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Advanced Solid TumorPhase 1NCT05932862

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

A Phase 1 study testing XL309 and Olaparib in people with Advanced Solid Tumor, run by Exelixis at 13 sites in United States.

Active, not recruiting

Under way, not looking for participants. Everyone needed has enrolled. The study is still running.

Official record
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Trial summary

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… Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Advanced Solid Tumor
What is being tested?
XL309 and Olaparib
Type of treatment
Pill or oral medicine
Could I receive a placebo?
No, everyone receives an active treatment
How many people
429 participants
Where
13 sitesUnited States
Study dates
3 Apr 2024to 31 Dec 2027
Phase
Phase 1
Are there results?
Not yet: the study is under way

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Capable of understanding and complying with protocol requirements.
  • Male or female aged 18 years or older.
  • Eastern Cooperative Oncology Group performance status 0 or 1.
  • Adequate bone marrow and organ function.
  • Participant-disease Characteristics
  • Dose-Escalation Stage Single Agent and Combination:
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  • 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:
  • 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.
  • Histologically confirmed locally advanced/metastatic high-grade serous ovarian cancer (HGSOC), including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC).
  • Histologically confirmed locally advanced/metastatic CRPC, with deleterious or suspected deleterious BRCA1/2 alteration.
  • Histologically confirmed locally advanced/metastatic pancreatic cancer with deleterious or suspected deleterious BRCA1/2 alteration.
  • 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:
  • HER2-negative breast cancer cohort: participants with histologically confirmed locally advanced/metastatic (HER2)-negative breast cancer with alterations in select HRR genes.
  • 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.
  • mCRPC cohort: participants with metastatic, castration-resistant adenocarcinoma of the prostate with alterations in select HRR genes.
  • HRRm advanced solid tumors cohort: participants with locally advanced/metastatic tumors with alterations in select HRR genes.
  • For all participants with solid tumors:
  • Participants in the Cohort-Expansion Stage must have at least 1 measurable target lesion.
  • Recovery to baseline or ≤ Grade 1 CTCAE v5 from AE(s) related to any prior treatments.

Who cannot join

  • Prior anticancer treatment including:
  • Small molecule-targeted therapy < 5 half-lives from first dose of study treatment, or 3 weeks (whichever is shorter).
  • Any antibody therapy < 5 half-lives from first dose of study treatment (or 4 weeks since last therapy, whichever is shorter).
  • 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.
  • 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.
  • 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.
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  • 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 judgment of the investigator, would make the participant 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.
  • Prior treatment with a ubiquitin specific peptidase 1 (USP1) inhibitor.

Trial locations and contacts

13 sites in 1 country.

13 sites in 1 country

United States13 sites

  • Exelixis Clinical Site #4

    Austin, Texas, 78758

  • Exelixis Clinical Site #7

    Cleveland, Ohio, 44106

  • Exelixis Clinical Site #11

    Germantown, Tennessee, 38138

  • Exelixis Clinical Site #1

    Houston, Texas, 77030

  • Exelixis Clinical Site #15

    Jacksonville, Florida, 32224

  • Exelixis Clinical Site #6

    Nashville, Tennessee, 37203

  • Exelixis Clinical Site #9

    New Brunswick, New Jersey, 08901

  • Exelixis Clinical Site #5

    New York, New York, 10029

  • Exelixis Clinical Site #13

    Oklahoma City, Oklahoma, 73104

  • Exelixis Clinical Site #8

    Orlando, Florida, 32827

  • Exelixis Clinical Site #14

    Rochester, Minnesota, 55905

  • Exelixis Clinical Site #3

    San Antonio, Texas, 78229

  • Exelixis Clinical Site #16

    Tampa, Florida, 33612

Other trials in United States

About this study

Official 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

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.

Being tested
XL309, Olaparib
Keywords
Ovarian Cancer, Prostate Cancer, Pancreatic Cancer, Advanced HRRm Solid Tumors, Breast Cancer
Medical subject headings
Ovarian Neoplasms, Prostatic Neoplasms, Pancreatic Neoplasms, Breast Neoplasms

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • XL309Drug

    Also called ISM3091

    XL309 will be administered orally per assigned schedule.

  • OlaparibDrug

    Olaparib will be administered orally per assigned schedule.

Study groups in NCT05932862
Study groupRoleWhat they receive
Dose Escalation Single Agent EvaluationExperimentalParticipants will receive XL309 in sequential cohorts of increasing doses.
Receives: Drug: XL309
Dose Escalation Combination TherapyExperimentalParticipants will receive XL309 in sequential cohorts of increasing doses in combination with olaparib.
Receives: Drug: XL309; Drug: Olaparib
Cohort Expansion Stage Single Agent EvaluationExperimentalThe recommended dose as determined in the Escalation Stage will be further studied in advanced solid tumor-specific cohorts.
Receives: Drug: XL309
Cohort Expansion Stage Combination Therapy EvaluationExperimentalThe recommended dose as determined in the Escalation Stage will be further studied in combination with olaparib in advanced solid tumor-specific cohorts.
Receives: Drug: XL309; Drug: Olaparib

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. 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.

    Measured: Approximately 24 months

  2. Dose Escalation Stage: Incidence of Dose-Limiting Toxicities (DLTs)

    Measured: Approximately 24 months

  3. Dose Escalation Stage: XL309 Exposure Over Time Measured as Area Under the Plasma Concentration Curve (AUC)

    Measured: Approximately 24 months

  4. Dose Escalation Stage: XL309 Maximum Plasma Concentration (Cmax)

    Measured: Approximately 24 months

  5. Dose Escalation Stage: XL309 Time to Cmax

    Measured: Approximately 24 months

  6. Dose Escalation Stage: XL309 Trough Concentration (Ctrough)

    Lowest concentration of drug in the bloodstream, measured just before the next dose is administered.

    Measured: Approximately 24 months

  7. Dose Escalation Stage: XL309 Apparent Clearance (CL/F)

    Measured: Approximately 24 months

  8. 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.

    Measured: Approximately 24 months

  9. 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

    Measured: Approximately 24 months

Secondary outcomes (5)

  1. Dose Escalation Stage: Olaparib Exposure Over Time Measured as Area Under the Plasma Concentration Curve (AUC) at Steady State

    Measured: Approximately 24 months

  2. Dose Escalation Stage: Olaparib Cmax at Steady State

    Measured: Approximately 24 months

  3. Dose Escalation Stage: Olaparib Ctrough at Steady State

    Measured: Approximately 24 months

  4. Cohort Expansion Stage: Concentration of XL309 in Plasma at Specified Time Points

    Measured: Approximately 24 months

  5. Cohort Expansion Stage: Concentration of Olaparib in Plasma at Specified Time Points

    Measured: Approximately 24 months

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted6 Jul 2023
  2. Study start3 Apr 2024
  3. Primary completion30 Apr 2027 (estimated)
  4. Study completion31 Dec 2027 (estimated)

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 1
Primary purpose
Treatment
Allocation
Non-randomised
Intervention model
Sequential
Masking
None (open label)
Enrolment
429 participants (estimated)
IDs, dates and publications
ClinicalTrials.gov ID
NCT05932862
Sponsor's protocol ID
XL309-101
Status last verified
Oct 2026
First submitted
27 Jun 2023
Last updated
6 Nov 2026
Results posted
No
Data monitoring committee
Yes
FDA-regulated drug
Yes
FDA-regulated device
No

Publications

  • Mi X, Li Q, Long G, Pan Y, Xie Y, Lu S, Xiao L, Tang J, Zhou L. Deubiquitylating Enzymes in Hepatocellular Carcinoma. Int J Biol Sci. 2025 Jun 20;21(9):4270-4292. doi: 10.7150/ijbs.113193. eCollection 2025.

    PubMed 40607251

  • da Costa AA, Somuncu O, Ravindranathan R, Mukkavalli S, Martignetti DB, Nguyen H, Jiao Y, Lamarre BP, Sadatrezaei G, Moreau L, Liu J, Iyer DR, Lazaro JB, Shapiro GI, Parmar K, D'Andrea AD. Single-Stranded DNA Gap Accumulation Is a Functional Biomarker for USP1 Inhibitor Sensitivity. Cancer Res. 2024 Oct 15;84(20):3435-3446. doi: 10.1158/0008-5472.CAN-23-4007.

    PubMed 38885312

Questions about this trial

What is this clinical trial studying?

A Phase 1 study testing XL309 and Olaparib in people with Advanced Solid Tumor, run by Exelixis at 13 sites in United States.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 20 inclusion and 13 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: under way, not looking for participants, as of the sponsor's last update on 6 Nov 2026. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 13 sites in United States. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

This study is still under way. Results are not available in the source record yet.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Dose Escalation Stage: Incidence of TEAEs and SAEs; AEs Leading to Dose Modification, Discontinuation, or Death; and Laboratory Abnormalities (time frame: Approximately 24 months). The study lists 9 primary outcomes in all. It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT05932862, which also lists 2 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 6 Nov 2026; AzTrials last refreshed its copy on 7 Nov 2026.

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