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1.
Clin Genitourin Cancer ; 21(2): 278-285, 2023 04.
Article in English | MEDLINE | ID: mdl-36572571

ABSTRACT

BACKGROUND: Although androgen receptor-targeted agents prolong the lives of patients with metastatic prostate cancer, patients develop therapy resistance and most ultimately succumb to the disease. The PI3K/AKT/PTEN pathway has been associated with the development of resistance, raising the possibility that pathway inhibitors may produce a clinical benefit. This open-label phase Ib study examined the safety, tolerability, pharmacokinetics (PK) and preliminary clinical activity of adding capivasertib - a potent, selective inhibitor of AKT1/2/3 - to approved abiraterone acetate therapy. METHODS: Twenty-seven patients with metastatic castration-resistant prostate cancer who had undergone at least 1 prior line of systemic therapy received abiraterone acetate 1000 mg (orally administered once daily), plus oral prednisone 5 mg (twice daily) with capivasertib 400 mg (orally, twice daily, with an intermittent schedule of 4 days on, 3 days off). RESULTS: No dose-limiting toxicity was observed. The most frequent adverse events (all grade) were diarrhea (30%), anemia (26%), asthenia (22%), and nausea (22%). The most frequent grade 3 or higher adverse events were acute kidney injury (19%), hyperglycemia (7%), rash (7%), abdominal pain (7%), and asthenia (7%). Capivasertib and abiraterone PK were consistent with previously reported results from monotherapy dosing. Nine participants (33%) showed a 20% or greater decrease in prostate-specific antigen during study treatment. CONCLUSION: The combination of capivasertib and abiraterone acetate had an acceptable tolerability profile consistent with the known profile of each agent. These data support further evaluation of capivasertib and abiraterone acetate in patients with advanced prostate cancer.


Subject(s)
Abiraterone Acetate , Prostatic Neoplasms, Castration-Resistant , Male , Humans , Prostatic Neoplasms, Castration-Resistant/drug therapy , Prostatic Neoplasms, Castration-Resistant/pathology , Asthenia/chemically induced , Phosphatidylinositol 3-Kinases , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Prednisone
2.
Invest New Drugs ; 35(2): 198-206, 2017 04.
Article in English | MEDLINE | ID: mdl-27873130

ABSTRACT

Background To determine the recommended dose (RD) of a combination of PM01183 and gemcitabine in patients with advanced solid tumors. Methods Forty-five patients received escalating doses of PM01183/gemcitabine on Days 1 and 8 every 3 weeks (d1,8 q3wk) following a standard 3 + 3 design. Results PM01183 3.5 mg flat dose (FD)/gemcitabine 1000 mg/m2 was the highest dose level tested. Dose-limiting toxicities (DLTs) were mostly hematological and resulted in the expansion of a lower dose level (PM01183 3.5 mg FD/gemcitabine 800 mg/m2); 19 patients at this dose level were evaluable but >30% had DLT and >20% had febrile neutropenia. No DLT was observed in 11 patients treated at PM01183 3.0 mg FD/gemcitabine 800 mg/m2, which was defined as the RD. This regimen was feasible and tolerable with manageable toxicity; mainly grade 3/4 myelosuppression. Non-hematological toxicity comprised fatigue, nausea, vomiting, and transaminases increases. Fifteen (33%) patients received ≥6 cycles with no cumulative hematological toxicity. Pharmacokinetic analysis showed no evidence of drug-drug interaction. Nine of 38 patients had response as per RECIST (complete [3%] and partial [21%]), for an overall response rate (ORR) of 24% (95% Confidence Interval [CI] 12-40%). Eleven patients (29%) had disease stabilization ≥4 months. Responses were durable (median of 8.5 months): overall median progression-free survival (PFS) was 4.2 months (95% CI, 2.7-6.5 months). Conclusions The RD for this combination is PM01183 3.0 mg FD (or 1.6 mg/m2)/gemcitabine 800 mg/m2 d1,8 q3wk. This schedule is well tolerated and has antitumor activity in several advanced solid tumor types.


Subject(s)
Antineoplastic Agents , Antineoplastic Combined Chemotherapy Protocols , Carbolines , Deoxycytidine/analogs & derivatives , Heterocyclic Compounds, 4 or More Rings , Neoplasms/drug therapy , Adult , Aged , Antineoplastic Agents/administration & dosage , Antineoplastic Agents/adverse effects , Antineoplastic Agents/pharmacokinetics , Antineoplastic Agents/therapeutic use , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/adverse effects , Antineoplastic Combined Chemotherapy Protocols/pharmacokinetics , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Carbolines/administration & dosage , Carbolines/adverse effects , Carbolines/pharmacokinetics , Carbolines/therapeutic use , Deoxycytidine/administration & dosage , Deoxycytidine/adverse effects , Deoxycytidine/pharmacokinetics , Deoxycytidine/therapeutic use , Disease-Free Survival , Female , Heterocyclic Compounds, 4 or More Rings/administration & dosage , Heterocyclic Compounds, 4 or More Rings/adverse effects , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Humans , Male , Middle Aged , Neoplasms/metabolism , Treatment Outcome , Gemcitabine
3.
Clin Cancer Res ; 20(8): 2205-14, 2014 Apr 15.
Article in English | MEDLINE | ID: mdl-24563480

ABSTRACT

PURPOSE: Lurbinectedin (PM01183) binds covalently to DNA and has broad activity against tumor cell lines. This first-in-human phase I study evaluated dose-limiting toxicities (DLT) and defined a phase II recommended dose for PM01183 as a 1-hour intravenous infusion every three weeks (q3wk). EXPERIMENTAL DESIGN: Thirty-one patients with advanced solid tumors received escalating doses of PM01183 following an accelerated titration design. RESULTS: PM01183 was safely escalated over 200-fold, from 0.02 to 5.0 mg/m(2). Dose doubling was utilized, requiring 15 patients and nine dose levels to identify DLT. The recommended dose was 4.0 mg/m(2), with one of 15 patients having DLT (grade 4 thrombocytopenia). Clearance was independent of body surface area; thus, a flat dose of 7.0 mg was used during expansion. Myelosuppression, mostly grade 4 neutropenia, occurred in 40% of patients but was transient and manageable, and none was febrile. All other toxicity was mild and fatigue, nausea and vomiting were the most common at the recommended dose. Pharmacokinetic parameters showed high interindividual variation, though linearity was observed. At or above the recommended dose, the myelosuppressive effect was significantly associated with the area under the concentration-time curve from time zero to infinity (white blood cells, P = 0.0007; absolute neutrophil count, P = 0.016). A partial response was observed in one patient with pancreatic adenocarcinoma at the recommended dose. CONCLUSION: A flat dose of 7.0 mg is the recommended dose for PM01183 as a 1-hour infusion q3wk. This dose is tolerated and active. Severe neutropenia occurred at this dose, although it was transient and with no clinical consequences in this study.


Subject(s)
Carbolines/therapeutic use , Heterocyclic Compounds, 4 or More Rings/therapeutic use , Neoplasms/drug therapy , Adult , Aged , Anemia/chemically induced , Area Under Curve , Carbolines/adverse effects , Carbolines/pharmacokinetics , Dose-Response Relationship, Drug , Drug Administration Schedule , Fatigue/chemically induced , Female , Heterocyclic Compounds, 4 or More Rings/adverse effects , Heterocyclic Compounds, 4 or More Rings/pharmacokinetics , Humans , Infusions, Intravenous , Male , Metabolic Clearance Rate , Middle Aged , Nausea/chemically induced , Neoplasms/pathology , Treatment Outcome , Vomiting/chemically induced , Young Adult
4.
Eur J Pharm Biopharm ; 56(2): 197-206, 2003 Sep.
Article in English | MEDLINE | ID: mdl-12957633

ABSTRACT

The topological-substructural molecular design approach was used to estimate the human bioavailability (F) and the minimum inhibitory concentration (MIC90) against Streptococcus pneumoniae from a data set of 17 and 19 fluoroquinolone derivatives, respectively. Both pharmacokinetics and pharmacological properties were well described by the present approach. The total spectral moments and local spectral moments that include the different fluoroquinolone rings, polar and non-polar areas and their interactions were calculated and weighted with the standard dipole moments and the electronegative difference between the atoms that form a bond. In order to obtain a qualitative model that permits the classification of drugs with high and moderate bioavailability, a linear discriminant analysis was carried out. The percentage of correct classification was 100% for compounds of the training set. The leave-one-out cross validation procedure showed an 88.23% of correct classification. Also, a quantitative model, by the piecewise linear regression was developed. The theoretically predicted values for human bioavailability was assessed by a correlation with in vivo rat bioavailability and the regression equation was used to predict this biopharmaceutical property for two new pre-clinical 6-fluoroquinolone derivatives. On the other hand, a linear regression model that explained the 84% of variance was developed to predict the MIC90 values. Finally, the role of a pharmacokinetic and pharmacological relationship in the design of new fluoroquinolones was evaluated in the Sitafloxacin framework, where 13 substituents were analyzed; halogens and methoxy groups had the best contributions to both properties. The present approach proved to be a good method for studying the pharmacokinetics and the pharmacological properties of new 6-fluoroquinolone candidates in drug development studies.


Subject(s)
Drug Design , Fluoroquinolones/chemistry , Fluoroquinolones/pharmacokinetics , Molecular Structure , Animals , Biological Availability , Humans , Male , Rats , Rats, Wistar
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