Overview

This is a FIH, multicenter, open-label Phase I study to investigate the safety, tolerability, preliminary antitumor activity, as well as PK and pharmacodynamics of XL309 (previously ISM3091) administered alone or in combination with olaparib in subjects with advanced solid tumors.

Eligibility

Key Inclusion Criteria:

1. Capable of understanding and complying with protocol requirements
2. Male or female aged 18 years or older
3. Eastern Cooperative Oncology Group performance status 0 or 1.
4. Adequate bone marrow and organ function

   Dose-Escalation Stage Single Agent and Combination:

   1. Subjects who relapsed, progressed, or were intolerant to standard therapy, have a disease for which no therapy with a known overall survival benefit exists or are not a candidate for these therapies, and have one of the following cancers: i. Histologically confirmed locally advanced/metastatic HER2-negative breast cancer, with deleterious or suspected deleterious BRCA1/2 mutation, that progressed on, was intolerant to, was refused, or ineligible for (PARPi).

     ii. Histologically confirmed locally advanced/metastatic HGSOC (high-grade serous
     ovarian cancer), including primary peritoneal cancer (PPC) and fallopian tube cancer
     (FTC), that progressed on, was intolerant to, refused, or ineligible to maintenance
     treatment with a PARPi.
     iii. Histologically confirmed locally advanced/metastatic CRPC, with deleterious or
     suspected deleterious BRCA1/2 mutation, that progressed on, was intolerant to,
     refused, or ineligible for PARPi.
     iv. Histologically confirmed locally advanced/metastatic pancreatic cancer with
     deleterious or suspected deleterious BRCA1/2 mutation that progressed on, was
     intolerant to, refused, or ineligible for maintenance treatment with a PARPi.
     v. Locally advanced/metastatic tumors with deleterious or suspected deleterious
     germline or somatic HRR mutation or HRD phenotype.
     Cohort-Expansion Stage Single Agent and Combination:
     b) HER2-negative BRCAm Breast cancer cohort: i. Histologically confirmed locally
     advanced/metastatic HER2-negative Breast cancer with deleterious or suspected
     deleterious BRCA1/2 mutation have documented radiographic disease progression during
     or following their last systemic anticancer therapy and that progressed on, was
     intolerant to, refused, or ineligible for treatment with a PARPi.
     c) Platinum-resistant HGSOC cohort: i. Histologically confirmed locally
     advanced/metastatic HGSOC, including primary peritoneal cancer (PPC) and fallopian
     tube cancer (FTC), that progressed on, was intolerant to, refused, or ineligible to
     maintenance treatment with a PARPi and who have platinum-resistant disease, defined
     by platinum free interval of less than 6 months ii. Platinum-refractory disease
     (progression on first-line treatment or within 4 weeks of completion) are excluded.
     d) Platinum-sensitive HGSOC cohort - expansion combination only: i. Histologically
     confirmed locally advanced/metastatic HGSOC, including PPC and FTC, that progressed
     on, refused, or ineligible to maintenance treatment with a PARPi, and who have
     platinum-sensitive disease, defined by platinum free interval of more than 6 months
     e) mCRPC cohort: i. Subjects with metastatic, castration-resistant adenocarcinoma of
     the prostate with deleterious or suspected deleterious BRCA1/2 mutation, that
     progressed on, or was intolerant, refused, or ineligible to PARPi.
     f) HRRm advanced solid tumors cohort: i. Locally advanced/metastatic tumors with
     deleterious or suspected deleterious germline or somatic HRR mutation or HRD
     phenotype.
     For all subjects with solid tumors:

5. Subjects in the Cohort-Expansion Stage must have at least 1 measurable target lesion

6. Recovery to baseline or ≤ Grade 1 CTCAE v5 from AE(s) related to any prior

treatments

Key Exclusion Criteria

1. Prior anticancer treatment including:
   1. Chemotherapy or small molecule-targeted therapy < 3 weeks prior to first dose of study treatment.
   2. Any antibody therapy < 5 half-lives from first dose of study treatment (or 4 weeks since last therapy, whichever is the shortest).
   3. Chemotherapy with nitrosoureas or mitomycin C < 6 weeks from first dose of study treatment.
   4. Radiation therapy (including radiofrequency ablation) < 1 week prior to initiation of study treatment. Subjects with clinically relevant ongoing complications from prior radiation therapy are not eligible.
2. Known brain metastases or cranial epidural disease unless adequately treated with

   radiotherapy and/or surgery (including radiosurgery) and stable for at least 4 weeks before first dose of study treatment

3. History of hypersensitivity to any excipient of XL309, or history of allergic reactions attributed to drugs with a similar chemical or biologic structure or class to XL309
4. Lactating or pregnant females.
5. Clinically relevant cardiovascular disease
6. Known history of myelodysplastic syndrome.
7. Other severe, acute, or chronic medical condition or laboratory abnormality that may increase the risk associated with study participation or study drug administration, or that may interfere with the interpretation of the study results, and in the judgement of the investigator, would make the patient inappropriate for the study.
8. Inability or unwillingness to comply with requirement for oral drug administration or presence of a gastrointestinal condition that would preclude adequate absorption of XL309.