study of xl092 in combination with immuno-oncology agents in subjects with solid tumors

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

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.