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 activity of olaparib treatment in combination with durvalumab in patients with advanced cancers and tumours. Who is it for? All participants in this study must have completed screening as part of the Cancer Molecular Screening and Therapeutics (MoST) Program (ACTRN12616000908437), and been identified as having one of the following molecular targets: Germline or somatic deleterious mutations/deletions in BRCA1 or BRCA2; OR germline or somatic mutations/deletions in non-BRCA1/2 HR pathway genes (including ATM, PALB2, RAD51C, RAD51D, CHEK1, CHEK2, ATR, CDK12, BAP1, BARD1, BRIP1 and FANC genes). Study details: All participants in this study will take the oral drug olaparib for 28 days alone and then add the intravenous drug durvalumab once every 28 days. Treatment with durvalumab will be administered once every 28 days until 13 cycles are complete. Olaparib treatment will continue until progression, unacceptable toxicity or withdrawal. Retreatment with durvalumab after 13 cycles will be discussed with you by your doctor. All participants will undergo assessments at 8 weekly intervals or as clinically indicated in order to evaluate tumour response, safety and tolerability of treatment, health related quality of life during treatment, and overall survival. We cannot guarantee that patients will receive any benefits from this study. This study is being carried out to improve the way we treat cancer patients who may have limited treatment options available to them. It is hoped that treatment will be well tolerated and will improve outcomes for future patients, however, there may be no clear benefit from participation in this study.
Interventions
Olaparib will be administered orally twice daily at 300 mgs (2 tablets). Olaparib will be administered for 28 days before starting durvalumab on day 1 of cycle 2. Patients will receive a fixed dose of 1500 mg durvalumab via IV infusion every 4 weeks for up to 13 cycles (28 day cycles). Patients will be treated until they are no longer deriving benefit in the opinion of the treating clinician or the patient. Treatment will stop short of the 13 cycles if there is disease progression, intolerable
Olaparib will be administered orally twice daily at 300 mgs (2 tablets). Olaparib will be administered for 28 days before starting durvalumab on day 1 of cycle 2. Patients will receive a fixed dose of 1500 mg durvalumab via IV infusion every 4 weeks for up to 13 cycles (28 day cycles). Patients will be treated until they are no longer deriving benefit in the opinion of the treating clinician or the patient. Treatment will stop short of the 13 cycles if there is disease progression, intolerable toxicity or patient withdrawal for another reason. Retreatment with durvalumab is allowed (once only) for patients meeting the retreatment criteria below. The same treatment guidelines followed during the initial 13-cycle treatment period will be followed during the retreatment period, including the same dose and frequency of treatments and the same Schedule of Assessments. Patients who complete 13 cycles of treatment and achieve disease control (ie, CR, PR, or SD) through to the end of this treatment period may restart treatment with durvalumab upon evidence of progression, with or without confirmation according to RECIST 1.1. Before restarting treatment with durvalumab, the Investigator must ensure that the patient: a) Does not have any significant, unacceptable, or irreversible toxicities that indicate treatment will not further benefit the patient b) Still fulfils the eligibility criteria for treatment, including consenting to restart durvalumab c) Has not received an intervening systemic anticancer therapy after their assigned treatment discontinuation. d) Has had a baseline tumor assessment within 28 days of restarting durvalumab. All further scans will take place 8 weekly from the date of first treatment. Treatment through progression is at the Investigator’s discretion, and the Investigator must ensure that patients do not have any significant, unacceptable, or irreversible toxicities that indicate that continuing treatment will not further benefit the patient. Patients who the Investigator determines may not continue treatment will enter follow-up. Total treatment on this study will be approximately two years with further treatment to be discussed with the treating clinician. Participating institutions will maintain a record of drug dispensed for each patient and record any unused drug returned to the pharmacy.
Sponsors
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. Male or female patients, aged 18 years and older, with pathologically confirmed advanced and/or metastatic solid cancer of any histologic type or an earlier diagnosis of a poor prognosis cancer; 2. Patients with tumours carrying the following: Germline or somatic deleterious germline or somatic mutations/deletions in BRCA1 or BRCA 2 OR Germline or somatic mutations/deletions in non-BRCA1/2 HR pathway genes including ATM, PALB2, RAD51C, RAD51D, CHEK1, CHEK2, ATR, CDK12, BAP1, BARD1, BRIP1 and FANC genes. 3. Sufficient and accessible tissue for PDL-1 testing and for exploratory objectives; 4. Received and failed all standard anticancer therapy (where standard therapy exists) or have documented unsuitability for any further standard anticancer therapy – with the exception of current therapy patient is receiving. It is the intention to screen patients whilst they are receiving the last line of planned standard therapy. 5. ECOG performance status 0 or 1; 6. Willing and potentially able to comply with study requirements, including treatment, timing and/or nature of required assessments; 7. Adequate organ function These are some of the inclusion criteria. You will be assessed for all criteria when joining the study.
Exclusion criteria
1. Suitable for standard therapy or accepted standard care, if the patient has not been previously treated 2. Specific comorbidities or conditions (e.g. psychiatric) or concomitant medications which may contraindicate participation and/or interact with the investigational product(s); 3. Other comorbidities or conditions that may compromise assessment of key outcomes or in the opinion of the clinician, limit the ability of the patient to comply with the protocol; 4. For non central nervous system (CNS) cancers, patients with symptomatic CNS involvement of his/her cancer, unless the subject has stable neurological function without evidence of CNS progression within 12 weeks prior to study entry and does not require treatment with enzyme-inducing anticonvulsants or steroids (within 4 weeks prior to substudy inclusion and during substudy participation); 5. Administration of any non-oncologic investigational treatment within 30 days or 5 half-lives (whichever is longer) prior to receiving the first dose of study treatment; 6. History of another malignancy within 2 years prior to registration. Patients with a past history of adequately treated carcinoma-in-situ, basal cell carcinoma of the skin, squamous cell carcinoma of the skin, or superficial transitional cell carcinoma of the bladder are eligible; 7. Pregnancy, lactation, or inadequate contraception. Women must be post-menopausal, infertile, or use a reliable 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 barrier method of contraception (double barrier, if required). 8. Patients with BRCA1 or BRCA2 mutant breast, ovarian or prostate cancer 9. Patients who are eligible for other clinical studies involving durvalumab and/or olaparib 10. Blood transfusions within 28 days prior to registration 11. Any previous treatment with a PD1 or PD-L1 inhibitor, including durvalumab and/or a PARPi, including olaparib 12. Mean QT interval corrected for heart rate (QTc) greater than or equal to 470 ms calculated from 3 electrocardiograms (ECGs) using Fredericia’s Correction 13. Current or prior use of immunosuppressive medication within 7 days before the registration, including corticosteroids (greater than 10 mg/day of intranasal and inhaled prednisolone or equivalent systemic corticosteroids at physiological doses) 14. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Subjects without active disease in the last 5 years may be included at discretion of the Investigator. Subjects with the following conditions are eligible: vitiligo, alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, any chronic skin condition that does not require systemic therapy, celiac disease controlled by diet alone. 15. Current or prior use of immunosuppressive medication within 7 days before the registration, including corticosteroids (greater than 10 mg/day of intranasal and inhaled prednisolone or equivalent systemic corticosteroids at physiological doses) 16. History of primary immunodeficiency or allogeneic organ transplantation 17. History of leptomeningeal carcinomatosis 18. Active or prior documented autoimmune or inflammatory disorders (including inflammatory bowel disease [eg, colitis or Crohn's disease], systemic lupus erythematosus, Sarcoidosis syndrome, or Wegener syndrome [granulomatosis with polyangiitis, Graves' disease, rheumatoid arthritis, hypophysitis, uveitis, etc]). Subjects without active disease in the last 5 years may be included at discretion of the Investigator. Subjects with the following conditions are eligible: vitiligo, alopecia, hypothyroidism (eg, following Hashimoto syndrome) stable on hormone replacement, any chronic skin condition that does not require systemic therapy, celiac disease controlled by diet alone. 13. Receipt of live attenuated vaccination and influenza vaccine within 14 days prior to registration These are some of the exclusion criteria. You will be assessed for all criteria when joining the study.
Outcome results
None listed