A Phase I Dose Escalation Study of KW-2449, An Oral Multi-Kinase Inhibitor against FLT3, Abl, FGFR1 and Aurora in Patients with Relapsed/Refractory AML, ALL and MDS or Resistant/Intolerant CML

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2967-2967 ◽  
Author(s):  
Jorge Cortes ◽  
Gail J. Roboz ◽  
Hagop M. Kantarjian ◽  
Eric J. Feldman ◽  
Judith E. Karp ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Bone Marrow ◽  
Febrile Neutropenia ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Recovery Period ◽  
Post Dose ◽  
Grade 3 ◽  
Dose Levels ◽  
Bone Marrow Blasts

Abstract Background: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 30% of patients with de novo AML and confer a poor prognosis. KW-2449 is an oral multi-kinase inhibitor which is highly potent against mutant FLT3 (IC50=0 1–7 nmol/L) and other tyrosine kinases including FGFR1, TrkA, Abl (including T315I) and Aurora A serine threonine kinase. Based on the activity of KW-2449 and its metabolite (M1) in both in vitro and in vivo preclinical leukemia models, KW-2449 was evaluated in patients with leukemia and MDS in this first-in-man study. M1 is formed via monoamine oxidase-B and aldehyde oxidase mediated oxidation of KW-2449. Methods: The objectives were to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of KW-2449 in patients with refractory/relapsed AML, ALL and MDS, or resistant/intolerant CML. A range of daily doses of KW-2449 (12.5–250 mg twice daily, i.e. 25–500 mg/day) on 2 treatment schedules (14 or 28 days) with a recovery period of 7–28 days between cycles were evaluated. Dose limiting toxicity (DLT) and maximum tolerated dose (MTD) were assessed for the 1st cycle. The 28-day schedule was later eliminated. The plasma concentration of KW-2449 and M1 were analyzed by LC-MS/MS method. A plasma inhibitory activity (PIA) assay [Blood 108(10) 3477–83] for P-FLT3 and P-STAT5 was used to measure FLT3 inhibition. Results: 37 patients aged 26–88 years (16 male) were treated at 7 dose levels: 25, 50, 100, 200, 300, 400, and 500 mg daily. Thirty-one patients had AML, 5 CML and 1 ALL. The mean duration of therapy was 2 cycles in AML patients and 4 cycles in CML patients. KW-2449 was rapidly absorbed and metabolized to M1. The half-lives for KW-2449 and M1 were not dose-related and ranged from 2.4 to 4.9 hours and 2.6 to 6.6 hours, respectively. Administration of KW-2449 in a BID regimen led to minor accumulation and was consistent with the short half-life. The PIA assay demonstrated the near complete down-regulation of P-FLT3 and P-STAT5 2 hours post-dose at a dosing level of 400 mg daily. The extent of inhibition was lower at 8 hours and generally absent at 12 hours post-dose. The most frequently reported adverse events (AEs; any grade, regardless of causality) were nausea (70.3%), vomiting (48.6%), fatigue (45.9%), diarrhea (32.4%), dyspnea (29.7%), febrile neutropenia (29.7%), pain in extremity (29.7%), and arthralgia (27.0%). Febrile neutropenia (24.3%), pneumonia (10.8%), and thrombocytopenia (10.8%) were the most frequently reported Grade 3/4 AEs. DLTs occurred in 2 patients: Grade 3 atrial fibrillation (100 mg daily) and Grade 3 nausea and vomiting (500 mg daily). A total of 70 SAEs were reported in 27 patients including 11 on-study deaths; only atrial fibrillation and pleural effusion were considered possibly related to KW-2449. Eight of 31 patients with AML (26%) (FLT3 mutation: 5 positive and 3 negative) and 1 of 5 patients with CML (20%) exhibited a ³ 50% reduction in peripheral blasts and/or bone marrow blasts from baseline to the end of Cycle 1. One patient (500 mg daily) with AML exhibited a > 50% decrease in peripheral blasts, increased platelets, and ANC, and decreased WBC count. A patient with CML (Bcr-Abl T315I +) lost the mutant clone while on KW-2449 treatment. Conclusions: KW-2449 was safe and well tolerated at the dose levels evaluated. There were no complete or partial responses, but transient decreases in peripheral blood and bone marrow blasts were observed, justifying continued investigation of this agent. Sustained inhibition of P-STAT5 and P-FLT3 was not achieved at trough at the highest BID dose evaluated. TID and QID dosing schedules should be evaluated to accommodate the short t1/2 and to achieve sufficient target inhibition.

A Phase I Dose Escalation Study of KW-2449, an Oral Multi-Kinase Inhibitor Against FLT3, Abl, FGFR1 and Aurora in Patients with Relapsed/Refractory AML, Treatment Resistant/Intolerant CML, ALL and MDS.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 909-909 ◽  
Author(s):  
Jorge Cortes ◽  
Gail J. Roboz ◽  
Hagop Kantarjian ◽  
Eric Feldman ◽  
Judy Karp ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Tyrosine Kinase ◽  
Kinase Inhibitor ◽  
De Novo ◽  
Recovery Period ◽  
Plasma Concentrations ◽  
Treatment Resistant ◽  
Dose Levels ◽  
Bone Marrow Blasts

Abstract Background: Activating mutations of FMS-like tyrosine kinase 3 (FLT3) occur in 30% of patients (pts) with de novo AML and confer a worse prognosis. KW-2449 is an oral multi-kinase inhibitor highly potent against mutant FLT3 (IC50= 1–7 nmol/L) and other tyrosine kinases including FGFR1, TrkA, Abl (including T315I), JAK2, c-KIT, and c-SRC and Aurora A serine tyrosine kinase. Based on the anti-leukemia activity of KW-2449 demonstrated both in vitro and in vivo preclinical leukemia models, KW-2449 is being evaluated in hematologic conditions in the first-in-man study. Methods: The study objectives were to assess the safety, tolerability, pharmacokinetic (PK) and pharmacodynamic effects of KW-2449 in pts with refractory/relapsed AML or treatment resistant/intolerant CML/ALL and MDS. A range of daily doses of KW-2449 (25–500 mg/day) divided into q 12h dosing on 2 treatment schedules (14 days vs. 28 days) with a recovery period of 7–28 days between cycles. Dose limiting toxicity (DLT) and maximally tolerated dose were assessed for the 1st cycle. Serial samples for PK analysis were collected immediately before and after KW-2449 on treatment days 1, 14 and 28. The 28-day schedule was later eliminated. Plasma concentrations of KW-2449 and its active metabolite (M1) were analyzed by LC-MS/MS. A plasma inhibitory activity (PIA) assay [Blood 108(10) 3477–83] for P-FLT3 and P-STAT5 was used to measure FLT3 inhibition. Results: To date, 29 pts (15 female) have been enrolled (median age 60 years; range 25–82) and treated at 5 dose levels: 25, 50, 100, 200, and 300 mg daily. Twenty-five pts had AML and 4 CML (3 with T315I mutation); 24 pts completed at least 1 cycle. KW-2449 was rapidly absorbed and metabolized to M1. Elimination half-lives were 2.8–3.9 h for KW-2449 and 3.8–5.5 h for M1. Plasma levels of M1 were lower on Days 14 and 28 compared to Day 1, suggesting inhibition of this pathway upon multiple dosing. A single DLT of grade 3 pneumonia was reported on 100 mg but no further DLTs were seen in the expanded cohort at that dose or at 200 or 300 mg daily. A total of 33 SAEs were reported of which 6 were considered possibly related (by the Investigator) to KW-2449: dyspnea, pneumonia, atrial fibrillation, cardiac ischemia, ventricular arrhythmia, and pleural effusion. There have been 5 deaths on study (none drug-related): disease progression (2), neutropenic sepsis, infection with renal failure, and pneumonia. Seven pts had stable disease after 1 cycle. Three pts with AML (2 FLT3+) had ≥ 50% reduction in peripheral and/or bone marrow blasts in the 1st cycle. In vivo FLT3 inhibition, as measured directly in patient blasts, correlated with blast reduction. The extent and duration of FLT3 inhibition increased with increases in dose. Conclusions: KW-2449 appears safe and well tolerated at the dose levels evaluated. Transient decreases in peripheral blood and bone marrow blasts have been observed in a few patients justifying continued investigation with this agent. Accrual is ongoing and a different schedule to accommodate the short t1/2 will be explored.

Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with CD33-Positive Acute Myeloid Leukemia (AML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 623-623 ◽  
Author(s):  
Eytan M. Stein ◽  
Anthony Stein ◽  
Roland B. Walter ◽  
Amir T. Fathi ◽  
Jeffrey E. Lancet ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Research Funding ◽  
Phase 1 ◽  
Intensive Therapy ◽  
Employment Equity ◽  
Rapid Clearance ◽  
Equity Ownership ◽  
Grade 3 ◽  
Dose Levels ◽  
Bone Marrow Blasts

Abstract Background CD33 is expressed on the surface of myeloblasts in 85 to 90% of patients with AML and represents a promising target regardless of age, risk factors, or underlying mutational heterogeneity. SGN-CD33A is an anti-CD33 engineered cysteine antibody conjugated to an average of 2 molecules of a pyrrolobenzodiazepine (PBD) dimer, a highly potent DNA crosslinking agent. Upon binding to the cell surface, SGN-CD33A is internalized and transported to the lysosomes where PBD dimer is released within the cell through proteolytic cleavage of the linker, crosslinking DNA and leading to cell death. Methods This phase 1, open-label, 3+3 dose-escalation study (NCT01902329) is designed to evaluate the safety, tolerability, pharmacokinetics (PK), and anti-leukemic activity of SGN-CD33A. Eligible patients (ECOG 0-1) must have CD33-positive AML, and have either relapsed disease following initial remission (CR) of > 3 months, or have declined conventional induction/consolidation. SGN-CD33A is administered outpatient IV every 3 weeks for up to 4 cycles (Part A), followed by optional maintenance treatment for patients achieving a CR/CRi (Part B). Investigator assessment of response is per IWG criteria (Cheson 2003). Results To date, 40 patients (48% female) with a median age of 75 years (range, 27-86) have been treated. Twenty patients had relapsed AML after 1st CR with intensive therapy (3 of these had intensive frontline therapy plus 1 additional line of low intensity therapy); 20 had declined conventional intensive therapy (13 of these patients had received 1-2 prior low intensity therapies, primarily hypomethylating agents). Of the patients enrolled, 45% had underlying myelodysplasia and most had disease with intermediate (70%) or adverse (18%) cytogenetic risk, 8% with mutated NPM1 (without FLT3 mutation) and 13% with mutated FLT3. Dose levels tested were 5 mcg/kg (n=3), 10 mcg/kg (n=3), 20 mcg/kg (n=13), 40 mcg/kg (n=18), and 60 mcg/kg (n=3). To date, a maximum of 4 cycles was received in Part A and 10 cycles in Part B (total median of 2 cycles on treatment; range, 1-13 cycles). Thirteen patients remain on treatment and enrollment is ongoing. Two dose-limiting toxicities have been reported, a Grade 3 pulmonary embolism (20 mcg/kg) and a Grade 4 hypocellular marrow (>28 days; 40 mcg/kg). The only Grade 3 or higher adverse event (AE) reported in >10% of patients was febrile neutropenia (55%). Other treatment-emergent AEs regardless of relationship to study treatment reported in ˃10% of patients were fatigue (48%), diarrhea (20%), constipation (18%), cough (18%), dyspnea (18%), epistaxis (18%), peripheral edema (18%), malaise (15%), hypokalemia (13%), and pleural effusion (13%). The 30-day mortality was 2.5%, with no treatment-related deaths occurring during that time; 1 elderly patient died from a traumatic fall unrelated to SGN-CD33A. Blast clearance in marrow was obtained in 16 of 38 efficacy evaluable patients (42%) across all dose levels. A dose-response relationship is evolving with rapid and marked decreases in bone marrow blasts at 40 and 60 mcg/kg in 19 of 21 patients (Figure 1). Of 17 efficacy evaluable patients treated at 40 mcg/kg, 8 experienced clearance of marrow blasts; these patients achieved a best clinical response of CR (2), CRi (3), and morphologic leukemia-free state (mLFS; 3) thus far. In addition, complete remissions were observed at 5 mcg/kg (1 CR), 10 mcg/kg (1 CRi), and 20 mcg/kg (2 CRis). Preliminary PK data demonstrated rapid clearance of ADC, suggesting target-mediated disposition. Plasma ADC exposure generally increased with increasing dose levels. Conclusions A MTD for SGN-CD33A is not yet identified and enrollment continues. AEs observed were generally manageable, often associated with underlying myelosuppression. To date, SGN-CD33A has demonstrated antileukemic activity with 47% achieving blast clearance at the 40 mcg/kg dose level. The observed low 30-day mortality (2.5%) and rapid clearance of marrow blasts in patients with poor risk factors (median age 75, predominantly intermediate and adverse cytogenetic risk, and 45% underlying myelodysplasia) with outpatient administration are encouraging. Enrollment is ongoing to further define optimal dose and schedule. In addition, combinations of SGN-CD33A with standard AML and MDS agents will be evaluated. Figure 1: Bone Marrow Blasts Over Time Figure 1:. Bone Marrow Blasts Over Time Disclosures Stein: Seattle Genetics, Inc.: Research Funding; Janssen Pharmaceuticals: Consultancy. Off Label Use: SGN-CD33A is an investigational agent being studied in patients with AML. SGN-CD33A is not approved for use. Stein:Seattle Genetics, Inc.: Research Funding. Walter:Seattle Genetics, Inc.: Consultancy, Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Amgen: Research Funding; Amphivena Therapeutics, Inc.: Consultancy; Amgen: Research Funding. Fathi:Exelixis: Research Funding; Takeda Pharmaceuticals International Co.: Research Funding; Ariad: Consultancy; Seattle Genetics, Inc.: Consultancy, Research Funding. Lancet:Seattle Genetics, Inc.: Consultancy, Research Funding. Kovacsovics:Seattle Genetics, Inc.: Research Funding. Advani:Seattle Genetics, Inc.: Research Funding. DeAngelo:Seattle Genetics, Inc.: Research Funding. O'Meara:Seattle Genetics, Inc.: Employment, Equity Ownership. Zhao:Seattle Genetics, Inc.: Employment, Equity Ownership. Kennedy:Seattle Genetics, Inc.: Employment, Equity Ownership. Erba:Incyte: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Celgene: Consultancy, Speakers Bureau; Seattle Genetics, Inc.: Consultancy, Research Funding.

scholarly journals A Phase II Study of AT9283, an Aurora Kinase Inhibitor, in Patients with Relapased or Refractory Multiple Myloma; NCIC Clinical Trials Group IND.191

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5734-5734
Author(s):  
Annette E Hay ◽  
Alli Murugesan ◽  
Ashley M. DiPasquale ◽  
Tom Kouroukis ◽  
Irwindeep Sandhu ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Febrile Neutropenia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Histone H3 ◽  
Hematological Toxicity ◽  
Aurora B ◽  
Normal Range ◽  
Best Response ◽  
Grade 3

Abstract Background:Although outcomes for patients with multiple myeloma (MM) have improved, it remains an incurable malignancy for which new therapies are needed. Aurora kinases are overexpressed in MM. Inhibition of Aurora A kinase, a key component of the centrosome, in MM cell lines induces apoptotic cell death. Inhibition of Aurora B, a chromosome passenger protein, has therapeutic effects against myeloma lines, primary bone marrow plasma cells and murine xenografts. Histone H3 is a direct downstream substrate of Aurora B. The Aurora A and B kinase inhibitor AT9283 has shown anti-myeloma activity in pre-clinical studies. Based on an NCIC CTG phase I trial in patients with advanced malignancy the recommended phase 2 dose (RP2D) was 40 mg/m2 on days 1 and 8 of a 21 day cycle. This single arm phase II trial was designed to explore the efficacy of AT9283 in patients with relapsed and refractory multiple myeloma. Methods: Eligibility criteria included age ≥ 18, neutrophils ≥ 1 and platelets ≥ 70 x109/L. There was no upper limit on the number of prior regimens. The primary endpoint was response rate; secondary endpoints included toxicity and evaluation of potential biomarkers. According to the 2-stage design at least 1 response was required in the first 15 patients to proceed to a full sample size of 30, assuming an HA of ≥ 0.20. Initially AT9283 was administered by 24 hour continuous infusion at the RP2D. Hematological toxicity in the first 2 patients met protocol specified criteria for reduction of the starting dose to 30 mg/m2 for subsequent patients. Adverse events were graded according to CTCAE V4.0. Phosphorylated Histone H3 (Ser10), a marker of Aurora B activity, and total Histone H3 protein expression was measured by western blot analysis in baseline and day 21 bone marrow samples. Results:Over 18 months, eight eligible patients (3 male, 5 female) with MM (4 IgG, 2 IgA, 2 light chain) were accrued. All were evaluable for toxicity and 7 evaluable for response. Median age was 60 (range 48 – 75). The median number of prior regimens was 3 (range 1 - 5). Patients received between 1 – 4 cycles of AT9283 (median 1) with 25% of patients receiving ≥ 90% of the planned dose intensity. No responses were observed. The trial was closed due to slow accrual and toxicity, in particular myelosuppression. Transient neutropenia occurred in all patients (63% grade 3, 37% grade 4). Recovery from nadir to normal range was rapid in the majority (range 1 – 8 days, median 5) but prolonged in 2 patients who were neutropenic at baseline (11 and 13 weeks). Grade 3/4 thrombocytopenia occurred in 50% of patients. There were 3 infections ≥ grade 3 including 1 death. Grade 3 skin ulceration thought possibly related to AT9283 by the investigator occurred in 1 patient. The most common non-hematologic adverse events reported as possibly, probably or definitely related to AT9283 were grade 1-3 nausea (50%), grade 1 and 3 vomiting (38%), grade 4 febrile neutropenia (25%), grade 1/2 anorexia (25%), grade 1/2 diarrhea (25%) and grade 1/2 fatigue (25%). Paired baseline and day 21 bone marrow samples were provided from 4 patients; sufficient protein was extracted from both samples for western blot analysis from 3 patients. Of these, 2 showed a reduction in Histone 3 phosphorylation (H3-P) after the first cycle of treatment consistent with inhibition of Aurora B. Both of these patients had a best response of stable disease (SD). Abstract 5734. Table Patient Dose (mg/m2) Number of cycles Best response Non-hematological toxicity ≥ Grade 3* Reason off study H3-P/H3Baseline Day 21 1 40 1 PD Gr 3 skin ulceration Toxicity 0.3 0.5 2 40 1 SD Gr 3 lung infection Intercurrent illness 1.6 0.5 3 30 3 SD None PD 0.6 0.5 4 30 1 PD Gr 4 febrile neutropenia & gr 4 left ventricular systolic dysfunction Toxicity NE NE 5 30 1 NE Gr 4 febrile neutropenia & gr 5 sepsis** Death NE NE 6 30 4 PD Gr 3 nausea & vomiting PD NE NE 7 30 3 SD None PD NE NE 8 30 1 PD None Death NE NE * Reported as possibly, probably or definitely related to AT9283 by investigator ** Neutrophil count recovered to normal range prior to death PD progressive disease, NE not evaluable, Gr grade Conclusions: This study failed to reach full accrual. No objective responses were observed. Administration of AT9283 to patients with previously treated myeloma at this dose and schedule is associated with toxicity, particularly myelosuppression. Disclosures Sandhu: Janssen: Honoraria; Celgene: Honoraria; Novartis: Honoraria. Reece:Otsuka: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria, Research Funding; Millenium: Honoraria, Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Novartis: Honoraria, Research Funding; Amgen: Honoraria. Lyons:Astex: Employment. Seymour:Astex: Research Funding.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

2012 ◽  
Vol 18 (4) ◽  
pp. 440-444 ◽  
Author(s):  
Prathima Prodduturi ◽  
Anamarija M Perry ◽  
Patricia Aoun ◽  
Dennis D Weisenburger ◽  
Mojtaba Akhtari
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Bone Marrow Aplasia ◽  
Line Therapy ◽  
Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

Phase I Trial of Bortezomib (PS-341; NSC 681239) and Alvocidib (Flavopiridol; NSC 649890) in Patients with Recurrent or Refractory Indolent B-Cell Neoplasms - Update of the “Bolus” Infusion Schedule of Alvocidib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2959-2959
Author(s):  
Beata Holkova ◽  
Edward B. Perkins ◽  
Prithviraj Bose ◽  
Daniel M Sullivan ◽  
Rachid Baz ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Tumor Lysis ◽  
Mantle Cell ◽  
Infusion Schedule ◽  
Grade 3 ◽  
Dose Levels

Abstract Abstract 2959 Preclinical studies suggest that neoplastic cells may be particularly sensitive to simultaneous interruption of cell cycle and survival signaling pathways. We have previously reported that the cyclin-dependent kinase inhibitor alvocidib interacts with bortezomib, a proteasome inhibitor, to induce mitochondrial injury and apoptosis in human leukemia, myeloma, and lymphoma cells (Dai et al, Oncogene 22:7108, 2003; Dai et al, Blood 104:509, 2004). These actions were associated with inhibition of NF-κB DNA binding, increased expression of pJNK, and down-regulation of XIAP and Mcl-1. Based on these findings, a phase I trial was initiated in which bortezomib was administered in conjunction with alvocidib on the same days, according to 2 separate schedules: a “hybrid” infusion schedule (half the dose over 30 minutes and half over a 4-hour infusion); and a bolus infusion schedule in which alvocidib was administered over 1 hour. Results of the hybrid infusion schedule have recently been reported (Holkova et al, Clin Cancer Res 17:3388, 2011). The primary objective was to identify the maximum tolerated doses (MTDs) for the combination in the treatment of recurrent or refractory indolent B-cell neoplasms. Eligible patients included those with multiple myeloma (MM) or non-Hodgkin's lymphoma (NHL), with recurrent or refractory disease following at least 1 prior systemic therapy. To date, 43 patients have been treated at 9 dose levels. Patients with the following disease types have been treated: MM n=25 (Waldenstrom's macroglobulinemia n=2), NHL n=18 (mantle cell lymphoma n=5). The male:female ratio was n = 31 (72%):12 (28%); the median age was 65 (range: 40–79) years; ECOG performance scores ranged from 0–1; and the median number of prior therapies was 3 (range: 1–10). The schedule of administration was bortezomib via intravenous push over 3–5 seconds followed by alvocidib via intravenous 1-hour infusion on days 1, 4, 8, and 11; on a 21-day cycle, with indefinite continuation for responding patients and those with stable disease. Adverse events (AEs) were evaluated using CTCAE version 4. Dose limiting toxicities (DLTs) observed to date are shown in Table 1. Grade 3 and 4 AEs possibly, probably, or definitely related to study treatment tht occurred in ≥ 5% of patients were dehydration (7%), diarrhea (19%), fatigue (16%), febrile neutropenia (5%), leukopenia (37%), lymphopenia (28%), neutropenia (58%), peripheral neuropathy (12%), and thrombocytopenia (44%). No grade 5 events were observed. One patient developed tumor lysis syndrome and required hospitalization for 48 hours with complete recovery. Common grade 2 AEs possibly, probably or definitely related to treatment were anemia (30%), anorexia (28%), diarrhea (47%), fatigue (60%), leukopenia (47%), lymphopenia (28%), and thrombocytopenia (56%). Of the 43 patients treated, 38 have been evaluable for response. Patient responses are shown in Table 2. Correlative studies examining expression of pJNK, Mcl-1, XIAP, PARP, and NFκB are being collected for processing at the end of the study. Collectively, these findings indicate that the combination of bortezomib and alvocidib, the latter administered as a 1-hour infusion, is tolerable. The regimen appears active in patients with relapsed and/or refractory MM or NHL, justifying phase II studies to determine the activity of this regimen more definitively. The MTD has not yet been reached. Table 1. Dose levels and DLTs Dose Level Bortezomib (mg/m2) Alvocidib (mg/m2) Patients treated/# DLTs DLT 1 1.0 15 3/0 2 1.3 15 5/0 3 1.3 22 3/0 4 1.3 30 3/0 5 1.3 40 7/1 Grade 3 back pain 6* 1.3 50 5/1 Grade 3 fatigue 7** 1.3 60 8/2 Grade 3 febrile neutropenia Grade 3 tumor lysis syndrome 8** 1.3 75 6/2 Grade 3 diarrhea Grade 3 esophagitis/oral mucositis 9** 1.3 90 3/2 Grade 3 febrile neutropenia Grade 4 absolute neutrophil count decrease * Study is currently enrolling to dose level 6 ** Exceeded MTD Table 2. Response by diagnosis NHL MM Total (n = 15) (n = 23) (n = 38) Complete Remission 2b,c 1a 3 Partial Remission 3 7d,e 10 Complete + Partial Remission N(%) 5 (33) 8 (35) 13 (34) a Includes 1 patient with prior bortezomib b Includes 1 patient with prior autologous SCT c Includes 1 patient with mantle cell lymphoma d Includes 1 patient with Waldenstrom's macroglobulinemia e Includes 1 patient still under active treatment Disclosures: Baz: Celgene: Research Funding; Millennium: Research Funding; Bristol Myers Squibb: Research Funding; Novartis: Research Funding.

Dasatinib (D) in patients (pts) with chronic myelogenous leukemia (CML) in myeloid blast crisis (MBC) who are imatinib-resistant (IM-R) or IM-intolerant (IM-I): Results of the CA180006 ‘START-B’ study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6529-6529 ◽  
Author(s):  
J. E. Cortes ◽  
D. W. Kim ◽  
G. Rosti ◽  
P. Rousselot ◽  
E. Bleickardt ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitor ◽  
Blast Crisis ◽  
Initial Response ◽  
Preliminary Evidence ◽  
Marrow Transplant ◽  
Myelogenous Leukemia ◽  
Open Label ◽  
Hematologic Response ◽  
Grade 3

6529 Background: Dasatinib (D) (BMS-354825) is an oral, multitargeted tyrosine kinase inhibitor of Bcr-Abl and SRC with activity against IM-R cell lines. In a phase I study, there was preliminary evidence that D was active in MBC-CML patients (pts). Methods: START B is an open-label study of D in IM-R or IM-I MBC carried out in 46 sites worldwide. From December 2004 to May 2005, 124 MBC pts were accrued. D was given orally at 70 mg twice a day (BID) with dose escalation to 100 mg BID for poor initial response or dose reductions to 50 mg and 40 mg BID for toxicity. Pts had weekly blood counts and monthly bone marrow evaluations, including cytogenetics. The primary endpoint was confirmed (minimum 4 weeks duration) major hematologic response (MaHR). Results: Data are currently available on the first 74 pts (68 IM-R, 6 IM-I). Median age was 55 years, 55% were male. Other prior therapy included interferon in 55% of pts and bone marrow transplant (BMT) in 12%. Prior IM dose was >600 mg/day in 49% of pts and 47% of pts received IM for > 3 years. At baseline, the WBC count was ≥20 × 103/mm3 in 46%, the platelet count was < 100 × 103/mm3 in 72% of pts and 35% of pts had ≥ 50% bone marrow blasts. Mutations in the BCR-ABL domain were found in 27/63 (43%) pts. Median duration of therapy was 3.5 months. D doses were reduced in 35% pts, temporarily interrupted in 58% pts, and escalated in 41% pts. With a minimum of 6-month follow-up, hematologic response was seen in 39 (53%) pts: confirmed MaHR in 24 (32%) pts, Complete in 18 (24%) and No Evidence of Leukemia in 6 (8%). Major cytogenetic responses were documented in 22 (30%) pts and was complete in 20 (27%). The median time to MaHR was 56 days. There was no loss of response in pts with MaHR; the duration of MaHR ranged from 1.2+ to 7.8+ months. The median PFS had not been reached. Severe myelosuppression was very common. Non-hematologic toxicities were usually mild to moderate. Most common Grade 3–4 toxicities included diarrhea in (7%), pleural effusion (9%), nausea (4%). Peripheral edema was reported in 14% of pts (0% Grade 3–4), and rash in 11% of the pts (0% Grade 3–4). Conclusions: Dasatinib was highly effective in IM-R pts with MBC with durable MaHR. Data on all 124 pts will be presented at the meeting. [Table: see text]

A phase I study of the VEGF receptor tyrosine kinase inhibitor vatalanib (PTK787/ZK 222584) and gemcitabine in patients with advanced pancreatic cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 4122-4122 ◽  
Author(s):  
T. Kuo ◽  
A. Fitzgerald ◽  
H. Kaiser ◽  
B. I. Sikic ◽  
G. A. Fisher
Keyword(s):  
Pancreatic Cancer ◽  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitor ◽  
Phase I Study ◽  
Kinase Inhibitor ◽  
Advanced Pancreatic Cancer ◽  
Patient Cohort ◽  
Grade 3 ◽  
Dose Levels

4122 Background: The VEGF pathway is the predominant mediator of angiogenesis in pancreatic cancer. Vatalanib (PTK787/ZK 222584) is a small molecule tyrosine kinase inhibitor of all known VEGF receptors. We initiated a phase I study of vatalanib and gemcitabine for advanced pancreatic cancer. Methods: Patients with newly diagnosed unresectable or metastatic pancreatic adenocarcinoma were enrolled. Previous adjuvant chemoradiotherapy with fluorouracil was allowed. Gemcitabine was given by fixed-dose rate infusion weekly x 3 in a 28-day cycle, and vatalanib was given orally daily. Dose-limiting toxicities (DLT) are defined as any grade 3/4 toxicity during the first cycle. The dose levels are as follows: Results: To date, 11 patients are evaluable for toxicity (5M/6F; median age 62 years, range 40–82 years; median KPS 90%). Thus far, 42 cycles have been given, with a median of four cycles per patient. Two patients have experienced DLT. The first patient (cohort 1) experienced grade 3 diarrhea and hypokalemia and grade 4 neutropenia occurring simultaneously and treated without sequelae. The second patient (cohort 3) developed grade 3 deep vein thrombosis. Beyond the first cycle, grade 3 toxicities included neutropenia (1), anemia (3), thrombocytopenia (1), hypertension (2), diarrhea (1), hypokalemia (1), thrombosis (1), and proteinuria (1). Three of eleven patients (27%) did not complete treatment to the first evaluation timepoint (2 cycles); two discontinued due to toxicity and one discontinued due to disease progression. Two of eleven patients (18%) had a partial response by RECIST. Six of eleven patients (55%) had stable disease as the best response ranging from 2–6 months. Conclusions: The combination of gemcitabine and vatalanib is generally well-tolerated with most grade 3/4 toxicities occurring late in the treatment course. Antitumor responses have been observed at initial dose levels and accrual to the final cohort with BID dosing of vatalanib continues. [Table: see text] No significant financial relationships to disclose.

Regorafenib with TAS-102 (REGOTAS) in metastatic colorectal cancer patients who progressed after at least two standard therapies: Efficacy and safety results of a multicenter phase I study (REMETY).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 158-158 ◽  
Author(s):  
Markus H. Moehler ◽  
Alexander Stein ◽  
Jorg Trojan ◽  
Jens Uwe Marquardt ◽  
Julia Quidde ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Dose Finding ◽  
Hematologic Toxicity ◽  
Multicenter Phase ◽  
Risk Benefit Assessment ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Colorectal Cancer Patients ◽  
Dose Levels ◽  
Clinical Trial Information

158 Background: The multi-kinase inhibitor regorafenib (REGO) and oral fluoropyrimidine TAS-102 (TAS) show efficacies as single agents in treatment of refractory metastatic CRC patients (pts). We conducted a conventional 3+3 dose finding to determine a recommended phase II dose (RP2D) of its combination REGOTAS and efficacy in 3-4.-line. Methods: Eligible patients with ECOG 0-1, measurable mCRC, not amenable to surgery had at least 3rd-line treatments. Prior fluoropyrimidine-based and anti-VEGF (R) combinations were mandatory, and anti-EGFR for RAS WT tumors. TAS was given on days 1-5 and 8-12 (28-days cycle); REGO on days 2-22 (dose levels see table below). The following major AE categories were used to define DLTs if they occurred during the first 2 treatment cycles: any grade ≥3 non-hematologic toxicity (except vomiting, nausea, non-significant lab abnormalities), grade ≥3 hematological toxicities, grade ≥3 bleeding. Tumor response was assessed Q8W as per RECIST1.1. EudraCT 2016-001968-11; NCT03305913. Results: All observed toxicities were consistent with safety profile of individual IMPs. 6 pts were enrolled into each DL1 and DL2 (n=12 in total). One DLT was observed in 1/6 pts in DL1; 2 DLTs in 2/6 pts in DL2. All DLTs were only grade 3 hypertension was well manageable, causality was attributed to REGO. No DLT resulted in treatment discontinuation. Results indicate a RP2D of 25mg/m² TAS-102 BID + 120mg REGO daily. No remissions were observed. Overall disease control rate (DCR) after 8 weeks was promising with 58.3% (DCR of 33.3% for DL1 and 83.3% in DL2) and remarkably better as historical data with 41/44% for REGO/TAS102 alone, respectively (Lancet 2013/NEJM 2015). Conclusions: Toxicities of REGOTAS were consistent with safety profiles of REGO and TAS alone. No additional DLTs were attributed to REGOTAS. Thus, the risk-benefit assessment of REGOTAS was positive. DCR was clinically quite meaningful. Mature PFS and OS will be presented at the meeting. Clinical trial information: NCT03305913. [Table: see text]

Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3008-3008 ◽  
Author(s):  
J. H. Schellens ◽  
D. Boss ◽  
P. O. Witteveen ◽  
A. Zandvliet ◽  
J. H. Beijnen ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Kinase Inhibitor ◽  
Pharmacological Study ◽  
Human Study ◽  
Aurora Kinase ◽  
Maximum Tolerated Dose ◽  
Weekly Schedule ◽  
Aurora Kinase Inhibitor ◽  
Post Dose

3008 Background: AZD1152 is a specific aurora kinase inhibitor, selective for Aurora B, currently undergoing Phase I evaluation in patients with advanced solid malignancies. AZD1152 induces p53 independent cellular multinucleation and polyploidy, resulting in apoptosis. It is rapidly converted to the active moiety (AZD1152-HQPA) in plasma. This is the first human study, aimed at determining the maximum tolerated dose, dose limiting toxicities (DLT), pharmacokinetic profile (PK), and to recommend a dose and schedule for further clinical evaluation. Methods: AZD1152 is being administered as a 2-hour IV infusion given weekly in a dose-escalating manner, utilizing an accelerated titration design in patients for whom no other therapy of proven benefit exists. Patients with WHO-PS of 0-2 and adequate bone marrow, liver and renal function were eligible. Results: To date, a total of 13 patients have been recruited: 10M/3F, median age 58 yrs (range 52–71). Patients had colon cancer (n = 3), melanoma (n = 2), or various other solid tumors. Doses were escalated from 100 mg to 200, 300 and 450 mg. DLT was CTC grade 4 neutropenia in 3 patients at 450 mg, signifying a non-tolerated dose on this schedule. Bone marrow recovery was generally noted by 2 wks post-dose. Problematic non-hematological toxicities have not been reported to date. Five patients have remained on therapy for >12 wks (2 × 12+ wks, 16+ wks, 20+ wks and 28+ wks, respectively). AZD1152 is rapidly converted to AZD1152-HQPA with an apparent dose proportional increase in the systemic exposures of both. Population PK analysis of AZD1152-HQPA in the first eight patients revealed a linear three compartment model with clearance 22.4 ± 1.03 L/h. Interoccasion variability was low (CV 5.7%). Conclusions: To date, AZD1152 has been well tolerated when administered IV over 2 hours on a weekly schedule at doses up to 300 mg, however further patients are being enrolled to confirm. Neutropenia is the DLT at 450 mg and no other clinically significant toxicities have been reported. Both AZD1152 and AZD1152-HQPA appeared to have linear kinetics. Significant disease stabilization observed in this rapidly progressive disease setting supports continued clinical development. [Table: see text]

A phase I trial of bexarotene, a retinoid X receptor agonist, in non-M3 acute myeloid leukemia

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7061-7061
Author(s):  
D. E. Tsai ◽  
S. Luger ◽  
A. Kemner ◽  
C. Andreadis ◽  
A. Loren ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Median Number ◽  
Clinical Activity ◽  
Cell Transplant ◽  
Platelet Counts ◽  
Cytotoxic Treatment ◽  
Dose Levels ◽  
Bone Marrow Blasts

7061 Background: In vitro, bexarotene inhibits the proliferation of non-M3 AML cell lines and induces differentiation of leukemic blasts. This phase I study was designed to evaluate the safety of escalating doses of bexarotene in patients with non-M3 AML and has completed enrollment. Methods: Bexarotene was administered daily until disease progression occurred. Dose escalation occurred in cohorts of 3–6 patients through 6 dose levels ranging from 100–400mg/m2. Results: 27 patients were enrolled: 19M/8F, median age 69 (range 51–82), 13 prior MDS, 12 primary refractory, median number of induction attempts 2, no prior chemotherapy 3, prior autologous stem cell transplant 5, 26 blood transfusion dependent, 18 platelet transfusion dependent, and 20 neutropenic. Despite prophylactic use of antihyperlipidemic agents, 4 patients developed grade ≥3 hypertriglyceridemia. Two patients developed a syndrome reminiscent of retinoic acid syndrome, consisting of dyspnea, pleural/pericardial effusions, and edema in the setting of a rising neutrophil count. This syndrome resolved with stopping bexarotene and initiating steroids. Evidence of activity was noted with bone marrow blasts decreasing to ≤5% in 4 patients. Seven patients showed evidence of neutrophil response (pretreatment median ANC 364/μL, range 28–1,242/μL, treatment ANC 3,540/μL, range 1,200–26,207/μL). Flow sorted peripheral blood neutrophils were collected from 3 of these patients and examined by FISH. Between 92–100% of neutrophils contained the patient's leukemic cytogenetic abnormality suggesting differentiation of the leukemic blasts. Eleven patients with platelet counts <100,000/μL had increases in their platelet counts >20,000/μL (peak range 40- 292x103/μL). Five of these patients with platelet counts <20,000/μL had improvement to 40–91,000/μL and became transfusion independent. Conclusions: Bexarotene is well tolerated at the dose levels studied. Evidence for clinical activity has been seen as exemplified by improvement in platelet counts, increased neutrophil counts and decreased bone marrow blasts. We postulate that bexarotene may induce leukemic blast differentiation in non-M3 AML and represent a novel non-cytotoxic treatment. No significant financial relationships to disclose.

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