A Trial of Pamiparib With Tislelizumab in Patients With Advanced Tumours With Homologous Recombination Repair Defects

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 associatedwith HRD

• Cohort A - any of:
• A germline or somatic genetic alteration that is known or suspected to bedeleterious 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 inBRCA1 or BRCA2
• A prevalent mutational signature 3 as determined by WGS (≥ 20% of totalmutations attributed)
• The presence of a positive HRD status using a NGS assay that includesassessment for genomic instability
• Cohort A excludes high grade serous ovarian cancer, TNBC, and prostatecancer
• Cohort B - a pathogenic germline BRCA1 or BRCA2 mutation Note: Genomic featuresassociated with HRD must have been determined from a sample obtained ≤ 12 monthsbefore the date of registration into this study with the exception of germlinegenetic alterations which can have been determined from a sample obtained at anytime.

4. Patient agrees to the collection and use of their fresh tumour biopsy sample duringscreening for WGS Note: A fresh tumour biopsy not required for patients who have hadWGS 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 laboratoryresults obtained within 7 days prior to registration, independent of blood or platelettransfusion 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 beunconjugated. 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 DiseaseEpidemiology 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 ofmalabsorption or other chronic gastrointestinal disease, or other conditions that mayharm compliance and/or absorption of the study treatment
9. WOCBP must agree to use a highly effective method of birth control for the duration ofthe 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 effectivemethod of birth control for the duration of the study and for 6 months after the lastdose of study treatment. Non- sterile males must avoid sperm donation for the durationof 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 thestudy 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 studyincluding undergoing biopsies, treatment, and scheduled visits and examinationincluding follow up

Exclusion Criteria:

1. One or more of the exclusion criteria as per the TRIAGE Framework protocol applies
2. Any previous treatment with a PARP inhibitor Note: Prior immune checkpoint blockade is permitted provided all the criteria beloware met:

• Patients must not have received the immune checkpoint blockade within 28 days ofstudy registration
• Patients must not have experienced a toxicity that led to permanentdiscontinuation of prior immunotherapy
• All AEs while receiving prior immunotherapy must have completely resolved orresolved to grade 1 prior to screening for this study. Patients with an endocrine AE due toimmunotherapy are permitted provided they are stably maintained on appropriatereplacement therapy and are asymptomatic
• Must not have required the use of additional immunosuppression other thancorticosteroids for the management of an AE, not have experienced recurrence ofan AE if re-challenged, and not require maintenance doses of > 10 mg prednisoloneor equivalent per day

3. Any unresolved toxicity (≥CTCAE grade 2) from previous anti-cancer therapy, with theexception of alopecia Note: Patients with irreversible toxicity that is not reasonablyexpected to be exacerbated by the study treatment (e.g. hearing loss, peripheralneuropathy) are eligible
4. Treatment with strong CYP3A inducers within 10 days (or ≤ 5 half-lives, whichever isshorter) prior to registration. Known need for treatment with strong CYP3A4 inducersduring study treatment.
5. Symptomatic or current history of actively progressing CNS metastases. Patients with ahistory of treated CNS lesions are eligible, provided that all of the followingcriteria are met:

• Measurable disease per RECIST 1.1 must be present outside the CNS
• In patients who have received CNS-directed therapy, there is no clinical evidenceof interim progression between completion of CNS-directed therapy andregistration to the study (radiological re-assessment is not required)
• The patient has not received radiotherapy within 14 days prior to registrationNote: Anticonvulsant therapy at a stable dose is permitted Note: Patients with asymptomatic brain metastases in which CNS-directed therapy is notindicated are eligible

6. History of leptomeningeal disease
7. Mean QTc ≥ 470 ms calculated from triplicate ECGs using Fredericia's Correction
8. Active autoimmune disease or history of autoimmune disease that may relapse, with thefollowing exceptions:

• Controlled type 1 diabetes
• Hypothyroidism managed with no treatment other than with hormone replacementtherapy
• Controlled celiac disease
• Skin disease not requiring systemic treatment (e.g. vitiligo, psoriasis,alopecia)
• Any other disease that is not expected to recur in the absence of externaltriggering factors

9. Any condition that required systemic treatment with either corticosteroids (> 10 mgdaily of prednisone or equivalent) or other immunosuppressive medication within 2weeks prior to registration, with the following exceptions:

• Adrenal replacement steroid (dose ≤ 10 mg daily of prednisone or equivalent)
• Topical, ocular, intra-articular, intranasal, or inhalational corticosteroid withminimal systemic absorption
• Short course (≤ 7 days) of corticosteroid prescribed prophylactically or for thetreatment of a non- autoimmune condition

10. Positive HIV test at screening
11. Patients with active HBV (chronic or acute; defined as having a positive HBsAg test atscreening) or HCV Note: Patients with a past or resolved HBV infection (defined as thepresence of HBcAb and absence of HBsAg) are eligible. Patients positive for HCVantibody are eligible only if polymerase chain reaction is negative for HCV RNA
12. Patients with severe chronic or active infections requiring systemic antibacterial,antifungal or antiviral therapy, including active tuberculosis and COVID-19
13. Patients with a history of interstitial lung disease, non-infectious pneumonitis oruncontrolled systemic diseases, including diabetes, hypertension, pulmonary fibrosis,acute lung diseases, etc.
14. History of non-viral hepatitis or cirrhosis
15. Any of the following cardiovascular criteria:

• Current evidence of cardiac ischemia.
• Current symptomatic pulmonary embolism.
• Acute myocardial infarction ≤ 6 months prior to study registration.
• Heart failure of New York Heart Association Classification III or IV (SeeAppendix 6) ≤ 6 months prior to study registration.
• Grade ≥ 2 ventricular arrhythmia ≤ 6 months prior to study registration.
• History of cerebrovascular accident within 6 months before first dose of studydrugs.

16. Has been administered a live vaccine within 4 weeks prior to registration
17. Known sensitivity to any component of pamiparib and/or tislelizumab