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

Cancer Categories

Genitourinary (GU)

Karmanos Trial ID

2022-084

NCT ID

NCT05176483

Age Group

Adult

Scope

National

Phase

Phase I

Principal Investigator

Elisabeth
Heath, M.D., FACP
Oncology - Medical View Profile

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/relatlimab (triplet) in subjects with advanced cancers.

The endpoints used to achieve the objectives are as follows:

Primary:

Incidence and severity of adverse events (AEs) and serious adverse events (SAEs), including immune-mediated adverse events (imAEs)

Exploratory:

Objective response rate (ORR) and duration of response (DOR) as assessed by the Investigator per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1)
Progression-free survival (PFS) as assessed by the Investigator per RECIST 1.1
Concentration of study treatments (XL092, nivolumab, ipilimumab, and relatlimab) in plasma or serum at different timepoints
Correlation measured between PK of XL092 and selected biomarkers with respect to preliminary safety and efficacy outcomes
The number and percentage of subjects who develop antidrug antibody (ADA) response to nivolumab, ipilimumab, or relatlimab

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, isolate the contribution of treatment components if applicable, and further evaluate the plasma PK of daily oral XL092 administered as a single agent or in combination therapy in subjects with advanced solid tumors.

The endpoints used to achieve the objectives are as follows:

Primary:

ORR in subjects with measurable disease as assessed by the Investigator per RECIST 1.1
For Cohort 3 (metastatic castration-resistant prostate cancer [mCRPC]): duration of radiographic PFS as determined per Prostate Working Group 3 (PCWG3) criteria (Scher et al 2016) by Blinded Independent Radiology Committee (BIRC)
For Cohort 10 (CRC): Overall survival (OS) rate at 6 months.
Incidence and severity of nonserious AEs and SAEs, including imAEs

Secondary:

Duration of response (DOR) based on assessment by the Investigator per RECIST 1.1
Progression-free survival (PFS) for subjects with measurable disease as assessed by the Investigator per RECIST 1.1

Exploratory:

For Cohort 3 (mCRPC):

Proportion of subjects achieving a > 50% decrease in prostate-specific antigen (PSA) from baseline confirmed by a second consecutive PSA assessment at least 3 weeks later
Change in bone biomarkers

ORR, DOR, and PFS for subjects with measurable disease as assessed by a BIRC per RECIST 1.1 for selected cohorts as determined by the Sponsor
Overall survival (OS)
Concentration of study treatments (XL092, nivolumab, ipilimumab, and relatlimab) in plasma or serum at different timepoints
Change in tumor and blood biomarkers
The number and percentage of subjects who develop ADA response to nivolumab, ipilimumab, or relatlimab

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Eligibility

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.

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