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 advancedat a late stage, far along 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.
Intervention / Treatment
- Drug: Zanzalintinib
- Drug: Nivolumab
- Drug: Ipilimumab
- Drug: Nivolumab
- Drug: Nivolumab
- Drug: Nivolumab + Relatlimab
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 recurrenceto occur or happen again occurred 6 months after the last dosethe amount of medication taken.
- 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 carcinomacancer arising from tissues that line organs.
- Expansion Cohort 3 (mCRPC): Men with metastatic adenocarcinomacancer arising from mucus-producing glands in organs of the prostatea walnut-shaped gland in the male reproductive system that is responsible for producing semen - a bodily fluid that acts as a vessel for sperm transport during ejaculation.
- Must have progressed during or after one novel hormone therapymedication that alters the levels of certain hormones in the body, such as oestrogen and progesterone (NHT) given for castration-sensitive locally advanced (T3 or T4) or metastatic castration-sensitive prostate cancera disease where abnormal cells split without control and spread to other nearby body tissue and/or organs (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 bladdera hollow, muscular sac in the pelvis that stores urine, or urethrathe tube that carries urine from the bladder to outside of the body).
- 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 colonthe longest portion of the large bowel that absorbs water and salts from ingested food or rectumthe last section of the large intestine/bowel that holds waste until it is ready to be removed from the body.
- 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 tissuea group of cells that work together to perform a function material, if available, or fresh tumor tissue if it can be safely obtained.
- Recovery to baseline or ≤ Gradea description of how abnormal cancer cells and tissue look under a microscope when compared to healthy cells 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 screeningtesting for cancer or conditions that can lead to cancer before symptoms appear, also known as cancer screening.