A Phase I Study of INNO-406 in Patients with Advanced Philadelphia (Ph+) Chromosome-Positive Leukemias Who Are Resistant or Intolerant to Imatinib and Second Generation Tyrosine Kinase Inhibitors.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 469-469 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Jorge Cortes ◽  
Philipp le Coutre ◽  
Arnon Nagler ◽  
Javier Pinilla ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Complete Cytogenetic Response ◽  
Lyn Kinase ◽  
Ph Chromosome

Abstract Background: INNO-406 is an orally available, dual Abl/Lyn kinase inhibitor that is up to 55-times more potent than imatinib in Bcr-Abl expressing cell lines. Numerous Bcr-Abl mutant proteins are sensitive to INNO-406 in vitro, including the F317L mutant. Unlike other second generation tyrosine kinase inhibitors (TKIs), INNO-406 demonstrates specific Lyn kinase activity with no or limited activity against other Src-family member kinases. Methods: In this phase I dose finding study, patients (pts) with imatinib-resistant or -intolerant Philadelphia (Ph+) chromosome-positive leukemias were eligible for treatment with INNO-406 orally at doses ranging from 30 mg once daily (qd) through 480 mg twice daily (bid). Results: INNO-406 was administered to 41 pts (23M, 18F); median age 61 yrs (range, 20–76). Median duration of CML was 6 yrs (range, 0.1–23); median time on imatinib was 0.8 yrs (range, 0.1–6.5). Pts had CML in chronic phase (CP, n=21), accelerated phase (AP, n=7), or blast phase (BP, n=6), or Ph+ ALL (n=7). Previous treatment included nilotinib (n=9), dasatinib (n=13), and dasatinib/nilotinib (n=10). Pts have been treated with INNO-406 for a median of 42 days (range, 7–240+). Common mutations on study entry included Y253H (n=4), F311L (n=3), F317L (n=2), and T315I (n=2). Currently, 14 pts remain on study; 22 pts discontinued due to disease progression, 4 pts discontinued to pursue other treatment options, and 1 pt discontinued due to toxicity. Hematologic and cytogenetic responses have been reported. 2 of 7 CP pts who had failed only imatinib demonstrated a complete cytogenetic response, including 1 major molecular response. An additional pt had a minor cytogenetic response after 4 weeks of therapy before going off study to pursue an alternate treatment option. Among pts in CP who had failed more than one TKI, a complete cytogenetic response was reported in 1 pt who was intolerant to both imatinib (lung/skin toxicity) and dasatinib (pleural effusion). All 7 AP pts on study had failed multiple TKIs. In this population, 2 pts experienced complete hematologic responses. Additionally, in 1 pt, a reversion of the Y253H mutation was demonstrated, and 1 pt has experienced a disappearance of the F317L mutation. Related adverse events include reversible grade 2/3 elevation in the activity of transaminases. A DLT was reported in 1 pt in the 480 mg bid cohort (intrahepatic cholestasis and renal failure secondary to tumor lysis syndrome). Conclusions: INNO-406 is well tolerated in pts with clinical activity demonstrated across a range of dosing. Responses occur even in the setting of a heavily pretreated population thus making INNO-406 a viable option for CML therapy. The recommended phase II dose is anticipated to be 240 mg bid. Pivotal phase II studies are planned for late 2007.

scholarly journals Failure to achieve a complete hematologic response at the time of a major cytogenetic response with second-generation tyrosine kinase inhibitors is associated with a poor prognosis among patients with chronic myeloid leukemia in accelerated or blast phase

Blood ◽  
2009 ◽  
Vol 113 (21) ◽  
pp. 5058-5063 ◽  
Author(s):  
Carmen Fava ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
Nitin Jain ◽  
...  
Keyword(s):  
Survival Rate ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
Blast Phase ◽  
Complete Hematologic Response

Abstract Second-generation tyrosine kinase inhibitors are effective in Philadelphia chromosome–positive (Ph+) acute lymphoblastic leukemia (ALL) and chronic myeloid leukemia (CML). Occasionally, patients with Ph+ ALL, or accelerated phase (AP) or blast phase (BP) CML achieve a major cytogenetic response (MCyR) but not a complete hematologic response (CHR). We analyzed 126 patients with CML in AP or BP, or with Ph+ ALL treated with dasatinib or nilotinib after imatinib failure. Twenty patients received sequential treatment with both dasatinib and nilotinib for a total of 146 instances. CHR and MCyR rates were 54% and 37%, respectively in AP, 17% and 39% in BP, and 33% and 50% in Ph+ ALL. Failure to achieve a CHR at the time of achievement of a MCyR was associated with an inferior outcome, similar to that of patients without a MCyR (2-year survival rate, 37% and 35%, respectively). In contrast, patients with MCyR and concomitant CHR had a 77% 2-year survival rate. Twelve of 29 patients with MCyR without concomitant CHR later achieved a CHR; the 2-year survival rate for these patients was 55% compared with 22% for those who never achieved a CHR. These results suggest that achievement of a MCyR without concomitant CHR is associated with poor outcome.

Phase I/II study of a BNC105P/everolimus regimen for progressive metastatic renal cell carcinoma (mRCC) following prior tyrosine kinase inhibitors (Hoosier Oncology Group).

2012 ◽  
Vol 30 (5_suppl) ◽  
pp. 373-373 ◽  
Author(s):  
Thomas E. Hutson ◽  
Long H. Dang ◽  
Richard C. Lauer ◽  
Alexander Starodub ◽  
Ralph J. Hauke ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Kidney Tumors ◽  
Sequential Approach ◽  
Vascular Disruption ◽  
Randomized Phase Ii ◽  
Number Of Cycles

373 Background: BNC105P is a Vascular Disruption Agent (VDA) that destabilizes tubulin polymers leading to selective damage of tumor vasculature, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. Preclinical investigations demonstrated that BNC105P is effective at selectively damaging the vasculature in primary and metastatic lesions. Furthermore, BNC105P monotherapy compared well with sunitinib in mice bearing kidney tumors. It follows that the combined use of this VDA with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6 and 16 mg/m2; IV infusion Days 1 & 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: In the clinic the BNC105P / everolimus combination was well tolerated and no DLTs were observed in any of the phase I patients. Toxicities deemed to be drug-related included single events of Grade 2 anemia, thrombocytopenia and mucositis. Of the 12 patients enrolled to the phase I, 7 remain on treatment. The medium number of cycles is 3 (range: 1–14) and 3 patients have been administered >6 cycles of treatment. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.

Role of ABL Gene Mutations in Chronic Myeloid Leukemia Patients Resistant to Imatinib and Results of Treatment Shift to Second-Generation Tyrosine Kinase Inhibitors

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4442-4442
Author(s):  
Silvia Marce ◽  
Lurdes Zamora ◽  
Marta Cabezon ◽  
Blanca Xicoy ◽  
Concha Boqué ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Cytogenetic Response ◽  
The Other ◽  
Molecular Response ◽  
Imatinib Resistant

Abstract Abstract 4442 Introduction: Chronic myeloid leukemia (CML) is a model of disease in the development of targeted therapies. Tyrosine kinase inhibitors (TKIs) have transformed the approach to management of CML and have dramatically improved patients' outcome. Clinical response is obtained in the majority of patients. However, a significant proportion of patients do not achieve the optimal desirable outcome or are completely resistant to this treatment. ABL kinase domain mutations have been extensively implicated in the pathogenesis of TKI resistance. Treatment with second-generation TKIs has produced high rates of hematologic and cytogenetic response in mutated ABL patients. The aim of this study was analyzed the presence of ABL mutations in imatinib resistant patients and determine the importance of changing to second-generation TKIs treatment as soon as failure or suboptimal response is recognized. Patients and methods: From 420 CML patients diagnosed in 6 centers between 2004 and 2010, we have amplified and sequenced the ABL1 domain from BCR-ABL1 amplicon of 45 imatinib resistant patients (23 patients with suboptimal response, 14 with treatment failure, 4 who lost the molecular response and 4 patients who progressed to blast phase). The obtained sequences were compared with the published ABL1 sequence, GenBank U07563, using BLAST 2 software. Results: We have detected mutations in 15 of 45 patients (33%), some of them with more than one mutation (Table 1). Seven of these patients were treated with second-generation TKIs as a single treatment. Three of them achieve a major molecular response (MMR), one patient is in complete cytogenetic response (CCyR) and the other two patients are in major (MCyR) and partial (PCyR) cytogenetic response. Another patient received nilotinib followed by hematological stem cell transplantation (HSCT) and is in MMR. Two patients were submitted to a HSCT and achieve MMR. Only one patient treated with nilotinib as second option has not reach a cytogenetic response one year after detection of the mutation. Two of the patients with the T315I mutation were treated with IFN and nilotinib achieving PCyR and MCyR, respectively, and are still alive. The other T315I patient, and two patients in blast-crisis (BC) disease with the F317L mutation who received dasatinib prior to the study of ABL mutations, died before a change of treatment could have been performed. Conclusions: Disclosures: No relevant conflicts of interest to declare.

scholarly journals Front-Line Therapy With Second-Generation Tyrosine Kinase Inhibitors in Patients With Early Chronic Phase Chronic Myeloid Leukemia: What Is the Optimal Response?

2011 ◽  
Vol 29 (32) ◽  
pp. 4260-4265 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Jianqin Shan ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Second Generation ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Newly Diagnosed ◽  
Front Line ◽  
Line Therapy

Purpose The response definitions proposed by the European LeukemiaNet (ELN) are defined on the basis of imatinib front-line therapy. It is unknown whether these definitions apply to patients treated with second-generation tyrosine kinase inhibitors (TKIs). Patients and Methods One hundred sixty-seven patients with newly diagnosed chronic myelogenous leukemia (CML) in chronic phase were treated with second-generation TKIs in phase II trials (nilotinib, 81; dasatinib, 86). Median follow-up was 33 months. Event-free survival (EFS) was measured from the start of treatment to the date of loss of complete hematologic response, loss of complete or major cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, progression to accelerated or blastic phases, or death at any time. Results Overall, 155 patients (93%) achieved complete cytogenetic response (CCyR), including 146 (87%) with major molecular response (MMR; complete in 46 patients [28%]). According to the ELN definitions, the rates of suboptimal response were 0%, 2%, 1%, and 12% at 3, 6, 12, and 18 months of therapy, respectively. There was no difference in EFS and CCyR duration between patients who achieved CCyR with and without MMR across all the landmark times of 3, 6, 12, and 18 months. Conclusion The use of second-generation TKIs as initial therapy in CML induces high rates of CCyR at early time points. The ELN definitions of response proposed for imatinib therapy are not applicable in this setting. We propose that achievement of CCyR and partial cytogenetic response at 3 months should be considered optimal and suboptimal responses, respectively. The achievement of MMR offered no advantage over CCyR in defining long-term outcome in patients with newly diagnosed CML treated with second-generation TKIs.

Phase I results of a phase I/II trial of BNC105P with everolimus in metastatic renal cell carcinoma (mRCC) patients previously treated with VEGFR tyrosine kinase inhibitors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 4603-4603
Author(s):  
Thomas E. Hutson ◽  
Long H. Dang ◽  
Richard C. Lauer ◽  
Alexander Starodub ◽  
Ralph J. Hauke ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Phase I ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Single Agent ◽  
Sequential Approach ◽  
Investigational Agent ◽  
Randomized Phase Ii ◽  
Disease Stabilization

4603 Background: BNC105P is an investigational agent that destabilizes tubulin polymers leading to selective damage of tumor vasculature, causing disruption of blood flow to tumors, hypoxia and associated tumor necrosis. BNC105P also has a direct anti-proliferative action on cancer cells. Preclinical investigations have demonstrated that BNC105P is effective at selectively damaging the vasculature in both primary and metastatic lesions. Up regulation of the mTOR pathway has been identified as a survival response by the tumor to hypoxic insult. It follows that the combined use of BNC105P with an agent active against mTOR may improve clinical outcome in patients with progressive mRCC who are refractory to VEGFR-directed tyrosine kinase inhibitors (TKI). Methods: A phase I/II study in mRCC patients who have received 1-2 prior TKIs was undertaken. Using a classic 3+3 design, the phase I component of this study enrolled 12 subjects at 4 dose levels of BNC105P (4.2, 8.4, 12.6, 16 mg/m2; IV infusion Days 1 and 8, 21-day repeating cycle). Everolimus was administered concurrently (10 mg p.o.). PK analysis was performed during Cycle 1. Results: The phase I component has been completed. The BNC105P / everolimus combination was well tolerated. No DLTs (drug-related, during cycle 1) were observed in any of the phase I subjects. Toxicities on study deemed to be drug-related (either single agent or combination) included single grade 3 events of anemia and pericardial effusion. Grade 2 events (more than 1 occurrence) of fatigue, anemia and oral mucositis were also observed. Seven phase I subjects achieved at least disease stabilization with a minimum time on therapy of 18 weeks (6 cycles). Across all subjects a median of 6 cycles (range: 1-15) was administered. PK analysis confirmed no drug-drug interaction. The randomized phase II component of the study continues and will compare everolimus given in combination with BNC105P to a sequential approach (everolimus followed by BNC105P). Conclusions: The MTD of BNC105P (16 mg/m2) can be combined with full dose everolimus and is being evaluated in the randomized phase II study.

A Phase II Study of Oral Panobinostat (LBH589) for Chronic Phase Chronic Myeloid Leukemia (CML) with Resistance to ≥2 BCR-ABL Tyrosine Kinase Inhibitors

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4254-4254 ◽  
Author(s):  
Andrey Zaritskey ◽  
Giuliana Alimena ◽  
Lech Konopka ◽  
Jila Shamsazar ◽  
Priscille M. Bourquelot ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Phase Ii ◽  
Kinase Inhibitors ◽  
Phase Ii Study ◽  
Chronic Phase ◽  
Study Drug ◽  
Cytogenetic Response ◽  
Abl Tyrosine Kinase ◽  
Stage 1

Abstract Background: Panobinostat (LBH589) is a novel, high potent pan-deacetylase inhibitor, which acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. It induces degradation of wild-type, as well as BCR-ABL with the T315i and E255K mutations in BaF3 cells. Based on this encouraging data, we initiated a Phase II trial to investigate the efficacy and safety of oral panobinostat in patients (pts) with chronic phase (CP) CML who had received at least 2 prior BCR-ABL tyrosine kinase inhibitors (TKI). Methods: This was a single arm, 3-stage, open-label, multicenter, Phase II study. The primary objective was to estimate the proportion of pts attaining major cytogenetic response (MCyR). Complete hematologic response (CHR) was one secondary objective. All patients received panobinostat orally 20 mg/day on a thrice weekly, consecutive weekly schedule. If ≥3 confirmed MCyRs were observed among 25 pts in Stage 1, Stage 2 was planned to be opened with a total of 32 pts. Dose reduction to 10 and 5 mg/day for toxicity and re-escalation to 20 mg/day was allowed. Dose escalation beyond 20 mg/day for poor response was not foreseen. Results: 29 pts were enrolled in Stage 1 between February and November 2007. Median age was 56 years (yrs) (range 31–75). Time since diagnosis of CML was ≥5 yrs in 69% and <2 yrs in 3%. All pts met the study criteria for TKI resistance. Best cytogenetic response to any prior TKIs was evaluable in 26 pts: MCyR in 7 pts, minor in 6 pts, and no response in 13 pts. Median time since last treatment of any kind, including hydroxyurea, was 20 days (range 0–224). Median duration of panobinostat treatment was 26 days (1–334). No MCyR was observed, and therefore, Stage 2 of the study was not opened. However, one CHR, accompanied by the eradication of the BCR-ABL T315i mutated clone, occurred in Cycle 2 (Week 6). This pt remained on panobinostat without progression until Cycle 12 (Week 48). Overall, non-hematological AEs were similar to the safety profile of 20 mg/day panobinostat reported before.1 Gastrointestinal AEs were reported by 10 pts (nausea; all Gr 1–2, but 1 Gr 3), diarrhea in 7 pts, and vomiting in 5 pts. Fatigue was reported in 8 pts and asthenia in 3 pts. An atrial fibrillation (Gr 2) in 1 pt and a QTcF prolongation >500 ms (Gr 3) in another pt required study drug discontinuation. 5 serious AEs were reported as possibly related to study drug: pulmonary embolism and the QTcF prolongation (see above) in 1 pt, and sepsis, followed by multiple organ failure with fatal outcome in a second pt. SAEs considered as non-related to study drug included: 1 case each of DVT, lung infection, pericardial effusion, pleural effusion, and cardiac failure. To date, 452 post baseline ECGs were assessed: minimal QTcF prolongations (30–60 ms) were seen in 4 and >60 ms in 1 pt. Gr 3/4 hematologic lab abnormalities were: anemia and neutropenia in 4 pts each and thrombocytopenia in 3 pts. Nonhematologic lab abnormalities were: Gr 4 hypokalemia (1), Gr 3 hyponatremia (1), hyperkalemia (1), and hypermagnesemia (2). Conclusions: No MCyR but 1 CHR with eradication of the T315i mutation were observed in 29 TKI-resistant CP CML pts, treated orally with 20 mg/day panobinostat, thrice weekly. Since the number of MCyRs required by the protocol was not seen, Stage 2 of the study was not opened. Safety/tolerability were comparable to what was reported for the same dose/schedule in other panobinostat studies, and no new safety findings were identified. The explanation that no more CRs were seen might be 2-fold: a dosing issue considering encouraging responses reported with oral, thrice weekly ≥40 mg/day single-agent panobinostat in pts with refractory Hodgkin’s disease and AML1 and quite early hematologic progression in many pts, not allowing for longer exposure to panobinostat in this more resistant population.

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