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: 377 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) 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.

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Sequential Assignment

Masking: None (Open label)

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377 participants in 4 patient groups

Dose Escalation Single Agent Evaluation

Experimental group

Description:

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

Treatment:

Drug: XL309 (ISM3091)

Dose Escalation Combination Therapy

Experimental group

Description:

Patients 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