Clinical trial NCT05176483: Study of XL092 in Combination With Immuno-Oncology Agents in Subjects With Solid Tumors
Official 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Renal Cell Carcinoma
Metastatic Castration-resistant Prostate Cancer
Urothelial Carcinoma
Solid Tumor
Hepatocellular Carcinoma
Non-small Cell Lung Cancer
Colorectal Cancer
Head and Neck Squamous Cell Carcinoma
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2022-01-04
Enrollment: 1274
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: Dose-escalation followed by expansion phase with parallel assignment.
Primary purpose: TREATMENT

Brief 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), nivolumab + ipilimumab (triplet) and nivolumab + relatlimab (triplet) in subjects with advanced solid tumors.

In the Expansion Stage, the safety and efficacy of XL092 as monotherapy and in combination therapy will be further evaluated in tumor-specific Expansion Cohorts.


Eligibility 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): Subjects with unresectable 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): Subjects with 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 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 novel hormone therapy (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): Subjects with 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 \< 12 months from the end of last therapy.
  * Must have received no more than 1 prior line of systemic anticancer therapy for unresectable, locally advanced or metastatic disease.
* Expansion Cohort 5 (UC, ICI-experienced): Subjects with 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): Subjects with unresectable advanced or metastatic nccRCC of the following subtypes: Papillary, unclassified RCC, and translocation-associated, FH deficient and SDH deficient. 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): Subjects with locally advanced, or metastatic and/or unresectable HCC that is not amenable to curative treatment or locoregional therapy.
* Expansion Cohort 8 (NSCLC): Subjects with 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): Subjects with 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): Subjects with histologically confirmed unresectable, locally advanced, or metastatic adenocarcinoma of the colon or rectum.
* Expansion Cohort 11 (HNSCC): Subject with inoperable, refractory, recurrent or metastatic HNSCC of the oral cavity, oropharynx, hypopharynx, and larynx. PD-L1 combined positive score (CPS) ≥1.
* Expansion Cohort 12 (ccRCC): Subjects with unresectable advance or metastatic RCC with a clear cell component, including subjects who also have a sacromatoid feature.

  * Must have received no more than two prior lines of systemic anticancer therapy for unresectable advanced or metastatic renal cell carcinoma
* Expansion Cohort 13 (ccRCC): Subjects with unresectable advanced or metastatic RCC with a clear component, including subjects who also have a sacromatoid feature.
* For all Expansion Cohorts except Cohort 3: Measurable disease per RECIST 1.1 as determined by the Investigator.
* For Expansion Cohorts 1 - 11 Only: Archival tumor tissue material, if available, or fresh tumor tissue if it can be safely obtained.
* Recovery to baseline or ≤ Grade 1 common terminology criteria for adverse events (CTCAE) v5 from AE(s) related to any prior treatments unless AE(s) are deemed clinically nonsignificant by the Investigator and/or stable on supportive therapy.
* Karnofsky Performance Status (KPS) ≥ 70%.
* 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:

* For all Dose-Escalation cohorts: Prior treatment with XL092. For all Expansion Cohorts: Prior treatment with XL092, nivolumab, ipilimumab or relatlimab with the following exceptions: Prior PD-1/PD-L1, LAG-3 and CTLA-4 targeting therapy for locally advanced or metastatic disease is allowed for Cohort 2 (ccRCC), Cohort 5 (UC), Cohort 9 (NSCLC), and Cohort 12 (ccRCC), and prior treatment in the neoadjuvant or adjuvant setting is allowed for Cohort 13 (ccRCC).
* For all Dose-Escalation Cohorts and Expansion Cohort 2 (ccRCC), 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC), Cohort 10 (CRC), and Cohort 12: 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 Cohort 2 (ccRCC), Cohort 3 (mCRPC), Cohort 5 (UC), Cohort 9 (NSCLC) and Cohort 10 (CRC), and Cohort 12: Receipt of any type of anticancer antibody or systemic chemotherapy within 4 weeks before first dose of study treatment.
* Any complementary medications (eg, 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 for bone metastasis within 2 weeks, for other tumor sites within 4 weeks, and prior radium-223 therapy within 6 weeks before first dose of study treatment, unless otherwise specified.
* 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.
* Concomitant anticoagulation with oral anticoagulants, except for specified direct factor Xa inhibitors.
* Administration of a live, attenuated vaccine within 30 days prior to first dose.
* Uncontrolled, significant intercurrent or recent illness.
* Corrected QT interval calculated by the Fridericia formula (QTcF) \> 460 ms for females and \> 450 ms for males per electrocardiogram (ECG) within 14 days before first dose of study treatment.
* Subjects with inadequately treated adrenal insufficiency.
* Pregnant or lactating females.
* Any other active malignancy within two 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. Incidentally diagnosed prostate cancer is allowed if assessed as stage ≤ T2N0M0 and Gleason score ≤ 6.
* For Cohort 2 (ccRCC, 2L): Receipt of a prior triplet therapy including a VEGFR-TKI, a PD1 targeting mAb, and a CTLA-4 mAb.
* For Cohort 3 (mCRPC): Receipt of a taxane-based chemotherapy for mCRPC.
* For Cohort 4 (UC, ICI-naïve): Subjects who have had recurrence within the 6 months of completing adjuvant anti-PD-(L)1 treatment.
* For Cohort 6 (nccRCC, 1L): Subjects with chromophobe, renal medullary carcinoma, or pure collecting duct nccRCC.
* For Cohort 7 (HCC):

  * Documented hepatic encephalopathy (HE) within 6 months before the first dose.
  * Clinically meaningful ascites (ie, ascites requiring paracentesis or escalation in diuretics) within 6 months before randomization.
  * Subjects who have received any local anticancer therapy including surgery, PEI, RFA, MWA, transarterial chemoembolization (TACE), or transarterial radioembolization (TARE) within 28 days prior to first dose.
  * Subjects with known fibrolamellar carcinoma, sarcomatoid HCC, or mixed hepatocellular cholangiocarcinoma
* For Cohort 10 (CRC, 2L+): Receipt of prior therapy with regorafenib and/or trifluridine + tipiracil (TAS-102).
* For Cohort 11 (HNSCC): Primary tumor site of the nasopharyngeal area.
* For Cohorts 1 (ccRCC, 1L), 2 (ccRCC, 2L), 4, 5 (UC), 7 (HCC), 8 (NSCLC 1L PD-L1 low), 9 (NSCLC, 2L+), 10 (CRC, MSS, 2L+), and 11 (HNSCC):

  * Troponin T (TnT) or I (TnI) \> 2 × institutional ULN.

Note: Additional Inclusion and Exclusion criteria may apply.

Primary outcomes:
measure: Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including immune-mediated adverse events (imAEs)
timeFrame: up to 36 months
measure: Expansion Stage: Objective Response Rate (ORR)
timeFrame: up to 24 months
measure: Expansion Stage: Progression-Free Survival (PFS)
timeFrame: up to 24 months
measure: Expansion Stage: Overall Survival (OS)
timeFrame: 6 months
Secondary outcomes:
Other outcomes:
Locations:
city: Phoenix
country: United States
facility: Exelixis Clinical Site #67
state: Arizona
city: Tucson
country: United States
facility: Exelixis Clinical Site #1
state: Arizona
city: Palo Alto
country: United States
facility: Exelixis Clinical Site #123
state: California
city: Santa Barbara
country: United States
facility: Exelixis Clinical Site #59
state: California
city: Littleton
country: United States
facility: Exelixis Clinical Site #87
state: Colorado
city: New Haven
country: United States
facility: Exelixis Clinical Site #62
state: Connecticut
city: Newark
country: United States
facility: Exelixis Clinical Site #49
state: Delaware
city: Celebration
country: United States
facility: Exelixis Clinical Site #48
state: Florida
city: Gainesville
country: United States
facility: Exelixis Clinical Site #11
state: Florida
city: Jacksonville
country: United States
facility: Exelixis Clinical Site #78
state: Florida
city: Miami
country: United States
facility: Exelixis Clinical Site #47
state: Florida
city: Plantation
country: United States
facility: Exelixis Clinical Site #61
state: Florida
city: Tampa
country: United States
facility: Exelixis Clinical Site #8
state: Florida
city: Chicago
country: United States
facility: Exelixis Clinical Site #26
state: Illinois
city: Indianapolis
country: United States
facility: Exelixis Clinical Site #4
state: Indiana
city: Louisville
country: United States
facility: Exelixis Clinical Site #122
state: Kentucky
city: Baltimore
country: United States
facility: Exelixis Clinical Site #14
state: Maryland
city: Boston
country: United States
facility: Exelixis Clinical Site #7
state: Massachusetts
city: Detroit
country: United States
facility: Exelixis Clinical Site #65
state: Michigan
city: Detroit
country: United States
facility: Exelixis Clinical Site #13
state: Michigan
city: Rochester
country: United States
facility: Exelixis Clinical Site #68
state: Minnesota
city: Omaha
country: United States
facility: Exelixis Clinical Site #2
state: Nebraska
city: Omaha
country: United States
facility: Exelixis Clinical Site #5
state: Nebraska
city: Las Vegas
country: United States
facility: Exelixis Clinical Site #55
state: Nevada
city: East Brunswick
country: United States
facility: Exelixis Clinical Site #88
state: New Jersey
city: Hackensack
country: United States
facility: Exelixis Clinical Site #105
state: New Jersey
city: New York
country: United States
facility: Exelixis Clinical Site #60
state: New York
city: New York
country: United States
facility: Exelixis Clinical Site #6
state: New York
city: Syracuse
country: United States
facility: Exelixis Clinical Site #76
state: New York
city: Durham
country: United States
facility: Exelixis Clinical Site #12
state: North Carolina
city: Cleveland
country: United States
facility: Exelixis Clinical Site #10
state: Ohio
city: Portland
country: United States
facility: Exelixis Clinical Site #51
state: Oregon
city: Hershey
country: United States
facility: Exelixis Clinical Site #104
state: Pennsylvania
city: Philadelphia
country: United States
facility: Exelixis Clinical Site #98
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Exelixis Clinical Site #32
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Exelixis Clinical Site #24
state: Pennsylvania
city: Myrtle Beach
country: United States
facility: Exelixis Clinical Site #9
state: South Carolina
city: Nashville
country: United States
facility: Exelixis Clinical Site #3
state: Tennessee
city: Austin
country: United States
facility: Exelixis Clinical Site #46
state: Texas
city: Dallas
country: United States
facility: Exelixis Clinical Site #111
state: Texas
city: Dallas
country: United States
facility: Exelixis Clinical Site #89
state: Texas
city: Irving
country: United States
facility: Exelixis Clinical Site #73
state: Texas
city: Plano
country: United States
facility: Exelixis Clinical Site #50
state: Texas
city: Tyler
country: United States
facility: Exelixis Clinical Site #70
state: Texas
city: Charlottesville
country: United States
facility: Exelixis Clinical Site #66
state: Virginia
city: Milwaukee
country: United States
facility: Exelixis Clinical Site #33
state: Wisconsin
city: Albury
country: Australia
facility: Exelixis Clinical Site #116
city: Birtinya
country: Australia
facility: Exelixis Clinical Site #35
city: Brisbane
country: Australia
facility: Exelixis Clinical Site #16
city: Saint Leonards
country: Australia
facility: Exelixis Clinical Site #42
city: Sydney
country: Australia
facility: Exelixis Clinical Site #36
city: Graz
country: Austria
facility: Exelixis Clinical Site #94
city: Salzburg
country: Austria
facility: Exelixis Clinical Site #31
city: Wein
country: Austria
facility: Exelixis Clinical Site #106
city: Wien
country: Austria
facility: Exelixis Clinical Site #29
city: Anderlecht
country: Belgium
facility: Exelixis Clinical Site #39
city: Kortrijk
country: Belgium
facility: Exelixis Clinical Site #37
city: Besançon
country: France
facility: Exelixis Clinical Site #85
city: Bordeaux
country: France
facility: Exelixis Clinical Site #96
city: Caen
country: France
facility: Exelixis Clinical Site #79
city: Clermont-Ferrand
country: France
facility: Exelixis Clinical Site #118
city: Lyon
country: France
facility: Exelixis Clinical Site #109
city: Marseille
country: France
facility: Exelixis Clinical Site #92
city: Nice
country: France
facility: Exelixis Clinical Site #64
city: Paris
country: France
facility: Exelixis Clinical Site #83
city: Paris
country: France
facility: Exelixis Clinical Site #91
city: Rennes
country: France
facility: Exelixis Clinical Site #80
city: Saint-Herblain
country: France
facility: Exelixis Clinical Site #63
city: Strasbourg
country: France
facility: Exelixis Clinical Site #75
city: Vandœuvre-lès-Nancy
country: France
facility: Exelixis Clinical Site #84
city: Villejuif
country: France
facility: Exelixis Clinical Site #115
city: Essen
country: Germany
facility: Exelixis Clinical Site #103
city: Hamburg
country: Germany
facility: Exelixis Clinical Site #113
city: Heidelberg
country: Germany
facility: Exelixis Clinical Site #108
city: Herne
country: Germany
facility: Exelixis Clinical Site #82
city: Jena
country: Germany
facility: Exelixis Clinical Site #93
city: München
country: Germany
facility: Exelixis Clinical Site #112
city: Nürtingen
country: Germany
facility: Exelixis Clinical Site #102
city: Trier
country: Germany
facility: Exelixis Clinical Site #107
city: Tübingen
country: Germany
facility: Exelixis Clinical Site #95
city: Be'er Sheva
country: Israel
facility: Exelixis Clinical Site #86
city: Haifa
country: Israel
facility: Exelixis Clinical Site #72
city: Jerusalem
country: Israel
facility: Exelixis Clinical Site #52
city: Petah Tikva
country: Israel
facility: Exelixis Clinical Site #71
city: Tel Aviv
country: Israel
facility: Exelixis Clinical Site #69
city: Zerifin
country: Israel
facility: Exelixis Clinical Site #38
city: Ancona
country: Italy
facility: Exelixis Clinical Site #121
city: Bologna
country: Italy
facility: Exelixis Clinical Site #117
city: Firenze
country: Italy
facility: Exelixis Clinical Site #90
city: Milano
country: Italy
facility: Exelixis Clinical Site #101
city: Milano
country: Italy
facility: Exelixis Clinical Site #81
city: Napoli
country: Italy
facility: Exelixis Clinical Site #40
city: Ravenna
country: Italy
facility: Exelixis Clinical Site #74
city: Grafton
country: New Zealand
facility: Exelixis Clinical Site #30
city: Hamilton
country: New Zealand
facility: Exelixis Clinical Site #45
city: Bydgoszcz
country: Poland
facility: Exelixis Clinical Site #20
city: Gdańsk
country: Poland
facility: Exelixis Clinical Site #28
city: Otwock
country: Poland
facility: Exelixis Clinical Site #34
city: Poznań
country: Poland
facility: Exelixis Clinical Site #54
city: Wrocław
country: Poland
facility: Exelixis Clinical Site #114
city: Badajoz
country: Spain
facility: Exelixis Clinical Site #41
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #53
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #15
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #27
city: L'Hospitalet De Llobregat
country: Spain
facility: Exelixis Clinical Site #120
city: Madrid
country: Spain
facility: Exelixis Clinical Site #57
city: Madrid
country: Spain
facility: Exelixis Clinical Site #43
city: Madrid
country: Spain
facility: Exelixis Clinical Site #58
city: Madrid
country: Spain
facility: Exelixis Clinical Site #77
city: Madrid
country: Spain
facility: Exelixis Clinical Site #19
city: Madrid
country: Spain
facility: Exelixis Clinical Site #100
city: Pamplona
country: Spain
facility: Exelixis Clinical Site #18
city: Santander
country: Spain
facility: Exelixis Clinical Site #119
city: Seville
country: Spain
facility: Exelixis Clinical Site #23
city: Valencia
country: Spain
facility: Exelixis Clinical Site #56
city: Valencia
country: Spain
facility: Exelixis Clinical Site #25
city: Chur
country: Switzerland
facility: Exelixis Clinical Site #21
city: St. Gallen
country: Switzerland
facility: Exelixis Clinical Site #22
city: Winterthur
country: Switzerland
facility: Exelixis Clinical Site #44
city: Cambridge
country: United Kingdom
facility: Exelixis Clinical Site #110
city: London
country: United Kingdom
facility: Exelixis Clinical Site #99
city: Middlesex
country: United Kingdom
facility: Exelixis Clinical Site #97
Study officials:
References: