A Phase I Study of Dinaciclib in Combination With MK‐2206 in Patients With Advanced Pancreatic Cancer

The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK‐2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Pat...

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Bibliographic Details
Published in:Clinical and translational science 2020-11, Vol.13 (6), p.1178-1188
Main Authors: Murphy, Adrian G., Zahurak, Marianna, Shah, Mirat, Weekes, Colin D., Hansen, Aaron, Siu, Lillian L., Spreafico, Anna, LoConte, Noelle, Anders, Nicole M., Miles, Tearra, Rudek, Michelle A., Doyle, L. Austin, Nelkin, Barry, Maitra, Anirban, Azad, Nilofer S.
Format: Article
Language:English
Subjects:
1-Phosphatidylinositol 3-kinase
Administration, Oral
Adult
Aged
AKT protein
Antineoplastic Combined Chemotherapy Protocols - administration & dosage
Antineoplastic Combined Chemotherapy Protocols - toxicity
Antitumor activity
Apoptosis
Biopsy
Cancer therapies
Carcinoma, Pancreatic Ductal - diagnosis
Carcinoma, Pancreatic Ductal - drug therapy
Carcinoma, Pancreatic Ductal - mortality
Carcinoma, Pancreatic Ductal - pathology
Cell cycle
Cyclic N-Oxides - administration & dosage
Cyclic N-Oxides - toxicity
Drug delivery
Drug dosages
Enzyme inhibitors
Female
Heterocyclic Compounds, 3-Ring - administration & dosage
Heterocyclic Compounds, 3-Ring - toxicity
Humans
Hyperglycemia
Hyponatremia
Indolizines - administration & dosage
Indolizines - toxicity
Kinases
Leukopenia
Lymphopenia
Male
Maximum Tolerated Dose
Metastases
Metastasis
Middle Aged
Mutation
Neoplasm Staging
Neutropenia
Pancreas - drug effects
Pancreas - pathology
Pancreatic cancer
Pancreatic Neoplasms - diagnosis
Pancreatic Neoplasms - drug therapy
Pancreatic Neoplasms - mortality
Pancreatic Neoplasms - pathology
Patients
Protein Kinase Inhibitors - administration & dosage
Protein Kinase Inhibitors - toxicity
Pyridinium Compounds - administration & dosage
Pyridinium Compounds - toxicity
Survival
Survival Rate
Tomography
Treatment Outcome
Vital signs
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Summary:The combination of drugs targeting Ral and PI3K/AKT signaling has antitumor efficacy in preclinical models of pancreatic cancer. We combined dinaciclib (small molecule cyclin dependent kinase inhibitor with MK‐2206 (Akt inhibitor) in patients with previously treated/metastatic pancreatic cancer. Patients were treated with dinaciclib (6–12 mg/m2 i.v.) and MK‐2206 (60–135 mg p.o.) weekly. Tumor biopsies were performed to measure pAKT, pERK, and Ki67 at baseline and after one completed cycle (dose level 2 and beyond). Thirty‐nine patients participated in the study. The maximum tolerated doses were dinaciclib 9 mg/m2 and MK‐2206 135 mg. Treatment‐related grade 3 and 4 toxicities included neutropenia, lymphopenia, anemia, hyperglycemia, hyponatremia, and leukopenia. No objectives responses were observed. Four patients (10%) had stable disease as their best response. At the recommended dose, median survival was 2.2 months. Survival rates at 6 and 12 months were 11% and 5%, respectively. There was a nonsignificant reduction in pAKT composite scores between pretreatment and post‐treatment biopsies (mean 0.76 vs. 0.63; P = 0.635). The combination of dinaciclib and MK‐2206 was a safe regimen in patients with metastatic pancreatic cancer, although without clinical benefit, possibly due to not attaining biologically effective doses. Given the strong preclinical evidence of Ral and AKT inhibition, further studies with better tolerated agents should be considered.
ISSN:1752-8054
1752-8062
DOI:10.1111/cts.12802