Ganesh Mugundu

A Phase I Clinical Trial of AZD1775 in Combination with Neoadjuvant Weekly Docetaxel and Cisplatin before Definitive Therapy in Head and Neck Squamous Cell Carcinoma

Purpose: The WEE1 tyrosine kinase regulates G2–M transition and maintains genomic stability, particularly in p53-deficient tumors which require DNA repair after genotoxic therapy. Thus, a need arises to exploit the role of WEE1 inhibition in head and neck squamous cell carcinoma (HNSCC) mostly driven by tumor-suppressor loss. This completed phase I clinical trial represents the first published clinical experience using the WEE1 inhibitor, AZD1775, with cisplatin and docetaxel. Patients and Methods: We implemented an open-label phase I clinical trial using a 3+3 dose-escalation design for patients with stage III/IVB HNSCC with borderline-resectable or -unresectable disease, but who were candidates for definitive chemoradiation. Escalating AZD1775 was administered orally twice a day over 2.5 days on the first week, then in combination with fixed cisplatin (25 mg/m2) and docetaxel (35 mg/m2) for 3 additional weeks. The primary outcome measure was adverse events to establish MTD. Secondary measures included response rates, pharmacokinetics (PK), pharmacodynamics, and genomic data. Results: The MTD for AZD1775 was established at 150 mg orally twice per day for 2.5 days. RECISTv1.1 responses were seen in 5 of 10 patients; histologic adjustment revealed three additional responders. The only drug-limiting toxicity was grade 3 diarrhea. The PK C8hr target of 240 nmol/L was achieved on day 4 at all three doses tested. Pharmacodynamic analysis revealed a reduction in pY15-Cdk, and increases in γH2AX, CC3, and RPA32/RPA2 were noted in responders versus nonresponders. Conclusions: The triplet combination of AZD1775, cisplatin, and docetaxel is safe and tolerable. Preliminary results show promising antitumor efficacy in advanced HNSCC, meriting further investigation at the recommended phase II dose. Clin Cancer Res; 24(12); 2740–8. ©2018 AACR.

Abstract CT013: A phase Ib, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of AZD1775 monotherapy in patients with advanced solid tumors: initial findings

Many cancers are associated with DNA repair and cell cycle mutations that result in G1/S checkpoint deficiencies and higher levels of endogenous damage and replication stress. This can lead to dependency on WEE1 kinase, which provides an important G2/M checkpoint, allowing repair of DNA damage prior to cells entering mitosis. AZD1775 is a highly selective, small-molecule inhibitor of WEE1. A prior monotherapy study of oral AZD1775 in patients (pts) with refractory solid tumors established a maximum tolerated dose of 225 mg PO BID X 5 doses on weeks (wks) 1 and 2 every 3-wks and activity in pts with BRCA1/2 mutations (Do, JCO, 2015). A subsequent open-label Phase Ib study has been undertaken to further assess the safety and tolerability of AZD1775 monotherapy. Here we report initial safety and efficacy findings from this ongoing study. Pts with advanced solid tumors who have received prior chemotherapy are eligible. The primary objective is assessment of the safety and tolerability of AZD1775 dosing (capsules) BID x 6 doses on days (D) 1-3 and 8-10 every 21 D. Pts are treated until disease progression or intolerable toxicity, with restaging every 6 wks. PK analysis and tumor genetic profiling are performed. 12 pts with the following tumor types were recruited into the safety run-in: small-cell lung (SCLC) (4), non-small-cell lung (1), head and neck (2), ovarian (2), breast (1), pancreas (1), and unknown primary (1). The median number of prior regimens was 3 (range, 1-12). 7 pts were treated at the initial dose of 200 mg BID with 3 pts having dose-limiting toxicities (DLTs) including grade (G) 2 volume depletion/G3 anemia, G3 diarrhea, and G3 nausea/vomiting and were reduced to 175 mg BID. 5 additional pts were then treated with AZD1775 175 mg BID with the addition of antiemetic prophylaxis. Treatment (tx)-related toxicities for all pts included: nausea (75% G1-4; 17% G3/4), vomiting (67% G1-4; 17% G3/4), fatigue (58% G1-4; 8% G3/4), and diarrhea (58% G1-4; 17% G3/4); 4 pts experienced DLTs. As of 1/22/2016, 7 pts remain on tx. Responses: PR (2/12, 17%); SD (2/12, 17%); PD (7/12, 58%); not evaluable (1/12, 8%). Next generation sequencing data were generated for tumors from 10 pts. The 2 PRs were observed in pts with SCLC with somatic mutations in both TP53 and RB1. One of the pts also had a somatic mutation in BRCA1 and has been on tx for 6 months following 4 prior lines of tx. The second pt has been on tx for 5 months and had received 2 prior lines of tx. Tx is ongoing for both pts. Expansion cohorts have been initiated at 175 mg BID D1-3 and 8-10 in ovarian cancer, triple-negative breast cancer, and SCLC, with the objective of further evaluating safety, tolerability, and efficacy of AZD1775 and its association with molecular markers of G1/S deregulation, DNA damage repair deficiencies, and oncogenic driver mutations. Citation Format: Todd M. Bauer, Suzanne F. Jones, Carol Greenlees, Carl Cook, Ganesh M. Mugundu, Philip J. Jewsbury, Andrew J. Pierce, Mark J. O’Connor, Melissa L. Johnson, J. Thaddeus Beck, Kathleen N. Moore, Lowell L. Hart, Jeffery R. Infante, Howard A. Burris, David Spigel. A phase Ib, open-label, multicenter study to assess the safety, tolerability, pharmacokinetics, and antitumor activity of AZD1775 monotherapy in patients with advanced solid tumors: initial findings. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr CT013.

Abstract 2641: AZD4635 A2A receptor occupancy in cynomolgus monkey using PET and its application to an oncology clinical development program

Introduction AZD4635 is an A2A receptor antagonist currently being tested as monotherapy and in combination with durvalumab in patients with advanced solid cancers. High adenosine levels found in tumors are immune suppressive and therefore AZD4635 could potentiate immune checkpoint inhibitors such as durvalumab (anti-PDL1). Predictions of A2A receptor engagement in patients at different doses and at different time points may enable better interpretation of clinical biomarker data measuring effects on immune modulation. A quantitative assessment of the receptor occupancy in the brain of non-human primates was conducted for AZD4635 with PET imaging and the resulting PK/PD model was applied to predict occupancy in humans in tumors. Methods PET measurements of A2AR occupancy in brain was performed using the radioligand [18F]MNI-444 in three anesthetized cynomologus monkeys. PET data acquisition was performed for 120 min following IV-administration of [18F]MNI-444 at baseline and following pretreatment of AZD4635. Sampling for AZD4635 plasma exposure determination was performed. As part of PK/PD analysis of the occupancy data, a novel modification of the non Invasive-LOGAN data analysis of the PET data was performed to obtain a time course of occupancy for each dose. A bio-phase PK/PD mathematical model was then used to describe the relationship of occupancy with circulating concentrations of AZD4635. In parallel, a PK model for AZD4635 in humans was developed using data from cohort 1 (Clinical trial NCT02740985) after 125 mg and used for PK predictions for alternative doses of AZD4635 in the clinic. Results A clear Exposure-Effect relationship was observed for AZD4635-driven A2AR occupancy in cyno brain when dosed 30 min prior to PET measurement. The PK/PD analysis of cyno PET-determined receptor occupancy provided an Occ50 that is in line with the in vitro potency for the compound under physiological concentrations of adenosine in the brain. The resulting PK/PD model has then been applied to predict the level of occupancy in human tumours at other clinically relevant doses. Different simulations were done varying the amount of endogenous adenosine levels. Conclusions AZD4635 was shown to occupy A2AR in cyno brain in an exposure dependent manner. The resulting PK/PD model built using this dataset was used to run simulations of expected tumor receptor occupancy in man and aid clinical dose selection for AZD4635. Sensitivity analysis has shown that prediction of human occupancy in the tumour is highly dependent on adenosine concentrations in the tumour. Simulations with tumor adenosine concentrations of 1 μM indicate that AZD4635 is predicted to provide ~90% receptor occupancy over the whole dosing interval at a clinically relevant dose. Citation Format: Peter Johnstrom, Pablo Morentin Gutierrez, Katarina Varnas, Magnus Schou, Akihiro Takano, Lorraine Jones, Ganesh Mugundu, Patricia McCoon, Paul Lyne, Jeffrey Infante, Gerald Falchook, Manish Patel, Janet Karlix, Melinda Merchant, James Clarke, Alan Cross, Nicholas Seneca, Lars Farde, Miles Congreve, Jon S. Mason, Fiona H. Marshall. AZD4635 A2A receptor occupancy in cynomolgus monkey using PET and its application to an oncology clinical development program [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2641. doi:10.1158/1538-7445.AM2017-2641

Abstract LB-C14: Using Drug Exposure as a Metric for Predicting Clinical Response to Targeted Cancer Therapeutics from Preclinical Efficacy: A Retrospective Preclinical to Clinical Correlation

Objective The objective of this retrospective analysis was to evaluate the correlation between preclinical and clinical markers of efficacy, using available monotherapy data for AstraZeneca targeted oncology drugs. Methods For each drug, preclinical/clinical parameters were identified, including; dose/dosing schedule, tumor model,pharmacokinetic parameters (AUC, t1/2), clinically relevant dose (CRD), tumor growth inhibition (TGI), objective response rate (ORR), disease control rate (DCR), mean tumor shrinkage (MTS), and protein binding. Drugs were first examined to compare the concentrations (Cav) seen at CRDs to preclinical thresholds defined by the concentration required for 50% target inhibition (IC50). Each drug had a number of associated IC50 values, and in vivo values were preferentially used as the concentration target when available. Free Cav values were calculated from AUCs, and a ratio of Cav/IC50 > 1 was used to determine whether the clinical drug exposure exceeded the preclinical efficacy target concentration. The second objective was to determine the correlation between preclinical and clinical efficacy. This was accomplished by estimating murine TGI for each drug at either the allometrically-scaled, mouse-equivalent CRD or at the free exposure (CRE) seen in humans using a variety of dose-response models. Linear regression, weighted by the number of patients from whom clinical data was available, was performed on each comparison, and ANOVA was used to test the significance of each relationship using R v.3.2.2. Results Seventeen targeted drugs with clinical efficacy data were identified. A total of 9/15 (60%) drugs with available data exceeded a free Cav /IC50 ratio of 1 (ratio range of target attaining drugs: 3.6-63.3), indicating that target concentration had been achieved in those drugs. Tumor growth inhibition predicted by the mouse-equivalent CRD ranged from 0.5-155.7% across 13 drugs, while it ranged from 53.4-179.9% across 9 drugs for which TGI could be predicted from the CRE. The weighted correlation between CRD-TGI and clinical ORR was significant (r = 0.71, p Conclusions Comparison of preclinical concentration targets and clinical exposures suggests that the CRD is only achieving the preclinical target in just over half of the drugs, highlighting the importance of choosing a relevant in vivo preclinical concentration to target clinically. Conversely, a high correlation between CRD-based TGI and clinical ORR was observed suggesting that this marker may be more appropriate for prediction of clinical efficacy from preclinical data. Overall, this study demonstrated a correlation between dose-predicted TGI and clinical efficacy. Although this is a small data set, this study confirmed the importance of setting an efficacy threshold preclinically before moving into the clinic with oncology targeted drugs. Citation Format: Matthew Linakis, James Yates, Eric Masson, Ganesh Mugundu. Using Drug Exposure as a Metric for Predicting Clinical Response to Targeted Cancer Therapeutics from Preclinical Efficacy: A Retrospective Preclinical to Clinical Correlation. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr LB-C14.