Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Belzutifan · 23 trials · 50 indications
PFS is defined as the time from randomization to the first documented disease progression per Response Evaluation Criteria in Solid Tumors Version 1.1 (RECIST 1.1) based on blinded independent central review (BICR) or death due to any cause, whichever occurs first.
OS is defined as the time from randomization to death due to any cause.
Overall survival is defined as the time from randomization or the first dose of any study intervention in the parent study to death due to any cause.
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. PD will be assessed by Response Criteria in Solid Tumors Version 1.1 (RECIST 1.1). PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review (BICR) will be presented.
DFS is defined as the time from randomization to the first documented local recurrence, or occurrence of distant kidney cancer metastasis(es) as assessed by investigator, or death due to any cause, whichever occurs first. The DFS for all participants will be presented.
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review will be presented.
PFS is defined as the time from randomization to the first documented progressive disease (PD) or death due to any cause, whichever occurs first. Per RECIST 1.1, PD is defined as ≥20% increase in the sum of diameters of target lesions. In addition to the relative increase of 20%, the sum must also demonstrate an absolute increase of ≥5 mm. The appearance of one or more new lesions is also considered PD. PFS as assessed by blinded independent central review is presented here.
ORR is defined as the percentage of participants achieving complete response (CR) or partial response (PR) on treatment based on RECIST 1.1 criteria. Per RECIST 1.1 for target lesions: CR is complete disappearance of all target lesions and PR is at least a 30% decrease in the sum of longest diameter (LD) of target lesions, taking as reference baseline sum LD. PR or better overall response assumes at a minimum incomplete
Progression-Free Survival at 6 Months (PFS6) is defined as the proportion of participants who are alive without disease progression for at least 6 months after initiating study treatment.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants that experience AEs will be reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention. The number of participants that discontinue study intervention due to an AE will be reported.
ORR is the percentage of participants with complete response (CR: disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions, taking as reference the baseline sum of the diameters of target lesions) until progressive disease (PD, at least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest sum on study. The appearance of one or more new lesions is also considered progression) or death due to any cause, whichever occurs first.
ORR was defined as the percentage of participants who had a complete response (CR: Disappearance of all target lesions) or a partial response (PR: At least a 30% decrease in the sum of diameters of target lesions) per RECIST 1.1. The percentage of participants who experienced a CR or PR as assessed by blinded independent central review based on RECIST 1.1 was presented.
ORR is defined as the percentage of participants with a best confirmed response of Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: ≥30% decrease in the sum of diameters of target lesions) as determined by the investigator using Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1).
ORR is defined as the percentage of participants in the analysis population who have a best confirmed response of Complete Response (CR: Disappearance of all target lesions) or a Partial Response (PR: At least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria in Solid Tumors version 1.1 (RECIST 1.1). ORR will be assessed by independent review committee (ICR) for the primary analysis.
Blood samples will be collected to determine the AUC0-inf of metformin in plasma.
DLTs are defined as any of a pre-specified list of toxicities if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
DLTs are defined as any of a pre-specified list of toxicities if assessed by the investigator to be possibly, probably, or definitely related to study treatment administration, excluding toxicities clearly not related to the drug, such as disease progression, environmental factors, unrelated trauma, etc.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory finding), symptom, or disease (new or exacerbated) temporally associated with the use of a study intervention.
ORR is defined as the percentage of participants with Complete Response (CR: disappearance of all target lesions) or Partial Response (PR: at least a 30% decrease in the sum of diameters of target lesions) per Response Evaluation Criteria In Solid Tumors Version 1.1 (RECIST 1.1). The percentage of participants who experience CR or PR as assessed by Blinded Independent Central Review (BICR) will be presented.
Blood samples will be collected to determine the AUC0-inf of belzutifan.
A DLT consists of one or more of the following toxicities: Grade (Gr) 3 or 4 hypoxia or dyspnea; Gr 3 or 4 nausea, vomiting, or diarrhea if persistent for \>48 hours despite therapy; Gr 3 or 4 cardiovascular, vascular, or thrombotic events; Nonhematologic AE ≥Gr 3 in severity with exceptions; Gr 3 rash that does not resolve within 2 weeks; Gr 3 nonhematologic toxicity if persisting despite optimal medical treatment; Gr 3 or 4 hematologic toxicities; Gr 3 or 4 febrile neutropenia; Gr 3 or 4 nonhematologic laboratory value; Any aspartate aminotransferase or alanine aminotransferase \>8x the upper limit of normal (ULN) or 5 to 8x ULN persisting for \>2 weeks; \>2 weeks delay in dosing due to intervention-related toxicity; Intervention-related toxicity causing intervention discontinuation in the first 28 days of dosing; Missing \>20% of intervention doses due to drug-related AEs; Gr 5 toxicity. The number of participants who experience at least one DLT will be reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The number of participants who experience at least one AE will be reported.
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. The number of participants who discontinued from the study treatment due to an AE will be reported.
AUC0-inf was defined as the area under the concentration-time curve of belzutifan from time zero to infinity. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0-inf of belzutifan in plasma.
AUC0-24 was defined as the area under the concentration-time curve of belzutifan from time zero to 24 hours postdose. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0-24 of belzutifan in plasma.
Cmax is the maximum concentration of belzutifan observed in plasma. Blood samples collected predose and at multiple timepoints postdose were used to determine Cmax of belzutifan in plasma.
Tmax is the amount of time that belzutifan is present at the maximum concentration observed in plasma. Blood samples collected predose and at multiple timepoints postdose were used to determine Tmax of belzutifan in plasma.
t1/2 is defined as the time required to divide plasma concentration of belzutifan by half. Blood samples collected predose and at multiple timepoints postdose were used to determine the apparent terminal t1/2 of belzutifan in plasma.
AUC0-24hrs was defined as the area under the concentration-time curve of belzutifan from time zero to 24 hours postdose. Blood samples collected predose and at multiple timepoints postdose were used to determine AUC0 to 24 hours of belzutifan.
Apparent terminal half-life (t1/2) was defined as the time needed to reduce the level of belzutifan in the blood by one-half (1/2). Blood samples collected predose and at multiple timepoints postdose were used to determine the apparent terminal half-life (t1/2) of belzutifan.
A DLT is defined as an event with toxicity including the type, severity, time of onset, time of resolution, and the probable association with study treatment that are not due to pre-existing conditions as defined by the Common Terminology Criteria for Adverse Events Version 5.0 (CTCAE 5.0). Number of participants who experience a DLT per CTCAE 5.0 will be reported.
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who experience an AE in the study will be reported.
An AE is any unfavorable and unintended sign, symptom, or disease temporally associated with the use of a medicinal product or protocol-specified procedure, whether or not considered related to the medicinal product or protocol-specified procedure. Any worsening of a preexisting condition that is temporally associated with the use of the Sponsor's product, is also an AE. The number of participants who discontinued from the study treatment due to an AE will be reported.
AUC is a measure of plasma drug concentration and time and is estimated as the area under the plot of plasma concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUC0-24 of belzutifan.
Cmax is the maximum concentration of the drug observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax of belzutifan.
Tmax is the amount of time that a drug is present at the maximum concentration is observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of belzutifan.
AUC0-24,ss is a measure of plasma drug concentration and time and is estimated as the area under the plot of plasma concentration against time after drug administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine AUC0-24,ss of belzutifan.
Cmax,ss is the maximum concentration of the drug observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Cmax,ss of belzutifan.
Tmax is the amount of time that a drug is present at the maximum concentration is observed in plasma. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine the Tmax of belzutifan.
T1/2 is a measure of how long it takes to clear 50% of the drug after reaching Cmax. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine t1/2 of belzutifan.
Ctrough,ss is the lowest concentration reached by a drug before the next dose is administered. Blood samples taken at predose and at specified times post dose will be used to determine Ctrough,ss of belzutifan.
RAC is the ratio of accumulation of a drug under steady state conditions after repeated administration as compared to a single dose. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine RAC of belzutifan.
CL/F is the apparent total clearance of the drug from plasma after oral administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine CL/F of belzutifan.
Vz/F is the apparent volume of distribution of the drug during terminal phase after non-intravenous administration. Blood samples collected pre dose and at multiple timepoints post dose will be used to determine Vz/F of belzutifan.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who experience at least one AE will be reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who discontinue study treatment due to an AE will be reported.
An AE is any untoward medical occurrence in a clinical study participant, temporally associated with the use of study intervention, whether or not considered related to the study intervention. The percentage of participants who modify or interrupt study treatment due to an AE will be reported.
A DLT consists of one or more of the following toxicities: (1) Grade 3 or 4 hypoxia or dyspnea (2) Grade 3 or 4 nausea, vomiting, or diarrhea if persistent for \>48 hours despite therapy (3) Grade 3 or 4 cardiovascular, vascular, or thrombotic events (4) Nonhematologic AE ≥Grade 3 in severity (5) Grade 4 nonhematologic toxicity (6) Grade 3 or 4 hematologic toxicities (7) Grade 3 or 4 febrile neutropenia (8) Grade 3 or 4 nonhematologic laboratory value (9) \>2 weeks delay in dosing due to intervention-related toxicity (10) Intervention-related toxicity causing intervention discontinuation in the first 21 days of dosing (11) Missing \>20% of belzutifan doses due to drug-related AEs in the first 21 days. (12) Grade 5 toxicity. The percentage of participants who experience at least one DLT will be reported.
Blood samples to assess concentrations of belzutifan will be collected throughout the sampling time frame
21-Day Dose Limiting Toxicity Observation Period per Dose Group
| Arm | Type | Description |
|---|---|---|
| Belzutifan + Zanzalintinib | EXPERIMENTAL | Participants will receive 120 mg belzutifan orally and 60 mg zanzalintinib once daily for approximately 24 months. |
| Belzutifan + Placebo | ACTIVE_COMPARATOR | Participants will receive 120 mg belzutifan orally and zanzalintinib-matching placebo once daily for approximately 24 months. |
| Cohort A: Belzutifan Monotherapy | EXPERIMENTAL | Participants on active treatment assigned to belzutifan monotherapy in a parent study are transitioned to this extension study. Participants will continue the same dose and frequency of intervention as they were receiving in the parent study at the time of the transition. Treatment will continue until progressive disease (PD), unacceptable toxicity, withdrawal of consent, death, investigator decision, or study termination. |
| Cohort B: Belzutifan Combination Therapy | EXPERIMENTAL | Participants on active treatment assigned to a belzutifan combination therapy in a parent study are transitioned to this extension study. Participants will continue the same dose and frequency of intervention as they were receiving in the parent study at the time of the transition. Treatment will continue until PD, unacceptable toxicity, withdrawal of consent, death, investigator decision, or study termination. |
| Cohort C: Non-Belzutifan Therapy | ACTIVE_COMPARATOR | Participants on active treatment assigned to a non-belzutifan therapy in a parent study are transitioned to this extension study. Participants will continue the same dose and frequency of intervention as they were receiving in the parent study at the time of the transition. Treatment will continue until PD, unacceptable toxicity, withdrawal of consent, death, investigator decision, or study termination. |
| Belzutifan plus Zanzalintinib | EXPERIMENTAL | Participants will receive belzutifan orally once daily (QD) PLUS zanzalintinib orally QD until one of the reasons for discontinuation of study intervention are met. |
| Cabozantinib | ACTIVE_COMPARATOR | Participants will receive cabozantinib orally QD until one of the reasons for discontinuation of study intervention are met. |
| Belzutifan + Pembrolizumab | EXPERIMENTAL | Participants receive belzutifan 120 mg orally once daily (QD) for up to approximately 54 weeks PLUS pembrolizumab 400 mg via intravenous (IV) infusion once every 6 weeks (Q6W) for up to 9 administrations (up to approximately 54 weeks). |
| Placebo + Pembrolizumab | EXPERIMENTAL | Participants receive placebo orally QD for up to approximately 54 weeks PLUS pembrolizumab 400 mg via IV infusion once Q6W for up to 9 administrations (up to approximately 54 weeks). |
| Belzutifan + Lenvatinib | EXPERIMENTAL | Belzutifan 120 mg and lenvatinib 20 mg orally once a day |
| Belzutifan | EXPERIMENTAL | Randomized participants received 120 mg of belzutifan orally once daily (QD), until disease progression or discontinuation. |
| Everolimus | ACTIVE_COMPARATOR | Randomized participants received 10 mg of Everolimus orally QD, until disease progression or discontinuation. |
| Safety Run-In | EXPERIMENTAL | Non-Randomized participants enrolled into the Safety Run-in received up to 120 mg of belzutifan QD. |
| Belzutifan + Fulvestrant | EXPERIMENTAL | Participants will receive belzutifan 120 mg orally once daily (QD) PLUS fulvestrant 500 mg via intramuscular (IM) injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter until progressive disease or discontinuation. |
| Everolimus + ET (fulvestrant or exemestane) | ACTIVE_COMPARATOR | Participants will receive everolimus 10 mg orally QD PLUS investigator's choice of fulvestrant 500 mg via IM injection on Days 1 and 15 of Cycle 1, and Day 1 of each 28-day cycle thereafter OR exemestane 25 mg orally QD until progressive disease or discontinuation. |
| Belzutifan 200 mg | EXPERIMENTAL | Participants receive 200 mg of belzutifan by oral administration, once a day (QD), until disease progression or discontinuation. |
| Belzutifan 120 mg | EXPERIMENTAL | Participants receive 120 mg of belzutifan by oral administration, QD, until disease progression or discontinuation. |
| Belzutifan + Cabozantinib: Treatment Naïve (Cohort 1) | EXPERIMENTAL | Naïve participants will receive 120 mg belzutifan and 60 mg cabozantinib orally once daily (QD) at the same time. |
| Belzutifan + Cabozantinib: Prior Immunotherapy (Cohort 2) | EXPERIMENTAL | Participants who have received prior immunotherapy will receive 120 mg belzutifan and 60 mg cabozantinib orally QD at the same time. |
| Open Label Belzutifan | EXPERIMENTAL | Participants receive 120 mg belzutifan orally once daily. Participants may continue to receive belzutifan in the absence of unacceptable treatment related toxicity or unequivocal disease progression. |
| Metformin | EXPERIMENTAL | On Day 1 of Period 1, a single dose of metformin will be administered. |
| Belzutifan with Metformin | EXPERIMENTAL | In Period 2, belzutifan will be administered every day for 5 consecutive days with a single dose of metformin coadministered on Day 4. |
| Zanzalintinib at Dose Level 1 or 2 + Belzutifan | EXPERIMENTAL | Participants will be allocated to receive zanzalintinib at dose level 1 or 2 + belzutifan daily until progressive disease or discontinuation |
| Belzutifan + Phenytoin | EXPERIMENTAL | Participants receive belzutifan during study Period 1, followed by a washout period, then they receive belzutifan and phenytoin during study Period 2. |
| Beltuzifan 120 mg + Palbociclib 75 mg | EXPERIMENTAL | Participants receive beltuzifan 120 mg orally once per day (QD) and palbociclib 75 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. |
| Beltuzifan 120 mg + Palbociclib 100 mg | EXPERIMENTAL | Participants receive beltuzifan 120 mg orally QD and palbociclib 100 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. |
| Beltuzifan 120 mg + Palbociclib 125 mg | EXPERIMENTAL | Participants receive beltuzifan 120 mg orally QD and palbociclib 125 mg orally QD in a 28-day schedule (21 days on followed by 7 days off), until progressive disease or discontinuation. |
| Belzutifan in Participants with ESRD | EXPERIMENTAL | In period 1, participants with ESRD will receive a single, oral dose of belzutifan 120 mg on Day 1 after HD. In period 2, participants with ESRD will receive a single, oral dose of belzutifan 120 mg on Day 1 before HD. Each period is 4 days. |
| Belzutifan in Healthy Participants | EXPERIMENTAL | In period 1, healthy participants will receive a single, oral dose of belzutifan 120 mg on Day 1 of a 4-day period. |
| Moderate Hepatic Impairment | EXPERIMENTAL | Participants with moderate hepatic impairment will receive a single oral 80 mg dose of belzutifan on Day 1. |
| Healthy | EXPERIMENTAL | Participants with normal hepatic function will receive a single oral 80 mg dose of belzutifan on Day 1. |
| Belzutifan + Lenvatinib + Pembrolizumab | EXPERIMENTAL | Participants will receive an intravenous dose of 400 mg of pembrolizumab once every six weeks for up to 18 infusions (up to 2 years) in combination with a daily oral dose of 120 mg of belzutifan and a daily oral dose of 20 mg of lenvatinib until progressive disease or discontinuation. |
| Belzutifan 160 mg BID | EXPERIMENTAL | Participants will receive belzutifan 160 mg orally twice daily (BID). Treatment will continue until progressive disease or discontinuation. |
| Belzutifan 160 mg TID | EXPERIMENTAL | Participants will receive belzutifan 160 mg orally three times daily (TID). Treatment will continue until progressive disease or discontinuation. |
| Belzutifan 200 mg TID | EXPERIMENTAL | Participants will receive belzutifan 200 mg orally TID. Treatment will continue until progressive disease or discontinuation. |
| Belzutifan 120 mg QD | EXPERIMENTAL | Participants will receive belzutifan 120 mg orally once daily (QD). Treatment will continue until progressive disease or discontinuation. |
| Fasting | EXPERIMENTAL | Belzutifan tablets taken after fasting |
| Non-Fasting | EXPERIMENTAL | Belzutifan taken after eating a high calorie meal |
| Part 1A | EXPERIMENTAL | Drug: PART 1A: Belzutifan for the treatment of advanced solid tumors Belzutifan inhibits HIF-2α and is a novel approach to treatment of solid tumors. |
| Part 1B | EXPERIMENTAL | Drug: PART 1B: Belzutifan for the treatment of advanced ccRCC Belzutifan inhibits HIF-2α and is a novel approach to treatment of ccRCC. |
| Part 2 | EXPERIMENTAL | Drug: Part 2: Belzutifan for the treatment of other specified solid tumors Belzutifan inhibits HIF-2α and is a novel approach to treatment of specified solid tumors. |
| Part 2A | EXPERIMENTAL | Drug: Part 2A: Belzutifan for the treatment of patients with recurrent GBM who have been previously treated with radiation therapy and temozolomide Belzutifan inhibits HIF-2α and is a novel approach to treatment of specified solid tumors. |
| Name | Type | Description |
|---|---|---|
| Belzutifan | DRUG | Tablet for oral administration. |
| Zanzalintinib | DRUG | Tablet for oral administration. |
| Placebo | DRUG | Zanzalintinib-matching placebo tablet for oral administration. |
| Nivolumab | DRUG | Nivolumab is administered intravenously at 480 mg until PD, unacceptable toxicity, withdrawal of consent, death, investigator decision, or study termination. |
| Lenvatinib | DRUG | Lenvatinib is administered orally at 20 mg qd until PD, unacceptable toxicity, withdrawal of consent, death, investigator decision, or study termination. |
| Cabozantinib | DRUG | Cabozantinib is administered orally at 60 mg qd until PD, unacceptable toxicity, withdrawal of consent, death, investigator decision, or study termination. |
| Pembrolizumab | BIOLOGICAL | 400 mg via IV infusion |
| Everolimus | DRUG | Oral tablets |
| Fulvestrant | DRUG | Fulvestrant 500 mg administered as an IM injection. |
| Exemestane | DRUG | Administered at 25 mg via oral tablets QD. |
| Metformin | DRUG | Oral Tablet |
| Phenytoin | DRUG | Oral administration |
| Palbociclib | DRUG | 75, 100, or 125 mg tablet administered orally according to randomized dose for 21 days consecutive days followed by 7 days off. |
Inclusion Criteria: The main inclusion criteria include but are not limited to the following: * Has a histologically confirmed diagnosis of unresectable, advanced renal cell carcinoma (RCC) with clear cell component (with or without sarcomatoid features) ie, Stage IV RCC per American Joint Committ...