Clinical trial NCT03845166: 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
Study type: INTERVENTIONAL
Overall status: ACTIVE_NOT_RECRUITING
Phase: PHASE1
Conditions: Neoplasm Malignant
Renal Cell Carcinoma
Hormone Receptor Positive Breast Carcinoma
Metastatic Castration-resistant Prostate Cancer
Colorectal Cancer
Lead sponsor: Exelixis
Sponsor class: INDUSTRY
First posted: 2019-02-19
Enrollment: 325
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Intervention model description: single-agent and combination therapy dose-escalation followed by cohort-expansion
Primary purpose: TREATMENT

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.


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 Cohorts: Subjects must have measurable disease per RECIST 1.1.
* 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, and H 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.

Primary outcomes:
measure: Dose-Escalation Stage: MTD/recommended dose for XL092
timeFrame: Up to 24 months
measure: Cohort-Expansion Stage: Objective Response Rate (ORR)
timeFrame: Up to 24 months
measure: Cohort-Expansion Stage (except Cohort H): Progression-Free Survival (PFS)
timeFrame: Up to 24 months
measure: Cohort-Expansion Stage (Cohort H only): Overall Survival (OS)
timeFrame: Up to 24 months
Secondary outcomes:
measure: Incidence and Severity of Nonserious Adverse Events (AEs) and Serious Adverse Events (SAEs)
timeFrame: Up to 36 months
measure: Dose-Escalation Stage: Time to Maximum Plasma Concentration (Tmax)
timeFrame: Up to 24 months
measure: Dose-Escalation Stage: Maximum Plasma Concentration (Cmax)
timeFrame: Up to 24 months
measure: Dose-Escalation Stage: Area Under the Plasma Concentration-Time Curve Over the Last 24-hour Dosing Interval (AUC 0-24)
timeFrame: Up to 24 months
measure: Dose-Escalation Stage: Terminal Half-Life
timeFrame: Up to 24 months
measure: Dose-Escalation Stage: Apparent Clearance (CL/F)
timeFrame: Up to 24 months
Other outcomes:
Locations:
city: Duarte
country: United States
facility: Exelixis Clinical Site #6
state: California
city: La Jolla
country: United States
facility: Exelixis Clinical Site #49
state: California
city: Los Angeles
country: United States
facility: Exelixis Clinical Site #7
state: California
city: Los Angeles
country: United States
facility: Exelixis Clinical Site #84
state: California
city: San Francisco
country: United States
facility: Exelixis Clinical Site #66
state: California
city: Stanford
country: United States
facility: Exelixis Clinical Site #71
state: California
city: Lake Mary
country: United States
facility: Exelixis Clinical Site #15
state: Florida
city: Miami
country: United States
facility: Exelixis Clinical Site #24
state: Florida
city: Atlanta
country: United States
facility: Exelixis Clinical Site #11
state: Georgia
city: Atlanta
country: United States
facility: Exelixis Clinical Site #80
state: Georgia
city: Iowa City
country: United States
facility: Exelixis Clinical Site #41
state: Iowa
city: Westwood
country: United States
facility: Exelixis Clinical Site #36
state: Kansas
city: Scarborough
country: United States
facility: Exelixis Clinical Site #62
state: Maine
city: Baltimore
country: United States
facility: Exelixis Clinical Site #44
state: Maryland
city: Boston
country: United States
facility: Exelixis Clinical Site #4
state: Massachusetts
city: Ann Arbor
country: United States
facility: Exelixis Clinical Site #45
state: Michigan
city: Grand Rapids
country: United States
facility: Exelixis Clinical Site #2
state: Michigan
city: Saint Paul
country: United States
facility: Exelixis Clinical Site #25
state: Minnesota
city: Omaha
country: United States
facility: Exelixis Clinical Site #13
state: Nebraska
city: East Brunswick
country: United States
facility: Exelixis Clinical Site #9
state: New Jersey
city: New Brunswick
country: United States
facility: Exelixis Clinical Site #83
state: New Jersey
city: Bronx
country: United States
facility: Exelixis Clinical Site #85
state: New York
city: New York
country: United States
facility: Exelixis Clinical Site #86
state: New York
city: New York
country: United States
facility: Exelixis Clinical Site #35
state: New York
city: New York
country: United States
facility: Exelixis Clinical #78
state: New York
city: Cincinnati
country: United States
facility: Exelixis Clinical #74
state: Ohio
city: Cleveland
country: United States
facility: Exelixis Clinical Site #60
state: Ohio
city: Hershey
country: United States
facility: Exelixis Clinical Site #59
state: Pennsylvania
city: Philadelphia
country: United States
facility: Exelixis Clinical Site #58
state: Pennsylvania
city: Pittsburgh
country: United States
facility: Exelixis Clinical Site #12
state: Pennsylvania
city: Charleston
country: United States
facility: Exelixis Clinical Site #61
state: South Carolina
city: Myrtle Beach
country: United States
facility: Exelixis Clinical Site #50
state: South Carolina
city: Germantown
country: United States
facility: Exelixis Clinical Site #33
state: Tennessee
city: Nashville
country: United States
facility: Exelixis Clinical Site #87
state: Tennessee
city: Houston
country: United States
facility: Exelixis Clinical Site #3
state: Texas
city: San Antonio
country: United States
facility: Exelixis Clinical Site #1
state: Texas
city: Salt Lake City
country: United States
facility: Exelixis Clinical Site #5
state: Utah
city: Charlottesville
country: United States
facility: Exelixis Clinical Site #8
state: Virginia
city: Richmond
country: United States
facility: Exelixis Clinical Site #43
state: Virginia
city: Spokane
country: United States
facility: Exelixis Clinical Site #26
state: Washington
city: Darlinghurst
country: Australia
facility: Exelixis Clinical Site #52
state: New South Wales
city: Liverpool
country: Australia
facility: Exelixis Clinical Site #53
state: New South Wales
city: South Brisbane
country: Australia
facility: Exelixis Clinical #75
state: Queensland
city: Kurralta Park
country: Australia
facility: Exelixis Clinical Site #56
state: South Australia
city: Heidelberg
country: Australia
facility: Exelixis Clinical Site #63
state: Victoria
city: Edegem
country: Belgium
facility: Exelixis Clinical Site #44
state: Antwerpen
city: Gent
country: Belgium
facility: Exelixis Clinical Site #65
state: Oost-Vlaanderen
city: Brussels
country: Belgium
facility: Exelixis Clinical Site #51
city: Brno
country: Czechia
facility: Exelixis Clinical Site #21
city: Hradec Králové
country: Czechia
facility: Exelixis Clinical Site #42
city: Olomouc
country: Czechia
facility: Exelixis Clinical Site #10
city: Praha
country: Czechia
facility: Exelixis Clinical Site #27
city: Clermont
country: France
facility: Exelixis Clinical Site #46
state: Ferrand
city: Saint-Herblain Cedex
country: France
facility: Exelixis Clinical Site #37
state: Loire Atlantique
city: Bordeaux
country: France
facility: Exelixis Clinical #72
city: Caen Cedex 5
country: France
facility: Exelixis Clinical Site #32
city: Marseille
country: France
facility: Exelixis Clinical Site #48
city: Paris
country: France
facility: Exelixis Clinical Site #14
city: Pierre-Bénite
country: France
facility: Exelixis Clinical Site #39
city: Poitiers
country: France
facility: Exelixis Clinical Site #47
city: Suresnes
country: France
facility: Exelixis Clinical Site #22
city: Toulouse Cedex 9
country: France
facility: Exelixis Clinical Site #57
city: Villejuif
country: France
facility: Exelixis Clinical #77
city: Nürtingen
country: Germany
facility: Exelixis Clinical Site #38
state: Baden-Wuerttemberg
city: Münster
country: Germany
facility: Exelixis Clinical Site #31
state: Nordrhein-Westfalen
city: Hamburg
country: Germany
facility: Exelixis Clinical Site #64
city: Milan
country: Italy
facility: Exelixis Clinical Site #67
state: MI
city: Pavia
country: Italy
facility: Exelixis Clinical Site #69
state: PV
city: Milan
country: Italy
facility: Exelixis Clinical Site #54
city: Napoli
country: Italy
facility: Exelixis Clinical #73
city: Amsterdam
country: Netherlands
facility: Exelixis Clinical Site #79
state: Noord-Holland
city: Rotterdam
country: Netherlands
facility: Exelixis Clinical #76
state: South Holland
city: Sabadell
country: Spain
facility: Exelixis Clinical Site #23
state: Barcelona
city: Santiago De Compostela
country: Spain
facility: Exelixis Clinical Site #20
state: La Coruna
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #18
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #19
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #29
city: Barcelona
country: Spain
facility: Exelixis Clinical Site #30
city: Madrid
country: Spain
facility: Exelixis Clinical Site #81
city: Madrid
country: Spain
facility: Exelixis Clinical Site #34
city: Madrid
country: Spain
facility: Exelixis Clinical Site #55
city: Madrid
country: Spain
facility: Exelixis Clinical Site #17
city: Sevilla
country: Spain
facility: Exelixis Clinical Site #16
city: London
country: United Kingdom
facility: Exelixis Clinical #70
state: England
city: Sutton
country: United Kingdom
facility: Exelixis Clinical Site #40
state: England
city: Preston
country: United Kingdom
facility: Exelixis Clinical Site #68
state: Lancashire
Study officials:
References: