Condition category
Cancer
Date applied
13/02/2017
Date assigned
07/03/2017
Last edited
26/07/2017
Prospective/Retrospective
Prospectively registered
Overall trial status
Ongoing
Recruitment status
Recruiting

Contact information

Type

Public

Primary contact

Mr Joshua Caddy

ORCID ID

Contact details

Southampton Clinical Trials Unit
MP131
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Type

Scientific

Additional contact

Ms Debbie Hamid

ORCID ID

http://orcid.org/0000-0003-2329-805X

Contact details

Southampton Clinical Trials Unit
MP131
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom
+44 23 8120 5328
d.hamid@soton.ac.uk

Additional identifiers

EudraCT number

2015-003213-18

ClinicalTrials.gov number

Protocol/serial number

33203

Study information

Scientific title

A Phase Ib/II combination trial of acalabrutinib with rituximab, cyclophosphamide, doxorubicin,vincristine and prednisolone (R-CHOP) for patients with diffuse large B-cell lymphoma (DLBCL)

Acronym

ACCEPT

Study hypothesis

The aim of this study is to determine a suitable tolerated dose and efficacy of acalabrutinib in combination with standard R-CHOP immunochemotherapy to treat patients with diffuse large B-cell lymphoma (DLCBL).

Ethics approval

South Central - Berkshire Research Ethics Committee, 26/01/2017, ref :16/SC/0657

Study design

Non-randomised; Interventional; Design type: Treatment, Screening, Diagnosis, Drug

Primary study design

Interventional

Secondary study design

Non randomised study

Trial setting

Hospitals

Trial type

Treatment

Patient information sheet

Not available in web format, please use the contact details below to request a patient information sheet

Condition

Specialty: Cancer, Primary sub-specialty: Haematological Oncology; UKCRC code/ Disease: Cancer/ Malignant neoplasms, stated or presumed to be primary, of lymphoid, haematopoietic and related tissue

Intervention

A multicentre open-label non-randomised phase Ib/II clinical trial conducted in two stages recruiting approximately 40 patients.

Phase I Dose Escalation Cohort 1
The first 6 patients registered (cohort 1) will receive a first cycle of R-CHOP. Acalabrutinib, at a starting dose of 100 mg od, will be added from cycle 2 to 6. This will be followed by cycles 7 and 8 of acalabrutinib only 100mg od for 28 days for each cycle. Dose escalation to 200 mg daily (100 mg bd) of acalabrutinib will be decided by the Safety Review Committee based on safety data and patients’ compliance assessment

Phase I Dose Escalation Cohort 2
The first 6 patients of cohort 2 will start acalabrutinib + R-CHOP at the daily dose of 200mg administered as 100mg bd from cycle 2 after the Safety Review Committee has approved dose escalation based on all the safety data from cohort 1. the Safety Review Committee will assess the safety of 200mg. If one or two instances of DLT is observed among the initial six patients of cohort 2, the cohort will be expanded to a further six patients. Depending on tolerability as set out, cohort 2 patients should receive cycle 1 of R-CHOP, cycles 2-6 R-CHOP plus acalabrutinib and then cycles 7 and 8 of acalabrutinib only at 200mg administered as 100mg bd.
If a DLT attributable to acalabrutinib occurs, acalabrutinib will be withheld for that patient and reintroduced at 100 mg od when toxicity has resolved to < grade 1, all other patients will continue at acalabrutinib dosage of 200mg. If ≥ 3DLTs are attributable to acalabrutinib in the initial six patients acalabrutinib will be withheld from the patient(s) who have suffered the DLT and reintroduced at 100 mg od after toxicity has resolved to < grade 1 and all other patients dosage will be decreased to 100 mg od.
When all patients have completed all 6 cycles of therapy, the Safety Review Committee will review patients’ compliance assessment, PK/PD measurements if available and safety data, including the identified MTD and MAD, to determine the recommended dose for Phase II (RP2D) which will be a dose where ≤ 33% of patients had a DLT.

Phase II
Fifteen patients will be recruited for stage 2 of the study. Following informed consent, they will receive 6 cycles of conventionally dosed R-CHOP with the addition of acalabrutinib at the RP2D on cycle 2 onwards.

Intervention type

Other

Phase

Drug names

Primary outcome measures

Phase I
1. Dose limiting toxicity of acalabrutinib combined to R-CHOP is measured using a physical examination, vital signs, laboratory tests FBC, renal and liver function, ECOG, at baseline and for all cycles and repeated for specific cycles day 8 and day 15 for cycle 2 and day 8 at cycle 4.*

Phase II
1. Overall response rate of the combination acalabrutinib and R-CHOP is measured using PET/CT at baseline, cycle 7, month 12, month 24 End of treatment using the Lugano classification for NHL
2. Safety of the combination acalabrutinib and R-CHOP is measured using a physical examination, vital signs, laboratory tests FBC, renal and liver function, ECOG at baseline and for all cycles and repeated for specific cycles day 8 and day 15 for cycle 2 and day 8 at cycle 4.*

*There will be 8 cycles if chemotheraphy administered. Cycle 1-6 will be 21 days and Cycle 7 and 8 will be 28 days Aclabrutinib will be administered from cycle 2 and will be taken from cycle 2 to cycle 7.

Secondary outcome measures

1. Pharmacokinetic of acalabrutinib, AUC, Cmax, Tmax, half-life T1/2 and other PK parameter is measured using serum concentration taken at cycle 2, Day 1, day 8 and day 15 half hour before the administration of acalabrutinib. Once acalabrutinib is administered serum concentration will be taken 45 mins, 1 hour, 2 hours and 8 hours and once again before acalabrutinib is administered at cycle 3
2. Overall response rate of the combination acalabrutinib and R-CHOP according to cell of origin is measured using of BCR DNA extracted from tumour material will be used to perform mutation detection on BCR pathway (eg Btk, PI3K, CD79b). Genetic abnormalities of BCR pathway will be correlated with clinical outcomes and the expression pathway target genes at baseline
3. Two years progression-free survival rate is measured using CT at 24 months
4. Two years overall survival rate is measured using CT at 24 months

Overall trial start date

01/08/2015

Overall trial end date

31/12/2021

Reason abandoned

Eligibility

Participant inclusion criteria

1. Histologically confirmed DLBCL, expressing CD20. Sufficient diagnostic material should be available to forward to a central laboratory for gene expression profiling and pathology review
2. Measurable disease of at least 15mm
3. Not previously treated for lymphoma and fit enough to receive combination chemoimmunotherapy with curative intent
4. 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 are not eligible
5. ECOG performance status 0-2 or 3 if this is directly attributable to lymphoma
6. Adequate bone marrow function with platelets > 100x109/L; neutrophils > 1.0x109/L at study entry, unless lower figures are attributable to lymphoma
7. 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 (umolL)]
8. Serum bilirubin < 35μmol/L and transaminases < 2.5x upper limit of normal at time of study entry
9. 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%
10. No concurrent uncontrolled medical condition
11. Life expectancy > 3 months
12. Aged 16 years or above
13. Willing and able to participate in all required evaluations and procedures in this study protocol including swallowing capsules without difficulty
14. Ability to understand the purpose and risks of the study and provide signed and dated informed consent

Participant type

Patient

Age group

Adult

Gender

Both

Target number of participants

Planned Sample Size: 40; UK Sample Size: 40

Participant exclusion criteria

1. 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
2. Diagnosis of primary mediastinal lymphoma
3. Diagnosis of primary Central Nervous System lymphoma.
4. History of stroke or intracranial haemorrhage in preceding 6 months
5. History of bleeding diathesis (eg. haemophilia, von Willebrand disease)
6. 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
7. Prior exposure to a BCR inhibitor(eg. BtK inhibitors, phosphoinositide-3 kinase (PI3K), or SyK inhibitors) or BCL-2 inhibitor (eg. ABT-199)
8. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
9. 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.
10. Uncontrolled systemic infection
11. 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
12. 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.
13. 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. - Positive test results for chronic HBV infection (defined as positive HBsAg serology) will not be eligible. Patients with occult or prior HBV infection (defined as negative HBsAg and positive total HBcAb) will not be eligible. Patients who have protective titres of hepatitis B surface antibody (HBsAb) after vaccination will be eligible. - Positive test results for hepatitis C virus (HCV) antibody serology will not be eligible.
14. Women who are sexually active and can bear children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7 14. Breastfeeding or pregnant
15. Men who are sexually active and can potentially father children must agree to use highly effective forms of contraception during the study and for 90 days after the last dose of acalabrutinib. Highly effective forms of contraception are defined in Section 4.7
16. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug.
17. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent
18. Prior malignancy (other than DLBCL), except for adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, or other cancer from which the subject has been disease free for ≥ 2 years or which will not limit survival to < 2 years. Note: these cases must be discussed with SCTU
19. Malabsorption syndrome, disease significantly affecting gastrointestinal function, resection of the stomach or small bowel, gastric bypass, symptomatic inflammatory bowel disease, or partial or complete bowel obstruction or gastric restrictions and bariatric surgery, such as gastric bypass
20. Any immunotherapy within 4 weeks of 1st dose of the study
21. Concurrent participation in another therapeutic clinical trial

Recruitment start date

01/04/2017

Recruitment end date

01/04/2021

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Trial participating centre

Queen's Medical Centre
Derby Road
Nottingham
NG7 2UH
United Kingdom

Trial participating centre

Churchill Hospital
Old Road
Oxford
OX3 7LE
United Kingdom

Trial participating centre

University College London Hospital
253 Euston Road
London
NW1 2PG
United Kingdom

Trial participating centre

Christie Hospital
550 Wilmslow Road, Witinggton
Manchester
MX20 4BX
United Kingdom

Trial participating centre

St. James's University Hospital
Beckett Street
Leeds
LS9 7TF
United Kingdom

Trial participating centre

Derriord Hospital
Derriord Road
Plymouth
PL6 8DH
United Kingdom

Sponsor information

Organisation

University Hospital Southampton NHS Foundation Trust

Sponsor details

Mailpoint 18
Southampton General Hospital
Tremona Road
Southampton
SO16 6YD
United Kingdom

Sponsor type

Hospital/treatment centre

Website

Funders

Funder type

Industry

Funder name

Acerta Pharma

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

The result will be presented and published. Participating clinicians will be supplied with a lay summary of the results once the definitive analysis is presented publicly, in order to make this available to patients that they entered into the trial. The summary will also be submitted to the Lymphoma Association Newsletter and uploaded to the NCRN and cancer help website. No identifiable personal data will be captured on the study database. The study team will present results at national and international conferences and publish in a peer reviewed journal. Results will be published on clinicaltrials.gov and we will send a lay summary of results to participants.

IPD sharing statement:
The data sharing plans for the current study are unknown and will be made available at a later date.

Intention to publish date

31/12/2019

Participant level data

To be made available at a later date

Results - basic reporting

Publication summary

Publication citations

Additional files

Editorial Notes

26/07/2017: added intention to publish date. 20/07/2017: Added publication and dissemination plan. Added individual participant level data sharing statement. 06/06/2017: Cancer Help UK lay summary link added to plain English summary field