A Study of XL092 as Single-Agent and Combination Therapy in Subjects With Solid Tumors (STELLAR-001)

• ClinicalTrials.gov Identifier: NCT03845166
• Recruitment Status: Recruiting
• First Posted: February 19, 2019
• Last Update Posted: December 23, 2022
• Sponsor: Exelixis
• Information provided by (Responsible Party): Exelixis

Tracking Information

• First Submitted Date: February 15, 2019
• First Posted Date: February 19, 2019
• Last Update Posted Date: December 23, 2022
• Actual Study Start Date: March 20, 2019
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: September 21, 2022)

• Dose-Escalation Stage: MTD/recommended dose for XL092 [ Time Frame: Up to 24 months ]
  To determine the maximum tolerated dose (MTD) and/or recommended dose (RD) for further evaluation of XL092 when administered alone and in combination with immune checkpoint inhibitors (ICIs) to subjects with advanced solid tumors
• Cohort-Expansion Stage: Objective Response Rate (ORR) [ Time Frame: Up to 24 months ]
  To evaluate preliminary efficacy of XL092 when administered alone and in combination with ICIs by estimating ORR as assessed by the Investigator per RECIST 1.1
• Cohort-Expansion Stage (except Cohort H): Progression-Free Survival (PFS) [ Time Frame: Up to 24 months ]
  To evaluate preliminary efficacy of single-agent XL092 and XL092 in combination with ICIs for specific cohorts by estimating the percentage of subjects with PFS at 6 months (PFS rate) per RECIST 1.1 as assessed by the Investigator
• Cohort-Expansion Stage (Cohort H only): Overall Survival (OS) [ Time Frame: Up to 24 months ]
  To evaluate preliminary efficacy of single-agent XL092 and XL092 in combination with atezolizumab for subjects with RAS wild-type CRC (Cohort H Treatment Arms H-A and H-B) by estimating overall survival (OS)

Original Primary Outcome Measures (submitted: February 18, 2019)

• MTD/recommended dose for XL092 [ Time Frame: Up to 12 months ]
  To determine the maximum tolerated dose (MTD) and/or recommended dose
• Pharmacokinetics of XL092 [ Time Frame: Up to 24 months ]
  To evaluate the plasma pharmacokinetics of XL092
• Safety and tolerability of XL092 assessed through the evaluation of dose-limiting toxicities and the incidence and severity of nonserious adverse events (AEs) and serious adverse events (SAEs) [ Time Frame: Up to 24 months ]
  To assess safety of XL092 through the evaluation of dose-limiting toxicities and the incidence and severity of nonserious adverse events (AEs) and serious adverse events (SAEs)

Current Secondary Outcome Measures (submitted: June 2, 2021)

• Incidence and Severity of Nonserious Adverse Events (AEs) and Serious Adverse Events (SAEs) [ Time Frame: Up to 36 months ]
  To evaluate the safety of XL092 when administered alone and in combination with ICIs through the evaluation of incidence and severity of nonserious AEs and SAEs, including immune-related adverse events (irAEs), and adverse events of special interest (AESIs)
• Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax) [ Time Frame: Up to 24 months ]
  To evaluate the Tmax of XL092 alone and in combination with ICI
• Dose-Escalation Stage: Maximum Plasma Concentration (Cmax) [ Time Frame: Up to 24 months ]
  To evaluate the Cmax of XL092 alone and in combination with ICI
• Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24) [ Time Frame: Up to 24 months ]
  To evaluate the AUC 0-24 of XL092 alone and in combination with ICI
• Dose-Escalation Stage: Terminal Half-Life [ Time Frame: Up to 24 months ]
  To evaluate the terminal half-life of XL092 alone and in combination with ICI
• Dose-Escalation Stage: Apparent Clearance (CL/F) [ Time Frame: Up to 24 months ]
  To evaluate the CL/F of XL092 alone and in combination with ICI

Original Secondary Outcome Measures (submitted: February 18, 2019)

Preliminary activity of XL092 [ Time Frame: Up to 24 months ]

To evaluate the preliminary antitumor activity of XL092 as assessed by objective responses

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: A Study of XL092 as Single-Agent and Combination Therapy in Subjects With Solid Tumors
• Official Title: A Dose-Escalation and Expansion Study of the Safety and Pharmacokinetics of XL092 as Single-Agent and Combination Therapy in Subjects With Inoperable Locally Advanced or Metastatic Solid Tumors
• Brief Summary: This is a Phase 1, open-label, dose-escalation and expansion study, evaluating the safety, tolerability, pharmacokinetics (PK), preliminary antitumor activity, and effect on biomarkers of XL092 administered alone, in combination with atezolizumab, and in combination with avelumab to subjects with advanced solid tumors.
• Detailed Description: Not Provided
• Study Type: Interventional
• Study Phase: Phase 1

Study Design

Allocation: Non-Randomized
Intervention Model: Sequential Assignment
Intervention Model Description:

single-agent and combination therapy dose-escalation followed by cohort-expansion

Masking: None (Open Label)
Primary Purpose: Treatment

Condition

• Neoplasm Malignant
• Renal Cell Carcinoma
• Hormone Receptor Positive Breast Carcinoma
• Metastatic Castration-resistant Prostate Cancer
• Urothelial Carcinoma
• Colorectal Cancer

Intervention

• Drug: XL092
  oral doses of XL092
• Drug: Atezolizumab
  Supplied as 1200 mg/20 mL vials; administered as a 1200 mg IV infusion once every 3 weeks (q3w)
  Other Name: Tecentriq®
• Drug: Avelumab
  Supplied as 200 mg/10 mL vials; administered as an 800 mg IV infusion once every 2 weeks (q2w)
  Other Name: Bavencio®

Study Arms

• Experimental: XL092 Single-Agent Dose-Escalation Cohorts
  Subjects will accrue in cohorts of 3-6 subjects in a standard "3 plus 3" design.
  Intervention: Drug: XL092
• Experimental: XL092 Single-Agent Expansion Cohorts
  The MTD or recommended dose from the dose-escalation stage may be further explored in clear cell renal cell carcinoma (ccRCC), non-clear cell renal cell carcinoma (nccRCC), hormone receptor-positive breast cancer (HR+ BC), and metastatic castration-resistant prostate cancer (mCRPC).
  Intervention: Drug: XL092
• Experimental: XL092 + Atezolizumab Dose-Escalation Cohorts
  Subjects will accrue in cohorts of 2-6 subjects in a "rolling 6" design.
  Interventions:

  • Drug: XL092
  • Drug: Atezolizumab
• Experimental: XL092 + Atezolizumab Expansion Cohorts
  The MTD or recommended dose from the dose-escalation stage may be further explored in non-clear cell renal cell carcinoma (nccRCC), hormone receptor-positive breast cancer (HR+ BC), metastatic castration-resistant prostate cancer (mCRPC), and colorectal cancer (CRC).
  Interventions:

  • Drug: XL092
  • Drug: Atezolizumab
• Experimental: XL092 + Avelumab Dose-Escalation Cohorts
  Subjects will accrue in cohorts of 2-6 subjects in a "rolling 6" design.
  Interventions:

  • Drug: XL092
  • Drug: Avelumab
• Experimental: XL092 + Avelumab Expansion Cohorts
  The MTD or recommended dose from the dose-escalation stage may be further explored in advanced urothelial carcinoma (UC).
  Interventions:

  • Drug: XL092
  • Drug: Avelumab

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Recruiting
• Estimated Enrollment (submitted: September 21, 2022): 1195
• Original Estimated Enrollment (submitted: February 18, 2019): 100
• Estimated Study Completion Date: November 2024
• Estimated Primary Completion Date: November 2023 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria:

• Cytologically or histologically confirmed solid tumor that is inoperable locally advanced, metastatic, or recurrent.
• Dose-escalation (single-agent and combination therapy): Subjects with a solid tumor that is unresectable or metastatic and for which life-prolonging therapies do not exist or available therapies are intolerable or no longer effective.
• Expansion Cohort A (ccRCC): Subjects with previously treated advanced RCC with clear cell histology (including those with a sarcomatoid component) who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts B and E (nccRCC): Subjects with previously treated advanced RCC with non-clear cell histology who have radiographically progressed following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts C and F (HR+ BC): Subjects with breast cancer that is hormone receptor positive (ER+ and/or PR+) and negative for human epidermal growth factor receptor 2 (HER-2) and who have radiographically progressed during or following treatment with at least one prior systemic anticancer regimen for inoperable locally advanced or metastatic disease.
• Expansion Cohorts D and G (mCRPC): Subjects with metastatic CRPC (adenocarcinoma of the prostate). Neuroendocrine differentiation and other features permitted if adenocarcinoma is the primary histology.

• Expansion Cohort H (CRC): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum, KRAS/NRAS wild-type (confirmed via local testing report) and determined NOT to have microsatellite instability high (MSI-high) or mismatch repair deficient (dMMR) by local testing, who received the following standard of care chemotherapy regimens as prior therapy for metastatic CRC:

  • Fluoropyrimidine, irinotecan and oxaliplatin, with or without an anti-VEGF monoclonal antibody (bevacizumab)
  • Anti-EGFR monoclonal antibody (cetuximab or panitumumab)
  • BRAF inhibitor (in combination with cetuximab +/- binimetinib) for subjects with BRAF V600E mutations
• Expansion Cohort I (UC, Maintenance Therapy): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who received first-line chemotherapy of gemcitabine + cisplatin and/or gemcitabine + carboplatin.
• Expansion Cohort J (UC, ICI-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after PD-1/PD-L1 targeting ICI therapy.
• Expansion Cohort K (UC, platinum-refractory): Subjects with histologically confirmed, unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra) who progressed on or after first-line platinum-based combination therapy.
• Expansion Cohorts: Subjects must have measurable disease per RECIST 1.1, with exception of Cohort I (UC, Maintenance Therapy).

• Tumor tissue material:

  • Subjects in the non-biomarker cohort provide archival, if available, or fresh tumor tissue if it can be safely obtained.
• Recovery to baseline or ≤ Grade 1 severity (CTCAE v5) from adverse events (AEs), including immune-related adverse events (irAEs), related to any prior treatments, unless AE(s) are clinically nonsignificant and/or stable on supportive therapy.
• Eastern Cooperative Oncology Group (ECOG) Performance Status of 0-1.
• Adequate organ and marrow function.
• Sexually active fertile subjects and their partners must agree to use highly effective methods of contraception.
• Female subjects of childbearing potential must not be pregnant at screening.

Exclusion Criteria:

• Prior treatment with XL092 (all cohorts), prior treatment with PD-L1/PD-1 targeting immune checkpoint inhibitor (Cohorts E, F, G, H, I, and K only), prior treatment with avelumab (Cohort J only), or prior treatment with regorafenib and/or TAS-102 (Cohort H only).
• Receipt of any type of small molecule kinase inhibitor within 2 weeks before first dose of study treatment.
• Receipt of any type of anticancer antibody, systemic chemotherapy, or hormonal anticancer therapy within 4 weeks before first dose of study treatment.
• Radiation therapy for bone metastasis within 2 weeks, any other radiation therapy within 4 weeks before first dose of study treatment. Subjects 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.
• Uncontrolled, significant intercurrent or recent illness.
• Concomitant use of certain medications.
• Corrected QT interval calculated by the Fridericia formula (QTcF) > 450 ms for males and > 470 ms for females. Single ECGs are no longer permitted.
• Pregnant or lactating females.
• Diagnosis of another malignancy within 2 years before first dose of study treatment, except for superficial skin cancers, or localized, low grade tumors deemed cured and not treated with systemic therapy.

Additional Exclusion Criteria for XL092 + Atezolizumab Combination Therapy Cohorts ONLY:

• Diagnosis of immunodeficiency or is receiving systemic steroid therapy or any other form of immunosuppressive therapy within 2 weeks prior to first dose of study treatment.
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.

Additional Exclusion Criteria for XL092 + Avelumab Combination Therapy Cohorts ONLY:

• Active autoimmune disease that might deteriorate when receiving an immunostimulatory agent.
• Administration of a live, attenuated vaccine within 30 days before first dose of study treatment.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Contacts

Contact: Exelixis Clinical Trials; 1-888-EXELIXIS (888-393-5494); druginfo@exelixis.com

Contact: Backup or International; 650-837-7400

• Listed Location Countries: Australia, Belgium, Czechia, France, Germany, Italy, Netherlands, Spain, United Kingdom, United States

Administrative Information

• NCT Number: NCT03845166
• Other Study ID Numbers: XL092-001; 2020-003569-21 ( EudraCT Number )
• Has Data Monitoring Committee: Yes

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No

• IPD Sharing Statement: Not Provided
• Current Responsible Party: Exelixis
• Original Responsible Party: Same as current
• Current Study Sponsor: Exelixis
• Original Study Sponsor: Same as current
• Collaborators: Not Provided
• Investigators: Not Provided
• PRS Account: Exelixis
• Verification Date: December 2022