Clinical Trial 23255

• Overview

  Study Title:

  An Open-Label, Multicenter Study to Investigate the Safety, Tolerability, Pharmacokinetics, and Preliminary Efficacy of XL309 (ISM3091) as Single-Agent and Combination Therapy in Patients with Advanced Solid Tumors

  Summary:

  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.

  Objective:

  Dose-Escalation stage: Primary Objective: * To assess the safety and tolerability and to establish a preliminary RD of XL309 as monotherapy and in combination with olaparib Secondary Objectives: * To characterize the PK of XL309 alone and when given in combination with olaparib following a single dose administration and at a steady state after multiple dosing * To characterize the PK of olaparib following a single dose and at a steady state after multiple dosing in combination with XL309 Cohort-Expansion stage: Primary Objectives: * To further assess the safety and tolerability of XL309 as monotherapy and in combination with olaparib * To assess preliminary efficacy of XL309 as monotherapy and in combination with olaparib Secondary Objectives: * To characterize the PK of XL309 alone and when given in combination with olaparib following a single dose administration and at a steady state after multiple dosing * To characterize the PK of olaparib following a single dose and at a steady state after multiple dosing in combination with XL309

• Treatments

  Therapies:

  Chemotherapy (NOS); Therapy (NOS)

  Medications:

  Olaparib (Lynparza); XL309 ()

• Inclusion Criteria

  Inclusion Criteria:
  • Capable of understanding and complying with protocol requirements
  • Male or female aged 18 years or older
  • Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1.
  • Adequate bone marrow and organ function
  • Dose-Escalation Stage Single Agent and Combination: a) 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 alteration, including promoter hypermethylation, 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 alteration, including promoter hypermethylation, 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 alteration, including promoter hypermethylation 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 alteration, including promoter hypermethylation 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:
  • Subjects in the Cohort-Expansion Stage must have at least 1 measurable target lesion
  • Recovery to baseline or Grade 1 or less CTCAE v5 from AE(s) related to any prior treatments

• Exclusion Criteria

  Exclusion Criteria:
  • Prior anticancer treatment including: Chemotherapy or small molecule-targeted therapy > 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
  • 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
  • Lactating or pregnant females.
  • Clinically relevant cardiovascular disease
  • Known history of myelodysplastic syndrome.
  • 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.
  • Inability or unwillingness to comply with requirement for oral drug administration or presence of a gastrointestinal condition that would preclude adequate absorption of XL309.

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