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Purpose: Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer. Patients and Methods: This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics. Results: During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity. Conclusions: AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

Gemcitabina; Cáncer avanzado Gemcitabina; Càncer avançat Gemcitabine; Advanced cancer Purpose: This was a Phase I/II trial of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737 given in combination with gemcitabine. Its objectives were to establish the safety profile, recommended Phase 2 dose (RP2D), pharmacokinetics profile, and clinical activity of SRA737. Patients and Methods: Patients with advanced solid tumors were enrolled into dose-escalation cohorts and treated in 28-day cycles with oral SRA737 on days 2, 3, 9, 10, 16, and 17, and intravenous gemcitabine on days 1, 8, and 15. Treatment was continued until progression. Each expansion cohort included up to 20 patients with specific genetically defined tumors. Results: The RP2D was determined to be 500 mg SRA737 combined with low-dose (250 mg/m2) gemcitabine. Of 143 enrolled patients, 77 were treated at doses of at least 500 mg SRA737 combined with 250 mg/m2 gemcitabine. Common toxicities of nausea, vomiting, fatigue, and diarrhea were primarily mild to moderate, and rarely led to treatment discontinuation. Anemia, neutropenia, and thrombocytopenia were grade ≥3 in 11.7%, 16.7%, and 10% of patients treated at the RP2D, respectively. The objective response rate (ORR) was 10.8% overall and notably the ORR in anogenital cancer was 25%. Partial tumor responses were observed in anogenital cancer, cervical cancer, high-grade serous ovarian cancer, rectal cancer, and small cell lung cancer. Conclusions: SRA737 in combination with low-dose gemcitabine was well tolerated with lower myelotoxicity than has been seen at standard doses of gemcitabine or with other combinations of Chk1 inhibitors with gemcitabine. Tumor responses were observed in anogenital and other solid tumors. The trial was sponsored by Sierra Oncology, Inc. Medical writing support was provided by Tina Ippolito, an independent consultant funded by Sierra Oncology. Andrew Dye, an employee of Sierra Oncology, also provided medical writing support and data curation. Bryan Strouse, an employee of Sierra Oncology, also contributed to data curation for this report. UK clinical trial sites acknowledge infrastructural funding from the Experimental Cancer Medical Center and National Institute of Health and Care Research Biomedical Research Centers. The ICR/RMH in addition acknowledges Cancer Research UK funding to Cancer Centre Funding and funding to the Cancer Therapeutics Unit. U. Banerji is a recipient of the NIHR RP-2016–07–028. The publication costs of this article were defrayed in part by the payment of publication fees. Therefore, and solely to indicate this fact, this article is hereby marked “advertisement” in accordance with 18 USC section 1734.

Purpose: CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR–overexpressing tumors. Patients and Methods: A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1–6 mg/m2 weekly and 2–12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts. Results: 109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR. Conclusions: The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

Background This was a first-in-human Phase 1/2 open-label dose-escalation study of the novel checkpoint kinase 1 (Chk1) inhibitor SRA737. Methods Patients with advanced solid tumours enrolled in dose-escalation cohorts and received SRA737 monotherapy orally on a continuous daily (QD) dosing schedule in 28-day cycles. Expansion cohorts included up to 20 patients with prospectively selected, pre-specified response predictive biomarkers. Results In total, 107 patients were treated at dose levels from 20–1300 mg. The maximum tolerated dose (MTD) of SRA737 was 1000 mg QD, the recommended Phase 2 dose (RP2D) was 800 mg QD. Common toxicities of diarrhoea, nausea and vomiting were generally mild to moderate. Dose-limiting toxicity at daily doses of 1000 and 1300 mg QD SRA737 included gastrointestinal events, neutropenia and thrombocytopenia. Pharmacokinetic analysis at the 800 mg QD dose showed a mean Cmin of 312 ng/mL (546 nM), exceeding levels required to cause growth delay in xenograft models. No partial or complete responses were seen. Conclusions SRA737 was well tolerated at doses that achieved preclinically relevant drug concentrations but single agent activity did not warrant further development as monotherapy. Given its mechanism of action resulting in abrogating DNA damage repair, further clinical development of SRA737 should be as combination therapy. Clinical trial registration Clinicaltrials.gov NCT02797964.

Purpose:Inhibition of monocarboxylate transporter (MCT) 1–mediated lactate transport may have cytostatic and/or cytotoxic effects on tumor cells. We report results from the dose-escalation part of a first-in-human trial of AZD3965, a first-in-class MCT1 inhibitor, in advanced cancer.Patients and Methods:This multicentre, phase I, dose-escalation and dose-expansion trial enrolled patients with advanced solid tumors or lymphoma and no standard therapy options. Exclusion criteria included history of retinal and/or cardiac disease, due to MCT1 expression in the eye and heart. Patients received daily oral AZD3965 according to a 3+3 then rolling six design. Primary objectives were to assess safety and determine the MTD and/or recommended phase II dose (RP2D). Secondary objectives for dose escalation included measurement of pharmacokinetic and pharmacodynamic activity. Exploratory biomarkers included tumor expression of MCT1 and MCT4, functional imaging of biological impact, and metabolomics.Results:During dose escalation, 40 patients received AZD3965 at 5–30 mg once daily or 10 or 15 mg twice daily. Treatment-emergent adverse events were primarily grade 1 and/or 2, most commonly electroretinogram changes (retinopathy), fatigue, anorexia, and constipation. Seven patients receiving ≥20 mg daily experienced dose-limiting toxicities (DLT): grade 3 cardiac troponin rise (n = 1), asymptomatic ocular DLTs (n = 5), and grade 3 acidosis (n = 1). Plasma pharmacokinetics demonstrated attainment of target concentrations; pharmacodynamic measurements indicated on-target activity.Conclusions:AZD3965 is tolerated at doses that produce target engagement. DLTs were on-target and primarily dose-dependent, asymptomatic, reversible ocular changes. An RP2D of 10 mg twice daily was established for use in dose expansion in cancers that generally express high MCT1/low MCT4).

Table S1: KRAS mutations in colorectal, lung and pancreatic cell lines. Table S2: Assay variability. Table S3: Significant changes in phosphoproteins seen in more than 50% of cell lines. Table S4: The GI50 concentrations of the two pan-PI3K inhibitors pictilisib and buparlisib used in validation experiments in Figure 4B.

Figure S1. KRAS-dependency and effect of Cas9 expression on response to PI3K inhibition. Figure S2. Whole-genome CRISPR screen shows good replicate correlation and identifies enhancers and suppressors of GDC0941 antiproliferative activity. Figure S3. Expression of Cas9 does not alter response to BYL719 or GDC0941. Figure S4. Population doublings, replicate correlation and alternative analysis of the minipool screen. Figure S5. PI3K signalling is reduced following serum starvation. Figure S6. Combined inhibition of PI3K and mTOR results in potent antiproliferative activity in pancreatic cancer cell lines. Figure S7. Combined p110� and mTOR or ERBB-family inhibition leads to sustained suppression of S6 phosphorylation. Figure S8. CRISPR and drug combination screens implicate the ERBB-PI3K-MTOR signalling axis as a key vulnerability of pancreatic cancer cells.

Preclinical studies have demonstrated synergy between PARP and PI3K/AKT pathway inhibitors in BRCA1 and BRCA2 (BRCA1/2)–deficient and BRCA1/2-proficient tumors. We conducted an investigator-initiated phase I trial utilizing a prospective intrapatient dose- escalation design to assess two schedules of capivasertib (AKT inhibitor) with olaparib (PARP inhibitor) in 64 patients with advanced solid tumors. Dose expansions enrolled germline BRCA1/2-mutant tumors, or BRCA1/2 wild-type cancers harboring somatic DNA damage response (DDR) or PI3K–AKT pathway alterations. The combination was well tolerated. Recommended phase II doses for the two schedules were: olaparib 300 mg twice a day with either capivasertib 400 mg twice a day 4 days on, 3 days off, or capivasertib 640 mg twice a day 2 days on, 5 days off. Pharmacokinetics were dose proportional. Pharmacodynamic studies confirmed phosphorylated (p) GSK3β suppression, increased pERK, and decreased BRCA1 expression. Twenty-five (44.6%) of 56 evaluable patients achieved clinical benefit (RECIST complete response/partial response or stable disease ≥ 4 months), including patients with tumors harboring germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without DDR and PI3K–AKT pathway alterations.Significance:In the first trial to combine PARP and AKT inhibitors, a prospective intrapatient dose- escalation design demonstrated safety, tolerability, and pharmacokinetic–pharmacodynamic activity and assessed predictive biomarkers of response/resistance. Antitumor activity was observed in patients harboring tumors with germline BRCA1/2 mutations and BRCA1/2 wild-type cancers with or without somatic DDR and/or PI3K–AKT pathway alterations.This article is highlighted in the In This Issue feature, p. 1426

Supplementary Tables 1-7; Supplementary Figures 1-2; Supplementary Methods

Through the use of an unbiased, genome-scale CRISPR modifier screen, we identified NF1 suppression as a mechanism of resistance to EGFR inhibition in NRAS/KRAS/BRAFV600-wild-type colorectal cancer cells. Reduced NF1 expression permitted sustained signaling through the MAPK pathway to promote cell proliferation in the presence of EGFR inhibition. Targeting of MEK in combination with EGFR inhibition leads to synergistic antiproliferative activity. Human KRAS/NRAS/BRAFV600-wild-type colorectal cancer cell lines with NF1 mutations displayed reduced NF1 mRNA or protein expression and were resistant to EGFR blockade by gefitinib or cetuximab. Cooccurring loss-of-function mutations in PTEN were associated with resistance to dual EGFR/MEK inhibition but cotreatment with a PI3K inhibitor further suppressed proliferation. Loss of NF1 may be a useful biomarker to identify patients that are less likely to benefit from single-agent anti-EGFR therapy in colorectal cancer and may direct potential combination strategies.Implications:This study suggests that further clinical validation of NF1 status as predictor of response to anti-EGFR targeting antibodies in patients with colorectal cancer with KRAS/NRAS/BRAFV600-wild-type tumors is warranted.

PDF file, 47KB, Reproducibility of immunomagnetic separation and ELISA.

Figure S3. Representation of sgRNAs targeting the 2nd, 3rd and 4th-ranked genes across the CRISPR screening arms.

Table S2. Details of sgRNAs used in this study.

PDF file, 80KB, Experiments detailing the validation of immunomagnetic separation and ELISA.

PDF file, 63KB.

PDF file, 66KB, Oncogenes and mutations detected using the OncoCarta Panel v1.0.

Supplementary Table from Individualized Prediction of Drug Response and Rational Combination Therapy in NSCLC Using Artificial Intelligence–Enabled Studies of Acute Phosphoproteomic Changes

PDF file, 63KB, Survival based on signalling output in total population of 88 patients.

Figure S1: Hierarchically clustered heat map of mutations in the cell line panel. Figure S2: Heat map of median-centered CCLE cell line basal mRNA. Figure S3: Changes in pAKTSer473 quantified by ELISA.

PDF file, 71KB, Efficiency of immunomagnetic separation.

Tables S1-S26. Includes details of antibodies, shRNAs and sgRNAs used in this study. CRISPR and drug screening data.

Cell lines, culture medium, drug concentrations, cell culture, methods for producing Figure 1

PDF file, 44KB, Probes for PIK3CA, AKT2 and PTEN.

We hypothesize that the study of acute protein perturbation in signal transduction by targeted anticancer drugs can predict drug sensitivity of these agents used as single agents and rational combination therapy. We assayed dynamic changes in 52 phosphoproteins caused by an acute exposure (1 hour) to clinically relevant concentrations of seven targeted anticancer drugs in 35 non–small cell lung cancer (NSCLC) cell lines and 16 samples of NSCLC cells isolated from pleural effusions. We studied drug sensitivities across 35 cell lines and synergy of combinations of all drugs in six cell lines (252 combinations). We developed orthogonal machine-learning approaches to predict drug response and rational combination therapy. Our methods predicted the most and least sensitive quartiles of drug sensitivity with an AUC of 0.79 and 0.78, respectively, whereas predictions based on mutations in three genes commonly known to predict response to the drug studied, for example, EGFR, PIK3CA, and KRAS, did not predict sensitivity (AUC of 0.5 across all quartiles). The machine-learning predictions of combinations that were compared with experimentally generated data showed a bias to the highest quartile of Bliss synergy scores (P = 0.0243). We confirmed feasibility of running such assays on 16 patient samples of freshly isolated NSCLC cells from pleural effusions. We have provided proof of concept for novel methods of using acute ex vivo exposure of cancer cells to targeted anticancer drugs to predict response as single agents or combinations. These approaches could complement current approaches using gene mutations/amplifications/rearrangements as biomarkers and demonstrate the utility of proteomics data to inform treatment selection in the clinic.

Time of day variation in metabolites in healthy volunteers and in patients treated with the MEK inhibitor.

Supplementary Note

Supplementary Figure from A Phase I Trial of CT900, a Novel α-Folate Receptor–Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer

Supplementary Table from A Phase I Trial of CT900, a Novel α-Folate Receptor–Mediated Thymidylate Synthase Inhibitor, in Patients with Solid Tumors with Expansion Cohorts in Patients with High-Grade Serous Ovarian Cancer

supplementary data: Methods, tables, figure.

Purpose:CT900 is a novel small molecule thymidylate synthase inhibitor that binds to α-folate receptor (α-FR) and thus is selectively taken up by α-FR–overexpressing tumors.Patients and Methods:A 3+3 dose escalation design was used. During dose escalation, CT900 doses of 1–6 mg/m2 weekly and 2–12 mg/m2 every 2 weeks (q2Wk) intravenously were evaluated. Patients with high-grade serous ovarian cancer were enrolled in the expansion cohorts.Results:109 patients were enrolled: 42 patients in the dose escalation and 67 patients in the expansion cohorts. At the dose/schedule of 12 mg/m2/q2Wk (with and without dexamethasone, n = 40), the most common treatment-related adverse events were fatigue, nausea, diarrhea, cough, anemia, and pneumonitis, which were predominantly grade 1 and grade 2. Levels of CT900 more than 600 nmol/L needed for growth inhibition in preclinical models were achieved for >65 hours at a dose of 12 mg/m2. In the expansion cohorts, the overall response rate (ORR), was 14/64 (21.9%). Thirty-eight response-evaluable patients in the expansion cohorts receiving 12 mg/m2/q2Wk had tumor evaluable for quantification of α-FR. Patients with high or medium expression had an objective response rate of 9/25 (36%) compared with 1/13 (7.7%) in patients with negative/very low or low expression of α-FR.Conclusions:The dose of 12 mg/m2/q2Wk was declared the recommended phase II dose/schedule. At this dose/schedule, CT900 exhibited an acceptable side effect profile with clinical benefit in patients with high/medium α-FR expression and warrants further investigation.

PDF file - 42K, CHR-3996

Demographic Profile

Figure S1A. Correlation of patterns of DILD as per ATS/ERS classification and clinical severity. Figure S1B. A higher RMH DILD score predicts for increasing clinical severity of DILD as per CTCAE grading.

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.

PDF file 76K, Demographic characteristics of Patients

Supplementary Figure 1. The arithmetic mean concentration-time profiles for AUY922 and BJP762. Supplementary Table 1. The most common adverse events of AUY922. Supplementary Table 2. Adverse events with CTCAE grades 3 and 4. Supplementary Table 3. The SUVmax of 89Zr-trastuzumab before and during treatment with AUY922. Supplementary Table 4. SUVmax of 89Zr-bevacizumab before and during treatment with AUY922.

Purpose:AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity.Patients and Methods:The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon–Wed–Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3β levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies.Results:Fifty-one patients were treated on study. The safety of 5–300 mg of AT13148 was studied. Further, the doses of 120–180–240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean Cmax and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies.Conclusions:AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer.