A phase 1 study was conducted to evaluate the safety, pharmacokinetics (PK), efficacy and pharmacogenetic characteristics of clofarabine in seven Japanese pediatric patients with relapsed/refractory acute lymphoblastic leukemia (ALL). Patients in Cohort 1 received clofarabine 30 mg/m(2)/day for 5 days, followed by 52 mg/m(2)/day for 5 days in subsequent cycles. Cohort 2 patients were consistently treated with 52 mg/m(2)/day for 5 days. No more than six cycles were performed. Every patient had at least one ≥Grade 3 adverse event (AE). AEs (≥Grade 3) related to clofarabine were anaemia, neutropenia, febrile neutropenia, thrombocytopenia, alanine aminotransferase increased, aspartate aminotransferase increased, haemoglobin decreased, and platelet (PLT) count decreased. C max and AUC of clofarabine increased in a dose-dependent fashion, but its elimination half-life (T 1/2) did not appear to be dependent on dose or duration of treatment. Clofarabine at 52 mg/m(2)/day shows similarly tolerable safety and PK profiles compared to those in previous studies. No complete remission (CR), CR without PLT recovery, or partial remission was observed. Since clofarabine is already used as a key drug for relapsed/refractory ALL patients in many countries, the efficacy of clofarabine in Japanese pediatric patients should be evaluated in larger study including more patients, such as by post-marketing surveillance.

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On April 18, 2016 ChemoCentryx, Inc., (Nasdaq:CCXI), a clinical-stage biopharmaceutical company developing orally-administered therapeutics to treat autoimmune diseases, inflammatory disorders, and cancer, reported the presentation of data from its immuno-oncology program at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) 2016 Annual Meeting, being held April 16-20, 2016 in New Orleans, Louisiana (Press release, ChemoCentryx, APR 18, 2016, View Source [SID:1234510968]). The preclinical data highlight the synergistic effect of employing an antibody against the checkpoint inhibitor PD-L1 in conjunction with CCX9588, in a model of triple negative breast cancer. CCX9588 is a small molecule inhibitor of the chemokine receptor known as CCR1 and is currently in preclinical development for certain oncology indications targeting both solid and liquid tumors.

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The preclinical results were presented in a poster titled, "Combination therapy of chemokine receptor inhibition plus PD-L1 blockade potentiates anti-tumor effects in a murine model of breast cancer" (Abstract #3298, April 17, 1:00 to 5:00 p.m. ET, Session: Immune Modulating Agents 1, Convention Center, Halls G-J, Poster Section 26).

The presentation from the Company’s ongoing preclinical research investigating the effects of combining CCX9588 with an anti-PD-L1 antibody includes the following results and data:

The combination of CCX9588 and the anti-PD-L1 antibody ("Combination Treatment") significantly decreased circulating and tumor infiltrating granulocytic myeloid-derived suppressor cells, or G-MDSC’s.
G-MDSCs are known to be responsible for the induction of an immunosuppressive environment around the growing tumor, as well as a metastatic phenotype in primary tumors which can lead to the early dissemination of cancer cells.
G-MDSCs were demonstrated to be attracted by chemokines produced by the breast cancer cells, and directed migration of the G-MDSCs were shown to be specifically blocked by inhibiting CCR1 with CCX9588.
Combination Treatment increased the number of effector T cells in the tumor infiltrate, which is known to have an anti-cancer effect.

Overall tumor size and progression was also significantly reduced by the Combination Treatment.
"These results suggest that an orally-administered CCR1 inhibitor, such as CCX9588, combined with an antibody against the checkpoint inhibitor PD-L1, may be of utility in treating triple negative breast cancer, which we modeled in these experiments," said Pirow Bekker, MD, PhD, Chief Medical Officer, ChemoCentryx. "These data reveal an important role for the chemokine receptor CCR1 in modulating the suppressive nature of the tumor microenvironment, and suggest that blocking CCR1 could significantly help to unleash the potential of the body’s own immune system to attack cancer."

About the ChemoCentryx Immuno-Oncology Program

Myeloid derived suppressor cells (MDSCs) are thought to possess an immunosuppressive behavior, effectively helping tumors hide from the body’s natural cytotoxic immune response to tumor cells. These cells are thought to express chemokine receptors such CCR1 and CCR2 and are guided to the tumor microenvironment by the action of these receptors. Inhibiting CCR1 and CCR2 may lead to a reduction of MDSCs in the tumor microenvironment, and the concomitant liberation of the cytotoxic immune response against tumor cells, reduced tumor burden, and potentially lead to improved patient survival.

The Company currently has an ongoing clinical trial of CCX872, an inhibitor of the chemokine receptor known as CCR2, in patients with non-resectable pancreatic cancer. In addition, the Company is conducting preclinical research with various chemokine receptor inhibitors in combination with checkpoint inhibitors, such as those inhibiting the PD-L1 pathway, which may result in a greater anti-tumor effect than with checkpoint inhibition alone. CCX9588 is a small molecule inhibitor of CCR1 and is currently in preclinical development for certain oncology indications targeting both solid and liquid tumors.

On April 18, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that an investigator-initiated clinical study at a university was reported as suspended on www.clinicaltrials.gov (Press release, Celator Pharmaceuticals, APR 18, 2016, View Source [SID:1234510991]). The study had previously been suspended due to institutional resource considerations at the university, unrelated to VYXEOS (CPX-351). The study is a phase 2 study of VYXEOS for the treatment of acute myeloid leukemia or higher risk myelodysplastic syndrome patients, who relapsed, or were refractory to, prior therapy with hypomethylating agents. Celator understands that the study has since been re-opened.

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"To eliminate any confusion, we want to inform investors, the medical community and study participants of these circumstances," said Scott Jackson, Chief Executive Officer of Celator Pharmaceuticals.

On April 18, 2016 Mersana Therapeutics, Inc. reported that preclinical data for its new immunoconjugate product candidate, XMT-1536, demonstrated significant anti-cancer activity in non-small cell lung cancer (NSCLC) and ovarian cancer tumor models (Press release, Mersana Therapeutics, APR 18, 2016, View Source [SID:1234513852]). The data were presented today during a poster session at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA.

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XMT-1536 is a highly potent anti-sodium-dependent phosphate transport protein 2B (anti-NaPi2b) immunoconjugate comprised of an average of 15 auristatin molecules conjugated to XMT-1535, a novel humanized anti-NaPi2b antibody, via the Dolaflexin antibody-drug conjugate (ADC) platform. Dolaflexin is one of Mersana’s proprietary Fleximer immunoconjugate platforms.

"We are encouraged by the durable regressions XMT-1536 achieved in non-small cell lung cancer and ovarian cancer tumor models, as well as the excellent tolerability and pharmacokinetics in non-human primate exploratory toxicology studies," said Donald A. Bergstrom, MD, PhD, Chief Medical Officer of Mersana. "Based on these data, we are advancing XMT-1536 into IND-enabling studies for the treatment of patients with NaPi2b-expressing tumors."

The study evaluated XMT-1536 in non-squamous NSCLC and non-mucinous ovarian cancer tumor models, indications in which NaPi2b is highly expressed. XMT-1536 demonstrated significant efficacy in all four patient-derived xenograft models representative of the target patient populations. In three patient-derived models of NSCLC, including KRAS-mutant NSCLC, XMT-1536 induced tumor regressions after three weekly doses of 3 mg/kg. In an ovarian cancer xenograft model, XMT-1536 induced partial tumor regressions after a single dose of 3 mg/kg, and complete tumor regressions after a single dose of 5 mg/kg or three weekly doses of 3 mg/kg. XMT-1536 was well-tolerated with no evidence of bone marrow toxicity in non-human primates at up to seven times the dose associated with tumor regression in the mouse xenograft models.

"XMT-1536 further validates the ability of Mersana’s Fleximer platform to generate targeted therapies that have the potential to address unmet needs and improve outcomes for patients with cancer. While there have been recent advancements in the treatment of non-small cell lung cancer and ovarian cancer, there remains tremendous need to address the significant proportion of patients who do not derive full benefit from currently available treatments," said Anna Protopapas, President and Chief Executive Officer of Mersana. "We look forward to the continued development of this second product candidate in our growing pipeline of Fleximer-based immunoconjugate therapies, as we prepare to enter the clinic with XMT-1522 this year."

The aim of this analysis was to establish the safety profile and tolerability of empagliflozin in patients with type 2 diabetes mellitus (T2DM) according to pooled data from several clinical trials.
Pooled data were analyzed from patients with T2DM treated with placebo (n = 3695), empagliflozin 10 mg (n = 3806), or empagliflozin 25 mg (n = 4782) in 17 randomized, Phase I, II, and III clinical trials plus 6 extension studies. Adverse events (AEs) were assessed descriptively in patients who took ≥1 dose of the study drug. AE incidence rates per 100 patient-years were calculated to adjust for differences in drug exposure across trials.
Total exposure was 3254, 3840, and 5649 patient-years in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively. The incidence of any AEs, AEs leading to treatment discontinuation, severe AEs, and serious AEs was no higher in patients treated with empagliflozin than with placebo. Empagliflozin was not associated with an increased risk of hypoglycemia versus placebo, except in patients on background sulfonylurea and/or insulin. The incidence of events consistent with urinary tract infection was similar across treatment groups (9.4-11.3/100 patient-years); 0.4%, 0.2%, and 0.3% of patients in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had urinary tract infections that required or prolonged hospitalization. The incidence of events consistent with genital infection was higher in patients treated with empagliflozin (4.7 and 5.0/100 patient-years for empagliflozin 10 and 25 mg, respectively) than placebo (1.3/100 patient-years), but only 0.1%, 0.1%, and <0.1% in the placebo, empagliflozin 10 mg, and empagliflozin 25 mg groups, respectively, had genital infections that required or prolonged hospitalization. The incidence of AEs consistent with volume depletion was similar with placebo, empagliflozin 10 mg, and empagliflozin 25 mg (1.6, 1.5, and 1.3/100 patient-years, respectively) and was higher with empagliflozin 25 mg than placebo or empagliflozin 10 mg in patients aged >75 years (4.4 vs 2.3 and 2.5/100 patient-years, respectively). The incidences of bone fractures, malignancies, decreased renal function, hepatic injury, venous thromboembolic events, and diabetic ketoacidosis were low and similar across the treatment groups.
In this predefined analysis that was based on >9000 patient-years’ exposure to empagliflozin, empagliflozin 10 mg, and empagliflozin 25 mg were well tolerated in patients with T2DM.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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