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

NCT03571308 | Completed Phase 1 DMC

• 1 other identifier: RHM CAN 1129
• Study Type: interventional
• Target: 39
• Locations: 1 country
• Sites: 7

Brief Summary

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

Conditions

Non Hodgkin Lymphoma

Keywords

Diffused Large B-Cell Lymphoma; Acalabrunitib; Bruton Tyrosine Kinase; R-CHOP; Molecular Profiling; Chemoimmunotherapy

Outcome Measures

Primary Outcomes (3)

• Phase I: Dose limiting toxicity of acalabrutinib combined to R-CHOP

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

  18 months

• Phase II: Overall response rate of the combination acalabrutinib and R-CHOP

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

  36 months

• Safety of the combination acalabrutinib and R-CHOP as determined by treatment-related adverse events as assessed by CTCAE v4.03.

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

  12 months

Secondary Outcomes (7)

• Pharmacokinetics of acalabrutinib using area under the plasma concentration versus time curve (AUC)

  24 months

• Maximum Plasma Concentration (Cmax) of acalabrutinib

  24 months

• Time after administration when maximum concentration of acalabrutinib in the plasma is reached (Tmax)

  24 months

• Time required for concentration of acalabrutinib to reach half original value (T1/2)

  24 months

• Overall response rate of the combination acalabrutinib and R-CHOP according to cell of origin.

  24 months

Study Arms (1)

R-CHOP + Acalabrutinib

EXPERIMENTAL

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.

Drug: R-CHOP + acalabrutinib

Interventions

R-CHOP + acalabrutinib DRUG

Patient will be given R-CHOP and acalabrutinib

Also known as: Rituximab, Cyclophosphamide, Vincristine, Doxorubicin, Prednisolone, Acalabrutinib

R-CHOP + Acalabrutinib

Eligibility Criteria

• Age: 16 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64), Older Adult (65+)

You may qualify if:

• Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to a central laboratory for gene expression profiling and pathology review.
• Measurable disease of at least 15mm.
• Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent.
• Stage IAX (bulk defined as lymph node diameter \>10cm) to stage IV disease and deemed to require a full course of chemotherapy. Patients with non-bulky IE disease will not be eligible.
• ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma.
• Adequate bone marrow function with platelets \> 100x109/L; neutrophils \> 1.0x109/L at study entry, unless lower figures are attributable to lymphoma.
• Measured or calculated creatinine clearance \> 30mls/min, (calculated using the formula of Cockcroft and Gault \[(140-Age) x Mass (kg) x (1.04 (for women) or 1.23 (for men))/Serum Creatinine (µmolL)\].
• Serum bilirubin \< 35μmol/L and transaminases \< 2.5x upper limit of normal at time of study entry
• Cardiac function sufficient to tolerate 300mg/m2 of doxorubicin. A pre-treatment echocardiogram or MUGA is required to establish baseline LVEF equal to or greater than 55%.
• No concurrent uncontrolled medical condition.
• Life expectancy \> 3 months.
• Aged 16 years or above.
• Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty.
• Ability to understand the purpose and risks of the study and provide signed and dated informed consent.

You may not qualify if:

• Patients will be excluded from the study entry if any of the following criteria are met:
• Previous history of treated or untreated indolent lymphoma. However newly diagnosed patients with DLBCL who are found to also have small cell infiltration of the bone marrow or other diagnostic material (discordant lymphoma) will be eligible.
• Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible.
• Diagnosis of primary mediastinal lymphoma.
• Diagnosis of primary Central Nervous System lymphoma.
• History of stroke or intracranial haemorrhage in preceding 6 months.
• History of bleeding diathesis (eg, haemophilia, von Willebrand disease).
• Requires or receiving anticoagulation with warfarin or equivalent antagonists (eg, phenprocoumon) within 7 days of first dose of acalabrutinib. However patients using therapeutic low molecule weight heparin or low dose aspirin will be eligible.
• Prior exposure to a BCR inhibitor (eg, Btk inhibitors, phosphoinositide-3 kinase (PI3K), or Syk inhibitors) or BCL-2 inhibitor (eg, ABT-199)
• Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer.
• Requires treatment with proton pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Patients receiving proton pump inhibitors who switch to short-acting H2-receptor antagonists or antacids are eligible for enrolment into this study.
• Uncontrolled systemic infection.
• Major surgery in the preceding 4 weeks of first dose of study drug. If a subject had major surgery, they must have recovered adequately from any toxicity and/or complications from the intervention before the first dose of study drug.
• Significant cardiovascular disease such as uncontrolled or symptomatic arrhythmias, congestive heart failure, or myocardial infarction within 6 months of screening, or any Class 3 or 4 cardiac disease as defined by the New York Heart Association Functional Classification, or corrected QT interval (QTc) \> 480 msec at screening.
• Serological positivity for Hepatitis B, C, or known HIV infection. As per standard of care, prior to initiation of immunochemotherapy, the results of hepatitis serology should be known prior to commencement of therapy.

Sponsors & Collaborators

• University Hospital Southampton NHS Foundation Trust: lead

Study Sites (7)

Southampton University Hospitals NHS Tust

Southampton, Hampshire, SO16 6YD, United Kingdom

Location

St James's University Hospital

Leeds, LS9 7TF, United Kingdom

Location

University College London Hospitals

London, NW12PG, United Kingdom

Location

The Christie NHS Foundation Trust

Manchester, M204XB, United Kingdom

Location

Nottingham City Hospital Campus

Nottingham, NG51PB, United Kingdom

Location

Churchill Hospital

Oxford, OX37LE, United Kingdom

Location

Derriford Hospital

Plymouth, PL68DH, United Kingdom

Location

Related Links

• ASH 62nd Annual Meeting 2020 abstract

MeSH Terms

Conditions

Lymphoma, Non-Hodgkin

Interventions

acalabrutinib; Rituximab; Cyclophosphamide; Vincristine; Doxorubicin; Prednisolone

Condition Hierarchy (Ancestors)

Lymphoma; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Intervention Hierarchy (Ancestors)

Antibodies, Monoclonal, Murine-Derived; Antibodies, Monoclonal; Antibodies; Immunoglobulins; Immunoproteins; Blood Proteins; Proteins; Amino Acids, Peptides, and Proteins; Serum Globulins; Globulins; Phosphoramide Mustards; Nitrogen Mustard Compounds; Mustard Compounds; Hydrocarbons, Halogenated; Hydrocarbons; Organic Chemicals; Phosphoramides; Organophosphorus Compounds; Vinca Alkaloids; Secologanin Tryptamine Alkaloids; Indole Alkaloids; Alkaloids; Heterocyclic Compounds; Indoles; Heterocyclic Compounds, 2-Ring; Heterocyclic Compounds, Fused-Ring; Indolizidines; Indolizines; Daunorubicin; Anthracyclines; Naphthacenes; Polycyclic Aromatic Hydrocarbons; Hydrocarbons, Aromatic; Hydrocarbons, Cyclic; Polycyclic Compounds; Aminoglycosides; Glycosides; Carbohydrates; Pregnadienetriols; Pregnadienes; Pregnanes; Steroids; Fused-Ring Compounds

Study Officials

• Andy Davies

  Southampton University Hospital NHS Foundation Trust

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Masking Details: 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.
• Purpose: TREATMENT
• Intervention Model: SEQUENTIAL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: October 6, 2017
• First Posted: June 27, 2018
• Study Start: June 2, 2017
• Primary Completion: January 2, 2020
• Study Completion: August 31, 2023
• Last Updated: September 28, 2023

Record last verified: 2023-09

Data Sharing

• IPD Sharing: Will not share

Locations

GB (7)