cause.
Participants who are alive at the time of analysis will be censored at date last seen.

Overall response (randomised component only) after cycle 6, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the post-cycle-6 assessment or do not have the post-cycle-6 assessment will be considered non-responders.

Overall response (cohorts 1 only) after 12 weeks, defined by the modified Cheson criteria (Appendix 1). CR and PR are considered to be positive responses for assessment of this outcome. Participants who withdraw prior to the 12-week assessment or do not have the 12- week assessment will be considered non-responders.

PFS (single-arm cohorts only) defined as the time from date of registration to date of progression or death from any cause. Progression will be defined by the modified Cheson criteria (Appendix 1). Participants who are alive and progression free at the time of analysis will be censored at date last seen. Any patients who withdraw or are lost to follow-up will also be censored at date last seen.

QoL, (assessed using ECOG performance status [Appendix 7]), and the CLL17 and NHLHG29 questionnaires (Appendix 2)) at the end of cycles 4 and 6 for participants receiving CHOP-R as part of their treatment (randomised cohorts and Cohort 2), and at 12 and 24 weeks for participants receiving acalabrutinib monotherapy (Cohort 1).

Toxicity defined as the number of participants who experience one or more adverse event grade 3 or higher or serious adverse event of any grade.

Measured as proportion of patients proceeding to transplant on each treatment arm, at confirmation of partial or complete remission

University of Birmingham

Bloodwise

Acerta Pharma, LLC

45 Gy in 25 fractions of 1.8 Gy per fraction over 5 weeks Involved Field radiotherapy (IFRT)/ Involved Site Radiotherapy (ISRT)

36 Gy in 20 fractions of 1.8 Gy per fraction over 4 weeks Involved Field radiotherapy (IFRT)/ Involved Site Radiotherapy (ISRT)

NonHodgkin Lymphoma

Radiation will be started within 3-4 weeks of completion of chemotherapy. Computed Tomography (CT)scan will be acquired for treatment planning, which will be done using External Beam Planning System. The target volumes will be defined by clinical examination, staging Positron Emission Tomography with CT (PET-CT) and response PET-CT. The staging PET-CT will be fused and co-registered with the planning CT scans for target volume delineation. For Involved Field Radiotherapy,Clinical target volume (CTV) will include the entire nodal region depending on the site involved. For Involved Site RT , CTV will include the involved nodal volume in the staging PET-CT. For extranodal sites, the CTV will include the involved extranodal region as per the staging PET-CT. The total dose will be prescribed to the Planning Target Volume based on dose uniformity guidelines. All patients will be treated with 3 Dimensional Conformal Radiotherapy or Intensity Modulated Radiotherapy where indicated.

Standard Arm

Radiation will be started within 3-4 weeks of completion of chemotherapy. Computed Tomography (CT)scan will be acquired for treatment planning, which will be done using External Beam Planning System. The target volumes will be defined by clinical examination, staging Positron Emission Tomography with CT (PET-CT) and response PET-CT. The staging PET-CT will be fused and co-registered with the planning CT scans for target volume delineation. For Involved Field Radiotherapy,Clinical target volume (CTV) will include the entire nodal region depending on the site involved. For Involved Site RT,CTV will include the involved nodal volume in the staging PET-CT. For extranodal sites, the CTV will include the involved extranodal region as per the staging PET-CT. The total dose will be prescribed to the Planning Target Volume based on dose uniformity guidelines. All patients will be treated with 3 Dimensional Conformal Radiotherapy or Intensity Modulated Radiotherapy where indicated.

Experimental Arm

Tata Memorial Center

Radiation Dose Optimization in Diffuse Large B- Cell Lymphoma.

Radiation Dose Optimization in Diffuse Large B- Cell Lymphoma (DOBL) - A Randomised Phase III Non- Inferiority Trial.

From the time of randomization till relapse or progression or death due to any cause or death due to disease.
Assessment by physiological parameter

From the time of randomization till the disease is controlled at the site of radiation.
Assessment by physiological parameter.

From the time of randomization to death due to any cause /death due to disease. assessment by physiological parameter

vincristine/accident vascular cerebral

A Trial of CHOP-R Therapy, With or Without Acalabrutinib, in Patients With Newly Diagnosed Richter's Syndrome

Radiation Dose Optimization in Diffuse Large B- Cell Lymphoma.

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