Clinical trial NCT05932862: A Phase 1 Study of XL309 (ISM3091) Alone and in Combination in Patients With Advanced Solid Tumors
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
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE1
Conditions: Advanced Solid Tumor
Keywords: ovarian cancer
prostate cancer
pancreatic cancer
Advanced HRRm solid tumors
breast cancer
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2023-07-06
Enrollment: 425
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief 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.


Eligibility 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.

Primary outcomes:
measure: Dose Escalation Stage: Incidence of TEAEs, SAEs, and AEs and SAEs Leading to Dose Modification, Discontinuation, or Death
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: Incidence of Dose-Limiting Toxicities (DLTs)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: XL309 Exposure Over Time Measured as Area Under the Plasma Concentration Curve (AUC)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: XL309 Maximum Plasma Concentration (Cmax)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: XL309 Time to Maximum Concentration (Tmax)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: XL309 Trough Concentration (Ctrough)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: XL309 Apparent Clearance (CL/F)
timeFrame: Approximately 24 months
measure: Cohort Expansion Stage: Incidence of TEAEs, SAEs, AEs and SAEs Leading to Dose Modification, Discontinuation or Death
timeFrame: Approximately 24 months
measure: Cohort Expansion Stage: Objective Response Rate (ORR)
timeFrame: Approximately 24 months
Secondary outcomes:
measure: Dose Escalation Stage: Olaparib Exposure Over Time Measured as Area Under the Plasma Concentration Curve (AUC)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: Olaparib Maximum Plasma Concentration (Cmax)
timeFrame: Approximately 24 months
measure: Dose Escalation Stage: Olaparib Trough Concentration (Ctrough)
timeFrame: Approximately 24 months
measure: Cohort Expansion Stage: Concentration of XL309 in Plasma at Specified Time Points
timeFrame: Approximately 24 months
measure: Cohort Expansion Stage: Concentration of Olaparib in Plasma at Specified Time Points
timeFrame: Approximately 24 months
Other outcomes:
Locations:
city: Fountain Valley
country: United States
facility: Exelixis Clinical Site #12
state: California
city: Jacksonville
country: United States
facility: Exelixis Clinical Site #15
state: Florida
city: Orlando
country: United States
facility: Exelixis Clinical Site #8
state: Florida
city: Tampa
country: United States
facility: Exelixis Clinical Site #16
state: Florida
city: Rochester
country: United States
facility: Exelixis Clinical Site #14
state: Minnesota
city: Kansas City
country: United States
facility: Exelixis Clinical Site #10
state: Missouri
city: New Brunswick
country: United States
facility: Exelixis Clinical Site #9
state: New Jersey
city: New York
country: United States
facility: Exelixis Clinical Site #5
state: New York
city: Cleveland
country: United States
facility: Exelixis Clinical Site #7
state: Ohio
city: Oklahoma City
country: United States
facility: Exelixis Clinical Site #13
state: Oklahoma
city: Germantown
country: United States
facility: Exelixis Clinical Site #11
state: Tennessee
city: Nashville
country: United States
facility: Exelixis Clinical Site #6
state: Tennessee
city: Austin
country: United States
facility: Exelixis Clinical Site #4
state: Texas
city: Houston
country: United States
facility: Exelixis Clinical Site #1
state: Texas
city: Houston
country: United States
facility: Exelixis Clinical Site #2
state: Texas
city: San Antonio
country: United States
facility: Exelixis Clinical Site #3
state: Texas
Study officials:
References: