A pharmacokinetically (PK) and pharmacodynamically (PD) driven phase I trial of the pan-AKT inhibitor AZD5363 with expansion cohorts in PIK3CA mutant breast and gynecological cancers.

3027 Background: Two rational strategies to interrogate the IGF-1R pathway were investigated in this parallel-arm phase I trial: 1) vertical inhibition with D and MK-2206 to potentiate PI3K pathway targeting, 2) horizontal crosstalk inhibition with D and MK-0752 to exert effects against cellular proliferation, angiogenesis and stem cell propagation. Methods: Patients (pts) with advanced solid tumors and no prior exposure to agents of the same targets were eligible. Dose escalation was based on a modified toxicity probability interval method (Ji et al, 2010). Arm A is comprised of fixed D dose of 10 mg/m2 IV weekly plus MK-2206 at escalating doses of 90-200 mg PO weekly. Arm B is comprised of fixed MK-0752 dose of 1800 mg PO weekly plus D at escalating doses of 7.5-10 mg/m2 IV weekly. Each cycle = 4 weeks in both arms. Primary objectives were to determine DLT and RP2D of these combinations. Results: 30 patients were enrolled in the dose escalation phase (18 in Arm A and 12 in Arm B) with: median age = 56 (range 36-74); M:F = 13:17; ECOG 0:1 = 12:18; primary diagnosis = colorectal (CRC) (9), NSCLC (3), others (17); prior metastatic regimens = 3 (range 1-4). In Arm A, 1/6 DLT was observed with MK-2206 at 135 mg (G3 serum sickness-like reaction); 2/3 DLTs with MK-2206 at 200 mg (G4 leukopenia/neutropenia; G3 rash). No other G4 or worse adverse events (AEs) were observed. RP2D of Arm A = D 10mg/m2 IV weekly and MK-2206 150 mg PO weekly. Other common AEs in Arm A included: fatigue, rash and nausea. In Arm B, 2/6 DLTs were observed with D at 10 mg/m2 (G3 rash; G3 nausea/vomiting). RP2D of Arm B = D 10mg/m2 IV weekly and MK-0752 at 1800 mg PO weekly based on Ji et al. Other common AEs in Arm B included: anorexia, nausea and fatigue. No PR was observed and SD > 4 months occurred in 4 pts (all in Arm A). PK analyses are ongoing. Conclusions: Targeted combinations of D with MK-2206 or with MK-0752 were both tolerable. Expansion cohorts based on biomarker selection are underway, specifically ovarian cancer with high IGF1 expression/low RAS score for Arm A; and KRAS wild-type CRC with high IGF1/low IGF2 expression for Arm B.

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Phase I trial of temsirolimus (TEM) and perifosine (PER) for recurrent or progressive malignant glioma (MG).

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.15_suppl.2095 ◽

2013 ◽

Vol 31 (15_suppl) ◽

pp. 2095-2095 ◽

Cited By ~ 3

Author(s):

Thomas Joseph Kaley ◽

Elena Pentsova ◽

Antonio Marcilio Padula Omuro ◽

Ingo K. Mellinghoff ◽

Craig Nolan ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase I Trial ◽

Combined Therapy ◽

Akt Inhibitor ◽

Potential Therapeutic Target ◽

Cycle Arrest ◽

Level 3 ◽

Grade 3 ◽

Clinical Trial Information

2095 Background: PI3K/AKT/mTOR signaling is important in MG biology, and therefore a potential therapeutic target. The mTOR inhibitor TEM and the AKT inhibitor PER are well tolerated as single agents but have limited activity. Preclinical data demonstrate synergistic anti-tumor effects during combined therapy including extensive tumor apoptosis, cell-cycle arrest among surviving cells, and inhibition of both AKT and mTOR. Therefore, we initiated a phase I trial of combined therapy in recurrent MGs. Methods: Adults with recurrent MG, KPS≥60, and not taking enzyme inducing AEDs were enrolled. There was no limitation on prior therapies except prior RT and temozolomide were mandatory. The dose of TEM was escalated in each cohort using standard 3 + 3 design from 15 mg to 170 mg administered once weekly. The dose of PER was fixed as a 600 mg load on day 1 followed by 100 mg nightly (the single dose MTD) until dose level 7 when the load increased to 900mg. Results: Thirty-four patients (24 men) with median age 52 (range, 21-71) and median KPS 80 (range, 60-100) participated. Diagnoses included GBM (18), AA (7), AO (7) or transformed LGG (2). Twenty-one received bevacizumab previously. There were a total of 5 DLTs: 1 at dose level 3 (50mg TEM), then 2 at dose level 7 expansion (170mg TEM), and then 2 at dose level 6 expansion (170mg TEM). DLTs included thrombocytopenia (n=3), intracerebral hemorrhage (n=1) and lung infection (n=1). Two uPR were seen at 170mg TEM. Grade 3 non-dose limiting toxicities per patient included lymphopenia (7), hyperglycemia (4), anemia (2), neutropenia (1), transaminitis (3), hypophosphatemia (3), hypercholesterolemia (3), thrombocytopenia (2), and mucositis (2). The MTD is defined as 115mg TEM (dose level 5). Conclusions: Combination therapy with TEM 115 mg weekly and PER 100 mg daily (following 600 mg load) is tolerable in heavily pre-treated adults with recurrent MGs. Clinical trial information: NCT01051557.

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