Karen E Swales

Interrogating Two Schedules of the AKT Inhibitor MK-2206 in Patients with Advanced Solid Tumors Incorporating Novel Pharmacodynamic and Functional Imaging Biomarkers

Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60–80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing. Experimental Design: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic–pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI. Results: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial. Conclusions: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672–85. ©2014 AACR.

The clinical development candidate CCT245737 is an orally active CHK1 inhibitor with preclinical activity in RAS mutant NSCLC and Eµ-MYC driven B-cell lymphoma

CCT245737 is the first orally active, clinical development candidate CHK1 inhibitor to be described. The IC50 was 1.4nM against CHK1 enzyme and it exhibited>1,000-fold selectivity against CHK2 and CDK1. CCT245737 potently inhibited cellular CHK1 activity (IC50 30-220nM) and enhanced gemcitabine and SN38 cytotoxicity in multiple human tumor cell lines and human tumor xenograft models. Mouse oral bioavailability was complete (100%) with extensive tumor exposure. Genotoxic-induced CHK1 activity (pS296 CHK1) and cell cycle arrest (pY15 CDK1) were inhibited both in vitro and in human tumor xenografts by CCT245737, causing increased DNA damage and apoptosis. Uniquely, we show CCT245737 enhanced gemcitabine antitumor activity to a greater degree than for higher doses of either agent alone, without increasing toxicity, indicating a true therapeutic advantage for this combination. Furthermore, development of a novel ELISA assay for pS296 CHK1 autophosphorylation, allowed the quantitative measurement of target inhibition in a RAS mutant human tumor xenograft of NSCLC at efficacious doses of CCT245737. Finally, CCT245737 also showed significant single-agent activity against a MYC-driven mouse model of B-cell lymphoma. In conclusion, CCT245737 is a new CHK1 inhibitor clinical development candidate scheduled for a first in man Phase I clinical trial, that will use the novel pS296 CHK1 ELISA to monitor target inhibition.

First-in-Human Study of CH5132799, an Oral Class I PI3K Inhibitor, Studying Toxicity, Pharmacokinetics, and Pharmacodynamics, in Patients with Metastatic Cancer

Purpose: This phase I dose-escalation study investigated the maximum-tolerated dose (MTD), dose-limiting toxicities (DLT), safety, pharmacokinetics (PK), pharmacodynamics (PD), and preliminary clinical activity of CH5132799. Experimental Design: Patients with metastatic solid tumors were eligible for the study. CH5132799 was administered orally once daily or twice daily in 28-day cycles. Results: Thirty-eight patients with solid tumors received CH5132799 at 2 to 96 mg once daily or 48 to 72 mg twice daily. The MTD was 48 mg on the twice-daily schedule but was not reached on the once daily schedule. DLTs were grade 3 elevated liver function tests (LFT), grade 3 fatigue, grade 3 encephalopathy, grade 3 diarrhea, and grade 3 diarrhea with grade 3 stomatitis; all DLTs were reversible. Most drug-related adverse events were grade 1/2. Diarrhea (34%) and nausea (32%) were the most common events. Mean Cmax and AUC0-24 in steady state at MTD were 175 ng/mL and 1,550 ng·h/mL, respectively, consistent with efficacious exposure based on preclinical modeling. Reduction in SUVmax with [18F] fluorodeoxyglucose positron emission tomography (FDG-PET) was observed in 5 of 7 patients at MTD. A patient with PIK3CA-mutated clear cell carcinoma of the ovary achieved a partial response by GCIG CA125 criteria and further, a heavily pretreated patient with triple-negative breast cancer had marked improvement in her cutaneous skin lesions lasting six cycles. Conclusion: CH5132799 is well tolerated at the MTD dose of 48 mg twice daily. At this dose, the drug had a favorable PK and PD profile and preliminary evidence of clinical activity. Clin Cancer Res; 20(23); 5908–17. ©2014 AACR.

A first-time-in-human study of GSK2636771, a phosphoinositide 3 kinase beta-selective inhibitor, in patients with advanced solid tumors

Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ. Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25–500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D. Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile. Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981–92. ©2017 AACR.

Activation of the Farnesoid X-receptor in breast cancer cell lines results in cytotoxicity but not increased migration potential

Breast cancer is the commonest form of cancer in women, but successful treatment is confounded by the heterogeneous nature of breast tumours: Effective treatments exist for hormone-sensitive tumours, but triple-negative breast cancer results in poor survival. An area of increasing interest is metabolic reprogramming, whereby drug-induced alterations in the metabolic landscape of a tumour slow tumour growth and/or increase sensitivity to existing therapeutics. Nuclear receptors are transcription factors central to the expression of metabolic and transport proteins, and thus represent potential targets for metabolic reprogramming. We show that activation of the nuclear receptor FXR, either by its endogenous ligand CDCA or the synthetic GW4064, leads to cell death in four breast cancer cell lines with distinct phenotypes: MCF-10A (normal), MCF-7 (receptor positive), MDA-MB-231 and MDA-MB-468 (triple negative). Furthermore, we show that the mechanism of cell death is predominantly through the intrinsic apoptotic pathway. Finally, we demonstrate that FXR agonists do not stimulate migration in breast cancer cell lines, an important potential adverse effect. Together, our data support the continued examination of FXR agonists as a novel class of therapeutics for the treatment of breast cancer.

Abstract CT323: Accelerated phase I trial of two schedules of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363 using a novel intrapatient dose escalation design in advanced cancer patients

Background: There is an urgent need for better trial designs to assess targeted drug combinations. We proposed a novel intrapatient (intrapt) dose escalation trial design to optimize drug exposures, minimize pharmacokinetic (PK) variability and reduce patient (pt) numbers needed (Yap et al, JCO 2013). In vivo synergy between PARP and PI3K pathway inhibition was seen in BRCA1-related and sporadic cancers (Juvekar et al; Ibrahim et al, Cancer Discov 2012), providing rationale for this study. Methods: Two-stage investigator initiated phase I trial: a) Intrapt dose escalation; b) Recommended phase II combination dose (RP2CD) expansion. Advanced cancer pts received escalating doses of AZD5363 (AZD) BID in 2 parallel arms (4 days on 3 days off [4/7 arm] at 320, 400, 480mg; 2 days on 5 days off [2/7 arm] at 480, 560, 640mg) with Olaparib (Ola) at 300mg BID in 3 weekly cycles. AZD was escalated after each cycle in each pt if drug related toxicities were ≤CTCAE G2. Dose limiting toxicities (DLT) were assessed during the 1st cycle of each dose level (DL). ≥6 evaluable pts were required at each DL. RECIST assessment was done every 3 cycles. Prior PARP or PI3K/AKT inhibitor use was allowed. PK and pharmacodynamics (PD) were assessed in tumor and normal tissue. Targeted +/- whole exome next generation sequencing was assessed in tumor and serial plasma DNA samples in all pts for predictive biomarkers of response. Results: Dose escalation was completed in 7.5 months (m) in 20 pts in 1 center; ≥6 evaluable pts were treated at each of the 3 DLs in both arms. Common (>15%) G1-2 toxicities were nausea, vomiting, fatigue, diarrhea and anemia. A DLT of G3 rash was seen at 480mg BID 4/7 AZD + 300mg BID Ola. Non DLT G3 anemia (n = 2), diarrhea (n = 2), fatigue (n = 1) and vomiting (n = 1) were seen in 4/7 arm; G3 hyperglycemia (n = 1), transaminitis (n = 1) and fatigue (n = 2) in 2/7 arm. No significant PK interactions were seen between Ola and AZD. Intrapt dose escalation of AZD showed dose dependent increases in PK exposures. Platelet-rich plasma PD showed significant decreases in pSer9 GSK3β post-therapy at all DLs (mean ≥55% [p Conclusion: This novel trial design led to rapid completion of dose escalation. RP2CD expansion (n = 40) is ongoing in: a) germline BRCA mut cancers; b) sporadic cancers with relevant somatic mutations. Citation Format: Vasiliki Michalarea, David Lorente, Juanita Lopez, Suzanne Carreira, Hasina Hassam, Mona Parmar, Nitharsan Sathiyayogan, Alison Turner, Emma Hall, Sonia Serrano Fandos, Satyanarayana Seeramreddi, Shaun Decordova, Karen Swales, Ruth Ruddle, Florence Raynaud, Nina Tunariu, Gerhardt Attard, L. Rhoda Molife, Udai Banerji, Ruth Plummer, Johann S. de Bono, Timothy A. Yap. Accelerated phase I trial of two schedules of the combination of the PARP inhibitor olaparib and AKT inhibitor AZD5363 using a novel intrapatient dose escalation design in advanced cancer patients. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr CT323. doi:10.1158/1538-7445.AM2015-CT323

A phase I/II trial of AT9283, a selective inhibitor of aurora kinase in children with relapsed or refractory acute leukemia: challenges to run early phase clinical trials for children with leukemia

Aurora kinases regulate mitosis and are commonly overexpressed in leukemia. This phase I/IIa study of AT9283, a multikinase inhibitor, was designed to identify maximal tolerated doses, safety, pharmacokinetics, and pharmacodynamic activity in children with relapsed/refractory acute leukemia. The trial suffered from poor recruitment and terminated early, therefore failing to identify its primary endpoints. AT9283 caused tolerable toxicity, but failed to show clinical responses. Future trials should be based on robust preclinical data that provide an indication of which patients may benefit from the experimental agent, and recruitment should be improved through international collaborations and early combination with established treatment strategies.

Evaluation of the combination of the dual m-TORC1/2 inhibitor vistusertib (AZD2014) and paclitaxel in ovarian cancer models

Activation of the PI3K/mTOR pathway has been shown to be correlated with resistance to chemotherapy in ovarian cancer. We aimed to investigate the effects of combining inhibition of mTORC1 and 2 using the mTOR kinase inhibitor vistusertib (AZD2014) with paclitaxel in in vitro and in vivo ovarian cancer models. The combination of vistusertib and paclitaxel on cell growth was additive in a majority of cell lines in the panel (n = 12) studied. A cisplatin- resistant model (A2780Cis) was studied in vitro and in vivo. We demonstrated inhibition of mTORC1 and mTORC2 by vistusertib and the combination by showing reduction in p-S6 and p-AKT levels, respectively. In the A2780CisR xenograft model compared to control, there was a significant reduction in tumor volumes (p = 0.03) caused by the combination and not paclitaxel or vistusertib alone. In vivo, we observed a significant increase in apoptosis (cleaved PARP measured by immunohistochemistry; p = 0.0003). Decreases in phospholipid and bioenergetic metabolites were studied using magnetic resonance spectroscopy and significant changes in phosphocholine (p = 0.01), and ATP (p = 0.04) were seen in tumors treated with the combination when compared to vehicle-control. Based on this data, a clinical trial evaluating the combination of paclitaxel and vistusertib has been initiated (NCT02193633). Interestingly, treatment of ovarian cancer patients with paclitaxel caused an increase in p-AKT levels in platelet-rich plasma and it was possible to abrogate this increase with the co-treatment with vistusertib in 4/5 patients: we believe this combination will benefit patients with ovarian cancer.

468PPHASE I MULTICENTRE TAX-TORC TRIAL OF THE DUAL MTORC1/2 INHIBITOR AZD2014 (A) PLUS WEEKLY PACLITAXEL (P) IN PATIENTS (PTS) WITH SOLID TUMOURS (CRUKD/12/013)

ABSTRACT Aim: Activation of the PI3 kinase-AKT-mTOR pathway is hypothesized to contribute to resistance to chemotherapy and targeted agents in many cancers. Enhanced PI3 kinase pathway signaling has been shown in ovarian cancer cell lines and ascitic cells from pts showing chemoresistance. In a previous phase I trial the maximum tolerated dose (MTD) of the dual mTORC1/2 inhibitor AZD2014 (A) as monotherapy was defined as 50 mg bd 7/7. Preclinically, when A is combined with P, additive apoptosis is observed. Therefore, the combination of A and P was evaluated in a multicentre Phase I trial in patients with solid tumours (EudraCT 2012-003896-20). Study aims were to determine the MTD and recommended dose for the combination of fixed dose weekly P with two intermittent schedules of A, based on safety, tolerability, pharmacokinetics (PK) profile, pharmacodynamics (PD) and antitumour activity. Methods: A was administered orally bd either 3 days on 4 days off (3/7 schedule) or 2 days on 5 days off (2/7 schedule) starting on the same day as fixed dose weekly intravenous P 80mg/m2. A cycle comprised 6 weekly treatments every 49 days. A 3 + 3 dose escalation design was employed. Results: 17 pts have been treated in the study so far. On the 3/7 schedule (12 treated), 2 pts had dose-limiting toxicities (DLT) of grade (Gr) 3 fatigue and mucositis at 75 mg bd of A. On the 2/7 schedule (5 treated), 2 pts had DLT of Gr 3 rash at 100mg bd of A. Frequently observed adverse events of any grade were fatigue, diarrhoea, anaemia, mucositis and anorexia. PK and PD data for the 2 schedules will be presented. To date, 3/5 pts with taxane-pretreated ovarian cancer have achieved RECIST and/or GCIG CA125 partial response (PR). 2/2 pts with taxane-pretreated squamous NSCLC and 1/2 pts with EGFR-mutant lung adenocarcinoma have shown significant necrosis of their tumours and PR by RECIST. Conclusions: The MTD for the 3/7 schedule is P 80 mg/m2 plus A 50 mg bd. For the 2/7 schedule, 100mg bd A + weekly P is declared non-tolerated, based on 2 DLTs of Gr 3 rash. Expansions in relapsed ovarian cancer and squamous cell lung cancer are now planned. The study is supported by AstraZeneca, Cancer Research UK, Experimental Cancer Medicine Centre and NIHR Biomedical Research Centre Initiatives. It is co-sponsored by the Institute of Cancer Research/Royal Marsden NHS Foundation Trust. Disclosure: S. Banerjee, S.B. Kaye and J.S. De Bono: Served on Advisory Board for AstraZeneca. All other authors have declared no conflicts of interest.

Vistusertib (dual m-TORC1/2 inhibitor) in combination with paclitaxel in patients with high-grade serous ovarian and squamous non-small-cell lung cancer

Abstract Background We have previously shown that raised p-S6K levels correlate with resistance to chemotherapy in ovarian cancer. We hypothesised that inhibiting p-S6K signalling with the dual m-TORC1/2 inhibitor in patients receiving weekly paclitaxel could improve outcomes in such patients. Patients and methods In dose escalation, weekly paclitaxel (80 mg/m2) was given 6/7 weeks in combination with two intermittent schedules of vistusertib (dosing starting on the day of paclitaxel): schedule A, vistusertib dosed bd for 3 consecutive days per week (3/7 days) and schedule B, vistusertib dosed bd for 2 consecutive days per week (2/7 days). After establishing a recommended phase II dose (RP2D), expansion cohorts in high-grade serous ovarian cancer (HGSOC) and squamous non-small-cell lung cancer (sqNSCLC) were explored in 25 and 40 patients, respectively. Results The dose-escalation arms comprised 22 patients with advanced solid tumours. The dose-limiting toxicities were fatigue and mucositis in schedule A and rash in schedule B. On the basis of toxicity and pharmacokinetic (PK) and pharmacodynamic (PD) evaluations, the RP2D was established as 80 mg/m2 paclitaxel with 50 mg vistusertib bd 3/7 days for 6/7 weeks. In the HGSOC expansion, RECIST and GCIG CA125 response rates were 13/25 (52%) and 16/25 (64%), respectively, with median progression-free survival (mPFS) of 5.8 months (95% CI: 3.28–18.54). The RP2D was not well tolerated in the SqNSCLC expansion, but toxicities were manageable after the daily vistusertib dose was reduced to 25 mg bd for the following 23 patients. The RECIST response rate in this group was 8/23 (35%), and the mPFS was 5.8 months (95% CI: 2.76–21.25). Discussion In this phase I trial, we report a highly active and well-tolerated combination of vistusertib, administered as an intermittent schedule with weekly paclitaxel, in patients with HGSOC and SqNSCLC. Clinical trial registration ClinicialTrials.gov identifier: CNCT02193633