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Supplementary Table S1. Patient Demographics and Disease Characteristics. Supplementary Table S2. Treatment-Related Adverse Events of Grade 3 or Higher Observed in either Cycle 1 or Cycle greater than or equal to 2. Supplementary Table S3. Adverse Events in greater than or equal to 10% of Patients Regardless of Attribution. Supplementary Table S4. Adverse Events of Grade 3 or Higher Regardless of Attribution. Supplementary Figure S1. Trellis plot of individual and fitted tumor volumes to day 21 following treatment with taselisib (GDC-0032). Supplementary Figure S2. PI3K pathway suppression was evaluated in KPL-4 tumor xenografts following a single oral dose of 1, 5 and 25 mg/kg taselisib or MCT (0.5% methylcellulose/0.2% Tween-80) vehicle at the time points indicated. Supplementary Figure S3. Schematic showing the decision-making related to selection of recommended dose for future studies. Supplementary Figure S4. Mean plasma concentration vs. time following single dose on day 1 (A) and multiple dose on day 15 (B). Supplementary Figure S5. Duration of treatment of patients treated via PIK3CA mutation status and dose level. Supplementary Figure S6. Antitumor activity observed with taselisib treatment. Supplementary Figure S7. Example of patient with partial response upon taselisib treatment and changes in circulating tumor DNA (ctDNA).

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Purpose:ERK1/2 signaling can be dysregulated in cancer. GDC-0994 is an oral inhibitor of ERK1/2. A first-in-human, phase I dose escalation study of GDC-0994 was conducted in patients with locally advanced or metastatic solid tumors.Patients and Methods:GDC-0994 was administered once daily on a 21-day on/7-day off schedule to evaluate safety, pharmacokinetics, and preliminary signs of efficacy. Patients with pancreatic adenocarcinoma and BRAF-mutant colorectal cancer were enrolled in the expansion stage.Results:Forty-seven patients were enrolled in six successive cohorts (50–800 mg). A single DLT of grade 3 rash occurred at 600 mg. The most common drug-related adverse events (AE) were diarrhea, rash, nausea, fatigue, and vomiting. Pharmacokinetic data showed dose-proportional increases in exposure, with a mean half-life of 23 hours, supportive of once daily dosing. In evaluable paired biopsies, MAPK pathway inhibition ranged from 19% to 51%. Partial metabolic responses by FDG-PET were observed in 11 of 20 patients across dose levels in multiple tumor types. Overall, 15 of 45 (33%) patients had a best overall response of stable disease and 2 patients with BRAF-mutant colorectal cancer had a confirmed partial response.Conclusions:GDC-0994 had an acceptable safety profile and pharmacodynamic effects were observed by FDG-PET and in serial tumor biopsies. Single-agent activity was observed in 2 patients with BRAF-mutant colorectal cancer.

A. PET uptake in the circulation per cohort, as determined by region of interest drawn in left ventricle; cohort 1 (in blue) contained 2 patients (0 mg additional MMOT0530A), cohort 2 (in green) contained 9 patients (10 mg additional MMOT0530A). On X axis the different PET moments: 2, 4 and 7 days post injection. On the Y axis the mean SUVmax per cohort.

Supplemental Figure 1. Suppression of MAPK pathway activation at the RP2D in colorectal cancer and pancreatic cancer patients. GDC-0994 modulates MAPK pathway-regulated gene transcription at the RP2D. Note: there were no partial responses in this group of patients.

Supplemental Figure 2. MAPK pathway signature is specifically inhibited on treatment (A). Differential expression of 11 PROGENy (pathway) scores between pre and post-treatment samples (B). Only MAPK and EGFR scores are statistically significant (rank-sum test).

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Purpose: Mesothelin (MSLN) is frequently overexpressed in pancreatic and ovarian cancers, making it a potential drug target. We performed an 89Zr-PET imaging study with MMOT0530A, a MSLN antibody, in conjunction with a phase I study with the antibody–drug conjugate DMOT4039A, containing MMOT0530A bound to MMAE. The aim was to study antibody tumor uptake, whole-body distribution, and relation between uptake, response to treatment, and MSLN expression.Experimental Design: Before DMOT4039A treatment, patients received 37 MBq 89Zr-MMOT0530A followed by PET/CT imaging 2, 4, and 7 days postinjection. Tracer uptake was expressed as standardized uptake value (SUV). MSLN expression was determined with immunohistochemistry (IHC) on archival tumor tissue.Results: Eleven patients were included, 7 with pancreatic and 4 with ovarian cancer. IHC MSLN expression varied from absent to strong. Suitable tracer antibody dose was 10 mg MMOT0530A and optimal imaging time was 4 and 7 days postinjection. Tumor tracer uptake occurred in 37 lesions with mean SUVmax of 13.1 (±7.5) on PET 4 days postinjection, with 11.5 (±7.5) in (N = 17) pancreatic and 14.5 (±8.7) in (N = 20) ovarian cancer lesions. Within patients, a mean 2.4-fold (±1.10) difference in uptake between tumor lesions existed. Uptake in blood, liver, kidneys, spleen, and intestine reflected normal antibody distribution. Tracer tumor uptake was correlated to IHC. Best response to DMOT4039A was partial response in one patient.Conclusions: With 89Zr-MMOT0530A-PET, pancreatic and ovarian cancer lesions as well as antibody biodistribution could be visualized. This technique can potentially guide individualized antibody-based treatment. Clin Cancer Res; 22(7); 1642–52. ©2015 AACR.

The cannabinoid type-1 (CB1) receptor is one of the most abundant G-coupled protein receptors in the human body and is responsible for signal transduction of both endogenous and exogenous cannabinoids. The endocannabinoid system is strongly implicated in regulation of homeostasis and several neuropsychiatric disorders, obesity, and associated comorbidities, such as dyslipidemia and metabolic syndrome. We have used whole-body PET/CT to characterize the biodistribution and dosimetry of a novel high-affinity, subtype-selective radioligand, F-18-MK-9470, in healthy male and female subjects. Methods: Eight nonobese subjects (5 men, 3 women; age, 22-54 y) underwent serial whole-body PET/CT for 6 h after a bolus injection of 251 +/- 25 MBq F-18-MK-9470 (N-[2-(3-cyano-phenyl)-3-(4-(2-F-18-fluorethoxy)phenyl)-1-methylpropyl]-2-(5-methyl-2-pyridyloxy)-2-methylproponamide). Source organs were delineated 3-dimensionally using the combined morphologic and functional data. Residence times were derived from time-activity profiles using both the trapezoid rule and curve fitting. Individual organ doses and effective doses were determined using the OLINDA software package, with different approaches for gastrointestinal and urinary excretion modeling. Results: F-18-MK-9470 is taken up slowly in the brain, reaching a plateau at approximately 90-120 min after bolus injection and is excreted predominantly through the hepatobiliary system. The gallbladder, upper large intestine, small intestine, and liver are the organs with the highest absorbed dose (average: 159, 98, 87 and 86 mu Gy/MBq, respectively). The mean effective dose (ED) was 22.8 +/- 4.3 mu Sv/MBq, indicating relatively low intersubject variability and a mean value in the range of many commercially available F-18-labeled radiopharmaceuticals. Brain uptake was relatively high compared with that of existing central nervous system ligands for other receptors, between 3.2% and 4.9% of the injected dose. Conclusion: The estimated radiation bur-den of F-18-MK-9470 for PET CB1 receptor imaging shows relatively low variability between subjects and has an acceptable ED, which allows multiple serial cerebral scans of good image quality, while remaining within the risk category class II-b defined by the World Health Organization and the International Commission for Radiation Protection for a standard injected activity (185-370 MBq). ispartof: Journal of Nuclear Medicine vol:49 issue:3 pages:439-445 ispartof: location:United States status: published