None listed
Conditions
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.
Interventions
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 dis
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.
Sponsors
The University of Sydney
Study design
Allocation
Non-randomised trial
Intervention model
Single group
Primary purpose
Treatment
Masking
Open (masking not used)
Eligibility
Sex/Gender
All
Age
18 Years to No maximum
Healthy volunteers
No
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.
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.
Outcome results
None listed