Search

Supplementary Figure from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Purpose:To characterize safety and tolerability of the selective PI3Kβ inhibitor AZD8186, identify a recommended phase II dose (RP2D), and assess preliminary efficacy in combination with abiraterone acetate or vistusertib.Patients and Methods:This phase I open-label study included patients with advanced solid tumors, particularly prostate cancer, triple-negative breast cancer, and squamous non–small cell lung cancer. The study comprised four arms: (i) AZD8186 monotherapy dose finding; (ii) monotherapy dose expansion; (iii) AZD8186/abiraterone acetate (with prednisone); and (iv) AZD8186/vistusertib. The primary endpoints were safety, tolerability, and identification of the RP2D of AZD8186 monotherapy and in combination. Secondary endpoints included pharmacokinetics (PK), pharmacodynamics, and tumor and prostate-specific antigen (PSA) responses.Results:In total, 161 patients were enrolled. AZD8186 was well tolerated across all study arms, the most common adverse events being gastrointestinal symptoms. In the monotherapy dose-finding arm, four patients experienced dose-limiting toxicities (mainly rash). AZD8186 doses of 60-mg twice daily [BID; 5 days on, 2 days off (5:2)] and 120-mg BID (continuous and 5:2 dosing) were taken into subsequent arms. The PKs of AZD8186 were dose proportional, without interactions with abiraterone acetate or vistusertib, and target inhibition was observed in plasma and tumor tissue. Monotherapy and combination therapy showed preliminary evidence of limited antitumor activity by imaging and, in prostate cancer, PSA reduction.Conclusions:AZD8186 monotherapy had an acceptable safety and tolerability profile, and combination with abiraterone acetate/prednisone or vistusertib was also tolerated. There was preliminary evidence of antitumor activity, meriting further exploration of AZD8186 in subsequent studies in PI3Kβ pathway–dependent cancers.

Supplementary Data from A Phase I Study Investigating AZD8186, a Potent and Selective Inhibitor of PI3Kβ/δ, in Patients with Advanced Solid Tumors

Background: AcSé-ESMART is a proof-of-concept, phase I/II platform trial designed to explore targeted agents in a molecularly enriched pediatric population. WEE1 plays a role in DNA repair and cell cycle control and is overexpressed in pediatric cancers. Adavosertib combinations resulted in enhanced antitumor activity compared to single agent in neuroblastoma, rhabdomyosarcoma, medulloblastoma and high-grade glioma in vivo models. The efficacy and safety of the adavosertib-carboplatin combination has been established in adults with focus on TP53 mutated ovarian cancer. Arm C of AcSé-ESMART applied this regimen to children with advanced malignancies enriched for alterations in TP53, DNA repair/replication stress and cell cycle control. Methods: Adavosertib was administered orally, twice daily on Days 1 to 3 and carboplatin intravenously on Day 1 of a 21-day cycle. Dose finding used the continuous reassessment method starting at adavosertib 100 mg/m2/dose and carboplatin AUC 5. Pharmacokinetic (PK) and retrospective molecular bioinformatic analysis was performed. Results: Twenty patients (median age: 14.0 years, range 3.4-23.5) were included, 18 received a total of 69 cycles. Seven dose-limiting toxicities (DLTs) were observed leading to two de-escalations to adavosertib 75 mg/m2/dose and carboplatin AUC 4. All patients with DLT had thrombocytopenia grade 3/4 requiring transfusions for >7 days and/or neutropenia grade 4 for >7 days. Main overall treatment-related toxicities were hematologic and gastrointestinal. Based on the identified DLT risk, no recommended Phase 2 dose was defined. PK analysis demonstrated equivalent adavosertib exposure in children to that in adults and both doses (75 and 100 mg/m2) achieved the cell kill target. Two patients with neuroblastoma achieved partial response (PR), one with medulloblastoma unconfirmed PR, and five had stable disease (SD) >4 cycles. Patients with PR/SD >4 cycles were considered as clinical benefit (CB) for retrospective molecular analysis. There was no correlation between TP53 genomic alteration alone and response. However, 7 of 8 patients with CB but none of the 10 patients without CB had 1 to 3 genomic alterations in the DNA repair (BRCA2 mutation, 11q loss containing ATM, MRE11A, CHEK1), cell cycle control/replication stress (CCNE1 amplification, RB1 mutation/loss, SETD2 mutation/loss) and RAS pathway (KRAS mutation and amplification, NF1 loss, PTPN11 mutation) in their tumor. Conclusions: Adavosertib combined with carboplatin exhibited significant hematologic toxicity. Activity signals and identified potential molecular biomarkers suggest further combination studies with less hematotoxic DNA damaging therapy in molecularly enriched pediatric cancers. Citation Format: Susanne A. Gatz, Anne C. Harttrampf, Caroline Brard, Francisco J. Bautista, Nicolas André, Samuel Abbou, Jonathan Rubino, Windy Rondof, Marc Deloger, Marc Rübsam, Daniel Hübschmann, Lynley V. Marshall, Souad Nebchi, Isabelle Aerts, Estelle Thebaud, Emilie De Carli, Anne-Sophie Defachelles, Xavier Paoletti, Robert Godin, Kowser Miah, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the WEE1 inhibitor adavosertib in combination with carboplatin in children with advanced malignancies: arm C of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT087.

Background: AcSé-ESMART is a proof-of-concept, phase I/II, platform trial, designed to explore targeted agents in a molecularly enriched relapsed/refractory pediatric population. Arm D was evaluating the PARP inhibitor (PARPi) olaparib (ola) in combination with irinotecan (iri). In contrast to other PARPi/chemotherapy combination studies, we opted for a prolonged course of PARPi and low dose irinotecan as sensitizer. The Phase I part previously established the recommended Phase II dose (RP2D) (Gatz ASCO 2019). This is the report of the Phase II part of the trial assessing the activity in two separate expansion cohorts: cohort 1: homologous recombination repair defect (HRD) and cohort 2: Ewing sarcoma (ES). Methods: Ola was administered orally twice daily at 90 mg/m2 on Days 1 to 10 and iri intravenously at 20 mg/m2 on Days 4 to 8 of a 21-day cycle. Activity assessment followed a Minimax Simon 2-stage design. Each cohort was to progress to the second stage (additional 9 patients) if 2 or more confirmed responses were observed in the first 16 patients. Patients treated in the Phase I part at the RP2D were counting towards the respective expansion cohorts. Results: Seventy patients (median age: 14 years, range 5-23) were included in the whole study, 67 received treatment; 27 patients were treated in the dose escalation part, including 10 at the RP2D (8 in cohort 1 and 2 in cohort 2). Both cohorts passed the 1st stage and a total of 24 and 26 patients were recruited to cohort 1 and 2, respectively. Main diagnoses in cohort 1 were sarcoma (n=10), brain tumor (n=9), neuroblastoma (n=4). In cohort 1, 15 of 24 patients were considered enriched based on molecular alteration at relapse (ATM n=6; BRCA1 n=2; DNA signature 3 n=3; FANCD2, CHEK2, FANCA, ATRX all n=1); all patients in cohort 2 had presence of a ES fusion (ESWR1::FLI1 n=22; EWSR1::ERG n=4). Median number of treatment cycles were 2, range 1;51 in cohort 1 and 1;32+ in cohort 2. In cohort 1, 3 patients had a partial response (PR) (pinealoblastoma, neuroblastoma, choroid plexus carcinoma; treated with 12, 51, 25 cycles), 1 patient an unconfirmed PR (rhabdomyosarcoma, 6 cycles) and 7 patients stable disease (SD) (2 prolonged with 6 and 8 cycles). In cohort 2, 1 patient had a complete response (10 cycles) and 1 a PR (32+ cycles), 7 patients had SD (3 prolonged with 6, 10, 16 cycles). Molecular enrichment did not predict response. Retrospective correlative analysis of the molecular profiling data and tumor tissue expression analysis are ongoing to identify predictive biomarkers for PARPi combination trials and data will be presented. Conclusions: Encouraging clinical benefit was observed with the protracted ola-iri schedule in a subset of patients. Current molecular hypothesis is insufficient for patient selection and better biomarkers are needed. Citation Format: Susanne A. Gatz, Pablo Berlanga, Baptiste Archambaud, Yassine Bouchoucha, Nicolas André, Nadege Corradini, Windy Rondof, Jonathan Rubino, Souad Nebchi, Antonin Marchais, Estelle Thebaud, Alba Rubio San Simón, Natasha K. van Eijkelenburg, Lynley V. Marshall, Anne-Sophie Defachelles, Adela Canyete, Stephane Ducassou, Guy Makin, Michela Casanova, Emilie De Carli, Arnaud Petit, Gwenael Le Teuff, Xavier Paoletti, Peter G. Mortimer, Gilles Vassal, Birgit Geoerger. Phase I/II study of the PARP inhibitor olaparib in combination with irinotecan in children with advanced malignancies: arm D of the AcSé-ESMART trial [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 2 (Clinical Trials and Late-Breaking Research); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(8_Suppl):Abstract nr CT088.

Purpose: Ceralasertib is a potent and selective oral inhibitor of the serine/threonine protein kinase ataxia telangiectasia and Rad3-related (ATR) protein. Patients and Methods: Eligible patients with solid tumors, enriched for melanoma, received ceralasertib in combination with a fixed dose of paclitaxel (80 mg/m2 on D1, D8, D15) in 28-day cycles. The dose of ceralasertib was escalated to reach an MTD in a rolling 6 design. The starting dose of ceralasertib was 40 mg QD. Fifty-seven patients (33 patients with melanoma who failed prior PD1/L1 treatment) were enrolled in 7 dose cohorts ranging from 40 mg QD to 240 mg BD plus weekly paclitaxel. Results: The RP2D was established as ceralasertib 240 mg BD days 1–14 plus paclitaxel 80 mg/m2 on D1, D8, D15 every 28 days. The most common toxicities were neutropenia (n = 39, 68%), anemia (n = 25, 44%), and thrombocytopenia (n = 21, 37%). In the full analysis set of 57 patients, the overall response rate (ORR) was 22.6% (95% CI, 12.5–35.3). In 33 patients with melanoma, resistant to prior anti-PD1 therapy, the ORR was 33.3% (95% CI, 18.0–51.8). In the melanoma subset, the mPFS was 3.6 months (95% CI, 2.0–5.8), the median duration of response was 9.9 months (95% CI, 3.7–23.2), and the mOS was 7.4 months (95% CI, 5.7–11.9). Conclusions: Ceralasertib in combination with paclitaxel was well tolerated in patients with advanced malignancies and showed evidence of antitumor activity. Durable responses were observed in patients with advanced cutaneous, acral, and mucosal melanoma resistant to anti-PD1/L1 treatment. See related commentary by Ashworth, p. 4667

The VIKTORY (targeted agent eValuation In gastric cancer basket KORea) trial was designed to classify patients with metastatic gastric cancer based on clinical sequencing and focused on eight different biomarker groups (RAS aberration, TP53 mutation, PIK3CA mutation/amplification, MET amplification, MET overexpression, all negative, TSC2 deficient, or RICTOR amplification) to assign patients to one of the 10 associated clinical trials in second-line (2L) treatment. Capivasertib (AKT inhibitor), savolitinib (MET inhibitor), selumetinib (MEK inhibitor), adavosertib (WEE1 inhibitor), and vistusertib (TORC inhibitor) were tested with or without chemotherapy. Seven hundred seventy-two patients with gastric cancer were enrolled, and sequencing was successfully achieved in 715 patients (92.6%). When molecular screening was linked to seamless immediate access to parallel matched trials, 14.7% of patients received biomarker-assigned drug treatment. The biomarker-assigned treatment cohort had encouraging response rates and survival when compared with conventional 2L chemotherapy. Circulating tumor (ctDNA) analysis demonstrated good correlation between high MET copy number by ctDNA and response to savolitinib. Significance: Prospective clinical sequencing revealed that baseline heterogeneity between tumor samples from different patients affected response to biomarker-selected therapies. VIKTORY is the first and largest platform study in gastric cancer and supports both the feasibility of tumor profiling and its clinical utility. This article is highlighted in the In This Issue feature, p. 1325

Introduction: Olaparib is a PARP inhibitor (PARPi) that provides significant clinical benefit in several BRCA-mutant cancers, including ovarian, breast, pancreas and prostate. The benefit is reduced considerably in patients with multiple prior lines of therapy and olaparib resistance has no specific treatment. PARP inhibition results in replication stress (RS) due to unrepaired single strand DNA breaks (SSB) and PARP trapping in BRCA- and other HR repair-deficient tumors. ATR has critical roles in the cellular response to SSB and RS. This makes ATR inhibitors an attractive partner with olaparib, since ATR inhibition has the potential to reverse the two major mechanisms of PARP inhibitor resistance, including restored HR or stabilization of stalled replication forks. The OLAPCO trial (NCT02576444 clinicaltrials.gov) investigated. the combination of olaparib and AZD6738, an inhibitor of ATR, in relapsed, refractory cancer patients with tumors harboring HR repair mutations and in patients with BRCA-mutated PARPi pre-treated/resistant high-grade serous ovarian cancer (HGSOC). Methods: Patients with treatment-refractory, relapsed cancer were enrolled at 4 participating centers. Germline and somatic mutations had to be deleterious by COSMIC or ClinVar for eligibility. Performance status and organ function requirements were standard for early phase trials. Olaparib was given at 300 mg bid daily and AZD6738 at 160 mg daily days 1-7 in a 28-day cycle. Patients were treated until progression. Objective response was assessed by RECIST1.1 and toxicity was assessed by CTCAE4.0. Endpoints were confirmed complete [CR] or partial [PR] response rate and clinical benefit (CB) rate (response [PR] and stable disease [SD] for > 16 weeks). Results: We enrolled 24 patients; 17 (71%) females; median age 59 (36-78) years. Patients were heavily pretreated, with a median of 4 (0-10) prior regimens. Myelosuppression, especially anemia and thrombocytopenia, was the most frequent toxicity but no patient required discontinuation. Two patients required olaparib reductions for anemia. At the time of data cut-off, 20 patients are evaluable for response assessment. One of 5 patients with ATM mutations had a CR, 2 patients have CB ongoing at 12+ months. Of 7 patients with HGSOC resistant to platinum and PARP inhibitors (1-3 prior agents), 1 achieved a PR ( -90%), 3 had a best response of SD with regression < 30% (1 ongoing at 1 year) and 3 patients had progression (PD) as best response (Table 1). No other mutation or cancer type demonstrated objective response. Conclusions: The combination of olaparib and the ATR inhibitor AZD6738 demonstrated preliminary activity in patients with tumors harboring ATM mutations and in PARPi-resistant BRCA1/2-mutated HGSOC. Activity in ATM loss with an ATR inhibitor is consistent with the expected synthetic lethality of these interwoven DNA repair pathways. The encouraging data in HGSOC patients who have already progressed on a PARP inhibitor warrants additional study to further define the potential of this regimen to reverse PARPi resistance in BRCA-mutated HGSOC and other relevant solid tumors. The durability of responses in both groups (4 >1 year) is promising. Table 1MutationATMBRCA prostate pancreasBRCA Prior PARPi HGSOCCHEK2MUS81PALB2IDH and SDHD #5471142 CR1 PR0 1 SD > 4 mos213 11 PD 33112 Inevaluable110 11 Citation Format: Joseph Paul Eder, Davendra Sohal, Haider Mahdi, Khanh Do, Vicki Keedy, Navid Hafez, Deborah Doroshow, Manuel Avedissian, Peter Mortimer, Colin Glover, Patricia LoRusso, Juliane M Juergensmeier, Geoffrey I Shapiro. Olaparib and the ATR inhibitor AZD6738 in relapsed, refractory cancer patients with homologous recombination (HR) repair mutations – OLAPCO [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr A080. doi:10.1158/1535-7163.TARG-19-A080