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

Exelixis

Status and phase: Enrolling; Phase 1

Conditions: Advanced Solid Tumor

Treatments: Drug: Olaparib; Drug: XL309 (ISM3091)

Study type: Interventional

Funder types: Industry

Identifiers

NCT05932862

XL309-101

Details and patient eligibility

About

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.

Enrollment: 425 estimated patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

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:

   a) Participants whose tumor progressed, 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 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 high-grade serous ovarian cancer (HGSOC), including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC). Participants must have progressed on, be intolerant to, or refused PARPi therapy, if PARPi therapy is approved and available in the country where the participant is enrolled.

   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: participants with histologically confirmed locally advanced/metastatic HER2-negative Breast cancer with deleterious or suspected deleterious BRCA1/2 mutation and documented radiographic disease progression during or following their last systemic anticancer therapy and who progressed on, was intolerant to, refused, or was ineligible for treatment with a PARPi.

   c) Platinum-resistant HGSOC cohort: i. Participants with histologically confirmed locally advanced/metastatic HGSOC, including primary peritoneal cancer (PPC) and fallopian tube cancer (FTC), and who progressed on, was intolerant to, refused, or was ineligible for 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: 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: participants 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: participants with locally advanced/metastatic tumors with deleterious or suspected deleterious germline or somatic HRR mutation or HRD phenotype.

   For all participants with solid tumors:

5. Participants 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. 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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425 participants in 4 patient groups

Dose Escalation Single Agent Evaluation

Experimental group

Description:

Participants will receive XL309 once daily in sequential cohorts of increasing doses.

Treatment:

Drug: XL309 (ISM3091)

Dose Escalation Combination Therapy

Experimental group

Description:

Participants will receive XL309 once daily in sequential cohorts of increasing dose in combination with olaparib.

Treatment:

Drug: XL309 (ISM3091)

Drug: Olaparib

Cohort Expansion Stage Single Agent Evaluation

Experimental group

Description:

The recommended dose as determined in the Escalation Stage will be further studied in advanced solid tumor-specific cohorts.

Treatment:

Drug: XL309 (ISM3091)

Cohort Expansion Stage Combination Therapy Evaluation

Experimental group

Description:

The recommended dose as determined in the Escalation Stage will be further studied in combination with olaparib in advanced solid tumor-specific cohorts.

Treatment:

Drug: XL309 (ISM3091)

Drug: Olaparib