ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a Phase Ib/II open-label non-randomised clinical trial

Background and rationale

More than 13,000 new cases of non-Hodgkin’s lymphoma (NHL) were diagnosed in the UK between 2014–2016, with nearly 4,900 patients dying as a result of their disease in 2017¹. Diffuse large B-cell lymphoma (DLBCL) is the most common type of NHL, accounting for 30–40% of NHL cases in adults with an annual incidence of about 5,500 patients in the UK^1,2.

Cyclophosphamide, vincristine, doxorubicin and prednisolone (CHOP) used to be the standard of care for DLBCL. But, overall survival was disappointing; CHOP only cured about 30 percent of patients with advanced stages of intermediate-grade or high-grade NHL³. Addition of the anti-CD20 monoclonal antibody rituximab to CHOP resulted in higher response rates, longer event free survival and improved overall survival. R-CHOP is now accepted as the international standard, with cure rates around 75%^4–8.

Despite this improvement, many patients either fail to respond or relapse after having achieved an initial remission. Their prognosis is poor, because earlier rituximab therapy limits the success of salvage treatment and so the majority of these patients will die from their disease⁹. Consequently, there is an urgent need to improve the effectiveness of first line treatment.

Gene expression profiling of untreated DLBCL samples has identified three distinct sub-classifications of the disease: activated B-cell like [ABC-DLBCL]; germinal centre B-cell like [GCB- DLBCL] and unclassified DLBCL. Each has its own biological features and clinical outcomes when treated with CHOP or R-CHOP.

The cells of ABC type are driven by “chronic active” B-cell receptor (BCR) signalling¹⁰. The BCR signalling pathway can be disrupted using Bruton tyrosine kinase (Btk) inhibitors. Targeting BCR signalling by inhibiting Btk with ibrutinib (a first generation Btk inhibitor) in combination with R-CHOP is known to be safe for previously untreated B-cell NHL¹¹.

Acalabrutinib (Acerta Pharma B.V.) is a second generation Btk inhibitor with increased target selectivity compared to ibrutinib¹². As of 30 December 2018, acalabrutinib has been administered to over 2600 participants in clinical studies, including patients with haematologic malignancies, solid tumour, or rheumatoid arthritis, and participants who are healthy volunteers or with mild to moderate hepatic impairment. No serious adverse events (SAEs) have been reported in the hepatic impairment study or in the healthy volunteer studies. No expected SAEs have been identified for acalabrutinib to date.

We hypothesised that acalabrutinib would have improved target potency and specificity and is both active and tolerable in combination with R-CHOP.

Trial design

ACCEPT is a multicentre open-label non-randomised Phase Ib/II clinical trial conducted in two stages recruiting approximately 40 participants. Phase I will be dose escalation following the conventional rules of 6+6 modified design, escalation will proceed until a maximum tolerated dose (MTD) is defined or the maximal administered dose (MAD) is determined in order to define the RP2D. A six participant cohort design is employed to maximise patient safety¹³, which will result in 6–24 participants recruited. Phase II will be an expansion cohort in order to gain additional information on safety and efficacy at the RP2D from a total of 15 participants recruited (Figure 1).

Figure 1. Accept Trial schema.

Study setting

Seven secondary care hospitals in the UK are recruiting participants into ACCEPT. A list of study sites is available via contacting accept@soton.ac.uk.

Eligibility criteria

Inclusion criteria

Participants should fulfil the following criteria:

Exclusion criteria

Patients will be excluded from the study entry if any of the following criteria are met:

Consent

Who will take informed consent?

Consent to enter the trial will be sought from each participant only after a full explanation has been given, a Patient Information Sheet (PIS) offered (Extended data¹⁴) and time allowed for consideration. Signed participant consent will be obtained. Only site staff named on the Delegation Log and authorised to do so may obtain consent. Patients may refuse to participate without giving reasons and this will not prejudice their future treatment.

Additional consent provisions for collection and use of participant data and biological specimens

The trial’s Informed Consent Forms detail the consent provisions for collection and use of participant data and biological specimens in future research (Extended data¹⁴).

Interventions

Explanation for the choice of comparators

Rationale for combination of acalabrutinib in combination with R-CHOP in DLBCL

Dysregulation of BCR signalling is well recognised in DLBCL and other B-cell malignancies. Btk is central to signalling through the BCR. The safety and efficacy of a first generation Btk inhibitor, ibrutinib, in combination with R-CHOP has already been investigated by a Phase Ib study in patients with DLBCL, demonstrating that it is well tolerated with an overall response rate (ORR) of 91% (CR 70%)¹⁰.

Acalabrutinib is a second generation Btk inhibitor with enhanced kinase selectivity and potential for better efficacy and tolerability over first-generation inhibitors. It has a number of preclinical properties that would indicate the potential for favourable efficacy and safety over ibrutinib. These include preferential selectivity for Btk with the potential for less off-target effects (e.g. Epidermal Growth Factor Receptor and diarrhoea). Acalabrutinib does not appear to abrogate thrombus formation, compared to ibrutinib, mediated by off-target kinase activity, and would therefore potentially reduce the risk of bleeding and also compared to ibrutinib does not have a negative effect on ADCC, an important mediator of rituximab function.

Results from the study of acalabrutinib in patients with chronic lymphocytic leukaemia (CLL) demonstrate a favourable toxicity profile with an emergent lower rate of haematological toxicity compared to ibrutinib. No DLTs were reached and no SAEs reported to date at doses ≤400mg¹⁵.

Rationale for dose selection

Results from the study of ibrutinib in combination with R-CHOP indicated that the maximal tolerated dose was not reached and the recommended Phase II dose of ibrutinib was 560mg od¹⁰. This is the licensed single agent dose for use in mantle cell lymphoma. Given the favourable single agent toxicity profile of acalabrutinib in the CLL study compared to ibrutinib, it is anticipated that acalabrutinib may safely be given in combination with R-CHOP at doses close or equivalent to those being investigated as a single agent.

Preliminary data from the ongoing Phase I/II study in patients with relapsed/refractory or previously untreated CLL have shown that acalabrutinib is well tolerated at dosages of 100 to 400 mg od and 100 to 200 mg bd¹⁵. These data suggest that de novo synthesis of Btk can occur within 24 hours in peripheral blood cells. Twice daily dosing may ensure Btk inhibition for the entire 24 hours and thus may be beneficial in terms of increasing efficacy and/or decreasing development of resistance to acalabrutinib.

Taken together, the proposed starting dose of 100mg od is considered represent one where there is good pharmacodynamic evidence that the target is being suitably occupied without safety concerns in single agent studies and one supported by our pharmacokinetic knowledge of acalabrutinib. Escalation to twice daily dosing in the second cohort, addresses the continued inhibition of Btk based upon concerns about de novo synthesis during the 24-hour period.

Intervention description

All participants will receive 6 cycles of R-CHOP on a standard 21 day schedule with the addition of acalabrutinib in cycles 2–6. This will be followed by a continuation period of acalabrutinib only for 2 cycles each of 28 days. The Schedule of Events (Table 2) describes the trial interventions.

Phase I - Dose Escalation

Stage 1:

R-CHOP + Acalabrutinib (Cycle 2–6)

Cycle 7 (28 days) and 8 (28 days) - Acalabrutinib only

Acalabrutinib dosage:

The first six participants enrolled in the study (cohort 1) will receive 100mg od started on day 1 of the 2^nd cycle of R-CHOP. When participants of the first cohort have completed their third cycle, and their safety data has been reviewed by the Safety Review Committee, the decision for dose escalation to 100mg bd for cohort 2 could be taken.

Stage 2:

R-CHOP + Acalabrutinib (Cycle 2–6)

Cycle 7 (28 days) and 8 (28 days) - Acalabrutinib only

Phase II – Dose Expansion

R-CHOP + Acalabrutinib (Cycle 2–6)

Cycle 7 (28 days) and 8 (28 days) - Acalabrutinib only

Acalabrutinib, at RP2D taken orally for 56 days following end of treatment with 6 cycles R-CHOP.

Criteria for discontinuing or modifying allocated interventions

After the participant has entered the trial, the clinician remains free to give alternative treatment to that specified in the protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should be recorded. In these cases, participants will be withdrawn from protocol treatment but remain within the trial for the purposes of follow-up and data analysis. All participants are free to withdraw at any time from the protocol treatment without giving reasons and without prejudicing further treatment.

Strategies to improve adherence to interventions

The investigator and/or study personnel will assess participant compliance with acalabrutinib at each study visit using direct questioning, examination of participants’ drug administration diaries and pill counts.

Relevant concomitant care permitted or prohibited during the trial

Supportive care

Prohibited therapies

Acalabrutinib is not a strong direct inhibitor or inducer or CYP isoforms; thus, acalabrutinib, at the currently used clinical doses, is unlikely to be a perpetrator of a drug interaction at the level of inhibition or induction of CYP isoforms. Acalabrutinib is partially metabolised by CYP3A; its exposure is affected when co-administered with strong CYP3A4 inducers or inhibitors. Consequently, the concomitant use of strong inhibitors/inducers of CYP3A4 (see Table 3) should be avoided when possible.

Based on these considerations, patients who require therapy with drugs listed in Table 3 should not be enrolled into the study. If medically justified, patients may be enrolled if such inhibitors or inducers can be discontinued or alternative drugs that do not affect these enzymes can be substituted within 7 days before first dose of study drug. If a subject requires a strong CYP3A4 while on study, the subject will be monitored closely for potential drug-related toxicities.

The effect of agents that reduce gastric acidity (e.g., proton pump inhibitors, H2 receptor antagonists or antacids) on acalabrutinib absorption was evaluated in a healthy volunteer study (ACE-HV-004; Acalabrutinib Investigator Brochure v8 ACERTA PHARMA B.V.). Results from this study indicate that participants should avoid the use of calcium carbonate containing drugs or supplements (e.g., antacids and calcium supplements) for a period of at least 2 hours before and after taking acalabrutinib. Similarly, participants should avoid the use of H2-receptor antagonists for a period of 2 hours after taking the study drugs. Use of omeprazole, esomeprazole, lansoprazole or any other proton pump inhibitors while taking acalabrutinib is not recommended due to a potential decrease in study drug exposure. However, if a subject requires the use of a proton pump inhibitor while on study (e.g., to treat a gastric ulcer) treatment options will be discussed with SCTU.

In circumstances where treatment with ciprofloxacin is needed, the dose of acalabrutinib should be reduced to 100mg od.

Warfarin and equivalent Vitamin K antagonists are prohibited. However, participants may use therapeutic low molecule weight heparin or low dose aspirin.

Dietary restrictions

Acalabrutinib can be taken with or without food. Because acalabrutinib may be metabolized by CYP3A4, participants should be strongly cautioned against consumption of grapefruit, grapefruit juice, or Seville orange juice (which contain potent CYP3A4 inhibitors) or using herbal remedies or dietary supplements (in particular, St John’s Wort, which is a potent CYP3A4 inducer). Otherwise, participants should maintain a normal diet unless modifications are required to manage an AE such as diarrhoea, nausea or vomiting.

Contraception

Contraception is mandated from trial entry until 12 months after the last treatment dose for participants of reproductive potential.

Participants with reproductive potential must use two highly effective methods of contraception during the study, with male participants also agreeing to use additional barrier or abstinence due to the risk of exposure to a developing foetus if the female partner is already pregnant.

Hormonal contraception may be susceptible to interaction with study or other drugs, which may reduce the efficacy of the contraception method.

Both male and female patients must be counselled about future fertility prospects and sperm/ovarian preservation prior to study entry. Male patients must refrain from donating sperm once on study and during treatment and the 12 month follow-up period. Acalabrutinib is not known to confer long term reduction in fertility, however the cytotoxic drugs used in this protocol, i.e. doxorubicin and cyclophosphamide, may do.

Provisions for post-trial care

Participants completing the trial, or who withdraw their consent for follow-up, will be managed by standard clinical care from their usual treating clinician.

Outcomes

Primary outcomes

The Phase I study will be dose escalation that will proceed until an MTD is defined or the MAD is determined in order to define the RP2D of acalabrutinib in combined with R-CHOP. This dose will be used in the Phase II evaluation of acalabrutinib in combination with R-CHOP in participants with DLBCL.

The DLT will be defined using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) version 4.03. The MTD is defined as the highest dose level at which none of the first six treated participants, or no more than 2 of the first 12 treated participants, experiences a DLT.

The DLT reporting period is from the start of treatment until the end of cycle 3. Events meeting the below criteria following the end of cycle 3 will not be recorded as DLTs.

A DLT will be defined as the occurrence of the following:

If a DLT attributed to acalabrutinib per the investigator’s assessment occurred, dosing with acalabrutinib will be withheld. Acalabrutinib treatment will be resumed at a lower dose only after toxicity has resolved to ≤ grade 1. There will be no dose re-escalation for acalabrutinib after recovery from toxicity, and no intra-cohort participants dose escalation will be allowed. The study will terminate early if three DLT occur for the first six participants in Phase I (Table 4).

Dose adjustments for R-CHOP components, will follow conventional dose modification schedules.

Phase II will use ORR to document the anti-tumour activity of the acalabrutinib and R-CHOP combination therapy, as well as investigating treatment safety. Safety will be assessed throughout via:

Secondary outcomes

Tertiary outcomes

Participant timeline

The time schedule of enrolment, interventions, assessments, and visits for participants are fully detailed in the schedule of events (Table 2).

Sample size

There is no formal sample size calculation given the modified 6+6 classical design. Sample size for Phase I is based upon anticipated numbers to complete schedule of dose escalation to DLT or MAD (n=6 - 24 participants). For Phase II, the sample size (n=15) permits sufficient numbers of participants to gain additional safety information and to look for exploratory signal of efficacy in biological subgroups in a pooled analysis of both stages.

Recruitment

Patients are approached within a hospital setting and screened for eligibility by research staff to ensure all inclusion and exclusion criteria are met. Clinicians will seek informed consent to enter the trial from a patient only after the patient has received a full explanation of the trial, the patient has read the PIS and had enough time to consider taking part.

After the participant has entered the trial the clinician remains free to give alternative treatment to that specified in the protocol at any stage if he/she feels it is in the participant’s best interest, but the reasons for doing so should be recorded. In these cases, participants will be withdrawn from protocol treatment but remain within the trial for the purposes of follow-up and data analysis.

Assignment of interventions

ACCEPT is a non-randomised open-label study, consequently there is no allocation sequence and no-one involved in the trial is blinded to the intervention.

Data collection and management

Plans for assessment and collection of outcomes

Hospital research staff will enter participant data into the study eCRFs via a remote data collection tool (Medidata Rave). Only trained personnel with specific roles in the study will be granted access to the eCRFs. SCTU trial staff will regularly check the data for missing or anomalous values. Data queries will either be automatically generated within the eCRF, or manually raised with site by the SCTU team. Site staff will respond to explain or resolve the discrepancies.

Plans to promote participant retention and complete follow-up

ACCEPT has no specific plans for promoting retention to the trial. Participants who do not complete six cycles of treatment for reasons other than toxicity will be replaced.

Data management

Full details of the data management strategy for the study are available as Extended data¹⁴.

Confidentiality

Participant data is pseudonymised by assigning each participant a participant identifier code, which is used to identify the participant during the study and for any participant- specific communication between SCTU and site.

Plans for collection, laboratory evaluation and storage of biological specimens for genetic or molecular analysis in this trial/future use

Pharmacokinetic sampling

Acalabrutinib pharmacokinetics will be assessed in all participants by determination of serum concentrations of acalabrutinib by a fully validated assay that has already been used in human studies. The samples will be taken from participants as explained in Table 5.

Pharmocodynamic sampling

Acalabrutinib pharmacodynamics will be assessed in all participants by measurements of the following:

1. Evaluation of BTK occupancy in PBMCs.

PBMC will be incubated with a fluorescently-tagged analogue of acalabrutinib. Acalabrutinib and the probe bind covalently to Btk, with binding of the probe being prevented by acalabrutinib occupancy. Probe-binding will be detected by flow cytometry. PMBCs will be collected by blood sample on day 1 of cycle 2 pre-dose and at 4 hours post-dose and on day 8 of cycle 2 pre-dose, at 2 and 4 hours post dose (Table 6).

2. Impact of the addition of acalabrutinib on R-CHOP mediated ADCC

Blood samples will be collected on day 1 and day 8 cycle 2 pre- dose and 4 hours post dose. A fluorescent dye release assay measuring target cell lysis, coupled with flow cytometry will be employed to measure ADCC (Table 6).

3. BCR activation before and after R-CHOP + acalabrutinib

Blood samples for measurement of BCR activation will be collected on day 1 and day 8 cycle 2 pre-dose and on day 1 cycle 4 pre-dose. BCR activation will be determined by measurement of CD86 and CD69 expression on PBMC by flow cytometry (Table 6).

Translational research

This study will prospectively validate the cell of origin (ABC versus GCB) model of DLBCL and its practicality and utility, as well as assessing the benefit/toxicity of the addition of acalabrutinib to R-CHOP.

For all participants, sufficient diagnostic material should be available to forward to a central laboratory for pathological review and gene expression profiling. FFPE lymph node biopsies should be forwarded to Haematological Malignancy Diagnostic Service (HMDS) where molecular phenotyping will be performed using a reliable array platform requiring the extraction of RNA. Central pathological review will be performed as quality check but not fed back to site unless findings untoward. There must be sufficient tumour block to test for H/E morphological check of compatibility of DLBCL diagnosis, immunophenotyping, RNA for gene expression profiling. Additional material will be used for immunohistochemical, cytogenetic and molecular genetic studies FISH, DNA for mutation, Transcription Mediated Amplification. Material will only be retained if the sample size is sufficient for removal of material without compromising its value as archived diagnostic material. This may include the generation of extended full section immunohistochemical studies, tissue microarrays and DNA extraction. The remaining FFPE block will be returned to the local pathologist.

DNA extracted from tumour material will be used to perform mutation detection on BCR pathway (e.g. Btk, PI3K, CD79b). Genetic abnormalities of BCR pathway will be correlated with clinical outcomes and the expression of BCR pathway target genes.

Statistical methods

Statistical methods for primary and secondary outcomes

A full and detailed statistical analysis plan will be developed prior to the final analysis of the trial. The main features of the statistical analysis plan are:

Interim analyses

In Phase I the Safety Review Committee will review safety data and advise on dose escalation. The study will terminate early if three DLT occur for the first 6 participants in Phase I.

In Phase II an independent Data Monitoring & Ethics Committee (DMEC) will review outcome and safety data regularly during the trial advising the independent Trial Steering Committee (TSC) on continuation of the trial.

Methods for additional analyses (e.g. subgroup analyses)

Not applicable.

Methods in analysis to handle protocol non-adherence and any statistical methods to handle missing data

If the participant is discovered to be ineligible over the course of the study their participation will end. Where possible, participants who have withdrawn from trial treatment should remain in follow-up as per the trial schedule. If participants additionally withdraw consent for this, they should revert to standard clinical care as deemed by the responsible clinician. It would remain useful for the trial team to continue to collect survival follow-up data and unless the participant explicitly states otherwise, survival follow-up data will continue to be collected. Details of trial discontinuation (date, reason if known) should be recorded in the eCRF and medical record.

Plans to give access to the full protocol, participant level-data and statistical code

The full protocol is available as Extended data¹⁴. The ‘Dissemination plans’ section of this article describes how to access trial-related data.

Oversight and monitoring

Composition of the coordinating centre and trial steering committee

An independent TSC has been set up to monitor trial progress. The ACCEPT TSC charter defines the membership, terms of reference, roles, responsibilities, authority, decision-making and relationships of the TSC, including the timing of meetings, frequency and format of meetings and relationships with other trial committees.

The ACCEPT Trial Management Group includes representatives with expertise in haematology, oncology, translational science and medical statistics; as well as being supported by a Patient and Public Involvement contributor and CTU staff involved in the day-to-day running of the trial. Charters for these groups are available via accept@soton.ac.uk.

Composition of the data monitoring committee, its role and reporting structure

An independent DMEC comprising three clinicians and a statistician experienced in this research area (but not directly involved in this trial apart from DMEC membership) has been set up to monitor trial progress and safety. The Charter for this group is also available via accept@soton.ac.uk.

Adverse event reporting and harms

Data on AEs will be collected at treatment and follow-up visits. SAEs will be reported up to 30 days after the last administration of the trial drug to the SCTU safety desk. The trial also has a UK regulatory compliant real-time SAE reporting process to identify serious AEs and suspected unexpected SAEs that could suspend or stop the trial if warranted.

Frequency and plans for auditing trial conduct

The SCTU has undertaken a risk assessment for the ACCEPT trial, which includes the requirements for monitoring (both central and site). The SCTU undertakes a number of internal audits of its own systems and processes annually and has routine audits from both its sponsor and the independent Medicine and Health care products regulatory authority (MHRA).

Plans for communicating important protocol amendments to relevant parties (e.g. trial participants, ethical committees)

Research ethics committee/MHRA-approved protocol amendments will be communicated to sites via email and updated trial documentation provided centrally via the SCTU trial website (https://www.southampton.ac.uk/ctu). Trial registries will be amended where relevant with explanations for these changes.

End of the trial

The end of the study is defined as the date of the last follow-up visit of the last participant (expected to occur 24 months after the last participant receives their last study treatment). NB: The study will terminate early if three DLT occur for the first 6 participant in Phase I.

First use of drug in combination with R-CHOP

This is the first use of the second generation Btk inhibitor acalabrutinib in combination with R-CHOP. This has been addressed through use of an appropriate Phase I trial design and monitoring during the study. The protocol contains stopping criteria in response to side effects which may occur with dose levels. To maintain safety during the trial, the data will be monitored closely by a Safety Review Committee and an independent DMEC on an on-going basis. First generation Btk inhibitors have been used safely in combination with R-CHOP in this patient group.

Uncertainty

Previous preclinical and clinical observations make a compelling case for the clinical investigation of R-CHOP in combination with acalabrutinib for the treatment of patients with DLBCL. However, the clinical effects of acalabrutinib on DLCBL are unknown and the initial group of patients in particular are unlikely to derive benefit from low dose acalabrutinib. It will be made clear to all patients that the benefit of acalabrutinib is uncertain.

Biological samples to be taken specifically for this study

Multiple blood samples will be taken in this study. Participants may also be subjected to up to two bone marrow biopsies and a lumbar puncture. These study procedures have been designed to be as limited as possible to gain the necessary information and to be conducted in the least distressing way by experienced health care professionals.

Ionising radiation

Participants will have two PET/CT scans and a separate CT with contrast (Cycle 7). These are standard of care in DLBCL. In addition, they will undergo two additional CT scans to look for progression as a research investigation (months 12 and 24). Patients will be made fully aware of this and the risks of these scans prior to giving consent to their participation in the trial.

In addition, an Echocardiogram or MUGA will be performed for all patients to establish whether patients have a left ventricular ejection fraction of >55% to ensure they are suitable to receive 300mg/m² doxorubicin.

Legal issues

There are no particular legal concerns arising from this study. The SCTU at the University of Southampton will be the UK coordinating trials unit and the University Hospital Southampton NHS Foundation Trust the sponsor in the UK and responsible for all legal requirements of conducting a non-commercial clinical trial of an investigation product. The drug for this trial is provided by ACERTA Pharma, BV who are responsible for the Good Manufacturing Practice quality drug and who is also providing research funding.

Underlying data

No underlying data is associated with this article.

Extended data

Figshare: ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a phase Ib/II open-label non-randomised clinical trial, https://doi.org/10.6084/m9.figshare.11791275.v4¹⁴.

This project contains the following extended data:

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).

Reporting guidelines

Figshare: SPIRIT checklist for ‘ACCEPT - combining acalabrutinib with rituximab, cyclophosphamide, doxorubicin, vincristine and prednisolone (R-CHOP) for Diffuse Large B-cell Lymphoma (DLBCL): study protocol for a phase Ib/II open-label non-randomised clinical trial’, https://doi.org/10.6084/m9.figshare.11791275.v4¹⁴.

Data are available under the terms of the Creative Commons Attribution 4.0 International license (CC-BY 4.0).