Approval Probability
TA Base Rate
Adjusted LOA
ML Risk
Also known as Pimasertib
MSC1936369B · 4 trials · 5 indications
PFS was defined as the duration (in weeks) from randomization until the first progressive disease (PD) observation as assessed by the Investigator according to Response Evaluation Criteria for Solid Tumors (RECIST) version 1.1, or death due to any cause when death occurred within 12 weeks after the last tumor assessment (otherwise censored), whichever occurred first. PD was defined as at least a 20% increase in the sum of diameters of the target lesions, taking as reference the smallest sum since the treatment started (including baseline), or appearance of one or more new lesions, and/or unequivocal progression of existing non-target lesions.
Oral bioavailability (F) was calculated using the formula=AUC0-inf oral/dose oral) / (AUC0-inf iv/dose iv) \* 100%, where AUC0-inf is the area under the concentration time curve (AUC) from time zero to infinity.
Recovery of total \[14C\]-radioactivity was determined in excreta, i.e., urine and feces at each sampling period subsequent to oral administration of \[14C\]-pimasertib on Day 8. Cumulative recovery of total \[14C\]-radioactivity in terms of percentage of dose recovered in urine and feces and total percentage of dose recovered was reported for the outcome measure.
Plasma concentration of the Pimasertib metabolite M445 and M554 were presented for the outcome measure.
Identification and profiling of the metabolites was done. The total number of metabolites and the number of metabolites identified as major were reported.
DLT using the National Cancer Institute Common Terminology Criteria for Adverse Events(CTCAE) v3.0,was defined as any of the following toxicities at any dose level and judged to be possibly or probably related to trial medication by the Investigator and/or the Sponsor and relevant for the combination treatment: Grade 3/more non-hematological toxicity excluding: Subjects with liver involvement: Grade 4 asymptomatic increases in liver function tests and subject without liver involvement: Grade 3 asymptomatic increases in liver function tests reversible within 7 days. Grade 3 vomiting encountered despite adequate therapy. Grade 3 diarrhea encountered despite adequate anti diarrhea therapy. Grade 4 neutropenia greater (\>) 5 days duration or febrile neutropenia lasting for more than 1 day. Grade 4 thrombocytopenia \> 1 day/Grade 3 with bleeding. Grade 4 anemia: Any treatment delay \> 2 weeks due to drug-related adverse effects.
PFS was defined as the time from randomization to the first documentation of objective tumor progression (Complete Response (CR): Disappearance of all target lesions, Partial Response (PR): At least 30% decrease in the sum of the longest diameter of target lesions, taking as reference the sum of the longest diameter at baseline, Progressive Disease (PD): At least 20% increase in the sum of the longest diameter of target lesions, taking as reference the smallest sum of the longest diameter recorded since treatment started, or the appearance of 1 or more new lesions and stable disease: Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for PD, taking as reference the smallest sum of the longest diameter since treatment started) or to death due to any cause, whichever occurred first. PFS calculated as (Months) = Date of first PD or death or censoring date minus date of randomization plus 1) divided by 30.4375.
DLT was defined as any of following toxicities at any dose level according to using National Cancer Institute Common Terminology Criteria for Adverse Events (AEs) v3.0(CTCAE), probably or possibly related to trial medication by investigator or sponsor: a)Any Grade 3 or more non-haematological toxicity excluding: (i)Grade 3 asymptomatic increase in liver function tests (Aspartate Aminotransferase, Alanine transaminase, Alkaline Phosphatase reversible within 7 days for subjects without liver involvement, or grade 4 for subjects with liver involvement; (ii)Grade 3 vomiting if it is encountered despite adequate and optimal therapy (e.g. serotonin \[5HT3\] antagonists and corticosteroids); (iii)Grade 3 diarrhoea if it is encountered despite adequate and optimal anti diarrhoea therapy; b)Grade 4 neutropenia of \>5 days duration or febrile neutropenia lasting for more than 1 day; c)Grade 4 thrombocytopenia \>1 day or grade 3 with bleeding; d)Any treatment delay \>2 weeks due to drug-related AEs.
| Arm | Type | Description |
|---|---|---|
| Pimasertib | EXPERIMENTAL | - |
| Dacarbazine | ACTIVE_COMPARATOR | - |
| Safety Run-in Part: Regimen 1 | EXPERIMENTAL | Subjects will receive pimasertib capsule orally once daily (qd) doses of 15, 30, 45, 68, 90, and 120 milligram (mg) on Day 1, 2, 3, 4, 5, 8, 9, 10, 11, 12, 15,16, 17, 18, 19, 22, 23, 24, 25, 26 and gemcitabine 1000 milligram per square meter (mg/m\^2) intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks). |
| Safety Run-in Part: Regimen 2 | EXPERIMENTAL | Subjects will receive pimasertib capsule orally twice daily (bid) doses of 60 and 75 mg continuously for a 28-day cycle and gemcitabine 1000 mg/m\^2 intravenous (IV) infusion for 30 minutes on Days 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (1 Cycle = 8 weeks) (bid - continuous regimen). |
| Phase II: Arm 1 (Gemcitabine + Placebo) | ACTIVE_COMPARATOR | Subjects will receive gemcitabine 1000 mg/m\^2 IV infusion on for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and placebo matched to pimasertib orally bid - continuous regimen. |
| Phase II: Arm 2 (Gemcitabine + Pimasertib) | EXPERIMENTAL | Subjects will receive gemcitabine 1000 mg/m\^2 IV infusion for 30 minutes on Day 1, 8, 15, 22, 29, 36, and 43 followed by a 1-week rest (Cycle 1) then on Days 1, 8, and 15 of a 28-day cycle and pimasertib capsule orally bid - continuous regimen. |
| MSC1936369B Regimen 1 | EXPERIMENTAL | Subjects will be administered MSC1936369B (pimasertib) capsules 1 to 120 milligram (mg) orally, once daily (QD) on Days 1 to 5, 8 to 12, 15 to 19 of each 21-day treatment cycle until progressive disease (PD) or intolerable toxicity or investigator/subject decision. |
| MSC1936369B Regimen 2 | EXPERIMENTAL | MSC1936369B Regimen 2 (Without Food Effect): Subjects will be administered MSC1936369B capsules 1 to 255 mg orally QD on Days 1 to 15 of each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision. MSC1936369B Regimen 2 (With Food Effect): : Subjects will be administered MSC1936369B capsules 90 or 150 mg orally QD on Day 1 to 15 of each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision. Subjects in the Regimen 2 FE cohort were assigned in a 1:1 ratio to either the fed/fasted sequence or fasted/fed sequence for Day 1 of Cycle 1 and Day 1 of Cycle 2. |
| MSC1936369B Regimen 3 once daily | EXPERIMENTAL | Subjects will be administered MSC1936369B capsules 60 to 90 mg orally QD in each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision. |
| MSC1936369B Regimen 3 twice daily (BID) | EXPERIMENTAL | Subjects will be administered MSC1936369B capsules 45 to 75 mg orally BID in each 21-day treatment cycle until PD or intolerable toxicity or investigator/subject decision. |
| Name | Type | Description |
|---|---|---|
| Pimasertib | DRUG | Subjects will receive pimasertib orally as monotherapy at a dose of 60 milligram (mg) twice daily continuously. Treatment will consist of repeated 21-day cycles which will continue until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first. |
| Dacarbazine | DRUG | Subjects will receive dacarbazine intravenously at dose of 1000 milligram per square meter (mg/m\^2) of body surface area every 3 weeks on Day 1 of each 21-days cycle until progression of the disease, unacceptable toxicity, withdrawal of informed consent, or death, whichever occurs first. Eligible subjects with documented tumor progression on dacarbazine will offer to switch to pimasertib treatment. |
| Gemcitabine | DRUG | - |
| Placebo | DRUG | - |
| MSC1936369B | DRUG | - |
Inclusion Criteria: * Subjects with measurable, histologically or cytologically confirmed, locally advanced or metastatic cutaneous melanoma (stage III c or M1ac) N-Ras mutated. If N-Ras mutational status is unknown at screening, it must be prospectively defined before inclusion. If N-Ras mutationa...
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| Incyte Corporation | INCY | 1 | PHASE2 | Retifanlimab |
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| AstraZeneca PLC | AZN | 1 | - | Trastuzumab deruxtecan |