The anti-B-cell maturation antigen BiTE molecule AMG 420 was assessed in patients with relapsed/refractory multiple myeloma.
In this first-in-human study, up to 10 cycles of AMG 420 were given ...(4-week infusions/6-week cycles). Patients had progression after ≥ 2 lines of prior therapy and no extramedullary disease. Minimal residual disease (MRD) response was defined as < 1 tumor cell/10
bone marrow cells by flow cytometry.
Forty-two patients received AMG 420 at 0.2-800 μg/d. Median age was 65 years, and median disease duration was 5.2 years. Median exposure was 1 cycle (range, 1-10 cycles) and 7 cycles (range, 1-10 cycles) for responders. Patients discontinued for disease progression (n = 25), adverse events (AEs; n = 7), death (n = 4), completion of 10 cycles (n = 3), and consent withdrawal (n = 1). Two patients remain on treatment. There were 2 nontreatment-related deaths from AEs, influenza/aspergillosis and adenovirus-related hepatitis. Serious AEs (n = 20; 48%) included infections (n = 14) and polyneuropathy (n = 2); treatment-related serious AEs included 2 grade 3 polyneuropathies and 1 grade 3 edema. There were no grade ≥ 3 CNS toxicities or anti-AMG 420 antibodies. In this study, 800 μg/d was considered to not be tolerable because of 1 instance each of grade 3 cytokine release syndrome and grade 3 polyneuropathy, both of which resolved. The overall response rate was 31% (n = 13 of 42). At the maximum tolerated dose (MTD) of 400 μg/d, the response rate was 70% (n = 7 of 10). Of these, five patients experienced MRD-negative complete responses, and 1 had a partial response, and 1 had a very good partial response; all 7 patients responded during the first cycle, and some responses lasted > 1 year.
In this study of AMG 420 in patients with relapsed/refractory multiple myeloma, the response rate was 70%, including 50% MRD-negative complete responses, at 400 μg/d, the MTD for this study.
BI 2536 is a novel, potent, and highly specific inhibitor of polo-like kinase 1 (Plk1), which has an essential role in the regulation of mitotic progression. The aim of this trial was to identify the ...maximum tolerated dose (MTD) of BI 2536 and to determine the safety, pharmacokinetics, and antitumor activity in patients who had advanced solid tumors.
This phase I trial followed an open label, toxicity-guided, dose-titration design. Single doses of BI 2536 (25 to 250 mg) were administered as a 1-hour intravenous infusion; patients who experienced clinical benefit were eligible for additional treatment courses. Safety and pharmacokinetics were investigated. Tumor response was evaluated according to Response Evaluation Criteria in Solid Tumors Group guidelines.
The MTD was defined at 200 mg in a total of 40 patients entered; reversible neutropenia constituted the dose-limiting toxicity (DLT) and the most frequent adverse event at the MTD (grade 3 to 4; 56%). Nausea (52%), fatigue (52%), and anorexia (44%) also were common and were mostly of mild to moderate intensity (Common Terminology Criteria of Adverse Events <or= grade 2). One patient experienced a transient partial response. At doses equal to or greater than the MTD, 23% of patients experienced disease stabilization for 3 or more months. Dose-proportional increases in the maximum plasma concentration and total exposure were observed. BI 2536 showed a high total clearance and high distribution into tissue.
The MTD of BI 2536 when administered as a single-dose, 1-hour infusion was 200 mg; BI 2536 was well tolerated and showed a favorable pharmacokinetic profile. Antitumor activity of BI 2536 was observed.
Summary
Background
This trial evaluated the maximum tolerated dose (MTD), safety, pharmacokinetics, and activity of volasertib, a selective Polo-like kinase 1 inhibitor that induces mitotic arrest ...and apoptosis, combined with cisplatin or carboplatin in patients with advanced/metastatic solid tumors (NCT00969761; 1230.6).
Methods
Sequential patient cohorts (3 + 3 dose-escalation design) received a single infusion of volasertib (100–350 mg) with cisplatin (60–100 mg/m
2
) or carboplatin (area under the concentration versus time curve AUC4–AUC6) on day 1 every 3 weeks for up to six cycles. Sixty-one patients received volasertib/cisplatin (
n
= 30) or volasertib/carboplatin (
n
= 31) for a median of 3.5 (range, 1–6) and 2.0 (range, 1–6) treatment cycles, respectively.
Results
The most common cycle 1 dose-limiting toxicities (DLTs) were thrombocytopenia, neutropenia and fatigue. MTDs (based on cycle 1 DLTs) were determined to be volasertib 300 mg plus cisplatin 100 mg/m
2
and volasertib 300 mg plus carboplatin AUC6. Co-administration did not affect the pharmacokinetics of each drug. Partial responses were observed in two patients in each arm. Stable disease was achieved in 11 and six patients treated with volasertib/cisplatin and volasertib/carboplatin, respectively.
Conclusions
Volasertib plus cisplatin or carboplatin at full single-agent doses was generally manageable and demonstrated activity in heavily pretreated patients with advanced solid tumors.
Background: To determine the maximum tolerated dose (MTD) and dose-limiting toxicities (DLTs) of BIBF 1120, a triple angiokinase
inhibitor administered once-daily in patients with advanced multiple ...myeloma. Patients and Methods: This Phase I study included
17 patients. Planned dose escalations of BIBF 1120 were 100, 200, 250 and 300 mg. Safety and pharmacokinetic (PK) assessments
were performed. Results: Two DLTs (200 and 250 mg) occurred due to increased gamma-glutamyltransferase levels (CTC grade 3).
The 250 mg dose was well tolerated; no dose escalation beyond 250 mg was made. The most common adverse events included diarrhoea,
nausea and vomiting. No detectable deviation from dose linear PKs was observed. Regarding tumour control, two patients had
stable disease for â¥4 months. Conclusion: BIBF 1120 was safe and well tolerated up to 250 mg/day. The MTD was not reached.
Purpose: Novel drugs including targeted approaches have changed treatment paradigms for multiple myeloma (MM) and may also have therapeutic
potential in the poor-prognosis t(4;14) subset; t(4;14) ...results in overexpressed and activated fibroblast growth factor receptor
3 (FGFR3). Blocking this receptor tyrosine kinase (RTK) induces apoptosis in t(4;14)+ MM cells and decreases adhesion to bone
marrow stromal cells (BMSC). Using combinations of novel drugs, we investigated potential enhancement of single-agent activities
within the tumor cells, targeting of the marrow micromilieu, or circumvention of drug resistance in t(4;14)+ MM.
Experimental Design: We tested effects on apoptosis and related signaling pathways in the t(4;14)+ MM subset, applying drug combinations including
a FGFR3 tyrosine kinase inhibitor (RTKI), the proteasome inhibitor bortezomib, and dexamethasone.
Results: RTKI, bortezomib, and dexamethasone were active as single agents in t(4;14)+ MM. RTK inhibition triggered complementary proapoptotic
pathways (e.g., decrease of Mcl-1, down-regulation of p44/42 mitogen-activated protein kinase, and activation of proapoptotic
stress-activated protein/c-Jun NH 2 -terminal kinases). Synergistic or additive effects were found by combinations of RTKI with dexamethasone or bortezomib. In
selected cases of t(4;14)+ MM, triple combinations were superior to dual combinations tested. Prevention from MM cell apoptosis
by BMSC or exogenous interleukin-6 was circumvented by drug combinations. In t(4;14)+, N -ras–mutated NCI-H929 cells, resistance to RTKI was overcome by addition of dexamethasone. Notably, the combination of RTKI
and dexamethasone showed additive proapoptotic effects in bortezomib-insensitive t(4;14)+ MM.
Conclusions: Combining novel drugs in poor-prognosis t(4;14)+ MM should take into account at least bortezomib sensitivity and probably
Ras mutational status.
Abstract Background Volasertib (BI 6727) is a potent and selective cell-cycle kinase inhibitor that induces mitotic arrest and apoptosis by targeting Polo-like kinase (Plk). This phase I ...dose-escalation study evaluated the maximum tolerated dose (MTD) of volasertib, safety and efficacy, and pharmacokinetic (PK) parameters. Methods This trial followed an open-label, toxicity-guided dose-titration design. Patients with progressive advanced or metastatic solid tumours received a single 1-h infusion of volasertib every 3 weeks. A total of 65 patients were treated at doses of 12–450 mg. Results Reversible haematological toxicity was the main side-effect; thrombocytopenia, neutropenia, and febrile neutropenia constituting the main dose-limiting events. Anaemia (all grades 22%; grade 3: 8%), neutropenia (15%; grade 3/4: 14%), fatigue (15%; grade 3: 2%), and thrombocytopenia (14%; grade 3/4: 14%) were the most frequent drug-related adverse events. The MTD was 400 mg; however, 300 mg was the recommended dose for further development based on overall tolerability. Three patients achieved confirmed partial response. Stable disease as best response was reported in 40% of patients. Two patients remained progression free for >1 year. PK analysis showed no indication of deviation from ‘dose-linear PK’ behaviour, a large volume of distribution (>4000 l), moderate clearance and a long half-life (∼111 h). Conclusion This first-in-man trial demonstrated a favourable PK profile of volasertib, with manageable toxicities. As expected, the most common events were haematological. Encouraging preliminary antitumour activity has been observed, supporting Plk inhibition as a therapeutic approach. Clinical development of volasertib in phase II monotherapy and combination trials is ongoing.
In acute myeloid leukemia (AML), receptor tyrosine kinase ligands promote growth and survival and contribute to AML-associated
marrow neoangiogenesis. We have tested simultaneous inhibition of ...vascular endothelial growth factor, fibroblast growth factor,
and platelet-derived growth factor receptor signaling by novel indolinone derivatives using 14 myeloid, including 11 human
leukemic, cell lines. Compounds inhibited colony formation of all cell lines in a dose-dependent fashion. Inhibitory concentrations
for 50% of the colony formation/survival (IC 50 ) for BIBF1000 were <100 nmol/L for 3 of 11, ≤500 nmol/L for 6 of 11, and <1,000 nmol/L for 10 of 11 leukemic cell lines,
with one cell line being resistant in the dose range <1,000 nmol/L. BIBF1120 was less effective with 4 of 11 leukemic cell
lines being resistant within the dose range <1,000 nmol/L. Testing of myeloid 32D cells transfected with empty vector, wild-type
Flt3, or Flt3 carrying an internal tandem duplication mutation revealed higher resistance for the internal tandem duplication
mutant. These effects of the compounds were associated with inhibition of tyrosine phosphorylation and the mitogen-activated
protein kinase pathway. Furthermore, both compounds induced apoptosis in the sensitive cell lines. In Mono-Mac1 cells, the
compounds had a direct proapoptotic effect that was increasing the proapoptotic effect of 1-β- d -arabinofuranosylcytosine. The data provide a rationale for clinical evaluation of these tyrosine kinase inhibitors in AML.
Mol Cancer Ther 2006;5(12):3105–12
Background: BI 2536 is a highly potent, selective inhibitor of Polo-like kinase 1 (Plk1), a key regulator of mitotic progression. BI 2536 has demonstrated favorable tolerability and antitumor ...activity in Phase I trials in patients with solid tumors. Antitumor activity of BI 2536 was also shown in preclinical non-Hodgkin's lymphoma (NHL) models. We determined the maximum tolerated dose (MTD), overall safety, pharmacokinetics (PK) and efficacy of BI 2536 given as an intravenous infusion once every 3 weeks in patients with relapsed or refractory aggressive NHL of T- or B-cell origin.
Methods: Sequential cohorts of 3–6 patients with relapsed or refractory aggressive NHL received 1-hour infusions of BI 2536 following a toxicity-guided Phase 1 doseescalation design. Patients relapsed after peripheral stem cell transplantation and transplantation-naive patients were entered into different strata and the respective MTD determined independently. A single administration was given every 21 days. Patients with clinical benefit were eligible for further treatment courses after recovery from toxicity after a 3-week observation period. A total of 41 patients were entered into the trial: 24 patients in the transplant-naive (non-tr) stratum; and 17 patients in the transplant-failure (tr) stratum. Patients were treated at dose levels from 50 to 200 mg.
Results: The safety profile was similar in both strata with the MTD determined independently at 175 mg for both non-tr and tr patients. Neutropenia (tot: 33%; CTCAE Grade (gr)3/4: 21%), anemia (tot: 29%; gr3: 4%), thrombocytopenia (tot: 29%; gr3/4: 17%), fatigue (tot: 25%; gr3: 4%) and nausea (tot=gr1/2: 25%) were the most frequent adverse events in non-tr; and thrombocytopenia (tot: 59%; gr3/4: 41%), anemia (tot=gr1/2: 41%), fatigue (tot=gr1/2: 41%) and neutropenia (tot: 41%; gr3/4: 21%) were most frequent in tr patients. Dose-limiting toxicities (DLTs) consisted of reversible thrombocytopenia (six patients) and neutropenia (three patients). No relevant non-specific toxicity was observed. Pharmacokinetic analysis showed dose proportionality of Cmax and AUC0–∞ with a high clearance (~1,400 mL/min) and a high volume of distribution (>1,000 L). Patients were treated for up to 6 courses without evidence of cumulative toxicity. Three complete responses (CRs) and one partial response were observed. Stable disease as best response was noted in three (18%) of tr patients and nine (38%) of non-tr patients. All responders had relapsed after prior peripheral stem cell transplants and were treated at doses of 150–200 mg. Three of the four responders had a peripheral T-cell lymphoma (PTCL) NHL; one CR was observed in a patient with diffuse large B-cell lymphoma. The overall response rate (ORR) in the tr stratum was 23.5%; in the aggregate of both tr and non-tr, the ORR amounted to 9.7%. With three out of five patients responding, an ORR of 60% was observed in the T-cell subset. However, the responses were of short duration.
Conclusion: BI 2536 has a favorable safety and PK profile in patients with NHL. Safety profile and PK properties are comparable to data obtained in solid tumor patient populations. Encouraging, albeit transient, anti-lymphoma efficacy was observed in patients suffering from PTCL after autologous stem-cell transplantation.
To investigate the efficacy, safety, and pharmacokinetics of two dosing schedules of BI 2536, a novel polo-like kinase-1 inhibitor, in patients with relapsed stage IIIB/IV non-small cell lung cancer.
...Ninety-five patients were randomized to intravenous BI 2536 on day 1 (200 mg) or days 1 to 3 (50 or 60 mg) of a 21-day treatment course. BI 2536 doses were escalated beyond course 2 if well tolerated. The primary objective was response, and the secondary objectives were progression-free survival (PFS) and overall survival (OS), quality of life, safety, and pharmacokinetics. Primary statistical aim was to demonstrate the difference in objective response rate to historical placebo for both treatment groups.
Four patients (4.2%) had a partial response; two were confirmed by independent review. Median PFS was 8.3 weeks (58 days 95% confidence interval CI: 48–85) and 7 weeks (49 days 95% CI: 46–70) assessed by investigator and independent review, respectively. Median OS was 28.7 weeks (201 days 95% CI: 180–305). No statistically significant difference was observed between the two treatment schedules regarding clinical benefit, PFS, or OS. Grade 4 neutropenia occurred in 37% of patients; common nonhematologic adverse events were fatigue (31%) and nausea (27%). Two deaths (pulmonary hemorrhage and sepsis) were considered drug related. There was a trend in favor of the days 1 to 3 dosing schedule in quality of life. BI 2536 displayed moderate interpatient variability.
BI 2536 monotherapy has modest efficacy and favorable safety in relapsed non-small cell lung cancer. The findings support the further development of polo-like kinase-1 inhibitors within this indication.
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