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Teclistamab (JNJ-64007957), a B-cell maturation antigen × CD3 bispecific antibody, displayed potent T-cell-mediated cytotoxicity of multiple myeloma cells in preclinical studies.A first-in-human, Phase I, dose escalation study (MajesTEC-1) is evaluating teclistamab in patients with relapsed/refractory multiple myeloma.To estimate the efficacious therapeutic dosing range of teclistamab, pharmacokinetic (PK) data following the first cycle doses in the low-dose cohorts in the Phase I study were modeled using a 2-compartment model and simulated to predict the doses that would have average and trough serum teclistamab concentrations in the expected therapeutic range (between ECThe doses predicted to have average serum concentrations between the ECOur findings show that PK simulations of early clinical data together with ex vivo cytotoxicity estimates can inform the identification of a bispecific antibody's therapeutic range.NCT03145181, date of registration: May 9, 2017.

Tumor types and molecular alterations of enrolled patients

Supplementary Figures PDF file - 114K, Includes sequence information on KSP and VEGF siRNAs, murine Hep3B tumor model data with ALN-VSP, ALN-VSP Phase I study design, KSP and VEGF mRNA levels in tumor cell lines and normal liver, and comparison of ALN-VSP PK data in cancer patients and non-human primates

Supplementary Methods and Legends PDF file - 72K, Includes detailed methods for 5' RACE assay and DCE-MRI scans, as well as figure legends for the six supplementary figures

Supplementary Tables PDF file - 67K, Includes data showing effect of ALN-VSP on spleen in non-human primates, tumor response data from the Phase I trial, and safety data (including adverse events and dose-limiting toxicities) from the Phase I trial

Supplementary Table 1 - PDF file 54K, Patient description with tumor PTEN status available

Supplementary Figure S1. CA125 response to lifastuzumab vedotin in ovarian cancer patients. All patients with radiographic responses also had {greater than or equal to}50 decrease in CA125 from baseline levels.

Suppementary Table 4 - PDF file 38K, Correlation analysis of selected genes from aCGH data

Purpose: The objectives of this phase 1, first-in-human study were to determine the dose-limiting toxicities (DLT), maximum tolerated dose (MTD), safety, pharmacokinetics, and preliminary activity of the hypoxia-activated prodrug TH-302 in patients with advanced solid tumors.Experimental Design: TH-302 was administered intravenously over 30 to 60 minutes in two regimens: three times weekly dosing followed by 1 week off (arm A) and every 3-week dosing (arm B).Results: Fifty-seven patients enrolled (arm A: N = 37 and arm B: N = 20). The TH-302 dose was escalated from 7.5 to 670 mg/m2 in arm A and from 670 to 940 mg/m2 in arm B. The most common adverse events were nausea, skin rash, fatigue, and vomiting. Hematologic toxicity was mild and limited. Grade 3 skin and mucosal toxicities were dose limiting at 670 mg/m2 in arm A; the MTD was 575 mg/m2. In arm B, grade 3 fatigue and grade 3 vaginitis/proctitis were dose limiting at 940 mg/m2; the MTD was 670 mg/m2. Plasma concentrations of TH-302 and the active metabolite Br-IPM (brominated version of isophosphoramide mustard) increased proportionally with dose. Two partial responses were noted in patients with metastatic small cell lung cancer (SCLC) and melanoma in arm A at 480 and 670 mg/m2. Stable disease was observed in arms A and B in 18 and 9 patients, respectively.Conclusions: The MTD of TH-302 was 575 mg/m2 weekly and 670 mg/m2 every 3 weeks. Skin and mucosal toxicities were DLTs. On the basis of responses in metastatic melanoma and SCLC, further investigations in these indications were initiated. Clin Cancer Res; 17(9); 2997–3004. ©2011 AACR.

Visits after Day 57 were excluded for visual purposes. The excluded visits were: Days 71, 85, 99, 127, 155, 183, 211, 239, 267, 295, 323 and 351.

Supplementary Figures S1-S2.

Supplementary Table 2 - PDF file 42K, Correlation of PTEN immunohistochemistry and PTEN mutation/copy number status

Supplementary Figure 1: Study design

Supplemental Figure 3. Clinical trial tumor immunohistochemistry. Representative images from tumor biopsies were analyzed for pCDK1/2 and Ki-67expression. Representative images from a patient with NSCLC and unknown p53 mutation status were obtained 24 hours after administration of GDC-0425 alone (A, B), 48 hours after gemcitabine alone (C, D) and at a time point that was both 24 hours after GDC-0425 and 48 hours after gemcitabine (E, F). Quantitation of percent tumor cell Ki-67 positivity varied minimally between biopsies (G); pCDK1/2 increased from baseline after gemcitabine treatment, whereas the combination of GDC-0425 given 24 hours after gemcitabine suppressed the increase in pCDK1/2. Scale bar=40 µm.

Supplemental Methods

Supplemental Figure 1. Representative example from one patient showing the rash that was most frequently observed with ensartinib. The white arrow in the top figure points to the rash that is circled in the bottom figure.

The mean concentration of ensartinib in plasma and skin at multiple time points after a single dose of 50 mg/kg is listed in Supplemental Table 2. At 12 hours post-dose, the concentration of ensartinib was 9.0 higher in the skin than in the plasma.

Supplementary Figure 3: Glucose and insulin levels after treatment with GSK2636771 in fasted mice.

Purpose:The safety and preliminary efficacy of MEDI1873, an agonistic IgG1 fusion protein targeting glucocorticoid-induced TNF receptor–related protein (GITR), were evaluated in an open-label, first-in-human, phase I, dose escalation study in previously treated patients with advanced solid tumors.Patients and Methods:Two single-patient cohorts at 1.5 and 3 mg i.v. were followed by 3+3 dose escalation in six cohorts at 7.5, 25, 75, 250, 500, and 750 mg, all every 2 weeks, for up to 52 weeks. Primary endpoints were safety and tolerability, dose-limiting toxicities (DLT), and MTD. Secondary endpoints included antitumor activity, pharmacokinetics, immunogenicity, and pharmacodynamics.Results:Forty patients received MEDI1873. Three experienced DLTs: grade 3 worsening tumor pain (250 mg); grade 3 nausea, vomiting, and headache (500 mg); and grade 3 non-ST segment elevation myocardial infarction (750 mg). An MTD was not reached and treatment was well tolerated up to 500 mg. Most common treatment-related adverse events were headache (25%), infusion-related reaction (17.5%), and decreased appetite (17.5%). MEDI1873 exposure was dose proportional. Antidrug–antibody incidence was low. MEDI1873 increased peripheral CD4+ effector memory T-cell proliferation as well as cytokines associated with effector T-cell activation at dose levels ≥75 mg. The best response was stable disease (SD) in 17 patients (42.5%), including 1 unconfirmed partial response. Eight patients (20.0%) had SD ≥24 weeks.Conclusions:MEDI1873 showed acceptable safety up to 500 mg i.v. every 2 weeks with pharmacodynamics activity, and prolonged SD in some patients. However, further development is not planned because of lack of demonstrated tumor response.

Background: The PI3K/protein kinase B (AKT) pathway is commonly activated in several tumor types. Selective targeting of p110β could result in successful pathway inhibition while avoiding the on- and off-target effects of pan-PI3K inhibitors. GSK2636771 is a potent, orally bioavailable, adenosine triphosphate-competitive, selective inhibitor of PI3Kβ.Methods: We evaluated the safety, pharmacokinetics, pharmacodynamics and antitumor activity of GSK2636771 to define the recommended phase II dose (RP2D). During the dose-selection and dose-escalation stages (parts 1 and 2), patients with PTEN-deficient advanced solid tumors received escalating doses of GSK2636771 (25–500 mg once daily) using a modified 3+3 design to determine the RP2D; tumor type-specific expansion cohorts (part 3) were implemented to further assess tumor responses at the RP2D.Results: A total of 65 patients were enrolled; dose-limiting toxicities were hypophosphatemia and hypocalcemia. Adverse events included diarrhea (48%), nausea (40%), and vomiting (31%). Single- and repeat-dose exposure increased generally dose proportionally. GSK2636771 400 mg once daily was the RP2D. Phospho/total AKT ratio decreased with GSK2636771 in tumor and surrogate tissue. A castrate-resistant prostate cancer (CRPC) patient harboring PIK3CB amplification had a partial response for over a year; an additional 10 patients derived durable (≥24 weeks) clinical benefit, including two other patients with CRPC with PIK3CB alterations (≥34 weeks). GSK2636771 400 mg once daily orally induced sufficient exposure and target inhibition with a manageable safety profile.Conclusions: Genomic aberrations of PIK3CB may be associated with clinical benefit from GSK2636771. Clin Cancer Res; 23(19); 5981–92. ©2017 AACR.

Ensartinib was tested against wild-type ALK and 17 ALK variants in the Reaction Biology panel. Ensartinib potently inhibited all evaluated ALK variants, with in vitro IC50s

Supplementary material

PDF file, 76K.

Purpose:This phase I trial assessed the safety, tolerability, and preliminary antitumor activity of lifastuzumab vedotin (LIFA), an antibody–drug conjugate of anti-NaPi2b mAb (MNIB2126A) and a potent antimitotic agent (monomethyl auristatin E).Patients and Methods:LIFA was administered to patients with non–small cell lung cancer (NSCLC) and platinum-resistant ovarian cancer (PROC), once every 3 weeks, by intravenous infusion. The starting dose was 0.2 mg/kg in this 3+3 dose-escalation design, followed by cohort expansion at the recommended phase II dose (RP2D).Results:Overall, 87 patients were treated at doses between 0.2 and 2.8 mg/kg. The MTD was not reached; 2.4 mg/kg once every 3 weeks was selected as the RP2D based on overall tolerability profile. The most common adverse events of any grade and regardless of relationship to study drug were fatigue (59%), nausea (49%), decreased appetite (37%), vomiting (32%), and peripheral sensory neuropathy (29%). Most common treatment-related grade ≥3 toxicities among patients treated at the RP2D (n = 63) were neutropenia (10%), anemia (3%), and pneumonia (3%). The pharmacokinetic profile was dose proportional. At active doses ≥1.8 mg/kg, partial responses were observed in four of 51 (8%) patients with NSCLC and 11 of 24 (46%) patients with PROC per RECIST. All RECIST responses occurred in patients with NaPi2b-high by IHC. The CA-125 biomarker assessed for patients with PROC dosed at ≥1.8 mg/kg showed 13 of 24 (54%) had responses (≥50% decline from baseline).Conclusions:LIFA exhibited dose-proportional pharmacokinetics and an acceptable safety profile, with encouraging activity in patients with PROC at the single-agent RP2D of 2.4 mg/kg.

Purpose: BRAF-inhibition (BRAFi) therapy for advanced melanoma carries a high rate of secondary cutaneous squamous cell carcinoma (cSCC) and risk of other cancers. UV radiation and α-genus human papillomavirus (HPV) are highly associated with SCC, but a novel role for β-genus HPV is suspected in BRAFi-cSCC. Cutaneous β-HPV may act in concert with host and environmental factors in BRAFi-cSCC.Experimental Design: Primary BRAFi-cSCC tissue DNA isolated from patients receiving vemurafenib or dabrafenib from two cancer centers was analyzed for the presence of cutaneous oncogenic viruses and host genetic mutations. Diagnostic specimens underwent consensus dermatopathology review. Clinical parameters for UV exposure and disease course were statistically analyzed in conjunction with histopathology.Results: Twenty-nine patients contributed 69 BRAFi-cSCC lesions. BRAFi-cSCC had wart-like features (BRAFi-cSCC-WF) in 22% of specimens. During vemurafenib therapy, BRAFi-cSCC-WF arose 11.6 weeks more rapidly than conventional cSCC when controlled for gender and UV exposure (P value = 0.03). Among all BRAFi-cSCC, β-genus HPV-17, HPV-38, HPV-111 were most frequently isolated, and novel β-HPV genotypes were discovered (CTR, CRT-11, CRT-22). Sequencing revealed 63% of evaluated BRAFi-cSCCs harbored RAS mutations with PIK3CA, CKIT, ALK, and EGFR mutations also detected.Conclusions: We examined clinical, histopathologic, viral, and genetic parameters in BRAFi-cSCC demonstrating rapid onset; wart-like histomorphology; β-HPV-17, HPV-38, and HPV-111 infection; UV damage; and novel ALK and CKIT mutations. Discovered β-HPV genotypes expand the spectrum of tumor-associated viruses. These findings enhance our understanding of factors cooperating with BRAF inhibition that accelerate keratinocyte oncogenesis as well as broaden the knowledge base of multifactorial mediators of cancer in general. Clin Cancer Res; 21(11); 2624–34. ©2015 AACR.

Supplementary Methods, Figures 1-2, Tables 1-3. Phylogenetic analysis, novel HPV alignment and NGS gene panel. Figure S1 - β-genus HPV38, HPV17 and HPV111 are most frequently found in BRAFi-cSCC; Figure S2: Protein and nucleic acid sequence alignments of putative novel HPV genotypes; Table S1: HPV L1 sequences were obtained from NCBI for alignment and relatedness analysis; Table S2 Human Papillomavirus Taxonomy; Table S3: Ion Torrent Ampliseq panel targets.

Purpose: Dabrafenib is a selective, potent ATP-competitive inhibitor of the BRAFV600-mutant kinase that has demonstrated efficacy in clinical trials. We report the rationale for dose selection in the first-in-human study of dabrafenib, including pharmacokinetics, tissue pharmacodynamics, 2[18F]fluoro-2-deoxy-D-glucose-positron emission tomography (FDG-PET) pharmacodynamics, and dose–response relationship.Experimental Design: Dabrafenib was administered orally once, twice (BID), or three times daily (TID). Selected dose cohorts were expanded to collect adequate data on safety, pharmacokinetics, or pharmacodynamics. A recommended phase II dose (RP2D) was chosen based on safety, pharmacokinetic, pharmacodynamic, and response data.Results: One hundred and eighty-four patients were enrolled and treated with doses ranging from 12 mg once daily to 300 mg BID in 10 cohorts. Pharmacokinetic assessment of dabrafenib demonstrated a less-than-dose-proportional increase in exposure after repeat dosing above 150 mg BID. Similar to parent drug concentrations, exposure for all metabolites demonstrated less-than-dose-proportional increases. Predicted target inhibition of pERK (>80%) was achieved at 150 mg BID, with a similar magnitude of inhibition at higher doses in BRAFV600 mutation melanoma biopsy samples. Although there was large variability between patients, FDG uptake decreased with higher daily doses in patients with BRAFV600 mutation–positive melanoma. A favorable activity and tolerability profile was demonstrated at 150 mg BID. There was no improvement with TID dosing compared with BID dosing, based on FDG-PET and tumor response analyses in patients with melanoma.Conclusion: The RP2D of dabrafenib was determined to be 150 mg BID after considering multiple factors, including pharmacokinetics, tissue pharmacodynamics, FDG-PET pharmacodynamics, and the dose–response relationship. A maximum tolerated dose for dabrafenib was not determined. Clin Cancer Res; 20(17); 4449–58. ©2014 AACR.

PDF file, 584K, Supplementary Figures: S1. MLN8237 dose-escalation schema for relative bioavailability sub-study; S2. Relative bioavailability study schema: MLN8237 ECT versus PIC formulation. S3. Scans showing durable partial response after treatment with MLN8237 in a 52-year-old patient with platinum- and radiation-refractory ovarian cancer.

Supplementary Table 1: 3 + 3 dose escalation guidelines Supplementary Table 2: Customized sequencing panel Supplementary Table 3: Summary of AEs occurring in >20% of all patients, treatment-related AEs and SAEs Supplementary Table 4: PK parameters following single dose oral dosing of GSK2636771 (PK population) Supplementary Table 5: PK parameters following single daily oral dosing of GSK2636771 (PK population) Supplementary Table 6: PK parameters following multiple dose oral dosing of GSK2636771 (PK population)

Purpose: Dabrafenib is a selective inhibitor of V600-mutant BRAF kinase, which recently showed improved progression-free survival (PFS) as compared with dacarbazine, in metastatic melanoma patients. This study examined potential genetic markers associated with response and PFS in the phase I study of dabrafenib.Experimental Design: Baseline (pretreatment or archival) melanoma samples were evaluated in 41 patients using a custom genotyping melanoma-specific assay, sequencing of PTEN, and copy number analysis using multiplex ligation amplification and array-based comparative genomic hybridization. Nine patients had on-treatment and/or progression samples available.Results: All baseline patient samples had BRAFV600E/K confirmed. Baseline PTEN loss/mutation was not associated with best overall response to dabrafenib, but it showed a trend for shorter median PFS [18.3 (95% confidence interval, CI, 9.1–24.3) vs. 32.1 weeks (95% CI, 24.1–33), P = 0.059]. Higher copy number of CCND1 (P = 0.009) and lower copy number of CDKN2A (P = 0.012) at baseline were significantly associated with decreased PFS. Although no melanomas had high-level amplification of BRAF, the two patients with progressive disease as their best response had BRAF copy gain in their tumors.Conclusions: Copy number changes in CDKN2A, CCND1, and mutation/copy number changes in PTEN correlated with the duration of PFS in patients treated with dabrafenib. The results suggest that these markers should be considered in the design and interpretation of future trials with selective BRAF inhibitors in advanced melanoma patients. Clin Cancer Res; 19(17); 4868–78. ©2013 AACR.

Changes in peripheral GITR+ effector memory T-cells from baseline were measured in the 25 mg, 75 mg, 250 mg, and 500 mg cohorts.

Supplementary Figure 2 - PDF file 252K, Copy number in baseline samples comparing patients with V600E vs. V600K mutations

Supplementary Figure 2: LNCAP and DU-145 prostate cancer cells were treated with 1 or 10 μM GSK2636771 for up to 48 hours and probed with the indicated antibodies

Supplementary Methods - PDF file 95K, Supplementary Methods

Study design.

Supplemental Figure 2. Preclinical xenograft immunohistochemistry. HT-29 xenografts were analyzed for pCDK1/2 and Ki-67 expression. Representative images from 2 unique animals in each treatment group (n=5 animals per group) are shown. Ki-67 expression in surviving tumor cells is relatively consistent among treatment groups. pCDK1/2 expression increases from baseline (A, B) after gemcitabine treatment (I, J), whereas GDC-0425 alone (E, F) had little effect. In contrast, GDC-0425 given 16 hours after gemcitabine caused marked inhibition of the gemcitabine-induced expression of pCDK1/2. Scale bar=90 µm.

(A) Changes from baseline were measured in peripheral CD4+ Ki67+ T cells in the 25 mg, 75 mg, 250 mg, and 500 mg cohorts. (B) The associations between peripheral IFNy and GITR. GITR molecule equivalents of soluble fluorescence (MESF) were assessed.

Supplementary Table 7: Next-generation sequencing of tumor biopsy samples (see separate Excel file) Supplementary Table 8: Copy number variations for patients with tumor biopsy samples available (see separate Excel file) Supplementary Table 9: Summary of copy number variations as assessed by polymerase chain reaction (see separate Excel file)

Purpose: Chk1 inhibition potentiates DNA-damaging chemotherapy by overriding cell-cycle arrest and genome repair. This phase I study evaluated the Chk1 inhibitor GDC-0425 given in combination with gemcitabine to patients with advanced solid tumors.Experimental Design: Patients received GDC-0425 alone for a 1-week lead-in followed by 21-day cycles of gemcitabine plus GDC-0425. Gemcitabine was initially administered at 750 mg/m2 (Arm A), then increased to 1,000 mg/m2 (Arm B), on days 1 and 8 in a 3 + 3 + 3 dose escalation to establish maximum tolerated dose (MTD). GDC-0425 was initially administered daily for three consecutive days; however, dosing was abbreviated to a single day on the basis of pharmacokinetics and tolerability. TP53 mutations were evaluated in archival tumor tissue. On-treatment tumor biopsies underwent pharmacodynamic biomarker analyses.Results: Forty patients were treated with GDC-0425. The MTD of GDC-0425 was 60 mg when administered approximately 24 hours after gemcitabine 1,000 mg/m2. Dose-limiting toxicities included thrombocytopenia (n = 5), neutropenia (n = 4), dyspnea, nausea, pyrexia, syncope, and increased alanine aminotransferase (n = 1 each). Common related adverse events were nausea (48%); anemia, neutropenia, vomiting (45% each); fatigue (43%); pyrexia (40%); and thrombocytopenia (35%). The GDC-0425 half-life was approximately 15 hours. There were two confirmed partial responses in patients with triple-negative breast cancer (TP53-mutated) and melanoma (n = 1 each) and one unconfirmed partial response in a patient with cancer of unknown primary origin.Conclusions: Chk1 inhibition with GDC-0425 in combination with gemcitabine was tolerated with manageable bone marrow suppression. The observed preliminary clinical activity warrants further investigation of this chemopotentiation strategy. Clin Cancer Res; 23(10); 2423–32. ©2016 AACR.

Purpose: This phase I study evaluated the safety, pharmacokinetics, pharmacodynamics, and efficacy of the investigational oral drug MLN8237 (alisertib), a small-molecule Aurora A kinase (AAK) inhibitor, in 87 adult patients with advanced solid tumors.Experimental Design: Sequential cohorts of patients received MLN8237 5 to 150 mg orally once daily or twice daily for 7, 14, or 21 days, followed by 14 days' rest per cycle. MLN8237 pharmacokinetics was characterized, and the relative bioavailability of an enteric-coated tablet (ECT) formulation was evaluated in reference to the original powder-in-capsule (PIC) formulation. Pharmacodynamic effects of MLN8237 on inhibition of AAK activity were evaluated in skin biopsies. Tolerability and response to treatment were assessed.Results: Common toxicities included fatigue, nausea, and neutropenia. Plasma exposures increased dose proportionally (5–150 mg/d), and were similar for PIC and ECT. The terminal half-life was 23 hours. At the maximum tolerated dose of 50 mg twice daily on the 7-day schedule, the mitotic index of the skin basal epithelium was increased within 24 hours after MLN8237 administration on days 1 and 7, a finding consistent with AAK inhibition. One (1%) patient achieved a partial response lasting for more than 1 year and received MLN8237 for 51 cycles; 20 (23%) patients achieved stable disease for ≥3 months.Conclusions: This first-in-human trial of MLN8237 showed tolerability and favorable pharmacokinetics in this patient population. The recommended phase II dose of MLN8237 is 50 mg twice daily orally for 7 days in 21-day cycles, which is being evaluated further in the treatment of various solid tumors and hematologic malignancies. Clin Cancer Res; 18(17); 4775–84. ©2012 AACR.

The key pharmacokinetic (PK) parameters (Supplemental Table 3) at the recommended phase 2 dose of 225 mg show that food has minimal impact on absorption of ensartinib.

Supplementary Figure 1 - PDF file 214K, Copy number in baseline samples from patients with partial response compared to those with stable or progressive disease

Purpose: Ribociclib (an oral, highly specific cyclin-dependent kinase 4/6 inhibitor) inhibits tumor growth in preclinical models with intact retinoblastoma protein (Rb+). This first-in-human study investigated the MTD, recommended dose for expansion (RDE), safety, preliminary activity, pharmacokinetics, and pharmacodynamics of ribociclib in patients with Rb+ advanced solid tumors or lymphomas.Experimental Design: Patients received escalating doses of ribociclib (3-weeks-on/1-week-off or continuous). Dose escalation was guided by a Bayesian Logistic Regression Model with overdose control principle.Results: Among 132 patients, 125 received ribociclib 3-weeks-on/1-week-off and 7 were dosed continuously. Nine dose-limiting toxicities were observed among 70 MTD/RDE evaluable patients during cycle 1, most commonly neutropenia (n = 3) and thrombocytopenia (n = 2). The MTD and RDE were established as 900 and 600 mg/day 3-weeks-on/1-week-off, respectively. Common treatment-related adverse events were (all-grade; grade 3/4) neutropenia (46%; 27%), leukopenia (43%; 17%), fatigue (45%; 2%), and nausea (42%; 2%). Asymptomatic Fridericia's corrected QT prolongation was specific to doses ≥600 mg/day (9% of patients at 600 mg/day; 33% at doses >600 mg/day). Plasma exposure increases were slightly higher than dose proportional; mean half-life at the RDE was 32.6 hours. Reduced Ki67 was observed in paired skin and tumor biopsies, consistent with ribociclib-mediated antiproliferative activity. There were 3 partial responses and 43 patients achieved a best response of stable disease; 8 patients were progression-free for >6 months.Conclusions: Ribociclib demonstrated an acceptable safety profile, dose-dependent plasma exposure, and preliminary signs of clinical activity. Phase I–III studies of ribociclib are under way in various indications. Clin Cancer Res; 22(23); 5696–705. ©2016 AACR.

Supplementary Figure S2. Representative NaPi2b ICH images for PROC and NSCLC patients.

Supplementary Table S1. Adverse events regardless of relationship to study drug occurring in 10 or more patients Supplementary Table S2. Adverse events grades 3-5 regardless of relationship to study drug occurring in 2 or more patients Supplementary Table S3. Pulmonary adverse events by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S4. Pulmonary adverse events of NCI-CTCAE grade 3 or higher by frequency of occurrence in all patients regardless of relationship to study drug Supplementary Table S5. Mean (standard deviation) of the pharmacokinetic parameters for antibody-conjugated MMAE in plasma Supplementary Table S6. Mean (standard deviation) of the pharmacokinetic parameters for total antibody in plasma Supplementary Table S7. Mean (standard deviation) of the pharmacokinetic parameters for unconjugated MMAE in plasma Supplementary Table S8. Response outcomes and duration

PDF file, 59K, Summary of pharmacokinetic parameters for MLN8237 PIC formulation after multiple dose oral administration dosing in the 7-, 14-, and 21-day schedules.

Supplementary Table 1. Characteristics of patients with prolonged SD ({greater than or equal to}24 weeks)

Fig. S1. Waterfall plot of duration of exposure vs. best percentage change from baseline; Figure S2. Duration of exposure in patients with stable disease treated for at least four cycles; Figure S3. Duration of exposure, best percentage change in target lesion, and genetic profile for the 53 patients with available genetic data.