A phase Ib dose escalation study of oral monotherapy with KX2-391 in elderly patients with acute myeloid leukemia.

Poor tolerance to standard therapies and multi-drug resistance complicate treatment of elderly patients with acute myeloid leukemia (AML). It is therefore imperative to explore novel tolerable agents and target alternative pathways. KX2-391 is an oral non-ATP-competitive inhibitor of Src kinase and tubulin polymerization. This multi-center phase Ib open-label safety and activity study involved elderly patients with relapsed or refractory AML, or who declined standard chemotherapy. Twenty-four patients averaging 74 years of age were enrolled. The majority previously received hypomethylating agents. Five doses were tested: 40 mg (n = 1), 80 mg (n = 2), 120 mg (n = 8), 140 mg (n = 12), and 160 mg (n = 1). Seven patients were treated for 12 days or less, nine for 15-29 days, five for 33-58 days, and three for 77-165 days. One patient receiving 120 mg for 165 days had reduced splenomegaly and survived 373 days. Another had no evidence of disease progression for 154 days. One patient receiving 160 mg for 12 days remained treatment-free for about 18 months. Dose-limiting toxicities occurred in eight patients at: 120 mg (transaminitis, hyperbilirubinemia), 140 mg (mucositis, allergic reaction, transaminitis, acute kidney injury), and 160 mg (mucositis). The maximum tolerated dose for KX2-391 was 120 mg once daily. KX2-391 bone marrow concentrations were approximately similar to plasma concentrations. This is the first study to evaluate the safety of KX2-391 in elderly patients with AML. Further studies are warranted, including alternative dosing phase I trials evaluating shorter courses at higher doses and phase II trials. (Clinical Trial Registration:The study was registered at ClinicalTrials.gov: NCT01397799 (July 20, 2011)).

Sirolimus enhances remission induction in patients with high risk acute myeloid leukemia and mTORC1 target inhibition.

Background Mammalian Target of Rapamycin Complex 1 (mTORC1) inhibitors enhance chemotherapy response in acute myelogenous leukemia (AML) cells in vitro. However whether inhibiting mTORC1 enhances clinical response to AML chemotherapy remains controversial. We previously optimized measurement of mTORC1's kinase activity in AML blasts during clinical trials using serial phospho-specific flow cytometry of formaldehyde-fixed whole blood or marrow specimens. To validate mTORC1 as a therapeutic target in AML, we performed two clinical trials combining an mTORC1 inhibitor (sirolimus) and MEC (mitoxantrone, etoposide, cytarabine) in patients with relapsed, refractory, or untreated high-risk AML. Methods Flow cytometric measurements of ribosomal protein S6 phosphorylation (pS6) were performed before and during sirolimus treatment to determine whether mTORC1 inhibition enriched for chemotherapy response. Results In 51 evaluable subjects, the overall response rate (ORR) to the combination regimen was 47% (95% confidence interval 33-61%, 33% CR, 2% CRi, 12% PR) and similar toxicity to historic experience with MEC alone. 37 subjects had baseline pS6 measured pre-sirolimus, of whom 27 (73%) exhibited mTORC1 activity. ORR was not significantly different between subjects with and without baseline mTORC1 activity (52% vs 40%, respectively, p = 0.20). The ORR among subjects with baseline target activation and mTORC1 inhibition during therapy was 71% (12/17) compared to 20% (2/10) in subjects without target inhibition. Conclusions Fixed, whole blood pS6 by flow cytometry may be a predictive biomarker for clinical response to mTORC1 inhibitor-based regimens. These data provide clinical confirmation that mTORC1 activation mediates chemotherapy resistance in patients with AML.

Polo-like kinase and its inhibitors: Ready for the match to start?

Polo-like kinases (Plks) plays a central role in the normal cell cycle and their upregulation has been shown to play a role in the pathogenesis of multiple human cancers. Preclinical work demonstrates that targeting Plk has a significant impact on the treatment of both solid and hematologic malignancies in vitro and in vivo. We review here the basic science and clinical work to date with the Plks as well as future directions with this novel class of mitotic inhibitors.

Accrual-Monitoring Practices for Various Disease Trials among AACI Member Cancer Centers.

Progress in the management of rare diseases, including rare cancers, is dependent upon clinical trials; however, as many as 32% of rare-disease trials go uncompleted or unpublished due to insufficient accrual. Monitoring practices may differ between institutions. We sought to survey the regulatory standards for various trial types among major U.S. cancer centers. A 10-question survey was designed using Qualtrics assessment software. The survey was sent via email to an internal server of member institutions of the Association of American Cancer Institutes (AACI). Of 103 AACI centers, 31% completed the survey (n = 32). Respondents differed in their definitions of a rare disease, minimum expectations for rare tumor studies, and frequency of accrual monitoring by their institutional Protocol Review and Monitoring Committee. Seventy-three percent of respondents did not close trials based on low accrual. Strategies to optimize accrual included investigator incentives for high accrual and penalties for low accrual in 37% and 13% of respondents, respectively.

Update on the therapy for myelodysplastic syndrome.

The myelodysplastic syndromes (MDS) are a diverse group of clonal hematopoietic stem cell disorders characterized by cytopenias. Patients have a risk of developing acute leukemia though most succumb to complications of low blood counts. Over the past decade many novel treatments have been developed and investigation of new agents is ongoing. In this article, we discuss the classification and prognostic systems that are used in MDS, the agents available for treatment of MDS as well as review supportive and palliative care options for patients who are not candidates for, or opt against, newer treatment strategies.

Single-cell pharmacodynamic monitoring of S6 ribosomal protein phosphorylation in AML blasts during a clinical trial combining the mTOR inhibitor sirolimus and intensive chemotherapy.

PURPOSE: Integration of signal transduction inhibitors into chemotherapy regimens generally has generally not led to anticipated increases in response and survival. However, it remains unclear whether this is because of inadequate or inconsistent inhibition of target or other complex biology. The mTOR signaling pathway is frequently activated in acute myelogenous leukemia (AML) and we previously showed the safety of combining the mTOR inhibitor, sirolimus, with mitoxantrone, etoposide, and cytarabine (MEC) chemotherapy. However, we did not reliably determine the extent of mTOR inhibition on that study. Here, we sought to develop an assay that allowed us to serially quantify the activation state of mTOR kinase during therapy. EXPERIMENTAL DESIGN: To provide evidence of mTOR kinase activation and inhibition, we applied a validated whole blood fixation/permeabilization technique for flow cytometry to serially monitor S6 ribosomal protein (S6) phosphorylation in immunophenotypically identified AML blasts. RESULTS: With this approach, we show activation of mTOR signaling in 8 of 10 subjects' samples (80%) and conclusively show inhibition of mTOR in the majority of subjects' tumor cell during therapy. Of note, S6 phosphorylation in AML blasts is heterogeneous and, in some cases, intrinsically resistant to rapamycin at clinically achieved concentrations. CONCLUSIONS: The methodology described is rapid and reproducible. We show the feasibility of real-time, direct pharmacodynamic monitoring by flow cytometry during clinical trials combining intensive chemotherapy and signal transduction inhibitors. This approach greatly clarifies pharmacokinetic/pharmacodynamic relationships and has broad application to preclinical and clinical testing of drugs whose direct or downstream effects disrupt PI3K/AKT/mTOR signaling.

Novel targets for treatment of adult acute lymphocytic leukemia.

The treatment of acute lymphocytic leukemia (ALL) results in long-term disease-free survival in only 30-40% of adults. Conventional chemotherapy is toxic and woefully ineffective. Therefore, novel agents are being investigated. Among these agents are monoclonal antibodies such as rituximab, epratuzumab, and alemtuzumab and targeted therapies such as tyrosine kinase inhibitors, mTOR inhibitors, and mitogen-activated protein kinase (MEK) inhibitors. This article discusses such novel targets for the treatment of ALL.

The diabetes gene Pdx1 regulates the transcriptional network of pancreatic endocrine progenitor cells in mice.

Heterozygous mutations in the gene encoding the pancreatic homeodomain transcription factor pancreatic duodenal homeobox 1 (PDX1) are associated with maturity onset diabetes of the young, type 4 (MODY4) and type 2 diabetes. Pdx1 governs the early embryonic development of the pancreas and the later differentiation of the insulin-producing islet beta cells of the endocrine compartment. We derived a Pdx1 hypomorphic allele that reveals a role for Pdx1 in the specification of endocrine progenitors. Mice homozygous for this allele displayed a selective reduction in endocrine lineages associated with decreased numbers of endocrine progenitors and a marked reduction in levels of mRNA encoding the proendocrine transcription factor neurogenin 3 (Ngn3). During development, Pdx1 occupies an evolutionarily conserved enhancer region of Ngn3 and interacts with the transcription factor one cut homeobox 1 (Hnf6) to activate this enhancer. Furthermore, mRNA levels of all 4 members of the transcription factor network that regulates Ngn3 expression, SRY-box containing gene 9 (Sox9), Hnf6, Hnf1b, and forkhead box A2 (Foxa2), were decreased in homozygous mice. Pdx1 also occupied regulatory sequences in Foxa2 and Hnf1b. Thus, Pdx1 contributes to specification of endocrine progenitors both by regulating expression of Ngn3 directly and by participating in a cross-regulatory transcription factor network during early pancreas development. These results provide insights that may be applicable to beta cell replacement strategies involving the guided differentiation of ES cells or other progenitor cell types into the beta cell lineage, and they suggest a molecular mechanism whereby human PDX1 mutations cause diabetes.

A phase I study of the mammalian target of rapamycin inhibitor sirolimus and MEC chemotherapy in relapsed and refractory acute myelogenous leukemia.

PURPOSE: Inhibiting mammalian target of rapamycin (mTOR) signaling in acute myelogenous leukemia (AML) blasts and leukemic stem cells may enhance their sensitivity to cytotoxic agents. We sought to determine the safety and describe the toxicity of this approach by adding the mTOR inhibitor, sirolimus (rapamycin), to intensive AML induction chemotherapy. EXPERIMENTAL DESIGN: We performed a phase I dose escalation study of sirolimus with the chemotherapy regimen MEC (mitoxantrone, etoposide, and cytarabine) in patients with relapsed, refractory, or untreated secondary AML. RESULTS: Twenty-nine subjects received sirolimus and MEC across five dose levels. Dose-limiting toxicities were irreversible marrow aplasia and multiorgan failure. The maximum tolerated dose (MTD) of sirolimus was determined to be a 12 mg loading dose on day 1 followed by 4 mg/d on days 2 to 7, concurrent with MEC chemotherapy. Complete or partial remissions occurred in 6 (22%) of the 27 subjects who completed chemotherapy, including 3 (25%) of the 12 subjects treated at the MTD. At the MTD, measured rapamycin trough levels were within the therapeutic range for solid organ transplantation. However, direct measurement of the mTOR target p70 S6 kinase phosphorylation in marrow blasts from these subjects only showed definite target inhibition in one of five evaluable samples. CONCLUSIONS: Sirolimus and MEC is an active and feasible regimen. However, as administered in this study, the synergy between MEC and sirolimus was not confirmed. Future studies are planned with different schedules to clarify the clinical and biochemical effects of sirolimus in AML and to determine whether target inhibition predicts chemotherapy response.

Increased cerebral blood flow after leukapheresis for acute myelogenous leukemia.

Leukapheresis is often considered in the management of acute myelogenous leukemia (AML) with hyperleukocytosis and its sequelae, including myocardial infarction, pulmonary complications, and stroke. It is utilized on the assumption that leukapheresis improves blood rheology. We present a woman with AML and a history of meningioma encasing her left internal carotid artery. She presented with hyperleukocytosis and symptoms of ischemia. As her white blood cell continued to rise despite initiation of hydroxyurea therapy, she underwent leukapheresis emergently. Transcranial Doppler ultrasound demonstrated increased flow velocities in the left internal carotid and the right middle cerebral arteries, which normalized after leukapheresis. This is the first documentation that leukapheresis, in combination with hydroxyurea, improves cerebral hemodynamics in a patient with AML.