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Trial registered on ANZCTR


Registration number
ACTRN12621000507886
Ethics application status
Approved
Date submitted
10/02/2021
Date registered
30/04/2021
Date last updated
30/04/2021
Date data sharing statement initially provided
30/04/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
Cancer Molecular Screening and Therapeutics (MoST) Program Substudy Addendum 15 substudies 33-34: Durvalumab plus acalabrutinib
Scientific title
A single arm, open label, signal seeking, phase II trial of the activity of Durvalumab in combination with Acalabrutinib in patients with high-grade B cell lymphoma
Secondary ID [1] 302769 0
CTC0141- addendum 15
Universal Trial Number (UTN)
U1111-1182-6652
Trial acronym
MoST Addendum 15
Linked study record
This record is an addendum to the MoST framework protocol (ACTRN12616000908437). The MoST framework protocol consists of 1/molecular screening (genomic analysis to determine whether participants are suitable for a sub-study) and 2/ sub-study design structure (study treatment for specific genomic expression/participant population). Additionally, the sub-study shares the same study objectives and outcomes as the framework. Hence, this is a substudy that is linked to ACTRN12616000908437.

Health condition
Health condition(s) or problem(s) studied:
Cancer 319714 0
High grade B cell lymphoma 321635 0
Condition category
Condition code
Cancer 317643 317643 0 0
Lymphoma (non Hodgkin's lymphoma) - High grade lymphoma

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Participants will receive 2 drugs:
1/ Durvalumab, that will be given to participants via intravenous infusion by a qualified administrator at a dose of 1500 mg every 4 weeks
2/ Acalabrutinib in the form of a tablet taken orally by participants at a dose of 100mg twice daily.

The durvalumab may be withheld, whereas acalbrutinib dosage may be reduced to 100mg once daily if participants experience intolerable toxicity. If a further acalabrutinib dose reduction is required, participants should discontinue acalabrutinib.

Participants will receive both durvalumab and acalabrutinib treatments until disease progression is documented or when the participants experience intolerable toxicity or withdraw for another reason. Participants will be asked to return unused drug and empty drug containers at each return visit. The Pharmacy Department at participating institutions will maintain a record of drugs dispensed for each participant.
Intervention code [1] 319044 0
Treatment: Drugs
Comparator / control treatment
No control group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 325691 0
The primary objective is to evaluate the clinical activity of the combination of durvalumab and acalabrutinib, as measured by objective tumour response based on complete and partial responses using lymphoma specific (modified RECIL 2017) response criteria.
Timepoint [1] 325691 0
CT scans for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression.
Secondary outcome [1] 388764 0
Overall survival (OS) (death from any cause)
Timepoint [1] 388764 0
For the duration of the study. From the date of registration to date of death from any cause, or the date of last known follow-up alive.
Secondary outcome [2] 388813 0
Overall survival at 6 months
Timepoint [2] 388813 0
At 6 months from participant registration to date of death from any cause (or the date of last known follow-up alive within 6 months from registration).
Secondary outcome [3] 388814 0
Progression free survival. PFS is defined as the interval from date of registration to the date of first evidence of disease progression or death from any cause, whichever occurs first. Participants who do not progress or die will be censored on the date of their last clinical assessment or tumour assessment. Disease progression is defined according to modified RECIL 2017 criteria.
Timepoint [3] 388814 0
CT assessment for disease evaluation will take place every 8 weeks from first dose of study treatment until disease progression.
Secondary outcome [4] 388815 0
Progression free survival at 6 months. The proportion of participants on study who are alive and progression free at 6 months. The disease progression is defined according to modified RECIL 2017 response criteria guidelines.
Timepoint [4] 388815 0
At 6 months post participant registration via CT scan.
Secondary outcome [5] 388816 0
Safety and tolerability of treatment (rates of adverse events). All adverse events (AEs), including event grading as per NCI CTCAE criteria, will be captured from the first dose of study treatment until 30 days after cessation of study treatment. Reported AEs by participants will be documented by study site staff and subsequently transcribed onto the study electronic data capture (EDC) system. In order to evaluate the safety and tolerability of the study treatment, the entered AE types, frequency and severity in the EDC will be analysed.
Timepoint [5] 388816 0
Adverse events will be recorded from the first dose of study treatment until 30 days after the cessation of study treatment.
Secondary outcome [6] 388817 0
Health related quality of life during treatment. The EORTC QLQ-C30 and The Brief Pain Inventory Forms will be used to evaluate this composite outcome.
Timepoint [6] 388817 0
Every 4 weeks from first dose of study treatment until participants stop treatment due to intolerable toxicity or withdraw for another reason (apart from disease progression). After treatment discontinuation, the health-related quality of life will be assessed at every 8 weeks until disease progression is recorded.

Eligibility
Key inclusion criteria
1. Adults aged 18 years and older, with high grade B cell lymphoma or transformed low-grade B cell lymphoma that is refractory to, or relapsed following standard chemotherapy or radiation therapy. There are no limits to the number of lines of chemotherapy the patient may have received. Transplant eligible patients may be included on the study provided that a response assessment is possible after 3 months of therapy.
2. Review by the molecular tumour board (MTB). No specific actionable mutation is required for study entry. The MTB will review the clinical information, histology and tissue sample suitability, and will provide a tumour sequencing report. A preliminary recommendation may be issued where clinically relevant.
3. ECOG performance status less than or equal to 2.
4. Received and failed a standard anti-cancer therapy, or have documented unsuitability for any further standard therapy, if standard therapy exists.
5. Clinical or radiological measurable disease that qualifies as a RECIL target lesion at baseline. CT, PET or MRI must be performed within 21 days prior to registration. If there is no radiological measurable disease, percentage bone marrow infiltration or circulating lymphoma cells may be used as a surrogate for measurable disease.
6. Adequate organ system function as assessed by the following minimal laboratory requirements (within 7 days prior to first administration of study drug):
a. bone marrow function; platelets greater than or equal to 75 x 10^9/L, ANC greater than or equal to 1.0 x 10^9/L
b. liver function; ALT/AST less than or equal to 2.5 x ULN and total bilirubin less than or equal to 1.5xULN; Patients with confirmed Gilbert’s syndrome (persistent or recurrent hyperbilirubinemia that is predominantly unconjugated in the absence of haemolysis or hepatic pathology) are allowed after consultation with their physician and discussion with study PI.
c. renal function; Serum creatinine clearance greater than 40 mL/min by the Cockcroft-Gault formula or by 24-hour urine collection for determination of creatinine clearance.
7. Sufficient and accessible tissue (less than 90 days old) for PD-L1 immunohistochemistry assay and exploratory objectives.
8. Willing and able to comply with all study requirements, including treatment, timing and/or nature of required assessments.
9. Signed, written informed consent to participation in the specific treatment substudy
10. Life expectancy of at least 12 weeks.
11. Body weight greater than 30kg.
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Contraindications to investigational product
2. Known history of hypersensitivity to active or inactive components of investigational product
3. Previous treatment with a PD1/PD-L1 inhibitor or a Bruton’s kinase inhibitor
4. Specific co-morbidities or conditions (e.g. psychiatric) or concomitant medications which may interact with the investigational product(s) as assessed by the treating physician.
5. Co-morbidities or conditions that may compromise assessment of key outcomes or in the opinion of the treating physician, limit the ability of the patient to comply with the protocol; including clinically significant cardiovascular disease such as symptomatic arrhythmias, congestive heart failure (LV ejection fraction less than 40%), 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. Note: Subjects with controlled, asymptomatic atrial fibrillation can enrol on the study
6. Treatment with any of the following anti-cancer therapies prior to the first dose of study treatment:
a. Radiation therapy, surgery, or tumour embolization within 14 days prior to the first dose of study treatment. Palliative radiotherapy (for analgesia) is acceptable only if the irradiated field does not include target lesions.
b. Chemotherapy, biologic therapy, or hormonal therapy within 14 days or 5 half-lives of a drug prior to the first dose of study treatment or until recovery from previous therapy (whichever is longer); Concurrent use of hormonal therapy for non-cancer related conditions (eg. Hormone replacement therapy) is acceptable.
c. Prior allogeneic transplant (haematopoietic or solid organ)
d. Radiotherapy treatment to more than 30% of the bone marrow or with a wide field of radiation within 4 weeks of the first dose of study drug
7. Any unresolved toxicity (greater than CTCAE grade 2) from previous anti-cancer therapy. Subjects with irreversible toxicity that is not reasonably expected to be exacerbated by the investigational product may be included (e.g., hearing loss, peripheral neuropathy).
8. History of primary immunodeficiency.
9. Administration of any investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment.
10. Mean QT interval corrected for heart rate (QTc) greater than or equal to 470ms calculated from 3 consecutive electrocardiograms (ECGs) within 15 minutes, 5 minutes apart using Fredericia’s Correction.
11. Current or prior use of immunosuppressive medication within 14 days before the first dose of durvalumab or acalabrutinib. Exceptions include intranasal and inhaled corticosteroids or systemic corticosteroids at physiological doses (e.g. less than or equal 10 mg/day of prednisone or its equivalent); use of dexamethasone up to 4mg /day, and steroids as premedication for hypersensitivity reactions (e.g. CT scan premedication).
12. Active autoimmune disease or prior documented autoimmune or inflammatory disease including inflammatory bowel disease (e.g. colitis or Crohn’s disease), diverticulitis, systemic lupus erythematomus, Sarcoidosis syndrome, Graves’ disease, rheumatoid arthritis, hypophysitis and uveitis requiring systemic treatment within the past 2 years. Subjects with vitiligo, alopecia, hypothyroidism, or psoriasis not requiring systemic treatment (within the past 2 years) are eligible.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or uncontrolled infection sepsis, uncontrolled hypertension, unstable angina pectoris, cardiac arrhythmia, active peptic ulcer disease or gastritis, uncontrolled autoimmune haemolytic anaemia (AIHA) or idiopathic thrombocytopenic purpura (ITP), active bleeding diatheses (e.g. haemophilia or von Willebrands disease), active acute or chronic hepatitis B, hepatitis C or human immunodeficiency virus (HIV), or psychiatric illness/social situations that would limit compliance with study requirements or compromise the ability of the subject to give written informed consent as assessed by the treating physician.
14. Patients with symptomatic CNS involvement of lymphoma are excluded. Subjects with stable neurological function, on stable doses of steroids/anti-epileptics over 4 weeks, and with no evidence of CNS progression within 12 weeks prior to screening are eligible.
15. History of another malignancy within 2 years prior to molecular screening registration are excluded unless adequately treated and determined free of progressive and metastatic disease for at least 6 months. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, can be included.
16. Known history of active tuberculosis
17. Receipt of live attenuated vaccination within 30 days prior to study entry or within 30 days of receiving durvalumab or acalabrutinib
18. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a highly effective means of contraception. Women of childbearing potential must have a negative pregnancy test done within 7 days prior to registration. Men must have been surgically sterilised or use a (double if required) barrier method of contraception.
19. Concurrent enrolment in another clinical study, unless it is observational (non-interventional) clinical study or during the follow up period of an interventional study
20. Major surgical procedure (as defined by the Investigator) within 28 days prior to the first dose of IP. Note: local surgery of isolated lesions for palliative intent is acceptable.
21. Has difficulty with or is unable to swallow oral medication, or has gastrointestinal disease that would limit the absorption of oral medication
22. Requires treatment with a strong cytochrome P450 3A4 (CYP3A4) inhibitor/inducer
23. Required or receiving anticoagulation with warfarin or equivalent vitamin K antagonists
24. Prothrombin time/INR or aPTT (in the absence of Lupus antigoagulant) greater than 2 x ULN
25. Requires treatment with proton pump inhibitors (e.g. omeprazole, esomeprazole, lansoprazole, dexlansoprazole, rabeprazole, or pantoprazole). Note: Subjects receiving proton pump inhibitors who switch to H2-receptor antagonists or antacids are eligible for enrolment to this study.
26. History of significant cerebrovascular disease or event, including stroke or intracranial hemorrhage, within 6 months before the first dose of study drug.
27. Hepatitis B or C serologic status: subjects who are hepatitis B core antibody (anti-HBc) positive and who are hepatitis B surface antigen (HBsAg) negative will need to have a negative viral load before and during the study. Those who are HBsAg positive or hepatitis B viral load positive will be excluded. Subjects who are hepatitis C antibody positive will need to have a negative PCR result to be eligible. Those who are hepatitis C PCR positive will be excluded.
28. Any staff with involvement in the planning and/or conduct of the study.
29. Eligible for participation in another MoST substudy based on identification of an actionable mutation. Patients who have previously participated in another MoST substudy may subsequently participate in this study, all other inclusion and exclusion criteria being satisfied.
30. Participation in another clinical study with an investigational product during the last 4 weeks prior to study enrolment.
31. Any prior greater than or equal to Grade 3 immune-related adverse event (irAE) while receiving any previous immunotherapy agent, or any unresolved irAE greater than Grade 1.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Phase 2
Type of endpoint(s)
Safety/efficacy
Statistical methods / analysis
A group of 32 patients with high grade B cell lymphoma will be treated with durvalumab and acalabrutinib. For a sample size of 32 patients, we would conclude that the durvalumab and acalabrutinib combination demonstrates a promising signal of activity if 8 or more patients have a complete or partial response at 6 months.

A post-hoc analysis of tertiary and correlative outcomes will be conducted by correlating objective response against potential biomarkers, including but not limited to PD-L1 expression levels, and/or TMB

As described in the framework protocol (ACTRN12616000908437), substudies with greater than or equal to 3 out of 16 responding patients, will in general be sufficiently interesting to investigate further. As a general rule, substudies with less than 3 out of 16 responses will be considered to not support the molecular hypothesis behind the substudy.

If some activity is recognised in a 16 patient substudy cohort but further information is needed to inform development of phase II testing, iterative substudies may be opened to enrich for patients that harbour a specific common biomarker or histologic cancer subtype. Each such iteration would constitute a new substudy for the purposes of this framework.

The sample size and guiding definitions of what constitutes an interesting signal are determined empirically as the investigators considered these numbers of patients as sufficient for signal-seeking purpose.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD,SA
Recruitment hospital [1] 17998 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 17999 0
Royal Brisbane & Womens Hospital - Herston
Recruitment postcode(s) [1] 31957 0
5000 - Adelaide
Recruitment postcode(s) [2] 31958 0
4029 - Herston

Funding & Sponsors
Funding source category [1] 307185 0
Government body
Name [1] 307185 0
Office for Health and Medical Research
Address [1] 307185 0
Locked Bag 961, North Sydney NSW 2059
Country [1] 307185 0
Australia
Funding source category [2] 307186 0
Charities/Societies/Foundations
Name [2] 307186 0
Leukaemia Foundation
Address [2] 307186 0
Level 4, 44 Hampden Road
Artarmon NSW 2064
Country [2] 307186 0
Australia
Funding source category [3] 307629 0
Charities/Societies/Foundations
Name [3] 307629 0
Tour de Cure
Address [3] 307629 0
PO Box 6121
Frenchs Forest
NSW 2086
Country [3] 307629 0
Australia
Primary sponsor type
University
Name
The University of Sydney
Address
NHMRC Clinical Trials Centre
Locked Bag 77
Camperdown NSW 1450
Country
Australia
Secondary sponsor category [1] 307787 0
None
Name [1] 307787 0
Address [1] 307787 0
Country [1] 307787 0
Other collaborator category [1] 281649 0
Other Collaborative groups
Name [1] 281649 0
Australian Genomic Cancer Medicine Centre (AGCMC)
Address [1] 281649 0
Kinghorn Cancer Centre,
370 Victoria Street
Darlinghurst NSW 2010
Country [1] 281649 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307297 0
St Vincent's Hospital Human Research Ethics Committee
Ethics committee address [1] 307297 0
St Vincent's Hospital Research Office
Translational Research Centre
97-105 Boundary Street
Darlinghurst NSW 2010
Ethics committee country [1] 307297 0
Australia
Date submitted for ethics approval [1] 307297 0
19/11/2020
Approval date [1] 307297 0
05/02/2021
Ethics approval number [1] 307297 0
2020/ETH02725

Summary
Brief summary
This is a substudy of the Cancer Molecular Screening and Therapeutics (MoST) Program, which is registered on ANZCTR with ID ACTRN12616000908437. This substudy will evaluate the clinical activity of the combination of durvalumab and acalabrutinib in participants with high grade B cell lymphoma.

Who is it for?
You may be eligible to join the study if you are aged 18 years and older, with high grade B cell lymphoma.

Study details:
Participants will receive 2 drugs: 1/ durvalumab, to be administered via intravenous infusion at a dose of 1500mg every 4 weeks, and 2/ acalabrutinib, to be administered orally at a dose of 100mg twice daily. Both drugs will be given to participants continuously as long as they and their doctor agree there is a benefit from treatment. Participants will undergo clinical assessments at 4 weekly intervals from first treatment until end of treatment, then 8 weekly intervals until disease progression. Imaging will be at 8 weekly intervals until disease progression. Safety and tolerability of treatment will be assessed at 4 weekly intervals. Health related quality of life during treatment will be assessed at 4 weekly intervals and then every 8 weeks after end of treatment until progression.

We cannot guarantee that participants will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who have limited treatment options available to them. It is hoped that the combination of durvalumab and acalabrutinib will be well tolerated and will improve outcomes for future patients, however there may be no clear benefit from participation in this study.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 106734 0
A/Prof Steven Lane
Address 106734 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Brisbane QLD 4006
Country 106734 0
Australia
Phone 106734 0
+61 7 3845 3766
Fax 106734 0
Email 106734 0
steven.lane@qimrberghofer.edu.au
Contact person for public queries
Name 106735 0
Dr Lucille Sebastian
Address 106735 0
NHMRC Clinical Trials Centre
Medical Foundation Building
Level 6, 92-94 Parramatta Road
Camperdown NSW 2050
Country 106735 0
Australia
Phone 106735 0
+61 2 9562 5000
Fax 106735 0
Email 106735 0
most@ctc.usyd.edu.au
Contact person for scientific queries
Name 106736 0
A/Prof Steven Lane
Address 106736 0
QIMR Berghofer Medical Research Institute
300 Herston Road
Brisbane QLD 4006
Country 106736 0
Australia
Phone 106736 0
+61 7 3845 3766
Fax 106736 0
Email 106736 0
steven.lane@qimrberghofer.edu.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
There are no plans for this to occur at this time and participant consent is required for data sharing.
What supporting documents are/will be available?
No other documents available
Summary results
No Results