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Tyrosine

Open-label non-randomised phase Ib/II study conducted in two stages. Phase I will see two doses of acalabrutinib tested. R-CHOP + acalabrutinib will be given for 6 cycles on a 21 day cycle and then two cycles of acalabrutinib only for a total of 56 days. Acalabrutinib will be introduced at Cycle 2.

Phase II will see the recommended phase 2 dose used on the same treatment regimen.

Patient will be given R-CHOP and acalabrutinib

R-CHOP + acalabrutinib

Andy Davies

Previously untreated CD20 positive diffuse large B-cell lymphoma (DLBCL) requiring full course chemoimmunotherapy.

Open-label non-randomised phase Ib/II study conducted in two stages. Stage 1 will be dose escalation in a modified classical 6+6 design. Stage 2 will be an expansion cohort to gain additional information on safety and efficacy at the recommended phase II dose of acalabrutinib.

A multicentre open-label non-randomised phase Ib/II two stage trial. Stage 1 - dose escalation will proceed until a maximum tolerated dose (MTD) is defined or the maximal administered dose (MAD) is determined in order to define the recommended Phase II dose (RP2D). 6 - 24 patients. Stage 2 - expansion to gain additional information on safety and efficacy at the RP2D from a total of 15 patients recruited.

Patients will receive conventionally dosed R-CHOP chemotherapy for 6 cycles with acalabrutinib introduced on cycle 2 onwards, at a dosage according to cohort number. This will allow for both clarity in the toxicity profile of the combination and also assess the impact of acalabrutinib on ADCC.

patients who do not complete six cycles of treatment for reasons other than toxicity will be replaced.

A Combination of Acalabrutinib With R-CHOP for Patient Diffuse Large B-cell Lymphoma (DLBCL)

A Phase Ib/II Combination of Acalabrutinib With R-CHOP for Patient Diffuse Large B-cell Lymphoma (DLBCL)

Define recommended dose for Phase II evaluation of acalabrutinib with R-CHOP examining safety and toxicity of combination

Document anti-tumour activity of acalabrutinb in combination wit R-CHOP in patients with previously untreated CD20 positive DLBCL

To determine additional safety information of acalabrutinib in combination with R-CHOP by treatment-related adverse events as assessed by CTCAE v4.03.

To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCL

To determine the pharmacokinetic (PK) profile of acalabrutinib when given in combination with R-CHOP in patients with DLBCLPK parameter.

To evaluate the effect of acalabrutinib in combination with R-CHOP on outcomes according to cell of origin

To measure the duration of response to acalabrutinib in combination with R-CHOP over a follow-up period of 2 years

University Hospital Southampton NHS Foundation Trust

Prednisone

Antineoplastic Agents, Immunological

Protective Agents

6 cycles of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) immunochemotherapy every 21 days.

1 cycle of standard R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisolone) immunochemotherapy followed by 5 cycles of R-CHOP + acalabrutinib taken twice daily for 21 day cycles.

Arm A patients will receive R-CHOP alone.

R-CHOP

Arm B patients will receive R-CHOP in combination with acalabrutinib.

Nicole Keyworth

Joshua Caddy

Andrew Davies

This study evaluates the addition of Acalabrutinib to current standard therapy of Rituximab, Cyclophosphamide, Doxorubicin, Vincristine and Prednisolone (R-CHOP) for patients with previously untreated CD20 positive Diffuse Large B-cell Lymphoma (DLBCL) requiring full course chemoimmunotherapy.

All patients will receive one cycle of R-CHOP. Two thirds of patients (Arm B) will go on to receive a further 5 cycles (every 21 days) of R-CHOP with Acalabrutinib. Acalabrutinib will be taken orally twice daily continuously in 21 day cycles.

One third of patients (Arm A) will continue with 5 cycles of R-CHOP.

Patients will be followed up initially for 24 months and then for disease status and survival until 114 progression events have been observed.

Diffuse large B-cell lymphoma (DLBCL) is the most common of the non-Hodgkin's lymphomas. Whilst the majority of patients will respond well to conventional treatment (R-CHOP - rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone), a significant number of patients lymphoma will not respond to initial therapy or their disease will return after completion of therapy. In a number of B-cell diseases an enzyme called, Bruton tyrosine kinase (BTK) prevents death of tumour cells, including in DLBCL. Acalabrutinib is an orally active BTK-inhibitor and it is thought that stopping BTK being activated may help in treating B-cell diseases. It is hypothesised that the addition of Acalabrutinib to standard R-CHOP immunochemotherapy may improve outcomes of patients with DLBCL.

REMoDL-A is a randomised, phase II, open label, multicentre study that will be open in up to 50 centres. Up to 553 patients (453 randomised) will be recruited.

Following informed consent all patients will receive 1 cycle of conventional R-CHOP chemotherapy. At the same time the diagnostic pathology block will be sent for molecular profiling by the Haematological Malignancy Diagnostic Service (HMDS). The delivery of the first cycle of R-CHOP will allow a sufficient interval for real time determination of molecular phenotype. Patients whose biopsies yield sufficient tumour material for profiling will be randomised 2:1 in favour of the experimental arm (R-CHOP + acalabrutinib).

The primary objective will be to establish if combining acalabrutinib with R-CHOP improves efficacy, compared to R-CHOP alone, for the treatment of previously untreated patients with DLBCL to a degree that justifies further development of this approach.

Acalabrutinib in Combination With R-CHOP for Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)

A Randomised Phase II Evaluation of Molecular Guided Therapy for Diffuse Large B-Cell Lymphoma With Acalabrutinib

Applying the following techniques to FFPE tumour material: mutational panel, FISH analysis, immunohistochemical analysis for dual protein expression of Myc and Bcl2 and dynamic changes in ctDNA and methylation based ctDNA during treatment and follow up.

Tumour burden defined by metabolic tumour volume (MTV) and tumour lesion glycolysis (TLG). Bone marrow involvement defined by focal uptake in the bone marrow higher than liver uptake; diffuse bone marrow uptake higher than liver uptake will be recorded and correlated with bone marrow biopsy results where available (number and location of extranodal sites).

Progression-free survival (PFS) is defined as time from registration to progression/death from any cause.

PFS interaction with cell of origin phenotype (ABC, GCB and unclassifiable).

PFS interaction with clinical variables, including for example IPI, bulk, components of IPI, age and others to be determined in the SAP.

Overall survival (OS), defined as time from registration to death from any cause.

Event-free survival (EFS), or time to treatment failure, defined as time from registration to any treatment failure including disease progression, or discontinuation of treatment for any reason.

Disease-free survival (DFS), defined as time of documentation of disease-free state to disease recurrence or death as a result of lymphoma or acute toxicity of treatment.

Time to progression (TTP), defined as time from registration until documented lymphoma progression or death as a result of lymphoma. Deaths from other causes are censored at the time of death.

Response duration (DoR), defined as the time from documentation of response until the documentation of relapse or progression.

Assessment using the Lugano Response Criteria for Malignant Lymphoma.

Evaluation of toxicity according to CTCAE version 5.

Application of the EORTC QLQ-C30 and FACT-Lym questionnaires.

Study title	NCT ID	Conditions	Interventions	Eligibility	Organization	Link
A Combination of Acalabrutinib With R-CHOP for Patient Diffuse Large B-cell Lymphoma (DLBCL)	NCT03571308	Non Hodgkin Lym...	R-CHOP + acalab...	16 Years -	University Hospital Southampton NHS Foundation Trust
Acalabrutinib in Combination With R-CHOP for Previously Untreated Diffuse Large B-cell Lymphoma (DLBCL)	NCT04546620	Diffuse Large B...	R-CHOP R-CHOP + acalab...	16 Years -	University Hospital Southampton NHS Foundation Trust

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