Clinical Trial 21636

• Overview

  Study Title:

  A Dose-Escalation and Expansion Study of the Safety and Efficacy of XL092 in Combination with Immuno-Oncology Agents in Subjects with Unresectable Advanced or Metastatic Solid Tumors

  Summary:

  This is a multicenter Phase 1b, open label, dose-escalation and cohort-expansion study, evaluating the safety, tolerability, PK, preliminary antitumor activity, and effect of biomarkers of XL092 administered alone, and in combination with nivolumab (doublet) and nivolumab + ipilimumab (triplet) in patients with advanced solid tumors. In the Expansion Stage, the safety and efficacy of XL092 as combination therapy will be further evaluated in tumor-specific Expansion Cohorts, which will enroll patients with genitourinary cancers.

  Objective:

  Dose-Escalation Stage (XL092 Combination Therapy): The objectives of the Dose-Escalation Stage are to determine the recommended dose (RD) and evaluate the safety, tolerability, pharmacokinetics (PK), immunogenicity and pharmacodynamics of XL092 in combination with the immuno-oncology agents nivolumab (doublet), nivolumab + ipilimumab (triplet), and nivolumab + BEMPEG (triplet) in subjects with advanced cancers. Expansion Stage (XL092 Monotherapy and Combination Therapy): The objectives of the Expansion Stage are to assess the preliminary efficacy of XL092 alone and in combination therapy regimens in tumor-specific cohorts, determine the safety of the combination therapy regimens, determine the contribution of treatment components, and further evaluate the plasma PK of daily oral XL092 administered as a single agent or in combination therapy in subjects with advanced genitourinary cancers.

• Treatments

  Therapies:

  Immunotherapy

  Medications:

  BMS-936558 (Nivolumab); BMS-986016 (Relatlimab); Bempegaldesleukin (); Ipilimumab (); NKTR-214 (Bempegaldesleukin); Nivolumab (Opdivo); Relatlimab (); XL092 (); Yervoy (Ipilimumab)

• Inclusion Criteria

  Inclusion Criteria:
  • Cytologically or histologically confirmed solid tumor that is unresectable, locally advanced or metastatic
  • Dose-Escalation Cohorts: 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 1 (ccRCC): Sunresectable advanced or metastatic RCC with a clear cell component who have not received prior systemic therapy. Note: Prior non-VEGF targeted adjuvant or neoadjuvant is allowed if disease recurrence occurred 6 months after the last dose
  • Expansion Cohort 2 (ccRCC): unresectable advanced or metastatic RCC with a clear cell component. Must have radiographically progressed after a combination therapy consisting of a PD-1/PD-L1 targeting mAb with a VEGFR-TKI or a PD-1/PD-L1 targeting mAb with a CTLA-4 mAb as the preceding line of therapy. Must have received no more than one prior systemic anticancer therapy for unresectable advanced or metastatic renal cell carcinoma
  • Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinoma of the prostate. Must have progressed during or after one NHT given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancer (CSPC), M0 CRPC, or mCRPC
  • Expansion Cohort 4 (UC, ICI-naive): histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra). Must have progressed during or after prior first-line platinum-based combination therapy, including subjects who received prior neoadjuvant or adjuvant platinum-containing therapy with disease recurrence > Expansion Cohort 5 (UC, ICI-experienced): histologically confirmed unresectable, locally advanced or metastatic transitional cell carcinoma of the urothelium (including the renal pelvis, ureter, urinary bladder, or urethra). Must have progressed during or after prior PD-1/PD-L1 targeting ICI therapy given as monotherapy, combination therapy, maintenance therapy or adjuvant therapy. Must have received no more than 2 prior lines of systemic anticancer therapy for unresectable advanced or metastatic disease
  • Expansion Cohort 6 (nccRCC): unresectable advanced or metastatic nccRCC of the following subtypes: Papillary RCC (any type), unclassified RCC, and translocation-associated. Among the eligible histologic subtypes, sarcomatoid features are allowed. No prior systemic anticancer therapy is allowed except adjuvant or neoadjuvant therapy if disease recurrence occurred at least 6 months after the last dose
  • Expansion Cohort 7 (HCC, 1L) inoperable locally advanced, recurrent, or metastatic HCC that is not amenable to curative treatment or locoregional therapy
  • Must have not received prior systemic anticancer therapy for inoperable locally advanced, recurrent, or metastatic HCC
  • Expansion Cohort 8 (NSCLC, PD-L1 low, 1L): Stage IV non-squamous NSCLC with positive PD-L1 expression (tumor proportion score [TPS] 1-49%) and without prior systemic anticancer therapy for metastatic disease
  • Expansion Cohort 9 (NSCLC, 2L+): Stage IV non-squamous NSCLC who have radiologically progressed following treatment with one prior immune checkpoint inhibitor (anti-PD-1 or anti-PD-L1) for metastatic disease
  • Expansion Cohort 10 (CRC, 2L+): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum.
  • Expansion Cohort 11 (HNSCC, ICI-naive):Subject with inoperable, refractory, recurrent or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx. PD-L1 combined positive score (CPS) >1.

• Exclusion Criteria

  Exclusion Criteria:
  • For all Dose-Escalation cohorts: Prior treatment with XL092. For all Expansion Cohorts: Prior treatment with XL092, nivolumab, or ipilimumab with the following exceptions: Prior PD-1/PD-L1 and CTLA-4 targeting therapy for locally advanced or metastatic disease is allowed for Cohorts 2 (ccRCC 2L) and 5 (UC [ICI-experienced]).
  • For all Dose-Escalation Cohorts and Expansion Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC): Receipt of any type of small molecule kinase inhibitor (including investigational kinase inhibitor) within 2 weeks before first dose of study treatment.
  • For Cohort 3 (mCRPC): Receipt of abiraterone within 1 week; cyproterone within 10 days; or receipt of flutamide, nilutamide, bicalutamide, enzalutamide, or other androgen receptor inhibitors within 2 weeks before first dose of study treatment.
  • For all Dose-Escalation Cohorts and Expansion Cohorts 2 (ccRCC), 3 (mCRPC), 4 and 5 (UC): Receipt of any type of anticancer antibody or systemic chemotherapy within 4 weeks before first dose of study treatment.
  • Any complementary medications (e.g., herbal supplements or traditional Chinese medicines) to treat the disease under study within 2 weeks before first dose of study treatment.
  • Prior external radiation therapy within 2 weeks and prior radium-223 therapy within 6 weeks before first dose of study treatment.
  • Known brain metastases or cranial epidural disease unless adequately treated with radiotherapy (including radiosurgery) or surgically removed and stable for at least 4 weeks before first dose of study treatment.
  • Concomitant anticoagulation with oral anticoagulants and platelet inhibitors.
  • Administration of a live, attenuated vaccine within 30 days prior to enrollment.
  • Uncontrolled, significant intercurrent or recent illness.
  • Corrected QT interval calculated by the Fridericia formula (QTcF) > 480 ms per electrocardiogram (ECG) within 14 days before first dose of study treatment.
  • Patients with inadequately treated adrenal insufficiency.
  • Pregnant or lactating females.
  • Any other active malignancy within two years before first dose of study treatment, except for locally curable cancers that have been apparently cured such as basal or squamous cell skin cancer, superficial bladder cancer, or carcinoma in situ of the prostate, cervix, or breast. Note: Additional Inclusion and Exclusion criteria may apply.

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