Table 1.
Phase I/II clinical trials of some Akt inhibitors
| Trial ID | Official title | Akt inhibitor | Combination | Cancer type | Phase | Efficacy | Grade ≧ 3 adverse effects | Ref |
|---|---|---|---|---|---|---|---|---|
| NCT01042379 | ISPY-2 | MK-2206 | Neoadjuvant chemotherapy | Breast cancer | II | Estimated pCR: 61.8% with MK-2206 versus 35% with control for hormone receptor-negative/HER2-positive breast cancer |
Rash: 22.6% (MK-2206) versus 0 (control); Hyperglycemia: 4.3% (MK-2206) versus 0 (control) |
[181] |
| NCT02162719 | LOTUS | Ipatasertib | Paclitaxel | Metastatic TNBC | II |
Median PFS: 6.2 m with ipatasertib versus 4.9 m with placebo; Median PFS in the PIK3CA/AKT/PTEN-altered population: 9.0 m with ipatasertib versus 4.9 m with placebo; Median PFS in the PIK3CA/AKT/PTEN-non-altered population: 5.3 m with ipatasertib versus 3.7 m with placebo; Median OS: 23.1 m with ipatasertib versus 16.2 m with placebo in the PIK3CA/AKT/PTEN-altered population |
Rash: 2% (ipatasertib) versus 0 (placebo); Neutropenia: 10% (ipatasertib) versus 2% (placebo) |
[183] |
| NCT02301988 | FAIRLANE | Ipatasertib | Paclitaxel | Stage I-IIIa TNBC | II |
pCR: 17% with ipatasertib versus 13% with placebo in the overall population; 16% with ipatasertib versus 13% (placebo) in the PTEN-low population; 18% with ipatasertib versus 12% (placebo) in the PIK3CA/AKT/PTEN-altered population; rCR: 39% with ipatasertib versus 9% (placebo) in the PIK3CA/AKT/PTEN-altered population |
Diarrhea: 17% versus 1%Hyperglycemia: 0 versus 0; Rash: 1% versus 1% |
[194] |
| NCT01485861 | N.A | Ipatasertib | Abiraterone | Metastatic castration- resistant prostate cancer | II |
rPFS: 8.31 m with ipatasertib (200 mg) versus 6.37 m with placebo in molecularly unstratified population; Median OS: 21.5 m with ipatasertib (200 mg) versus 15.64 m with placebo; rPFS:11.1 m with ipatasertib (200 mg) versus 4.6 m with placebo in PTEN-loss population; 4.6 m with ipatasertib (200 mg) versus 5.6 m with placebo in PTEN-non-loss population |
Diarrhea: 14.3% (400 mg ipatasetib), 3.4% (200 mg ipatasertib) versus 1.2% (placebo); Asthenia: 7.2% (400 mg ipatasetib), 1.1% (200 mg ipatasertib) versus 1.2% (placebo) |
[195] |
| NCT01625286 | BEECH | Capivasertib | Paclitaxel | ER +/HER− metastatic breast cancer | II |
PFS: 10.9 m with capivasertib versus 8.4 m with placebo in the overall population; PFS: 10.9 m with capivasertib versus 10.8 m with placebo in the PIK3CA-mutated population |
Diarrhea: 22% with capivasertib versus 2% with placebo; Hyperglycemia:13% with capivasertib versus 0% with placebo; Maculopapular rash: 9% with capivasertib versus 0% with placebo |
[186] |
| NCT01992952 | FAKTION | Capivasertib | Fulvestrant | Aromatase inhibitor-resistant, advanced ER+/HER2− breast cancer | II |
PFS: 10.3 m with capivasertib plus fulvestrant versus 4.8 m with placebo plus fulvestrant in the overall population; Objective response: 29% in capivasertib group versus 8% in placebo group; CBR: 55% in capivasertib group versus 41% in placebo group; PFS: 10.3 m with capivasertib plus fulvestrant versus 4.8 m with placebo plus fulvestrant in the PI3K/PTEN pathway-nonaltered population; PFS: 9.5 m with capivasertib plus fulvestrant versus 5.2 m with placebo plus fulvestrant in the PI3K/PTEN pathway-altered population; OS: 30.5 m with capivasertib plus fulvestrant versus 18.7 m with placebo plus fulvestrant in the PI3K/PTEN pathway-altered population; 23.7 m with capivasertib plus fulvestrant versus 20.3 m with placebo plus fulvestrant in the PI3K/PTEN pathway-nonaltered population |
Hypertension: 32% in capivasertib group versus 24% in placebo group Diarrhea: 14% in capivasertib group versus 4% in placebo group; Rash: 20% in capivasertib group versus 0 in placebo group; Infection: 6% in capivasertib group versus 3% in placebo group |
[187] |
| NCT02423603 | PAKT | Capivasertib | Paclitaxel | Untreated metastatic TNBC | II |
PFS: 5.9 m with capivasertib plus paclitaxel versus 4.2 m with placebo plus paclitaxel in the overall population; PFS: 9.3 m with capivasertib plus paclitaxel versus 3.7 m with placebo plus paclitaxel in the PIK3CA/AKT1/PTEN-altered population; PFS: 5.3 m with capivasertib plus paclitaxel versus 4.4 m with placebo plus paclitaxel in the PIK3CA/AKT1/PTEN-nonaltered population; OS: 19.1 m with capivasertib plus paclitaxel versus 12.6 m with placebo plus paclitaxel in the overall population; Median duration of response: 13.3 m with capivasertib plus paclitaxel versus 3.5 m with placebo plus paclitaxel in the PIK3CA/AKT1/PTEN-altered population |
Diarrhea: 13% (capivasertib) versus 1% (placebo); Rash: 4% (capivasertib) versus 0% (placebo) Infection: 4% (capivasertib) versus 0% (placebo) Hyperglycemia: 1.5% with capivasertib versus 0% with placebo |
[191] |
| NCT01226316 | N.A | Capivasertib | None | Akt1 E17K mutant tumors | II | Median PFS: 5.5 m in ER+ breast cancer patients; 6.6 m in gyneologic cancer papatients; 4.2 m in other cancer patients | Hyperglycemia: 24%; diarrhea: 17%; rash: 15.5% Discontinuation rate: 12% | [199] |
| NCT01226316 | N.A | Capivasertib | Fulvestrant | Akt1 E17K mutant/ER+ metastatic breast cancer | I |
Combination therapy: ORR, 36%; CBR24, 50% in fulvestrant-pretreated patients; ORR, 20%; CBR24, 47% in fulvestrant-naïve patients. Capivasertib monotherapy: ORR, 20% |
Hyperglycemia: 30%; Rash: 20% |
[201] |
| NCT00700882 |
NCI-MATCH (EAY131-Y) |
Capivasertib | None | Akt1 E17K mutated metastatic tumor | II | ORR: 28.6%; CR: 1/35; PR: 9/35; Median duration of response: 4.4 m; SD: 46%; PD: 2/35; Median PFS: 5.5 m; Overall 6-month PFS: 50%; Median OS: 14.5 m |
Hyperglycemia: 26%; Maculopapular rash: 11% |
[200] |
| NCT02299648 | VICTORY | Capivasertib | Paclitaxel | PIK3CA-mutated/amplified gastric cancer | N.A |
ORR: 33.3% (8/24); 50% in PIK3CA E542K mutant population, 18.8% in the non-E542K cohort |
[202] |
CBR: clinical benefit rate; CR: complete response; ORR: objective response rate; OS: overall survival; pCR: pathologic complete response; PFS: progression-free survival; rPFS: radiographic progression-free survival; SD: stable disease; N.A.: not available