Clinical Trials Register

Summary
EudraCT Number:	2015-003213-18
Sponsor's Protocol Code Number:	RHMCAN1129
National Competent Authority:	UK - MHRA
Clinical Trial Type:	EEA CTA
Trial Status:	GB - no longer in EU/EEA
Date on which this record was first entered in the EudraCT database:	2016-12-07
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

UK - MHRA

A.2

EudraCT number

2015-003213-18

A.3

Full title of the trial

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)

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

A phase Ib/II combination trial of acalabrutinib with standard R-CHOP chemotherapy in patients with diffuse large B-cell lymphoma

A.3.2

Name or abbreviated title of the trial where available

A.4.1

Sponsor's protocol code number

RHMCAN1129

A.5.4

Other Identifiers

Name:

CR UK Trial Number

Number:

CRUKDE/16/006

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	University Hospital Southampton NHS Foundation Trust
B.1.3.4	Country	United Kingdom
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support
B.4.2	Country
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Hospital Southampton NHS Foundation Trust
B.5.2	Functional name of contact point	Ailsa Duckworth
B.5.3	Address:
B.5.3.1	Street Address	R&D office, E level, Southampton Centre for Biomedical Research
B.5.3.2	Town/ city	Southampton General Hospital, Tremona Road
B.5.3.3	Post code	SO16 6YD
B.5.3.4	Country	United Kingdom
B.5.4	Telephone number	023 8120 5131
B.5.6	E-mail	ailsa.duckworth@uhs.nhs.uk

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	Acalabrutinib
D.3.4	Pharmaceutical form	Capsule
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Acalabrutinib
D.3.9.1	CAS number	1420477-60-6
D.3.9.2	Current sponsor code	ACP-196 (Org 300196-0; SCH 900850)
D.3.9.4	EV Substance Code	AS1
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	up to
D.3.10.3	Concentration number	100 to 200
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	No
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Diffuse large B-cell lymphomas (most common type of non-Hodgkins lymphoma)

E.1.1.1

Medical condition in easily understood language

Diffuse large B-cell lymphomas (most common type of non-Hodgkins lymphoma)

E.1.1.2

Therapeutic area

Diseases [C] - Cancer [C04]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	19.1
E.1.2	Level	PT
E.1.2	Classification code	10012818
E.1.2	Term	Diffuse large B-cell lymphoma
E.1.2	System Organ Class	10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps)

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective at Stage 1 is to:
1. Examine the safety and toxicity profile of acalabrutinib in combination with R-CHOP and define the dose limiting toxicity (DLT) or maximum administered dose (MAD).

The primary objective at Stage 2 is to:
2. To document the anti-tumour activity of acalabrutinib in combination with R-CHOP in patients with previously untreated CD20 positive DLBCL.
3. To determine additional safety information on acalabrutinib in combination with R-CHOP.

E.2.2

Secondary objectives of the trial

Secondary and Tertiary objectives

Secondary Objectives

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

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

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

Tertiary Objectives

4. To determine BTK occupancy by acalabrutinib in peripheral blood mononuclear cells when given in combination with R-CHOP.

5. To determine BTK occupancy by acalabrutinib in tumour material taken 8 days after initiation of therapy when acalabrutinib is given in combination with R-CHOP (optional).

6. To determine the impact of the addition of acalabrutinib on R-CHOP mediated antibody dependent cellular cytotoxicity (ADCC).

7. To determine evidence of B-cell receptor activation (BCR) in patients before and after treatment with R-CHOP and acalabrutinib.

E.2.3

Trial contains a sub-study

E.3

Principal 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

E.4

Principal 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. Patients who have received immunisation with a live vaccine within four weeks prior to enrolment will be ineligible
3. Diagnosis of primary mediastinal lymphoma
4. Diagnosis of primary Central Nervous System lymphoma.
5. History of stroke or intracranial haemorrhage in preceding 6 months
6. History of bleeding diathesis (eg. haemophilia, von Willebrand disease)
7. 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
8. Prior exposure to a BCR inhibitor(eg. BtK inhibitors, phosphoinositide-3 kinase (PI3K), or SyK inhibitors) or BCL-2 inhibitor (eg. ABT-199)
9. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
10. 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.
11. Uncontrolled systemic infection
12. 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
13. 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.
14. 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.
15. 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
16. Breastfeeding or pregnant
17. 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
18. Men must agree to refrain from sperm donation during the study and for 90 days after the last dose of study drug.
19. Serious medical or psychiatric illness likely to affect participation or that may compromise the ability to give informed consent
20. 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
21. 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
22. Any immunotherapy within 4 weeks of 1st dose of the study
23. Concurrent participation in another therapeutic clinical trial

E.5 End points

E.5.1

Primary end point(s)

1. Dose limiting toxicity of acalabrutinib combined to R-CHOP

2. Overall response rate of the combination acalabrutinib and R-CHOP

3. Safety of the combination acalabrutinib and R-CHOP

E.5.1.1

Timepoint(s) of evaluation of this end point

For eligible patients AE collection and monitoring commences from the time the patient gives their written consent to participate in the trial and continues for two years after the last administration of acalabrutinib.

A CT scan (potentially bone marrow) at the end of therapy visit and continued monitoring through follow up will be used to assess overall response.

Follow up of AEs with a causality of possible, probable or highly probable will continue until the events resolve, stabilise or the patient starts another anticancer therapy.

E.5.2

Secondary end point(s)

1. Pharmokinetic of acalabrutinib, AUC, Cmax, Tmax, half-life T1/2 and other PK parameter.

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

3. 2-years progression-free survival; 2 years overall survival.

4. BTK occupancy by acalabrutinib on peripheral blood (PBMC) using fluorescent affinity probe assay.

5. BTK occupancy by acalabrutinib in repeat tumour core biopsy using a fluorescent affinity probe assay.

6. Antibody-dependent cell-mediated cytotoxicity (ADCC) of R-CHOP when combined to acalabrutinib, post 1st R-CHOP and at day 8, 2nd cycle acalabrutinib + R-CHOP.

7. CD86 and CD69 expression as a function of BCR activation by flow cytometry.

8. Tumour-specific DNA in plasma will be sequenced throughout treatment and compared with lymphoma tissue and clinical course

9. Apply the following techniques to FFPE tumour material: mutational panel, FISH analysis, immunohistochemical analysis for dual protein expression of Myc and Bcl2 and gene expression

E.5.2.1

Timepoint(s) of evaluation of this end point

1. PK samples: cycle 2 days 1, 8, 15; cycle 3 day 1;

2. Gene expression analysis on original biopsy sample.

3. Disease assessments at baseline, end of therapy visit, then 1 & 2 years post-treatment.

4. BTK occupancy in PBMCs: cycle 2 days 1 and 8.

5. Option ultrasound guided needle biopsy or fine needle aspirate at baseline and on cycle 2 day 8.

6. ADCC assay performed at cycle 2 days 1 and 8.

7. CD86 and CD69 expression: cycle 2 days 1, 8 and cycle 4 day 1.

8. Streck Plasma DNA Sample: Baseline, cycle 2 day 1, cycle 3 day 1, end of treatment and follow up visits 3, 6, 9, 12, 16, 20 and 24

9. Tests on baseline tumour sample.

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

Yes

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Yes

E.8.8

Definition of the end of the trial and justification where it is not the last visit of the last subject undergoing the trial

LVLS.
The end of the trial is defined as: The patient reaches the final follow up visit, which will be 2 years after receiving the last study treatment.

E.8.9 Initial estimate of the duration of the trial

E.8.9.1

In the Member State concerned years

E.8.9.1

In the Member State concerned months

E.8.9.1

In the Member State concerned days

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

F.1.1