Cancer
Conditions
Brief summary
This study will describe the efficacy of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with homologous recombination deficiency (HRD), agnostic of tumour origin. A tumour-agnostic approach has been adopted in this study due to the broad activity of PARP inhibitors across multiple tumour types. In addition, response to PARP inhibitors has been demonstrated in patients with genomic features associated with HRD, even in the absence of germline BRCA1 or BRCA2 mutations. These results suggest that the presence of HRD itself is the key predictive biomarker for PARP inhibitor efficacy. This paves the way for a precision-oncology, tumour-agnostic approach to patient selection for treatment, rather than the traditional tumour site-of-origin basis for which the current PARP inhibitor approvals exist. To investigate this, cohort A of this study includes patients with genomic features of HRD, but without a germline BRCA1 or BRCA2 mutation. Demonstration of clinical efficacy in this cohort will provide strong support to the tumour-agnostic, precision-oncology approach for patient selection for PARP inhibitor or PARP inhibitor combination treatment. This forms the primary objective of the study. The study will consist of two cohorts, broadly, cohort A - patients without a pathogenic BRCA1 or BRCA2 mutation but with other germline or somatic mutations in other HRD genes; cohort B- patients with a pathogenic BRCA1 or BRCA2
Interventions
DRUGPamiparib
40 mg orally twice a day
DRUGTislelizumab
200 mg IV every 21 days
Sponsors
Peter MacCallum Cancer Centre, Australia
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
1. Have provided written informed consent 2. Male or female ≥ 18 years of age 3. Patient has documentation of at least 1 of the following genomic features associated with HRD * Cohort A - any of: * A germline or somatic genetic alteration that is known or suspected to be deleterious in one of the following HR-related genes (ATM, CDK12, PALB2, ARID1A, ATRX, BLM, BARD1, BRIP1, CHEK1, CHEK2, FANCA, FANCF, FANCG, FANCI, FANCL, FANCM, MSH2, NBN, RAD50, RAD51C, RAD51D, WRN) * A somatic genetic alteration that is known or suspected to be deleterious in BRCA1 or BRCA2 * A prevalent mutational signature 3 as determined by WGS (≥ 20% of total mutations attributed) * The presence of a positive HRD status using a NGS assay that includes assessment for genomic instability * Cohort A excludes high grade serous ovarian cancer, TNBC, and prostate cancer * Cohort B - a pathogenic germline BRCA1 or BRCA2 mutation Note: Genomic features associated with HRD must have been determined from a sample obtained ≤ 12 months before the date of registration into this study with the exception of germline genetic alterations which can have been determined from a sample obtained at any time. 4. Patient agrees to the collection and use of their fresh tumour biopsy sample during screening for WGS Note: A fresh tumour biopsy not required for patients who have had WGS performed within 12 months prior to registration to the study 5. Continues to meet all the inclusion criteria as per the TRIAGE Framework protocol 6. Measurable disease, as defined by RECIST 1.1 (see Appendix 2) 7. Adequate haematological and end-organ function, defined by the following laboratory results obtained within 7 days prior to registration, independent of blood or platelet transfusion within 2 weeks: * Haemoglobin ≥ 90 g/L * ANC ≥ 1.5x109/L * Platelet count ≥ 100 x109/L * ALT ≤ 3.0 x the ULN, irrespective of the presence or absence of liver metastases * AST ≤ 3.0 x the ULN, irrespective of the presence or absence of liver metastases * Serum bilirubin ≤ 1.5 x ULN (On fractionation ≤ 90% of total bilirubin should be unconjugated. Total bilirubin must be \<4 x ULN for patients with Gilbert's Syndrome) * Serum creatinine ≤ 1.5x ULN or eGFR ≥ 30 mL/min/1.73 m2 by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation (appendix 5) * INR ≤ 1.5x ULN (≤2.5x ULN if on anticoagulants) 8. Patient has the ability to take oral medications without medical history of malabsorption or other chronic gastrointestinal disease, or other conditions that may harm compliance and/or absorption of the study treatment 9. WOCBP must agree to use a highly effective method of birth control for the duration of the study and for 6 months after the last dose of study treatment (see Appendix 3), and have a negative serum pregnancy test within 7 days of study registration 10. Non-sterile males and their female partners must agree to use a highly effective method of birth control for the duration of the study and for 6 months after the last dose of study treatment. Non- sterile males must avoid sperm donation for the duration of the study and for at least 6 months after the last study drug 11. Female patient must agree not to breastfeed starting at screening and throughout the study period, and for 6 months after the final study drug administration 12. Patient is willing and able to comply with the protocol for the duration of the study including undergoing biopsies, treatment, and scheduled visits and examination including follow up
Exclusion criteria
1. One or more of the
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Evaluation of clinical benefit rate (CBR) in patients with advanced tumours harbouring molecular profiles consistent with homologous recombination defeciency (HRD), without a known pathogenic germline BRCA1 or BRCA2 mutation. | 12 weeks after commencement of treatment | CBR, defined as the proportion of patients with either objective response (partial response (PR) + complete response (CR)) as best response, or stable disease (SD) at 12 weeks post registration, as determined by the Investigator by RECIST 1.1 in cohort A |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Efficacy of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with HRD, and without a known pathogenic germline BRCA1 or BRCA2 mutation | At the end of the study, approximately 4 years after the first participant commences treatment | Efficacy will be measured by: * overall response rate (ORR) - defined as the proportion of patients with an objective response (partial response + complete response) as best response (as determined by the Investigator by RECIST 1.1) |
| Evaluation of CBR of pamiparib in combination with tislelizumab in patients with advanced tumours harbouring molecular profiles consistent with HRD (independent of germline BRCA1 or BRCA2 mutation status) | 12 weeks post commencement of treatment | CBR, defined as the proportion of patients with either objective response (partial response (PR) + complete response (CR)) as best response, or stable disease (SD) at 12 weeks post registration, as determined by the Investigator by RECIST 1.1 in cohort A and B |
| Severity of Treatment -Emergent Events (Safety of pamiparib in combination with tiselizumab) | At the end of the study, approximately 4 years after the first participant commences treatment | Severity of adverse events as determined by NCI CTCAE 5.0 |
| Determination of HRD phenotype as a predictor of response | At the end of the study, approximately 4 years after the first participant commences treatment | A tumour based whole genome HRD assay will provide a binary outcome as to whether HRD is present or absent. Logistic regression models will be used to compare CBR between patients with tumours that have HRD present vs absent. |
Countries
Australia
Contacts
Primary ContactStephen Luen, MBBS
Backup ContactJayesh Desai, MBBS
Outcome results
None listed