First-in-human study of LY3039478, an oral Notch signaling inhibitor in advanced or metastatic cancer.

Background: Deregulated Notch signaling due to mutation or overexpression of ligands and/or receptors is implicated in various human malignancies. γ-Secretase inhibitors inhibit Notch signaling by preventing cleavage of transmembrane domain of Notch protein. LY3039478 is a novel, potent Notch inhibitor decreases Notch signaling and its downstream biologic effects. In this first-in-human study, we report the safety, pharmacokinetic (PK) profile, pharmacodynamic effects, and antitumor activity of LY3039478 in patients with advanced or metastatic cancer. Methods: This phase I, open-label, multicenter, nonrandomized, and dose-escalation phase study determined and confirmed the recommended phase II dose of LY3039478 (oral dose: 2.5-100 mg, thrice weekly (TIW) on a 28-day cycle). The primary objectives are to determine (part A) and confirm (part B) a recommended phase II dose that may be safely administered to patients with advanced or metastatic cancer, and secondary objectives include evaluation of safety, tolerability, PK parameters, and preliminary antitumor activity of LY3039478. Results: A total of 110 patients were treated with LY3039478 monotherapy between 31 October 2012 and 15 July 2016. Dose-limiting toxicities were thrombocytopenia, colitis, and nausea. Most adverse events were gastrointestinal. The recommended phase II dose was 50 mg TIW, because of its better tolerability compared with 75 mg. The PKs of LY3039478 appeared dose proportional. Pharmacodynamic data indicate an ∼80% inhibition of plasma Aß, and >50% inhibition of Notch-regulated genes hairy and enhancer of split-1, cyclin D1, and Notch-regulated ankyrin repeat at 45-100-mg dose. Clinical activity (tumor necrosis, metabolic response, or tumor shrinkage) was observed in patients with breast cancer, leiomyosarcoma, and adenoid cystic carcinoma. Conclusion: Potent inhibition of Notch signaling by LY3039478 was well tolerated at doses associated with target engagement, and demonstrated evidence of clinical activity in heavily pretreated patients. Further investigation with LY3039478 as monotherapy and in combination with targeted agent or chemotherapy is ongoing. Clinicaltrials.gov ID: NCT01695005.

[3H]Pramipexole: a selective radioligand for the high affinity dopamine D2 receptor in bovine striatal membranes.

The characterization of [3H]pramipexole binding to bovine striatal membranes is reported in full experimental detail. According to kinetic experiments, saturation and competition studies a single binding site can be selectively labeled which turned out to be the high affinity D2 receptor. Addition of GPP(NH)P resulted in almost complete loss of specific binding. The bovine D2 subtype shows high sequence identity with the human D2 receptor indicating that the heterologous competition assays are of interest for the evaluation of neurotropic drug candidates. Using the representative D2 agonists (+)-7-OH-DPAT, (-)-3-PPP and (S)-7-dipropylaminotetrahydroindolizine the same rank order of affinities was determined as described for rat striata labeled with [3H]pramipexole, however, the Ki values turned out to be significantly higher. Furthermore, the system facilitates structure activity relationship studied on D2 affinity modulating peptides. Using L-prolyl-L-leucyl-glycinamide as an example a significant increase of specific radioligand binding could be measured.

Ex-chiral pool synthesis and pharmacological aspects of 3-pyrrolidinylisoxazoles.

Employing the dopamine autoreceptor agonist (-)-3-PPP (3) as well as the cholinergic receptor ligands 4 and 5 as lead compounds the 3-pyrrolidinylisoxazoles 2a,b as well as its optical antipodes ent 2a,b were synthesized from (R)-aspartic acid (6) and (S)-aspartic acid (ent-6), respectively. Pharmacological properties of the target compounds were evaluated employing dopamine D2 receptor binding studies and functional experiments on muscarinic M2 receptors.

Enantiopure 4- and 5-aminopiperidin-2-ones: regiocontrolled synthesis and conformational characterization as bioactive beta-turn mimetics.

Starting from aspartic acid, we synthesized lactam-bridged beta- and gamma-amino acid equivalents. Using the 1,4-bis-electrophile 1b as a central intermediate, the 4- and 5-aminopiperidin-2-ones 4 and 8, respectively, were approached by regioselective functionalization and subsequent lactamization. Diastereoselective C-alkylation was performed after N-protection of the lactam functionality when exclusive trans configuration resulting in the formation of 5a-f was observed in the 4-amino series. On the other hand, cis selectivity was typical for the alkylations of the 5-amino lactams 5a,b. To investigate the ability of the lactam building blocks to induce reverse-turn structures by intramolecular hydrogen bonding, the model peptidomimetics 12 and 14 representing Homo-Freidinger lactams of type II and III were prepared from 4a and 8a, respectively. Conformational analyses in dilute solution (1 mM) by IR and NMR spectroscopy at room temperature clearly indicated that the 4-aminopiperidin-2-one derivative 12 predominantly adopts a reverse-turn structure stabilized by a CO-HN hydrogen bond in an 11-membered ring. VT NMR experiments showed a substantial temperature dependency of the terminal NH when Deltadelta(NH)/DeltaT = -6.5 indicated that the amount of intramolecular hydrogen bonding is higher at low temperature. An application in the field of medicinal chemistry was demonstrated. Thus, starting from the Homo-Freidinger lactam 11c and the enantiomer ent-11c, we synthesized the peptidomimetics 15c and 16c and investigated them as lactam-bridged analogues of the dopamine receptor modulating peptide Pro-Leu-Gly-NH(2) (PLG). Both test compounds turned out to enhance significantly the agonist binding of dopamine D2 receptors, when the isomer 15c revealed a potency comparable to the genuine ligand PLG.

Beta-analogs of PLG (L-prolyl-L-leucyl-glycinamide): ex-chiral pool syntheses and dopamine D2 receptor modulating effects.

Starting from (S)- and (R)-aspartic acid enantiomerically pure beta-proline derivatives were synthesized. These chiral building blocks were transformed into beta-analogs of the dopamine receptor modulating peptide PLG. According to dopamine receptor binding studies, significant enhancement of [3H]pramipexole binding was observed for the isomeres 1a,b and 2a-c. The derivative 1b revealed an activity comparable to PLG.

Antidepressant drug use: differences between psychiatrists and general practitioners. Results from a drug utilization observation study with fluoxetine.

Between 1990 and 1993, a series of drug utilization observation studies with fluoxetine (Flx) were conducted in Germany in several waves. 3,158 patients treated by psychiatrists/neurologists (PN) and 15,601 patients treated by general practitioners/internists (GPI) were included; data collection at start and end of treatment focussed on diagnoses, symptoms, prescription, comedication, efficacy (CGI, Zung scale), and adverse events. Differences between PN and GPI patients were of major interest. For more than 90% of both the PN and the GPI cases. Fix was used for the indication of "depression", with a dosis of 20 mg/day. More PN patients (47%) than GPI patients (28%) were diagnosed as "endogenous"; GPI patients more often presented with first episodes (36 vs. 24%). "suicidal ideation" was less prominent compared to PN subjects (17 vs. 28%). Psychotropic comedication was regarded as necessary in 39% (PN) and 10% (GPI) of the cases. Early treatment termination because of "remission/major improvement" was observed in 13% (PN) vs. 21% (GPI) and because of "adverse events" in 11% (PN) vs. 3% (GPI) of the patients. At observation end, 53% (PN) vs. 74% (GPI) were rated as "symptom-free/markedly improved" (CGI); self-ratings reflected comparable results, marked improvements over time, but still PN/GPI differences at the end. "Suicidality" related to depression was more pronounced in the PN group at both points in time. 24% (PN) vs. 6% (GPI) of the cases reported "routine" adverse events, while in 2% (PN) and 1% (GPI) "serious" adverse events were observed. (For all the above comparisons p < 0.001 to < 0.0001.) These findings reveal that-under routine conditions handled by PNs and GPIs-Fix shows an efficacy and safety consistent with clinical trial data. The body of data suggests that PN patients present with more severe depression and more suicidality, require more comedication, and end up with a poorer outcome. Differences in the physicians' perception of psychiatric and somatic symptomatology and their treatment routines may also have something to do with the PN/GPI group differences observed.

A phase II trial of pemetrexed in patients with metastatic renal cancer.

BACKGROUND: Metastatic renal cell carcinoma (RCC) is rising in incidence but remains difficult to treat. This clinical trial evaluated the effects of pemetrexed (multitargeted antifolate, ALIMTAR) for the treatment of metastatic RCC. PATIENTS AND METHODS: Patients were required to have histological diagnosis of metastatic RCC with measurable disease and no prior chemotherapy. In addition, patients were required to have a World Health Organization (WHO) performance status of 0-2 and adequate bone marrow reserve. Patients received pemetrexed at a dose of 600 mg/m2 as a 10 min infusion every 3 weeks. Patients did not receive folic acid or vitamin B12 supplementation. RESULTS: Thirty-nine patients were enrolled and thirty two were evaluable for response. Three patients had a partial response for a response rate of 9% (95% CI 2-25%). The median time to progressive disease was 10.5 months. Of the nonresponders, twenty two had stable disease (median duration was 5.8 months; range 1.5-27.7) and seven had progressive disease (median time to progression was 5.4 months). Median time to progression for all qualified patients was 5.7 months. Common toxicities experienced were diarrhea and infection. Fatigue, stomatitis, and rash were also reported. The most common hematologic toxicity was grade 3/4 lymphopenia in 76% of patients. Leukopenia, granulocytopenia, and thrombocytopenia were also frequently reported. CONCLUSION: Single-agent pemetrexed has moderate activity in the treatment of metastatic RCC and should be investigated in combination with other potential active agents, as first-line treatment.

Gemcitabine plus dose-escalated epirubicin in advanced breast cancer: results of a phase I study.

Gemcitabine has shown single-agent activity in metastatic breast cancer. Epirubicin is also widely used for the adjuvant and treatment of metastatic breast cancer. The toxicity profiles and modes of action are different which provides a good rationale for studying both drugs in combination. In a phase I study gemcitabine at a fixed dose of 1000 mg/m2 on days 1, 8, 15 of a 28 day cycle was combined with escalated weekly doses of epirubicin starting with an initial dose of 10 mg/m2. Patients had stage IV metastatic disease without previous chemotherapy except as adjuvant treatment. Nineteen patients were included in the study which defined the maximum tolerated dose (MTD) of epirubicin at 20 mg/m2. Myelosuppression was the dose limiting toxicity with leucopenia WHO grade 3 and 4 in 40.0% and 20.0%, neutropenia WHO grade 3 and 4 without neutropenic fever in 20.0% and 40.0% and thrombocytopenia WHO grade 4 in 20.0%. At the epirubicin 15 mg/m2 dose level, leucopenia (11.1% WHO grade 3) and neutropenia (12.5 and 37.5% WHO grade 3 and 4) were reported. Symptomatic toxicity was generally mild: nausea/vomiting in about 20% of patients (WHO grade 3 or 4) on both 15 and 20 mg/m2 epirubicin dose levels. Alopecia WHO grade 3 and 4 was seen in 2 patients at MTD. Four of 19 evaluable patients had a partial response. We conclude that the combination of gemcitabine and epirubicin is well tolerated and has promising activity. A phase II study is underway with gemcitabine 1000 mg/m2 and epirubicin 15 mg/m2 on days 1, 8 and 15 of a 28 day cycle.

Phase II study of gemcitabine as first-line chemotherapy in patients with advanced or metastatic breast cancer.

In this phase II study, the efficacy and tolerability of gemcitabine were studied in 42 patients with locally advanced or metastatic breast cancer who had received up to one prior chemotherapy regimen in an adjuvant setting. Ten patients had received adjuvant chemotherapy. Twenty-eight patients (67%) had visceral disease spread at entry. Gemcitabine (1000 mg/m2) was administered weekly on days 1, 8 and 15 of a 28-day cycle. The mean number of completed cycles was 3.9 and the mean dose delivered was 942.2 mg/m2. Ninety-seven percent of injections were administered as assigned. No complete responses were observed, but there were six partial responses and 24 patients with stable disease lasting 2-9 months. The overall response rate was 14.3% (95% CI 5.4-28.5%). The median survival for all patients was 15.2 months. Maximum WHO grade 3 and 4 toxicities were observed in five patients for nausea and vomiting, one patient for diarrhea, one patient for pain, seven patients for alanine transaminase, and eight patients for segmented neutrophils. There were no grade 3 and 4 toxicities for alopecia. These data confirm modest single-agent gemcitabine activity in advanced or metastatic breast cancer. Gemcitabine's favorable toxicity profile makes it an ideal candidate for combination chemotherapy.