Alison Turner

A Phase I clinical and pharmacological study of cis-diamminedichloro(2-methylpyridine) platinum II (AMD473)

AMD473 is a novel sterically hindered platinum cytotoxic with demonstrated ability to overcome acquired resistance to cisplatin in vitro and in human tumour xenografts. A single-agent dose escalating Phase I study was performed. AMD473 was initially administered intravenously as a 1 h infusion every 21 days to patients with advanced solid tumours. In total, 42 patients received a total of 147 cycles (median 3, range 1–8) of treatment at doses of 12, 24, 48, 96, 110, 120, 130, and 150 mg m−2. Dosing intervals of 21 and 28 days were explored at the recommended dose. Neutropenia and thrombocytopenia proved dose limiting. Other toxicities included moderate nausea, vomiting, anorexia, and a transient metallic taste. There was no significant alopecia. The maximum tolerated dose was 150 mg m−2. Plasma pharmacokinetics were linear. Two patients with heavily pretreated ovarian cancer showed partial response. Five patients (mesothelioma, ovary, nonsmall cell lung, and melanoma) showed prolonged stable disease. AMD473 demonstrates encouraging activity in patients, including those with prior platinum exposure. Toxicity is predictable with linear pharmacokinetics, as was predicted by preclinical studies. A dose of 120 mg m−2 every 21 days is recommended for Phase II evaluation although there is evidence that chemo-naive patients and those of good performance status may tolerate a higher dose.

Abstract CT010: Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations

Background: Preclinical synergy between PARP and PI3K pathway inhibition in BRCA m and sporadic cancers provided rationale for this trial. Methods: Ola 300mg BID was combined with 2 schedules of AZD BID: 4 days on 3 days off (4/7) and 2 days on 5 days off (2/7) using a novel intrapatient dose escalation design (Michalarea et al, AACR 2015). Cohort expansion of pts with gBRCA m tumors and sporadic tumors with relevant somatic mutations or BRCAness phenotype, assessed 2 regimens: (1) 300mg BID Ola + 400mg BID 4/7 AZD and (2) 300mg BID Ola + 640mg BID 2/7 AZD. Targeted next generation sequencing (NGS) of tumor and cell-free (cf)DNA from 3-weekly plasma samples with a 113 gene panel was undertaken in all pts. Results: 53 pts with advanced cancers (21 gBRCA m) were enrolled (20 in dose escalation; 33 in dose expansion), including ovarian (9/19 with BRCA m), breast (8/16 with BRCA m), prostate (3/4 with BRCA m) and bile duct (1/2 with BRCA m) cancers. Common G1-2 toxicities were nausea, fatigue, anemia, diarrhea, anorexia, mucositis and vomiting on both schedules. 1 dose limiting toxicity (DLT) of G3 rash was seen at 300mg BID Ola + 480mg BID 4/7 AZD. In 4/7 schedule (n = 23), non-DLT G3 toxicities were anemia (n = 3), diarrhea, vomiting and proteinuria (all n = 1). In 2/7 schedule (n = 30), non-DLT G3 toxicities were transaminitis, nausea, fatigue, anemia (all n = 2), rash, hyperglycemia and diarrhea (all n = 1). There were 10 RECIST complete or partial responses (CR/PR) out of 37 (15 BRCA m) evaluable pts, including gBRCA m breast (n = 4), platinum-resistant gBRCA m ovarian (n = 2), BRCA wildtype (WT) triple negative breast (n = 1), BRCA WT ovarian (n = 2) and BRCA unknown prostate (n = 1) cancer pts. A BRCA1 m prostate cancer pt has MRI and PSA responses for 21mths+. A PI3K/mTOR inhibitor resistant peritoneal mesothelioma pt had CA125 response and RECIST stable disease (SD) for 21m. Of 5 ovarian cancer pts who had prior PARP inhibitors, 1 pt had RECIST PR at 13wks+ and 2 pts had SD with tumor shrinkage (18 and 24 wks). 160 cfDNA samples from 38 pts underwent NGS (minimum coverage 500X). Driver mutations were detected and tracked from baseline in 28 (76%) pts. Concordance in mutation status between tumor and cfDNA was 100% in 24/28 (86%) pts. 70% of pts had DNA repair gene mutations, most frequently BRCA. TP53 (40%) and KRAS (25%) were the most commonly detected somatic mutations. Changes in cfDNA concentrations appeared to correlate with treatment response in 72% of pts, while tracking of mutation allele frequency in serial cfDNA samples during treatment showed potential clonal responses. Conclusion: The combination of Ola and AZD is well tolerated with multiple responses in both gBRCA and non-BRCA m tumors, and prior PARP inhibitor treated cancers. The recommended phase 2 doses are 300mg BID Ola + 400mg BID 4/7 AZD and 300mg BID Ola + 640mg BID 2/7 AZD. Citation Format: Vasiliki Michalarea, Desam Roda, Yvette Drew, Suzanne Carreira, Brent S. O’Carrigan, Heather Shaw, Rene Roux, Sanjeev Kumar, Sarah Ward, Mona Parmar, Alison Turner, Emma Hall, Sonia Serrano Fandos, Raquel Perez, Nina Tunariu, Florence Raynaud, Marie Cullberg, Andrew Foxley, Justin PO Lindemann, Martin Pass, Paul Rugman, Juanita S. Lopez, Udai Banerji, Bristi Basu, Ruth Plummer, Rebecca Kristeleit, Johann S. de Bono, Timothy A. Yap. Phase I trial combining the PARP inhibitor olaparib (Ola) and AKT inhibitor AZD5363 (AZD) in germline (g)BRCA and non-BRCA mutant (m) advanced cancer patients (pts) incorporating noninvasive monitoring of cancer mutations. [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 CT010.

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

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