A Phase 1 Study of XL309 (ISM3091) Alone and in Combination in Participants With Advanced Solid Tumors

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

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

Study Overview

• Status: Recruiting
• Conditions: Advanced Solid Tumor
• Intervention / Treatment: Drug: XL309; Drug: Olaparib

• Study Type: Interventional
• Enrollment (Estimated): 429
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Exelixis Clinical Trials; Phone Number: 1-888-393-5494); Email: druginfo@exelixis.com

Study Locations

• United States
  • California
    • Fountain Valley, California, United States, 92708
      • Withdrawn
      • Exelixis Clinical Site #12
  • Florida
    • Jacksonville, Florida, United States, 32224
      • Recruiting
      • Exelixis Clinical Site #15
    • Orlando, Florida, United States, 32827
      • Recruiting
      • Exelixis Clinical Site #8
    • Tampa, Florida, United States, 33612
      • Recruiting
      • Exelixis Clinical Site #16
  • Minnesota
    • Rochester, Minnesota, United States, 55905
      • Recruiting
      • Exelixis Clinical Site #14
  • Missouri
    • Kansas City, Missouri, United States, 64111
      • Withdrawn
      • Exelixis Clinical Site #10
  • New Jersey
    • New Brunswick, New Jersey, United States, 08901
      • Recruiting
      • Exelixis Clinical Site #9
  • New York
    • New York, New York, United States, 10029
      • Recruiting
      • Exelixis Clinical Site #5
  • Ohio
    • Cleveland, Ohio, United States, 44106
      • Recruiting
      • Exelixis Clinical Site #7
  • Oklahoma
    • Oklahoma City, Oklahoma, United States, 73104
      • Recruiting
      • Exelixis Clinical Site #13
  • Tennessee
    • Germantown, Tennessee, United States, 38138
      • Recruiting
      • Exelixis Clinical Site #11
    • Nashville, Tennessee, United States, 37203
      • Recruiting
      • Exelixis Clinical Site #6
  • Texas
    • Austin, Texas, United States, 78758
      • Recruiting
      • Exelixis Clinical Site #4
    • Houston, Texas, United States, 77030
      • Recruiting
      • Exelixis Clinical Site #1
    • Houston, Texas, United States, 77030
      • Withdrawn
      • Exelixis Clinical Site #2
    • San Antonio, Texas, United States, 78229
      • Recruiting
      • Exelixis Clinical Site #3

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: Adult; Older Adult
• Accepts Healthy Volunteers: No

Description

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.

5. Participant-disease Characteristics

   Dose-Escalation Stage Single Agent and Combination:

   a) Participants whose tumor progressed on, or who were intolerant to standard therapy, have a disease for which no therapy exists or are not a candidate for these therapies, and have one of the following cancers:

   i. Histologically confirmed locally advanced/metastatic human epidermal growth factor receptor-2 (HER2)-negative breast cancer, with deleterious or suspected deleterious breast cancer gene (BRCA)1/2 alteration.

   ii. Histologically confirmed locally advanced/metastatic high-grade serous ovarian cancer (HGSOC), including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC).

   iii. Histologically confirmed locally advanced/metastatic CRPC, with deleterious or suspected deleterious BRCA1/2 alteration.

   iv. Histologically confirmed locally advanced/metastatic pancreatic cancer with deleterious or suspected deleterious BRCA1/2 alteration.

   v. Locally advanced/metastatic tumors with deleterious or suspected deleterious germline or somatic homologous recombination repair (HRR) mutation or homologous recombination deficiency (HRD) phenotype.

   Cohort-Expansion Stage Single Agent and Combination:

   b) HER2-negative breast cancer cohort: participants with histologically confirmed locally advanced/metastatic (HER2)-negative breast cancer with alterations in select HRR genes.

   c) Platinum-sensitive HGSOC cohort: participants with histologically confirmed locally advanced/metastatic HGSOC, including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC), with positive HRD result using an approved diagnostic, and/or alterations in select HRR genes.

   d) mCRPC cohort: participants with metastatic, castration-resistant adenocarcinoma of the prostate with alterations in select HRR genes.

   e) HRRm advanced solid tumors cohort: participants with locally advanced/metastatic tumors with alterations in select HRR genes.

   For all participants with solid tumors:

6. Participants in the Cohort-Expansion Stage must have at least 1 measurable target lesion.
7. 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. Small molecule-targeted therapy < 5 half-lives from first dose of study treatment, or 3 weeks (whichever is shorter).
   2. Any antibody therapy < 5 half-lives from first dose of study treatment (or 4 weeks since last therapy, whichever is shorter).
   3. Chemotherapy with nitrosoureas or mitomycin C < 6 weeks from first dose of study treatment. Other chemotherapy < 3 weeks prior to first dose of study treatment.
   4. Radiation therapy (including radiofrequency ablation) < 1 week prior to initiation of study treatment. Participants 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 judgment of the investigator, would make the participant 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.
9. Prior treatment with a ubiquitin specific peptidase 1 (USP1) inhibitor.

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Non-Randomized
• Interventional Model: Sequential Assignment
• Masking: None (Open Label)

Number of Arms

4

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Cohort Expansion Stage Single Agent Evaluation; The recommended dose as determined in the Escalation Stage will be further studied in advanced solid tumor-specific cohorts.	Drug: XL309; XL309 will be administered orally per assigned schedule.; Other Names: ISM3091
Experimental: Cohort Expansion Stage Combination Therapy Evaluation; The recommended dose as determined in the Escalation Stage will be further studied in combination with olaparib in advanced solid tumor-specific cohorts.	Drug: XL309; XL309 will be administered orally per assigned schedule.; Other Names: ISM3091; Drug: Olaparib; Olaparib will be administered orally per assigned schedule.
Experimental: Dose Escalation Single Agent Evaluation; Participants will receive XL309 in sequential cohorts of increasing doses.	Drug: XL309; XL309 will be administered orally per assigned schedule.; Other Names: ISM3091
Experimental: Dose Escalation Combination Therapy; Participants will receive XL309 in sequential cohorts of increasing doses in combination with olaparib.	Drug: XL309; XL309 will be administered orally per assigned schedule.; Other Names: ISM3091; Drug: Olaparib; Olaparib will be administered orally per assigned schedule.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Dose Escalation Stage: Incidence of Dose-Limiting Toxicities (DLTs)		Approximately 24 months
Dose Escalation Stage: XL309 Exposure Over Time Measured as Area Under the Plasma Concentration Curve (AUC)		Approximately 24 months
Dose Escalation Stage: XL309 Maximum Plasma Concentration (Cmax)		Approximately 24 months
Dose Escalation Stage: XL309 Apparent Clearance (CL/F)		Approximately 24 months
Dose Escalation Stage: Incidence of TEAEs and SAEs; AEs Leading to Dose Modification, Discontinuation, or Death; and Laboratory Abnormalities	Adverse events will be recorded and severity graded using Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.	Approximately 24 months
Dose Escalation Stage: XL309 Time to Cmax		Approximately 24 months
Dose Escalation Stage: XL309 Trough Concentration (Ctrough)	Lowest concentration of drug in the bloodstream, measured just before the next dose is administered.	Approximately 24 months
Cohort Expansion Stage: Incidence of TEAEs and SAEs; AEs Leading to Dose Modification, Discontinuation, or Death; and Laboratory Abnormalities	Adverse events will be recorded and severity graded using CTCAE version 5.0.	Approximately 24 months
Cohort Expansion Stage: Objective Response Rate (ORR)	ORR will be measured per Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1, as assessed by the Investigator. ORR for prostate cancer will be based on Prostate Cancer Working Group 3 (PCWG3) criteria, as assessed by the Investigator	Approximately 24 months

Secondary Outcome Measures

Outcome Measure	Time Frame
Cohort Expansion Stage: Concentration of XL309 in Plasma at Specified Time Points	Approximately 24 months
Cohort Expansion Stage: Concentration of Olaparib in Plasma at Specified Time Points	Approximately 24 months
Dose Escalation Stage: Olaparib Exposure Over Time Measured as Area Under the Plasma Concentration Curve (AUC) at Steady State	Approximately 24 months
Dose Escalation Stage: Olaparib Cmax at Steady State	Approximately 24 months
Dose Escalation Stage: Olaparib Ctrough at Steady State	Approximately 24 months

Collaborators and Investigators

• Sponsor: Exelixis

Study record dates

Study Major Dates

• Study Start (Actual): April 3, 2024
• Primary Completion (Estimated): January 3, 2029
• Study Completion (Estimated): August 3, 2029

Study Registration Dates

• First Submitted: June 27, 2023
• First Submitted That Met QC Criteria: June 27, 2023
• First Posted (Actual): July 6, 2023

Study Record Updates

• Last Update Posted (Estimated): September 5, 2025
• Last Update Submitted That Met QC Criteria: August 28, 2025
• Last Verified: August 1, 2025

More Information

Terms related to this study

• Keywords: Breast Cancer; Prostate Cancer; Pancreatic Cancer; Ovarian Cancer; Advanced HRRm Solid Tumors
• Additional Relevant MeSH Terms: Urogenital Diseases; Genital Diseases; Endocrine System Diseases; Genital Neoplasms, Male; Urogenital Neoplasms; Neoplasms by Site; Neoplasms; Genital Diseases, Male; Prostatic Diseases; Male Urogenital Diseases; Female Urogenital Diseases; Female Urogenital Diseases and Pregnancy Complications; Digestive System Neoplasms; Digestive System Diseases; Genital Diseases, Female; Endocrine Gland Neoplasms; Pancreatic Diseases; Ovarian Diseases; Adnexal Diseases; Genital Neoplasms, Female; Gonadal Disorders; Skin Diseases; Breast Diseases; Skin and Connective Tissue Diseases; Prostatic Neoplasms; Ovarian Neoplasms; Breast Neoplasms; Pancreatic Neoplasms; Poly(ADP-ribose) Polymerase Inhibitors; Antineoplastic Agents; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; olaparib
• Other Study ID Numbers: XL309-101

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: No