Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Zanzalintinib · 20 trials · 51 indications
The proportion of participants who have not demonstrated radiographic progression as defined by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or demonstrated clinical progression-free survival (PFS) at 12 months after the start of study treatment. Twelve-month landmark PFS rate will be obtained with 95% confidence interval using the Kaplan-Meier method.
For soft tissue lesions, rPFS is defined as the date of Cycle 1 Day 1 to date of radiologic progression of soft tissue lesions per RECIST 1.1 or death whichever occurs first.
ORR is defined as the proportion of patients who achieve a confirmed complete response (CR) or partial response (PR) according to RECIST1.1.
PFS is defined as the time from the date of initiation of zanzalintinib treatment to progression or death, whichever occurs first. The alive patients without progression are censored at the last follow-up.
Recommended phase 2 dose (RP2D) of XL-092 with Durvalumab plus Tremelimumab will be determined per a Dose Limiting Toxicity period of 28 days during the Safety Lead-in period using CTCAE v5.0 criteria.
Proportion of patients with Complete Response (CR) or Partial Response (PR), per immune modified RECIST v1.1. Per imRECIST: CR: -100% Change in Sum of Diameters from Baseline (non-target lesion). PR: ≤ -30% change in sum of diameters from baseline.
Defined as the time from randomization to the earlier of either radiographic progressive disease (PD) per RECIST 1.1 as determined by the BICR or death from any cause
Defined as the time from randomization to death due to any cause
Rate of hematologic toxicity including neutropenia, anemia, or thrombocytopenia requiring intervention (transfusions or antibiotics)
Rate of non-hematologic toxicity
12-month PFS based on investigator determination of tumor progression (clinical, radiographic, and/or tumor markers including AFP and hCG)
The MTD will be defined as the dose combination with a dose-limiting toxicities (DLT) rate closest to the target DLT rate of 25%.
The RP2D will be defined as the MTD identified after enrollment to all cohorts.
DLTs are defined in the protocol.
Graded using CTCAE version 5.0.
The maximum tolerated dose (MTD) is defined as the dose level immediately below the dose level at which 2 patients of a cohort (of 2 to 6 patients) experience dose-limiting toxicity during the first cycle. Dose escalations will proceed until the MTD has been reached or, if the MTD is not reached, until 6 patients have been treated successfully at the highest dose level (which will then be termed the recommended phase II dose (RP2D)).
As assessed by the Investigator per Response Evaluation Criteria in Solid Tumors guideline version 1.1 (RECIST 1.1).
As assessed by the Investigator per RECIST 1.1.
As assessed by the Investigator per RECIST 1.1.
| Arm | Type | Description |
|---|---|---|
| Zanzalintinib + Pembrolizumab (+) Berahyaluronidase alfa | EXPERIMENTAL | Participants will receive zanzalintinib in combination with pembrolizumab (+) berahyaluronidase alfa for up to 2 years. |
| Zanzalintinib Monotherapy | EXPERIMENTAL | Participants will receive zanzalintinib for up to 2 years. |
| Placebo | EXPERIMENTAL | Participants will receive placebo to match zanzalintinib for up to 2 years. |
| Treatment (Zanzalintinib) | EXPERIMENTAL | Participants will receive 100 mg Zanzalintinib administered orally once a day in 28-day cycles, starting on cycle 1, day 1, and continued until criteria for removal from study are met. Investigator-choice bone-strengthening agent (BSA) will be selected and administered at a standard dose/interval starting within 30 days of cycle 1, day 1. Non-investigational RT for symptomatic metastases, including bone metastases, is allowed per investigator discretion. Participants must receive at least 1 dose of zanzalintinib prior to treatment pause for RT. Participants may continue study treatment until they are unable to tolerate treatment due to toxicity or demonstrate progression (per RECIST) from the time of initiating treatment. |
| Zanzalintinib | EXPERIMENTAL | Zanzalintinib 60mg orally (PO) will be given once daily in subjects with AVPC. |
| Zanzalintinib (XL092) and Nivolumab | EXPERIMENTAL | All subjects will receive zanzalintinib 100mg orally (PO) once daily plus nivolumab standard of care dosing (i.e., 240mg IV every 2 weeks or 480mg IV every 4 weeks) for a total of 12 weeks, followed by restaging scan/evaluation for surgical operability and an adaptive approach that includes (1) surgical resection if the participant is eligible for surgery (Cohort A), (2) up to 48 weeks total (from Cycle 1 Day 1) of zanzalintinib plus nivolumab if the participant has partial response or stable disease but remains inoperable (Cohort B1), or (3) stopping protocol mandated treatment to receive standard of care systemic therapy and continue follow up per protocol if the participant has disease progression (Cohort B2). |
| Safety Lead-in - Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) | EXPERIMENTAL | Safety Lead-in: XL-092: The first dose level (dose level 0) will follow the rolling 6 design\*. The participants enrolled in this study part will receive one cycle of XL-092 60 mg orally (PO) daily plus durvalumab 1500 mg intravenously (IV) every 28 days + tremelimumab 300 mg IV once. In cycle 2 and subsequent cycles, participants will receive XL-092 60 mg orally (PO) daily and durvalumab 1500mg IV every 28-day cycles. DLT period will be 28 days. One level dose reduction will be pursued based DLT read of the dose level 0 participants. For dose level -1, XL-092 will be used at 40mg daily dosing, in combo with the same flat dosings for Durvalumab and Tremelimumab. Safety lead in will be 6-12 patients. |
| Zanzalintinib (XL-092) + Tremelimumab (IV) + Durvalumab (IV) (Begin First Cyle Zanzalintinib) | ACTIVE_COMPARATOR | Phase 2: One cycle of XL-092 RP2D PO daily + durvalumab 1500 mg intravenously (IV) every 28 days + tremelimumab 300 mg IV once. XL- 092 RP2D daily and durvalumab will then be continued every 28 days cycles until discontinuation due to disease progression, intolerability, or withdrawal of consent. |
| Zanzalintinib (XL-092) + Durvalumab (IV) + Tremelimumab (IV) (Begin Second Cyle Zanzalintinib) | ACTIVE_COMPARATOR | Phase 2: One cycle of durvalumab 1500 mg IV + tremelimumab 300 mg IV once followed by XL-092 RP2D mg PO Daily + durvalumab 1500 mg IV every 28 days until discontinuation due to disease progression, intolerability, or withdrawal of consent. |
| Everolimus | ACTIVE_COMPARATOR | Participants will receive everolimus oral tablets once daily. |
| Zanzalintinib + Pembrolizumab | EXPERIMENTAL | Subjects with R/M HNSCC will receive zanzalintinib + pembrolizumab |
| Zanzalintinib-Matched Placebo + Pembrolizumab | PLACEBO_COMPARATOR | Subjects with R/M HNSCC will receive zanzalintinib-matched placebo + pembrolizumab |
| Phase 1 Dose Escalation | EXPERIMENTAL | - |
| Phase II Dose Expansion | EXPERIMENTAL | Patients will be added at highest zanzalintinib dose tolerated, 40mg or 60mg. |
| Dose Level 2 (Starting Dose): Zanzalintinib + Paclitaxel | EXPERIMENTAL | Patients will initiate paclitaxel on a 21-day cycle with the addition of zanzalintinib given on the same schedule. Dosing of zanzalintinib is dictated by the dose escalation schema. After 3 cycles, patients will be assessed for disease response. Patients who have progression will not continue on treatment. Patients who have a partial or complete response or stable disease will continue on treatment for another 3 cycles of paclitaxel + zanzalintinib at the assigned dose. Patients will be assessed for response again at the end of 6 cycles and may continue on treatment if they have partial response or stable disease. Up to 9 cycles of treatment with paclitaxel + zanzalintinib may be given. At the end of the 9 cycles, patients with a SD or PR can continue on maintenance zanzalintinib until progression. Patients with complete response after cycle 6 or 9 will continue single agent zanzalintinib as maintenance therapy until progression. |
| Dose Level 3: Zanzalintinib + Paclitaxel | EXPERIMENTAL | Patients will initiate paclitaxel on a 21-day cycle with the addition of zanzalintinib given on the same schedule. Dosing of zanzalintinib is dictated by the dose escalation schema. After 3 cycles, patients will be assessed for disease response. Patients who have progression will not continue on treatment. Patients who have a partial or complete response or stable disease will continue on treatment for another 3 cycles of paclitaxel + zanzalintinib at the assigned dose. Patients will be assessed for response again at the end of 6 cycles and may continue on treatment if they have partial response or stable disease. Up to 9 cycles of treatment with paclitaxel + zanzalintinib may be given. At the end of the 9 cycles, patients with a SD or PR can continue on maintenance zanzalintinib until progression. Patients with complete response after cycle 6 or 9 will continue single agent zanzalintinib as maintenance therapy until progression. |
| Dose Level 1 (Reduction): Zanzalintinib + Paclitaxel | EXPERIMENTAL | Patients will initiate paclitaxel on a 21-day cycle with the addition of zanzalintinib given on the same schedule. Dosing of zanzalintinib is dictated by the dose escalation schema. After 3 cycles, patients will be assessed for disease response. Patients who have progression will not continue on treatment. Patients who have a partial or complete response or stable disease will continue on treatment for another 3 cycles of paclitaxel + zanzalintinib at the assigned dose. Patients will be assessed for response again at the end of 6 cycles and may continue on treatment if they have partial response or stable disease. Up to 9 cycles of treatment with paclitaxel + zanzalintinib may be given. At the end of the 9 cycles, patients with a SD or PR can continue on maintenance zanzalintinib until progression. Patients with complete response after cycle 6 or 9 will continue single agent zanzalintinib as maintenance therapy until progression. |
| Dose Escalation (Dose Level -1) | EXPERIMENTAL | Participants receive the combination of the following drugs in 42-day cycles: * Zanzalintinib at a dose of 20 mg daily on days 1-42 of each cycle * Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle * Pembrolizumab 400 mg on day 1 of each cycle |
| Dose Escalation (Dose Level 0) | EXPERIMENTAL | Participants receive the combination of the following drugs in 42-day cycles: * Zanzalintinib at a dose of 40 mg daily on days 1-42 of each cycle * Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle * Pembrolizumab 400 mg on day 1 of each cycle This will be the first dose escalation enrolled. Dose Levels 1 and/or -1 will be enrolled depending on side effects seen in participants enrolled to this cohort. |
| Dose Escalation (Dose Level 1) | EXPERIMENTAL | Participants receive the combination of the following drugs in 42-day cycles: * Zanzalintinib at a dose of 60 mg daily on days 1-42 of each cycle * Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle * Pembrolizumab 400 mg on day 1 of each cycle |
| Dose Expansion | EXPERIMENTAL | Participants receive the combination of the following drugs in 42-day cycles: * Zanzalintinib will be dosed daily (days 1-42) at the dose identified as recommended phase 2 dose during dose escalation. * Cetuximab at a dose of 500 mg/m2 on days 1, 15, and 29 of each cycle * Pembrolizumab 400 mg on day 1 of each cycle The expansion cohort will begin enrollment after the dose escalation cohorts have completed enrollment. |
| Dose Escalation Dose Level 1 (starting dose): Zanzalintinib + Nivolumab + Ipilimumab | EXPERIMENTAL | Zanzalintinib 40 mg by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib. |
| Dose Escalation Dose Level 2: Zanzalintinib + Nivolumab + Ipilimumab | EXPERIMENTAL | Zanzalintinib 60 mg by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib. |
| Dose Escalation Dose Level -1: Zanzalintinib + Nivolumab + Ipilimumab | EXPERIMENTAL | Zanzalintinib 20 mg by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib. |
| Expansion: Zanzalintinib + Nivolumab + Ipilimumab | EXPERIMENTAL | Zanzalintinib dose determined in Dose Escalation by mouth once per day is self administered daily, and nivolumab 3 mg/kg intravenously and ipilimumab 1 mg/kg intravenously are administered intravenously every 3 weeks for a total of 4 doses. After completion of the first 4 cycles, ipilimumab is discontinued while nivolumab 480 mg intravenously is continued every 4 weeks in combination with daily zanzalintinib. |
| Dose Level 1 (starting dose): Zanzalintinib + Eribulin | EXPERIMENTAL | Patients will receive zanzalintinib 40 mg by mouth once daily on Days 1 through 21 and eribulin intravenously on Days 1 and 8 of a 21-day cycle. |
| Dose Level 2: Zanzalintinib + Eribulin | EXPERIMENTAL | Patients will receive zanzalintinib 60 mg by mouth once daily on Days 1 through 21 and eribulin intravenously on Days 1 and 8 of a 21-day cycle. |
| Dose Level -1: Zanzalintinib + Eribulin | EXPERIMENTAL | Patients will receive zanzalintinib 20 mg by mouth once daily on Days 1 through 21 and eribulin intravenously on Days 1 and 8 of a 21-day cycle. |
| Moderate HI | EXPERIMENTAL | Participants with moderate HI will receive a single oral dose of zanzalintinib tablet on Day 1. |
| Matched Healthy Control | ACTIVE_COMPARATOR | Matched healthy control participants will receive a single oral dose of zanzalintinib tablet on Day 1. |
| Zanzalintinib + Nivolumab Dose-Escalation Cohorts | EXPERIMENTAL | Approximately 12 participants will accrue across 1-2 dose levels of Zanzalintinib following the "rolling 6" design. |
| Zanzalintinib + Nivolumab + Ipilimumab Dose-Escalation Cohorts | EXPERIMENTAL | Approximately 12 participants will accrue across 1-2 dose levels of Zanzalintinib following the "rolling 6" design. |
| Zanzalintinib + Nivolumab Expansion Cohorts | EXPERIMENTAL | The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts. |
| Zanzalintinib + Nivolumab + Ipilimumab Expansion Cohorts | EXPERIMENTAL | The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts. |
| Zanzalintinib Single-Agent Expansion Cohorts | EXPERIMENTAL | - |
| Zanzalintinib + Nivolumab + Relatlimab Dose-Escalation Cohorts | EXPERIMENTAL | Approximately 12 participants will accrue across 1-2 dose levels of Zanzalintinib following the "rolling 6" design. |
| Zanzalintinib + Nivolumab + Relatlimab Expansion Cohorts | EXPERIMENTAL | The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts. |
| Zanzalintinib + Docetaxel + Prednisone Dose Expansion Cohort | EXPERIMENTAL | Participants with mCRPC, post-androgen receptor pathway inhibitor (post-ARPI), visceral metastases. The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts. |
| Zanzalintinib + DDI Probe Substrates Dose Expansion Cohort | EXPERIMENTAL | Participants in the DDI Cohort. The recommended dose from the dose-escalation stage may be further explored in tumor-specific cohorts. |
| Name | Type | Description |
|---|---|---|
| Zanzalintinib | DRUG | Oral tablets administered once daily. |
| Pembrolizumab (+) Berahyaluronidase alfa | BIOLOGICAL | Pembrolizumab + berahyaluronidase alfa fixed-dose combination administered via subcutaneous (SC) injection once every 3 weeks (Q3W). |
| Placebo | DRUG | Placebo to match zanzalintinib oral tablets administered once daily. |
| Investigator Choice of Bone Strengthening Agents (BSA) | DRUG | One BSA will be chosen, at the discretion of the investigator and given intravenously (IV) |
| Non-Investigational Radiation Therapy (RT) | RADIATION | Non-investigational RT is permitted for symptomatic bone metastases. |
| Bone Scan | PROCEDURE | Undergo Bone Scan |
| Computerized tomography (CT) Scan | PROCEDURE | Undergo Imaging |
| Nivolumab | DRUG | Nivolumab will be administered at either 240mg IV every 2 weeks or 480mg IV 4 every weeks for 12 weeks (all subjects) and up to 48 weeks from Cycle 1 Day 1 (Cohort B1). |
| Durvalumab | DRUG | Durvalumab is a human immunoglobulin G1 kappa (IgG1κ) monoclonal antibody that blocks the interaction of programmed cell death ligand 1 (PD-L1) with the PD-1 (CD279) |
| Tremelimumab | DRUG | Tremelimumab is a fully human monoclonal antibody used for the treatment of hepatocellular carcinoma designed to attach to and block CTLA-4, a protein that controls the activity of T cells |
| Everolimus | DRUG | Administered as specified in the treatment arm. |
| Zanzalintinib-matched Placebo | DRUG | Specified doses on specified days |
| Pembrolizumab | BIOLOGICAL | Specified doses on specified days |
| Etoposide Capsule | DRUG | Oral daily for 21 days of each 28 day cycle. |
| Paclitaxel | DRUG | 175 mg\^m2 intravenous over 3 hours. |
| Cetuximab | DRUG | Food and Drug Administration (FDA) approved monoclonal antibody directed against the epidermal growth factor (EGFR). |
| Ipilimumab | DRUG | Ipilimumab will be commercially sourced. |
| Eribulin | DRUG | 1.1 mg/m\^2 dose. |
| Nivolumab + Relatlimab | DRUG | IV administration of nivolumab + relatlimab |
| Prednisone | DRUG | Administered as IV infusion. |
| Docetaxel | DRUG | Administered as oral tablet. |
| DDI Probe Cocktail | DRUG | Midazolam, Warfarin, Omeprazole, and Caffeine administered orally. |
Key Inclusion Criteria: * Histologically confirmed diagnosis of Stage II or III adenocarcinoma of colon or rectum. * Documented local MSI and/or mismatch repair (MMR) test result demonstrating MSS, MSI-low, or pMMR status. * Colon or rectal cancer with completed definitive therapy. * ctDNA-positive...
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Zanzalintinib is an investigational small molecule kinase inhibitor being studied for multiple cancers, including hepatocellular carcinoma, advanced urothelial carcinoma, uterine and endometrial cancer, neuroendocrine tumors, and clear cell renal cell carcinoma. It is being evaluated in combination with other therapies and as a single agent in clinical trials.
Zanzalintinib is a kinase inhibitor, a class of drugs that block enzymes called kinases involved in cell signaling and growth. Its specific molecular targets have not been disclosed in available information, but it is being studied in oncology for its potential to inhibit tumor growth and progression.
Zanzalintinib is being developed by Exelixis, Inc., a biopharmaceutical company traded on NASDAQ under the ticker symbol EXEL. The company is conducting clinical trials to evaluate the drug's safety and efficacy in various cancer indications.
Zanzalintinib is in Phase 1 and Phase 2 clinical trials. It is an investigational drug, meaning it has not been approved by regulatory authorities and is still undergoing clinical development to assess its safety and effectiveness in treating various cancers.
Zanzalintinib is being studied in several trials, including NCT06698250 for unresectable hepatocellular carcinoma, NCT06795009 for recurrent high grade uterine cancer, NCT06943755 for neuroendocrine tumors, and NCT07185945 for advanced urothelial carcinoma. These trials are recruiting or not yet recruiting participants.
Zanzalintinib is also known as XL-092. In clinical trial NCT06698250, it is referred to as Zanzalintinib (XL-092), confirming that these names refer to the same investigational drug being developed by Exelixis.