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Analysis of GDC-0941 effects on cell proliferation ; Supplemental Figure 2 Legend

PDF file - 45K, Summary of adverse events suspected to be study-drug related by grade (safety set).

Purpose: Aurora A kinase (AAK) is a key regulator of mitosis and a target for anticancer drug development. This phase I study investigated the safety, pharmacokinetics, and pharmacodynamics of MLN8237 (alisertib), an investigational, oral, selective AAK inhibitor, in 59 adults with advanced solid tumors.Experimental Design: Patients received MLN8237 once daily or twice daily for 7, 14, or 21 consecutive days, followed by 14 days recovery, in 21-, 28-, or 35-day cycles. Dose-limiting toxicities (DLT) and the maximum-tolerated dose (MTD) for the 7- and 21-day schedules were determined. Pharmacokinetic parameters were derived from plasma concentration–time profiles. AAK inhibition in skin and tumor biopsies was evaluated and antitumor activity assessed.Results: Neutropenia and stomatitis were the most common DLTs. The MTD for the 7- and 21-day schedules was 50 mg twice daily and 50 mg once daily, respectively. MLN8237 absorption was fast (median time to maximum concentration, 2 hours). Mean terminal half-life was approximately 19 hours. At steady state, pharmacodynamic effects were shown by accumulation of mitotic and apoptotic cells in skin, and exposure-related increases in numbers of mitotic cells with characteristic spindle and chromosomal abnormalities in tumor specimens, supporting AAK inhibition by MLN8237. Stable disease was observed and was durable with repeat treatment cycles, administered over 6 months, in 6 patients, without notable cumulative toxicity.Conclusions: The recommended phase II dose of MLN8237 is 50 mg twice daily on the 7-day schedule, which is being evaluated further in a variety of malignancies, including in a phase III trial in peripheral T-cell lymphoma. Clin Cancer Res; 18(17); 4764–74. ©2012 AACR.

Forest plots for the test of association between changes between baseline and week 2 in ctDNA detection, tested either by taking differences for continuous variables or by taking subgroups of patients who had detectable ctDNA at baseline or not, and (A) pathological complete response (pCR) or (B) event-free survival. All tests are corrected for clinic-pathological characteristics. ctDNA: circulating tumor DNA; VAF: variant allele fraction; OR: odds ratio, HR: hazard ratio; Ci: confidence interval, p: p value.

Purpose:In the neoadjuvant treatment (NAT) setting, dual HER2-targeted therapy is associated with increased pathologic complete response (pCR) rates compared with each therapy alone. Biomarkers allowing to predict treatment response during NAT are needed. We aim to evaluate whether circulating tumor DNA (ctDNA) is associated with response to anti-HER2–targeted therapy.Experimental Design:Plasma DNA collected before NAT, at week 2, and before surgery from patients enrolled in the NeoALTTO trial was assessed using digital PCR for PIK3CA and TP53 mutation detection.Results:A total of 69 of 455 (15.2%) patients had a PIK3CA and/or TP53 mutation detected in the baseline tumor sample and evaluable ctDNA results from baseline samples. CtDNA was detected in 41%, 20%, and 5% patients before NAT, at week 2, and before surgery, respectively. ctDNA detection before NAT was significantly associated with older age and ER-negative status. ctDNA detection before NAT was associated with decreased odds of achieving pCR (OR = 0.15; 95% CI, 0.034–0.7; P = 0.0089), but not with event-free survival (EFS). Analyses for EFS were underpowered. Interestingly, the patients with HER2-enriched subtype tumors and undetectable ctDNA at baseline had the highest pCR rates. In contrast, patients with persistent ctDNA detection at baseline and week 2 had the lowest rate of pCR.Conclusions:ctDNA detection before neoadjuvant anti-HER2 therapies is associated with decreased pCR rates. Interestingly, patients with HER2-enriched tumors and undetectable ctDNA at baseline had the highest pCR rates, therefore appearing as the best candidates for treatment deescalation strategies.

PDF file - 1641K, Effect of SAR245408 on plasma fasting insulin and glucose.

Supplemental tables, figures, and methods

Purpose: SAR245408 is a pan-class I phosphoinositide 3-kinase (PI3K) inhibitor. This phase I study determined the maximum tolerated dose (MTD) of two dosing schedules [first 21 days of a 28-day period (21/7) and continuous once-daily dosing (CDD)], pharmacokinetic and pharmacodynamic profiles, and preliminary efficacy.Experimental Design: Patients with refractory advanced solid malignancies were treated with SAR245408 using a 3 + 3 design. Pharmacokinetic parameters were determined after single and repeated doses. Pharmacodynamic effects were evaluated in plasma, hair sheath cells, and skin and tumor biopsies.Results: Sixty-nine patients were enrolled. The MTD of both schedules was 600 mg; dose-limiting toxicities were maculopapular rash and hypersensitivity reaction. The most frequent drug-related adverse events included dermatologic toxicities, diarrhea, nausea, and decreased appetite. Plasma pharmacokinetics showed a median time to maximum concentration of 8 to 22 hours, mean terminal elimination half-life of 70 to 88 hours, and 5- to 13-fold accumulation after daily dosing (first cycle). Steady-state concentration was reached between days 15 and 21, and exposure was dose-proportional with doses up to 400 mg. SAR245408 inhibited the PI3K pathway (∼40%–80% reduction in phosphorylation of AKT, PRAS40, 4EBP1, and S6 in tumor and surrogate tissues) and, unexpectedly, also inhibited the MEK/ERK pathway. A partial response was seen in one patient with advanced non–small cell lung cancer. Eight patients were progression-free at 6 months. Pharmacodynamic and clinical activity were observed irrespective of tumor PI3K pathway molecular alterations.Conclusions: SAR245408 was tolerable at doses associated with PI3K pathway inhibition. The recommended phase II dose of the capsule formulation is 600 mg administered orally with CDD. Clin Cancer Res; 20(1); 233–45. ©2013 AACR.

PDF file, 92K, Supplementary Table S1. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 7-day schedule. Supplementary Table S2. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 14-day schedule. Supplementary Table S3. Summary of pharmacokinetic parameters for MLN8237 once-daily dosing on the 21-day schedule. Supplementary Table S4. Summary of pharmacokinetic parameters for MLN8237 twice-daily dosing on the 7-day schedule.

Supplemental File 1. Excel file with additional details on the mathematical model.

PDF file, 2004K, Figure S2. Changes in skin mitotic index on days 7, 14 and 21.

PDF file - 45KB, Ficlatuzumab Study P05670. Summary of Pharmacodynamic Markers.

PDF file - 73K, Safety of SAR245408.

BRAF V600E colorectal cancers are insensitive to RAF inhibitor monotherapy due to feedback reactivation of receptor tyrosine kinase signaling. Combined RAF and EGFR inhibition exerts a therapeutic effect, but resistance invariably develops through undefined mechanisms. In this study, we determined that colorectal cancer progression specimens invariably harbored lesions in elements of the RAS–RAF–MEK–ERK pathway. Genetic amplification of wild-type RAS was a recurrent mechanism of resistance in colorectal cancer patients that was not seen in similarly resistant melanomas. We show that wild-type RAS amplification increases receptor tyrosine kinase-dependent activation of RAS more potently in colorectal cancer than in melanoma and causes resistance only in the former. Currently approved RAF inhibitors inhibit RAF monomers but not dimers. All the drug-resistant lesions we identified activate BRAF V600E dimerization directly or by elevating RAS-GTP. Overall, our results show that mechanisms of resistance converge on formation of RAF dimers and that inhibiting EGFR and RAF dimers can effectively suppress ERK-driven growth of resistant colorectal cancer. Cancer Res; 77(23); 6513–23. ©2017 AACR.

PDF file - 97K, Reduction in glioma-associated oncogene homolog 1 in patients with available tumor and matching skin specimens.

PDF file - 96K, Reduction in PI3K pathway signaling in serial tumor biopsies.

Supplementary Figures 1-5: Supplementary Figure 1 - validation and characterization of acquired genomic alterations, Supplementary Figure 2 - RAS amplification leads to increased RAS-GTP and dimerization of RAF, Supplementary Figure 3 - Increase in NRAS expression is sufficient to cause resistance to RAF/EGFR inhibition in vitro in CRC, Supplementary Figure 4 - Increase in NRAS expression does not cause resistance to RAF inhibition in melanoma, Supplementary Figure 5 - Combined EGFR and RAF dimer inhibitors lead to better inhibition of signaling and tumor growth than RAF dimer inhibitor alone in BRAF V600E CRC.

PDF file - 6224K, Inhibition of MEK-ERK pathway signaling in tumor biopsies.

PDF file - 29K, Chemical structures of sonidegib and cyclopamine.

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PDF file - 91K, Anti-tumor activity in patients receiving treatment more than 16 weeks.

Assessment of cell proliferation upon inhibition of p110α ; Supplemental Figure 5 Legend

PDF file - 67K, Bayesian logistic regression model: dose-response curve and model inference results at the time of determination of the recommended Phase II dose.

Survival curves upon genetic inactivation of individual p110s ; Supplemental Figure 3 Legend

PDF file - 65K, Criteria for defining dose-limiting toxicities.

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PDF file, 1749K, Figure S4. Changes in tumor mitotic index on days 1, 7, and 21.

PDF file, 2119K, Figure S5. Changes in chromosome alignment and spindle bipolarity on days 1 and 21.

Purpose: Phosphoinositide 3-kinase (PI3K)/AKT/mTOR pathway activation in patients with HER2-positive (HER2+) breast cancer has been implicated in de novo and acquired trastuzumab resistance. The purpose of this study was to determine the clinical activity of the PI3K inhibitor buparlisib (BKM120) in patients with HER2+ advanced/metastatic breast cancer resistant to trastuzumab-based therapy.Experimental Design: In the dose-escalation portion of this phase I/II study, patients with trastuzumab-resistant locally advanced or metastatic HER2+ breast cancer were treated with daily oral doses of buparlisib and weekly intravenous trastuzumab (2 mg/kg). Dose escalation was guided by a Bayesian logistic regression model with overdose control.Results: Of 18 enrolled patients, 17 received buparlisib. One dose-limiting toxicity of grade 3 general weakness was reported at the 100-mg/day dose level (the single-agent maximum tolerated dose) and this dose level was declared the recommended phase II dose (RP2D) of buparlisib in combination with trastuzumab. Common (>25%) adverse events included rash (39%), hyperglycemia (33%), and diarrhea (28%). The pharmacokinetic profile of buparlisib was not affected by its combination with trastuzumab. At the RP2D, there were two (17%) partial responses, 7 (58%) patients had stable disease (≥6 weeks), and the disease control rate was 75%. Pharmacodynamic studies showed inhibition of the PI3K/AKT/mTOR and RAS/MEK/ERK pathways.Conclusions: In this patient population, the combination of buparlisib and trastuzumab was well tolerated, and preliminary signs of clinical activity were observed. The phase II portion of this study will further explore the safety and efficacy of this combination at the RP2D. Clin Cancer Res; 20(7); 1935–45. ©2014 AACR.

PDF file - 458K, Individual and mean SAR245408 pharmacokinetic parameters.

PDF file - 71K, Supplementary data includes a table summarizing cohort enrollment and dose-limiting toxicities (Table S1) and a table showing the association between tumor response and Hh pathway activity in medulloblastoma and basal cell carcinoma (Table S2).

PDF file, 2001K, Figure S3. Changes in skin apoptotic index on days 7, 14 and 21.

Supplementary Tables

Supplementary materials and methods

Supplemental File 2. Excel file with the cbioportal data the genomic data analysis is based on.

PDF file - 79K, Mean sonidegib plasma concentration-time profiles after single oral administration on day 1 of the pharmacokinetic run-in period before initiation of continuous dosing.

Analysis of PTEN expression in PanNETs ; Supplemental Figure 1 Legend

PDF file - 38K, Patient disposition (full analysis set).

Purpose: This phase I trial was undertaken to determine the maximum tolerated dose (MTD), dose-limiting toxicities (DLT), safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary antitumor activity of the novel smoothened inhibitor sonidegib (LDE225), a potent inhibitor of hedgehog signaling, in patients with advanced solid tumors.Experimental Design: Oral sonidegib was administered to 103 patients with advanced solid tumors, including medulloblastoma and basal cell carcinoma (BCC), at doses ranging from 100 to 3,000 mg daily and 250 to 750 mg twice daily, continuously, with a single-dose pharmacokinetics run-in period. Dose escalations were guided by a Bayesian logistic regression model. Safety, tolerability, efficacy, pharmacokinetics, and biomarkers in skin and tumor biopsies were assessed.Results: The MTDs of sonidegib were 800 mg daily and 250 mg twice daily. The main DLT of reversible grade 3/4 elevated serum creatine kinase (18% of patients) was observed at doses ≥ the MTD in an exposure-dependent manner. Common grade 1/2 adverse events included muscle spasm, myalgia, gastrointestinal toxicities, increased liver enzymes, fatigue, dysgeusia, and alopecia. Sonidegib exposure increased dose proportionally up to 400 mg daily, and displayed nonlinear pharmacokinetics at higher doses. Sonidegib exhibited exposure-dependent reduction in GLI1 mRNA expression. Tumor responses observed in patients with medulloblastoma and BCC were associated with evidence of hedgehog pathway activation.Conclusions: Sonidegib has an acceptable safety profile in patients with advanced solid tumors and exhibits antitumor activity in advanced BCC and relapsed medulloblastoma, both of which are strongly associated with activated hedgehog pathway, as determined by gene expression. Clin Cancer Res; 20(7); 1900–9. ©2014 AACR.

This file contains information about protein immunoblotting, histopathological analysis, and cell biological assays in cultured cells.

PDF file - 48K, Exposure to buparlisib and trastuzumab (safety set).

PDF file - 57KB, Ficlatuzumab Study P05670. Supplementary Methods for Immunohistochemistry of Tumor Samples.

Purpose:To investigate tolerability, efficacy, and pharmacokinetics/pharmacodynamics of Debio 1347, a selective FGFR inhibitor.Patients and Methods:This was a first-in-human, multicenter, open-label study in patients with advanced solid tumors harboring FGFR1–3 gene alterations. Eligible patients received oral Debio 1347 at escalating doses once daily until disease progression or intolerable toxicity. Dose-limiting toxicities (DLT) were evaluated during the first 4 weeks on treatment, pharmacokinetics/pharmacodynamics postfirst dose and after 4 weeks.Results:A total of 71 patients were screened and 58 treated with Debio 1347 at doses from 10 to 150 mg/day. Predominant tumor types were breast and biliary duct cancer, most common gene alterations were FGFR1 amplifications (40%) and mutations in FGFR2 (12%) and FGFR3 (17%); 12 patients (21%) showed FGFR fusions. Five patients at three dose levels had six DLTs (dry mouth/eyes, hyperamylasemia, hypercalcemia, hyperbilirubinemia, hyperphosphatemia, and stomatitis). The maximum tolerated dose was not reached, but dermatologic toxicity became sometimes dose limiting beyond the DLT period at ≥80 mg/day. Adverse events required dose modifications in 52% of patients, mostly due to dose-dependent, asymptomatic hyperphosphatemia (22%). RECIST responses were seen across tumor types and mechanisms of FGFR activation. Six patients, 3 with FGFR fusions, demonstrated partial responses, 10 additional patients' tumor size regressions of ≤30%. Plasma half-life was 11.5 hours. Serum phosphate increased with Debio 1347 plasma levels and confirmed target engagement at doses ≥60 mg/day.Conclusions:Preliminary efficacy was encouraging and tolerability acceptable up to 80 mg/day, which is now used in an extension part of the study.

PDF file - 62K, Summary of buparlisib pharmacokinetic parameters.

PDF file - 624K, Relationship between sonidegib area under the plasma concentration-time curve on day 15 and the incidence of grade 3/4 creatine kinase elevation.

Legend for Supplementary Figure 1