On April 18, 2016 AstraZeneca reported new data from multiple molecules in its industry-leading DNA Damage Response (DDR) pipeline at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA (Press release, AstraZeneca, APR 18, 2016, View Source [SID:1234511011]). These agents use a variety of different pathways to disrupt tumour cells’ natural ability to repair themselves as they replicate, eventually causing the tumour cells to die.7,8 Illustrating the unique breadth of AstraZeneca’s approaches to DDR, presentations at AACR (Free AACR Whitepaper) featured molecules that disrupt multiple tumour cell repair processes, including single-strand break repair, double-strand break repair, and cell cycle regulation.1-6

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Susan Galbraith, Head of AstraZeneca’s Oncology Innovative Medicines Unit said, "Taken together with the positive Phase II results of olaparib in patients with metastatic, castration-resistant prostate cancer published early this year,9 we are encouraged by the potential of PARP inhibition in multiple tumour types beyond ovarian cancer. The breadth of our pipeline showcases DDR monotherapies and combinations that could attack cancer in a multitude of novel ways – our first priority, as demonstrated here at AACR (Free AACR Whitepaper), is to follow the science to identify and quickly advance those molecules that have the potential to address the greatest unmet medical needs."

PARP Inhibition and Lynparza (olaparib): Beyond Ovarian Cancer

The PARP inhibitor olaparib is the cornerstone of AstraZeneca’s pipeline of personalised treatments targeting DDR mechanisms in cancer cells. Olaparib was combined with the investigational AKT inhibitor AZD5363 in a new Phase I trial of germline (g) BRCA and non-BRCA mutant (m) advanced cancer patients with ovarian, breast, prostate and bile duct cancers.1 Results showed that the olaparib-AZD5363 combination was well-tolerated with multiple responses, including 10 RECIST complete or partial responses (out of 37 evaluable patients) in both gBRCA and non-BRCAm tumours, as well as prior PARP inhibitor-treated cancers.1

Olaparib disrupts the repair of single-strand DNA breaks, a mode of action that has potential to work in a range of tumour types beyond ovarian cancer.10 AstraZeneca is researching how several different compounds can be combined with DDR molecules to provide a dual threat to tumour cells. For example, treatments such as AZD5363 that selectively inhibit the PI3K / AKT signalling pathway may complement olaparib’s interference with tumour DNA repair.1

Additional Mechanisms of DDR: Cell Cycle Disruption & Double-Strand Break Repair

AstraZeneca presented data on a variety of investigational compounds acting on different aspects of the DDR pathway, both in monotherapy and in combination. Most significant were early results from a Phase Ib open-label study of AZD1775, a novel small molecule designed to inhibit the Wee1 kinase.2 Wee1 is a protein kinase that helps regulate the cell cycle.5 In many tumours, Wee1 overexpression stops the cell cycle after DNA damage occurs, allowing tumour cells time to repair any damage.5,11 By inhibiting Wee1, the cell cycle continues despite damage, which can lead to tumour cell death.5 Assessing the safety, tolerability, pharmacokinetics and anti-tumour activity of AZD1775, the Phase Ib safety run-in included patients with small-cell lung, non-small cell lung, head and neck, ovarian, breast, pancreas and unknown primary tumours.2 Early results demonstrated a partial or stable response in a third of patients (4/12), and AstraZeneca has initiated expansion cohorts in ovarian, breast and small-cell lung cancer.2 Other studies currently recruiting include a Phase I multi-centre, dose escalation study of AZD1775 combined with olaparib in refractory solid tumours.12

Several other new molecules in the clinical pipeline are entering Phase I development, including the first-in-class Ataxia telangiectasia mutated (ATM) kinase inhibitor AZD0156.3 Pre-clinical in vivo activity of AZD0156 presented at AACR (Free AACR Whitepaper) demonstrated that inhibition of ATM during the DNA damage response enhanced the efficacy of a range of DNA-damaging agents, including olaparib, and support its further study in the clinical setting.3 AstraZeneca is now recruiting for a Phase I trial of AZD0156 as monotherapy or in combination with olaparib in patients with advanced solid tumours.13

Other ongoing DDR-focused studies include additional Phase I trials of the Aurora B kinase inhibitor AZD281114 and ATR inhibitor AZD6738 in solid tumours.15

In this analysis, we compared costs and explored the cost-effectiveness of subsequent-line treatment with cetuximab or panitumumab in patients with wild-type KRAS (exon 2) metastatic colorectal cancer (mCRC) after previous chemotherapy treatment failure. Data were used from ASPECCT (A Study of Panitumumab Efficacy and Safety Compared to Cetuximab in Patients With KRAS Wild-Type Metastatic Colorectal Cancer), a Phase III, head-to-head randomized noninferiority study comparing the efficacy and safety of panitumumab and cetuximab in this population.
A decision-analytic model was developed to perform a cost-minimization analysis and a semi-Markov model was created to evaluate the cost-effectiveness of panitumumab monotherapy versus cetuximab monotherapy in chemotherapy-resistant wild-type KRAS (exon 2) mCRC. The cost-minimization model assumed equivalent efficacy (progression-free survival) based on data from ASPECCT. The cost-effectiveness analysis was conducted with the full information (uncertainty) from ASPECCT. Both analyses were conducted from a US third-party payer perspective and calculated average anti-epidermal growth factor receptor doses from ASPECCT. Costs associated with drug acquisition, treatment administration (every 2 weeks for panitumumab, weekly for cetuximab), and incidence of infusion reactions were estimated in both models. The cost-effectiveness model also included physician visits, disease progression monitoring, best supportive care, and end-of-life costs and utility weights estimated from EuroQol 5-Dimension questionnaire responses from ASPECCT.
The cost-minimization model results demonstrated lower projected costs for patients who received panitumumab versus cetuximab, with a projected cost savings of $9468 (16.5%) per panitumumab-treated patient. In the cost-effectiveness model, the incremental cost per quality-adjusted life-year gained revealed panitumumab to be less costly, with marginally better outcomes than cetuximab.
These economic analyses comparing panitumumab and cetuximab in chemorefractory wild-type KRAS (exon 2) mCRC suggest benefits in favor of panitumumab. ClinicalTrials.gov identifier: NCT01001377.
Copyright © 2016 The Authors. Published by Elsevier Inc. All rights reserved.

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On April 18, 2016 Celator Pharmaceuticals, Inc. (Nasdaq: CPXX) reported that positive data for VYXEOS (cytarabine:daunorubicin) Liposome for Injection (also known as CPX-351), its lead product candidate, were presented at the American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting in New Orleans, LA, April 16-20, 2016 (Press release, Celator Pharmaceuticals, APR 18, 2016, View Source [SID:1234510967]).

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The presentation, titled "CPX-351 cytotoxicity against fresh AML blasts is increased for FLT3-ITD+ cells and correlates with drug uptake and clinical outcomes," was based on research conducted in the laboratory of Jeffrey Tyner, Ph.D. at Oregon Health & Science University and examined the ex vivo sensitivity of AML cells derived from newly diagnosed patients to VYXEOS.

The profile of ex vivo AML blast sensitivity to VYXEOS mirrors the efficacy profile observed clinically and may provide a means to identify specific AML patient genotypes/phenotypes that could benefit most from VYXEOS treatment. The increased sensitivity of FLT3-ITD+ (internal tandem duplication) blasts to VYXEOS is an example of how such analyses may identify additional AML patient populations warranting further clinical investigation.

FLT3-ITD mutant expression has historically been a predictor of poor patient outcomes to conventional treatment regimens. A notable result from this research was the observation that AML cells exhibiting the FLT3-ITD mutation were approximately five times more sensitive to VYXEOS than AML cells with normal FLT3. In addition, there was evidence that increased sensitivity to VYXEOS is associated with increased uptake of the drug-laden liposomes by leukemia cells.

"Testing cell killing activity against fresh AML cells outside the body allows us to identify specific AML cell-VYXEOS interactions that could be exploited clinically," said Dr. Tyner. "We are particularly excited about the marked increase in sensitivity of FLT3-ITD cells to VYXEOS and are working to better understand the mechanism underlying this phenomenon."

"VYXEOS continues to deliver positive efficacy read-outs," said Lawrence Mayer, Ph.D., President and Chief Scientific Officer at Celator. "The encouraging activity of VYXEOS against AML cells harboring the FLT3-ITD mutant phenotype opens exciting opportunities to test VYXEOS in this AML patient population. We will submit data from patients exhibiting this mutation, who were treated in the recently completed Phase 3 trial, to an upcoming medical conference."

The poster will be available on Celator’s website (www.celatorpharma.com) at the conclusion of the AACR (Free AACR Whitepaper) meeting.

On April 18, 2016 Calithera Biosciences, Inc. (Nasdaq:CALA), a clinical stage biotechnology company focused on the development of novel cancer therapeutics, reported preclinical data for each of its therapeutic candidates, CB-839 and CB-1158, at the 2016 American Association for Cancer Research (AACR) (Free AACR Whitepaper) Annual Meeting, taking place April 16-20, 2016, in New Orleans, Louisiana (Press release, Calithera Biosciences, APR 18, 2016, View Source;p=RssLanding&cat=news&id=2157903 [SID:1234510990]). CB-839 is a potent, selective, orally bioavailable glutaminase inhibitor currently in phase I clinical trials. CB-1158 is a first-in-class immuno-oncology agent targeting arginase, a key immuno-suppressive enzyme that limits T-cell proliferation in a wide range of tumors.

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"Both CB-839 and CB-1158 have the distinction of targeting metabolic checkpoints which we believe through rational combinations, have the potential to be transformational in the treatment of cancer. For CB-839, we look forward to initiating a trial in combination with anti-PD-1 in the second quarter. We have made significant progress on our CB-1158 program, and remain on track to file an IND application in mid-2016," said Susan Molineaux, PhD, President and Chief Executive Officer of Calithera.

CB-839

Preclinical data will be presented in a poster titled, "Glutaminase inhibition with CB-839 enhances anti-tumor activity of PD-1 and PD-L1 antibodies by overcoming a metabolic checkpoint blocking T cell activation," by Matt Gross, Director of Pharmacology at Calithera Biosciences (Abstract #2329). Included in the presentation are the results of studies investigating the preclinical anti-tumor activity of CB-839 in combination with an anti-PD-L1 or an anti-PD-1 antibody. The combination of CB-839 and anti-PD-L1 or anti-PD-1 increased the number of tumor regressions seen in the CT-26 syngeneic colon carcinoma model. Synergistic effects with CB-839 and anti-PD-L1 were also observed in a B16 melanoma model. The mechanism of action of anti-PD-L1 combined with CB-839, two agents that affect metabolism in the tumor microenvironment, is being explored in further studies.

The following two abstracts were also presented at the meeting by Calithera’s collaborators:

Neurofibromatosis type 1 (NF1) status determines sensitivity of soft tissue sarcoma and melanoma cell lines to glutaminase inhibitors (Abstract #19). Presenter: Tahir Sheikh, PhD, Laboratory of Gary Schwartz, MD, Columbia University

GLS inhibitor CB-839 modulates cellular metabolism in AML and potently suppresses AML cell growth when combined with 5-azacitidine (Abstract #1004). Presenter: Tianyu Cai, PhD, Laboratory of Marina Konopleva, MD, University of Texas MD Anderson Cancer Center

CB-1158

Preclinical data was presented in a poster titled, "Immuno-oncology agent CB-1158 is a potent and selective arginase inhibitor and causes an immune mediated anti-tumor response," by Melissa Works, PhD, Scientist at Calithera Biosciences (Abstract #552). CB-1158, a highly selective, orally bioavailable, small molecule inhibitor of human arginase with nanomolar potency, demonstrated single agent efficacy in animal models. Inhibition of tumor growth was accompanied by an increase in the local concentration of arginine, and the induction of multiple pro-inflammatory changes in the tumor microenvironment. CB-1158 increased CD8+ T-cell infiltrates in a lung tumor model. The addition of CB-1158 to anti-CTLA-4 and anti-PD-1, significantly inhibited tumor growth and reduced metastases in a mouse model that was resistant to dual checkpoint inhibitor therapy. CB-1158 was well tolerated as a single agent and in combination with checkpoint inhibitors in animal studies.

Arginase is a critical immunosuppressive enzyme that inhibits T-cell proliferation and function. Arginase depletes arginine, a nutrient that is critical for the activation, growth and survival of two of the body’s cancer-fighting immune cells, known as cytotoxic T -cells and natural killer (NK) cells. Arginase inhibitors can restore arginine levels and reverse the immuno-suppressive effect of arginase-secreting myeloid-derived suppressor cells (MDSCs). MDSCs are present in many human tumors and are correlated with poor prognosis. CB-1158 has the potential for anti-tumor activity in a variety of malignancies, including non-small cell lung cancer, colorectal cancer, gastric cancer and bladder cancer, among other tumor types that are highly infiltrated with MDSCs.

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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