IMPARP-HRD: This study is evaluating how effective a combined treatment of two targeted therapies (pamiparib and tislelizumab) is in people with advanced cancers that have molecular profiles consistent with homologous recombination deficiency (HRD)An Open Label, Signal Seeking, Translational, Phase II Trial of Pamiparib in Combination With Tislelizumab in Patients With Advanced Tumours With Homologous Recombination Repair Defects

Exclusion

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 below are met:

   • Patients must not have received the immune checkpoint blockade within 28 days of study registration
   • Patients must not have experienced a toxicity that led to permanent discontinuation of prior immunotherapy

   • All AEs while receiving prior immunotherapy must have completely resolved or resolved to grade

     1 prior to screening for this study. Patients with an endocrine AE due to immunotherapy are permitted provided they are stably maintained on appropriate replacement therapy and are asymptomatic

   • Must not have required the use of additional immunosuppression other than corticosteroids for the management of an AE, not have experienced recurrence of an AE if re-challenged, and not require maintenance doses of > 10 mg prednisolone or equivalent per day
3. Any unresolved toxicity (≥CTCAE grade 2) from previous anti-cancer therapy, with the exception of alopecia Note: Patients with irreversible toxicity that is not reasonably expected to be exacerbated by the study treatment (e.g. hearing loss, peripheral neuropathy) are eligible
4. Treatment with strong CYP3A inducers within 10 days (or ≤ 5 half-lives, whichever is shorter) prior to registration. Known need for treatment with strong CYP3A4 inducers during study treatment.

5. Symptomatic or current history of actively progressing CNS metastases. Patients with a history of treated CNS lesions are eligible, provided that all of the following criteria 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 evidence of interim progression between completion of CNS-directed therapy and registration to the study (radiological re-assessment is not required)
   • The patient has not received radiotherapy within 14 days prior to registration Note: Anticonvulsant therapy at a stable dose is permitted

   Note: Patients with asymptomatic brain metastases in which CNS-directed therapy is not indicated 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 the following exceptions:

   • Controlled type 1 diabetes
   • Hypothyroidism managed with no treatment other than with hormone replacement therapy
   • 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 external triggering factors

9. Any condition that required systemic treatment with either corticosteroids (> 10 mg daily of prednisone or equivalent) or other immunosuppressive medication within 2 weeks 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 with minimal systemic absorption
   • Short course (≤ 7 days) of corticosteroid prescribed prophylactically or for the treatment 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 at screening) or HCV Note: Patients with a past or resolved HBV infection (defined as the presence of HBcAb and absence of HBsAg) are eligible. Patients positive for HCV antibody 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 or uncontrolled 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 (See Appendix 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 study drugs.
16. Has been administered a live vaccine within 4 weeks prior to registration
17. Known sensitivity to any component of pamiparib and/or tislelizumab