Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Savolitinib · 11 trials · 16 indications
Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause.
Defined as time from randomisation until progression per RECIST 1.1 as assessed by BICR, or death due to any cause. The analysis will include all randomised participants as randomised, regardless of whether the participant withdraws from therapy, receives another anti-cancer therapy or clinically progresses prior to RECIST 1.1 progression.
Per Response Evaluation Criteria in Solid Tumours (RECIST v1.1) assessed by MRI or CT: Progressive Disease (PD): \>= 20% increase in the sum of diameters of TLs and an absolute increase in sum of diameters of \>=5mm (compared to the previous minimum sum) or progression of NTLs or a new lesion. PFS is the time from date of randomisation until the date of PD (defined by Recist 1.1 and confirmed by BICR) or death (by any cause in the absence of progression) regardless of whether the patient withdrew from randomised therapy or received another anti-cancer therapy prior to progression.
PFS (Progression-Free Survival ) will be defined as the time from first dose of study intervention until progression per RECIST 1.1 as assessed by the investigator or death due to any cause prior to progressive disease.
Determine brain exposure of \[11C\]savolitinib following single, IV administration of a microdose in healthy adult volunteers
To evaluate the effects of fluvoxamine on savolitinib Cmax in healthy male subjects after administration of a single oral dose.
To evaluate the effects of fluvoxamine on savolitinib AUCinf in healthy male subjects after administration of a single oral dose.
To evaluate AUCinf of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2)
To evaluate AUClast of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2)
To evaluate (AUC(0-t)) of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
To evaluate Cmax of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
To evaluate AUCinf ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
To evaluate AUC(0-t) ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
To evaluate Cmax ratio of drug cocktail components when administered alone (period 1) and in combination with savolitinib (period 2).
To assess the effect of savolitinib on the PK of midazolam.
To assess the effect of savolitinib on the PK of midazolam.
Cmax ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess effect of the gastric acid modifier, famotidine, on the PK of savolitinib.
AUC ratio of test treatment (savolitinib+famotidine) relative to reference treatment (savolitinib alone) to assess effect of the gastric acid modifier, famotidine, on the PK of savolitinib.
To assess the effect of itraconazole on the PK of savolitinib
To assess the effect of itraconazole on the PK of savolitinib
To assess the effect of rifampicin on the PK of savolitinib
To assess the effect of rifampicin on the PK of savolitinib
| Arm | Type | Description |
|---|---|---|
| Chemotherapy | ACTIVE_COMPARATOR | Pemetrexed (500 mg/m2) with either cisplatin (75 mg/m2) or carboplatin (AUC5) on Day 1 of 21-day cycles (Q3W) for 4 cycles, followed by pemetrexed maintenance (500 mg/m2) Q3W |
| Savolitinib + Osimertinib | EXPERIMENTAL | 300 mg savolitinib BID plus 80 mg osimertinib QD |
| Arm A | EXPERIMENTAL | savolitinib 600mg plus durvalumab 1500mg |
| Arm B | ACTIVE_COMPARATOR | sunitinib 50mg |
| Arm C | EXPERIMENTAL | durvalumab 1500mg |
| Savolitinib | EXPERIMENTAL | See: intervention description |
| Sunitinib | ACTIVE_COMPARATOR | See: intervention description |
| Savolitinib combine with Durvalumab | EXPERIMENTAL | single-arm |
| Healthy Volunteers | EXPERIMENTAL | Healthy volunteers will undergo two PET examinations and will receive 2 single IV doses of \[11C\]savolitinib (total ≤ 20 µg) and radioactivity of 400 ± 10% mBq/70 kg/per PET-CT examination, with total radiation exposure during the study of 3.86 mSv. Healthy volunteers will receive a single 300 mg dose of oral savolitinib approximately 2 hours after the end of the first PET examination and approximately 2 hours before the second IV dose of \[11C\]savolitinib. The second PET examination can be performed on a separate day, within 14 days after the first PET examination. Oral savolitinib will be given on the same day as the second PET examination. |
| Savolitinib/Savolitinib+Fluvoxamine | EXPERIMENTAL | In period 1, subjects will receive a single oral dose of savolitinib on Day 1 after overnight fasting. Following minimum 10 days of washout after the last dose of savolitinib, in period 2 subjects will take oral doses of fluvoxamine alone, twice daily from Days 1 to 4. On Day 5 subject will receive a single oral dose of savolitinib and a twice daily oral dose of fluvoxamine. On Day 6, subjects will receive a twice daily oral dose of fluvoxamine alone. |
| Drug cocktail/Savolitinib + Drug cocktail | EXPERIMENTAL | Subjects will receive two different interventions in two periods (Periods 1 and 2). In Period 1, the subjects will receive a single-dose of Drug cocktail components (digoxin Dose B, furosemide Dose C, metformin hydrochloride Dose D, and rosuvastatin Dose E). During Period 2, the subjects will receive savolitinib dose A in combination with the Drug cocktail components. |
| Midazolam + Savolitinib | EXPERIMENTAL | * Treatment Period 1: Single administration of midazolam (1 mg) will occur on Study Day 1, after a high fat, high calorie breakfast, followed by PK sampling for 24 hours. * Treatment Period 2: Single administration of midazolam 1 mg in combination with a single administration of savolitinib (600 mg), after a high fat, high calorie breakfast will occur on Study Day 5 and PK sampling will occur for 24 hours. |
| Savolitinib + Famotidine | EXPERIMENTAL | Subjects will receive savolitinib 600mg single dose after high-fat, high-calorie meal and after 1.5 hours (Part A) or 5.5 hours (Part B) of famotidine 40mg dose. Famotidine will be administered after an overnight fast of at least 8 hours with approximately 240 mL of water. |
| Savolitinib and/or Itraconazole | EXPERIMENTAL | Treatment Period 1: Single administration of savolitinib (200 mg) will occur on Study Day 1 after a high-fat, high-calorie breakfast followed by PK sampling for 48 hours Treatment Period 2: Itraconazole will be administered (200 mg BID) on Study Day 15, and (200 mg QD) on Study Days 16 and 17, 1 hour before breakfast (and before dinner, when applicable) Treatment Period 3: A single combination of itraconazole (200 mg) 1 hour before breakfast + savolitinib (200 mg) after a high-fat, high-calorie breakfast on Study Day 18, and a single dose of itraconazole (200 mg) on Study Day 19, 1 hour before breakfast |
| Savolitinib and/or Rifampicin | EXPERIMENTAL | Treatment Period 1 consists of 16 days starting with admission on Study Day -1, followed by a single dose administration of savolitinib on Day 1, followed by a washout period of at least 14 days. Subjects will be discharged from the Study Centre on Study Day 3, after the last PK sample is collected Treatment Period 2 consists of 6 days, starting with admission on Study Day 14, followed by QD dose administrations of rifampicin for 5 consecutive days (Study Day 15 to Study Day 19) Treatment Period 3 consists of 4 days, starting immediately after Treatment Period 2, comprising of a single dose administration of savolitinib on Study Day 20 and QD dose administration of rifampicin on Study Day 20 and Study Day 21. Subjects will be discharged from the Study Centre on Study Day 22, after the last PK sample is collected |
| Name | Type | Description |
|---|---|---|
| Savolitinib | DRUG | 300 mg savolitinib (3 × 100 mg tablets twice daily) Administrative route : oral |
| Osimertinib | DRUG | 80 mg osimertinib (1 × 80 mg tablet once daily) Administrative route : oral |
| Pemetrexed | DRUG | Pemetrexed (500 mg/m2) Administrative route : IV infusion |
| Cisplatin | DRUG | Cisplatin (75 mg/m2) Administrative route : IV infusion |
| Carboplatin | DRUG | Carboplatin (AUC5) Administrative route : IV infusion |
| durvalumab | DRUG | Concentrate for solution for IV infusion : 1500 mg durvalumab every 4 weeks |
| sunitinib | DRUG | Capsules : 2 x 25mg capsules once daily 4 weeks on, 2 weeks off |
| [11C]savolitinib | DRUG | Radiopharmaceutical; IMP; Sterile solution for IV injection, not more than 10 μg, single administration |
| Fluvoxamine | DRUG | Only fluvoxamine will be administered as a twice daily oral dose from Days 1 to 4 of Period 2. On Day 5 of Period 2, subject will receive a twice daily oral dose of fluvoxamine along with savolitinib. On Day 6 of Period 2, subject will receive a twice daily oral dose of fluvoxamine alone. |
| Digoxin | DRUG | The subjects will receive single dose of oral uncoated tablet of Digoxin Dose B on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal. |
| Metformin Hydrochloride | DRUG | The subjects will receive single dose of oral film-coated tablet of Metformin Hydrochloride Dose D on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal. |
| Rosuvastatin | DRUG | The subjects will receive single dose of oral film-coated tablet of Rosuvastatin Dose E on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal. |
| Furosemide | DRUG | The subjects will receive single dose of oral solution of Furosemide Dose C on Day 1 of Period 1 and Period 2 within 25 minutes \[+ 5 minutes\] from the start of meal. |
| Midazolam | DRUG | Single dose (alone) on Study Day 1 and single dose (together with savolitinib) on Study Day 5, both after a high fat, high calorie breakfast. |
| Famotidine | DRUG | Subjects will receive famotidine tablet 40mg orally after an overnight (minimum 8hours) of fasting. |
| Itraconazole | DRUG | Twice daily on first day of dosing (Study Day 15) followed by once daily for 4 days (Study Day 16 - Study Day 19) administered 1 hour before any breakfast (and 1 hour before dinner on Study Day 15) |
| Rifampicin | DRUG | Patients will receive Rifampicin once daily on Study Day 15, 16, 17, 18, 19, 20 and 21. Rifampicin will be administered 1 hour before breakfast. |
Inclusion Criteria: * Provision of signed and dated written ICF prior to any mandatory and non-mandatory study-specific procedures, sampling and analyses. * Participant must be ≥18 years (≥ 19 years of age in South Korea) at the time of signing the informed consent. All genders are permitted. * His...
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