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Purpose: Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors. Patients and Methods: Dose-escalation cohorts received eganelisib 10–60 mg as monotherapy (n = 39) and 20–40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE). Results: The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors. Conclusions: On the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

Background: Sacituzumab govitecan (SG) is an antibody-drug conjugate targeting Trop2 with an SN-38 payload recently approved for pretreated patients with locally advanced or metastatic triple-negative breast cancer (TNBC). The XenoSTART Patient-Derived Xenograft (XPDX) breast cancer platform includes over 180 models spanning all subtypes characterized with immunohistochemistry (IHC) including ER, PR, and HER2 protein levels, genomic and transcriptomic sequencing, and in vivo drug sensitivity. To better understand potential benefit of SG in breast cancers other than TNBC and further annotate our platform, Trop2 protein levels were determined in all breast models by IHC. We evaluated tumor growth inhibition by SG in 125 of our XPDX breast models and compared protein expression with agent activity. Methods: 180 breast XPDX models were evaluated for Trop2 expression (AF650, R&D Systems) and 125 were evaluated in vivo against SG; responses were grouped by ER and Trop2 status (+/-). Models were grown subcutaneously in female athymic nude mice and ER+ models supplemented with estradiol. Models were also characterized for PR, HER2, and AR protein expression by IHC and profiled using WES and RNAseq. For in vivo studies, SG was administered by intravenous injection biweekly for two cycles at 1 mg, flat; endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C< 0%) versus Day 0 tumor volume was also reported. Results: 180 breast models were examined by IHC with 75/180 (42%) classified as ER+ and 105/180 (58%) ER-. In ER+ models 38/75 (51%) were Trop2+ and 37/75 (49%) Trop2-, and in ER- models 41/105 (39%) were Trop2+ and 64/105 (61%) Trop2-. In vivo, 20% of ER+/Trop2+ models reported sensitivity to SG, most notably models from patients with acquired resistance to CDK4/6 inhibitors, including STM001 and ST4316B. Interestingly, >70% of ER+/HER2+/Trop2+ models were insensitive to SG, including ST225 and ST340. Of 41 ER-/Trop2+ models, approximately 40% reported some response to SG with 50% of these sensitive to therapy, including ST5954 established from a patient who began treatment with SG following sample collection and is currently in remission. >75% of Trop2- models were insensitive to SG regardless of ER status. Conclusion: We screened 180 models in our XPDX breast cancer platform for Trop2 expression and compared expression with in vivo SG efficacy in 125 models. Analysis is underway to correlate receptor and molecular profiles with SG sensitivity in breast models and we are expanding expression and in vivo testing to additional indications. Citation Format: Alyssa Simonson, Johnnie Flores, Ebony Anderson, Crystal Moreno, George Plasko, Kyriakos P. Papadopoulos, Amita Patnaik, Drew Rasco, Gladys Rodriguez, Amy Lang, Muralidhar Beeram, Luis Rodriguez, Ronald Drengler, Steven Abbate, Hanni Salih, Lon Smith, Maryam Elmi, Brittany DeBerry, Arthur Rosenthal, Tatiana Hernandez, Nehal Lakhani, Manish Sharma, Michael Wick. Correlation of Trop2 expression with in vivo sensitivity to sacituzumab govitecan in a panel of breast XPDX models [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P3-08-05.

Background: Trastuzumab deruxtecan (DS-8201a) is an antibody-drug conjugate (ADC), consisting of a humanized anti-HER2 (human epidermal growth factor receptor 2) monoclonal antibody linked to a topoisomerase I inhibitor payload using a cleavable tetrapeptide-based linker, approved for the treatment of HER2+ metastatic breast cancer patients refractory to anti-HER2 therapy including T-DM1. While some mechanisms for clinical T-DM1 resistance have been identified, less is known about innate or acquired resistance to DS-8201a. We established two XenoSTART Patient-Derived Xenograft (XPDX) models from tissue samples collected two years apart from a patient with ER+/HER2+ breast cancer before and after HER2 directed therapies. These models designated ST4565 and ST4565C were developed and characterized for receptor expression, genomic alterations, and in vivo drug sensitivities toward multiple chemotherapies and targeted agents, including T-DM1 and DS-8201a. Methods: Models ST4565 and ST4565C were established from breast samples collected from a Caucasian female with ER+/HER2+ metastatic breast cancer; ST4565 was collected at age 35 prior to therapy and ST4564C at age 37 following several treatment regimens including 5-FU/doxorubicin/cyclophosphamide, docetaxel/trastuzumab/pertuzumab, and T-DM1/anastrozole. Both were grown subcutaneously in female athymic nude mice supplemented with exogenous estradiol. The resulting models were passaged, and receptor expression confirmed immunohistochemically; genomic analysis, including WES and RNAseq, was performed to further characterize the models. For in vivo studies, both models were evaluated using several chemotherapy and targeted agents alone and in combination including: trastuzumab, pertuzumab, T-DM1, DS-8201a, neratinib, tucatinib, fulvestrant, alpelisib, sacituzumab, and irinotecan. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C=< 0) versus Day 0 tumor volume was also reported. Results: ST4565 and ST4565C retained comparable receptor expression (ER=2+/HER2=3+) over tested passages with similar histology compared to archival clinical samples. DNA/RNA sequencing identified several conserved variants including loss of CDKN2A/B and MTAP and a CNV=14 for CCND1. In vivo, ST4565 and ST4565C were found resistant to T-DM1 at 3 mg/kg weekly with a T/C of 100% in both models. However, DS-8201a treatment at 3 mg/kg weekly resulted in partial tumor regressions in ST4565 (T/C=-51%) while ST4565C was found resistant (T/C=49%). Both models were found resistant to all tested chemotherapies and all other targeted therapies but reported similar sensitivity to fulvestrant (T/C=~40%). Conclusion: We established two XPDX models representing T-DM1-resistant, ER+/HER2+ breast cancer from breast samples collected two years apart from the same patient that were found differentially responsive to DS-8201a. These models can be utilized as a valuable tool in better understanding innate resistance to T-DM1 and acquired resistance to DS-8201a. Citation Format: George Plasko, Johnnie Flores, Alyssa Simonson, Peter Forofontov, Ashwin Varma, Amy Lang, Gladys Rodriguez, Kyriakos P. Papadopoulos, Drew Rasco, Amita Patnaik, Bruce Conway, Joe Johnston, Michael Wick. Establishment and characterization of two T-DM1-resistant, ER+/HER2+ breast XPDX models developed sequentially from the same patient with differential in vivo sensitivity to trastuzumab deruxtecan (DS-8201a) [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-03.

Background: Several CDK4/6 inhibitors have recently been approved in combination with letrozole or fulvestrant in hormone receptor-positive breast cancer. Although this combination therapy has been found effective in some patients, resistance often develops. To aid in developing new therapies for CDK4/6i-resistant breast cancer and better understand potential resistance mechanisms, we established two XenoSTART Patient-Derived Xenograft (XPDX) models representing ER+/HER2- breast cancer from tissue samples collected seventeen months apart from the same patient before and after palbociclib therapy. These models designated ST4887 and ST4887B were developed and characterized for receptor expression, genomic alterations, and in vivo drug sensitivities toward multiple chemotherapies and targeted agents, including CDK4/6i and fulvestrant. Methods: Models ST4887 and ST4887B were established from metastatic samples collected from a Caucasian female with ER+/HER2- metastatic breast cancer; ST4887 was collected at age 38 from a femur mass biopsy following several treatment regimens including paclitaxel/doxorubicin/cyclophosphamide, radiation and tamoxifen. ST4887B was collected at age 39 from a liver biopsy following treatment with palbociclib/letrozole then palbociclib/fulvestrant, and finally ixabepilone/capecitabine. Both were grown subcutaneously in female athymic nude mice supplemented with exogenous estradiol. The resulting models were passaged, and receptor expression confirmed immunohistochemically; genomic analysis, including WES and RNAseq, was performed to further characterize models. For in vivo studies, both models were evaluated using several chemotherapy and targeted agents alone and in combination including cisplatin, docetaxel, CDK4/6i, fulvestrant, letrozole, olaparib, niraparib, and sacituzumab. In vivo study endpoints included tumor volume and time from treatment initiation with %T/C values and tumor regression reported at study completion; a T/C of ≤ 20% versus control was considered sensitive. Tumor regression (%T/C=< 0) versus Day 0 tumor volume was also reported. Results: ST4887 and ST4887B retained comparable receptor expression (ER=3+/HER2=1+) over tested passages with similar histology compared to archival clinical samples. DNA/RNA sequencing identified several conserved variants including a somatic BRCA2 truncation (BRCA2Y2660*); transcriptomic analysis revealed upregulation of several related genes but no notable fusions. In vivo, both models were insensitive to cisplatin or docetaxel, however ST4887 but not ST4887B was sensitive to fulvestrant or CDK4/6i therapies, although abemaciclib demonstrated some activity toward ST4887B. PARP inhibitors were active toward ST4887 and to a lesser extent ST4887B, while sacituzumab did not have a significant effect on either model. Conclusion: We established and characterized two XPDX models from the same patient before and after acquired resistance to the CDK4/6i palbociclib. Both models were found to retain receptor status and drug sensitivities similar to the patient at the time of sample collection. These models can be utilized as a valuable tool in better understanding acquired resistance to palbociclib. Citation Format: Ashwin Varma, Johnnie Flores, Alyssa Simonson, Anna Stackpole, Kyriakos P. Papadopoulos, Amita Patnaik, Drew Rasco, Muralidhar Beeram, Marisa Sandera, Michael Wick. Establishment and characterization of two ER+/HER2- XPDX models developed sequentially before and after acquired resistance to the CDK4/6 inhibitor palbociclib from a patient with metastatic breast cancer [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P1-13-22.

HER2-targeted therapies have substantially improved outcomes for patients with HER2-positive breast and gastric or gastro-oesophageal junction cancers. Several other cancers exhibit HER2 expression or amplification, suggesting that HER2-targeted agents can have broader therapeutic impact. Zanidatamab is a humanised, bispecific monoclonal antibody directed against two non-overlapping domains of HER2. The aim of this study was to evaluate the safety and anti-tumour activity of zanidatamab across a range of solid tumours with HER2 expression or amplification.This first-in-human, multicentre, phase 1, dose-escalation and expansion trial included patients aged 18 years and older, with a life expectancy of at least 3 months, with an Eastern Cooperative Oncology Group performance status of 0 or 1, and locally advanced or metastatic, HER2-expressing or HER2-amplified solid tumours of any kind who had received all available approved therapies. The primary objectives of part 1 were to identify the maximum tolerated dose, optimal biological dose, or recommended dose of zanidatamab; all patients were included in the primary analyses. Part 1 followed a 3 + 3 dose-escalation design, including different intravenous doses (from 5 mg/kg to 30 mg/kg) and intervals (every 1, 2, or 3 weeks). The primary objective of part 2 was to evaluate the safety and tolerability of zanidatamab monotherapy in solid tumours. This trial is registered with ClinicalTrials.gov (NCT02892123), and parts 1 and 2 of the trial are complete. Part 3 of the study evaluates the use of zanidatamab in combination with chemotherapy and is ongoing.Recruitment took place between Sept 1, 2016, and March 13, 2021. In Part 1 (n=46), no dose-limiting toxicities were detected and the maximum tolerated dose was not reached. The recommended dose for part 2 (n=22 for biliary tract cancer; n=28 for colorectal cancer; and n=36 for other HER2-expressing or HER2-amplified cancers excluding breast or gastro-oesophageal cancers; total n=86) was 20 mg/kg every 2 weeks. The most frequent treatment-related adverse events in part 1 of the study were diarrhoea (24 [52%] of 46 patients; all grade 1-2) and infusion reactions (20 [43%] of 46 patients; all grade 1-2). The most frequent treatment-related adverse events in part 2 of the study were diarrhoea (37 [43%] of 86 patients; all grade 1-2 except for one patient) and infusion reactions (29 [34%] of 86 patients; all grade 1-2). A total of six grade 3 treatment-related adverse events were reported in four (3%) of 132 patients. In part 2, 31 (37%; 95% CI 27·0-48·7) of 83 evaluable patients had a confirmed objective response. There were no treatment-related deaths.These results support that HER2 is an actionable target in various cancer histologies, including biliary tract cancer and colorectal cancer. Evaluation of zanidatamab continues in ongoing studies.Zymeworks.

Study IPI-549-01 progression-free survival censoring rules for efficacy analyses

Purpose:Eganelisib (IPI-549) is a first-in-class, orally administered, highly selective PI3Kγ inhibitor with antitumor activity alone and in combination with programmed cell death protein 1/ligand 1 (PD-1/PD-L1) inhibitors in preclinical studies. This phase 1/1b first-in-human, MAcrophage Reprogramming in Immuno-Oncology-1 (NCT02637531) study evaluated the safety and tolerability of once-daily eganelisib as monotherapy and in combination with nivolumab in patients with solid tumors.Patients and Methods:Dose-escalation cohorts received eganelisib 10–60 mg as monotherapy (n = 39) and 20–40 mg when combined with nivolumab (n = 180). Primary endpoints included incidence of dose-limiting toxicities (DLT) and adverse events (AE).Results:The most common treatment-related grade ≥3 toxicities with monotherapy were increased alanine aminotransferase (ALT; 18%), aspartate aminotransferase (AST; 18%), and alkaline phosphatase (5%). No DLTs occurred in the first 28 days; however, toxicities meeting DLT criteria (mostly grade 3 reversible hepatic enzyme elevations) occurred with eganelisib 60 mg in later treatment cycles. In combination, the most common treatment-related grade ≥3 toxicities were increased AST (13%) and increased ALT and rash (10%). Treatment-related serious AEs occurred in 5% of monotherapy patients (grade 4 bilirubin and hepatic enzyme increases in one patient each) and 13% in combination (pyrexia, rash, cytokine release syndrome, and infusion-related reaction in ≥2 patients each). Antitumor activity was observed in combination, including patients who had progressed on PD-1/PD-L1 inhibitors.Conclusions:On the basis of the observed safety profile, eganelisib doses of 30 and 40 mg once daily in combination with PD-1/PD-L1 inhibitors were chosen for phase 2 study.

Study IPI-549-01 full protocol inclusion and exclusion criteria

Representativeness of Study Participants

Study IPI-549-01 methodology and criteria for assessing MDSCs

Figure legend to Supplementary Figure S1.

Supplementary Table S2. Sym004 pharmacokinetic derived measures - dose-escalation and dose-expansion cohorts.

Supplementary Figure S1. Pharmacokinetic profile of Sym004.

Tumor growth in the context of EGFR inhibitor resistance may remain EGFR-dependent and is mediated by mechanisms including compensatory ligand upregulation and de novo gene alterations. Sym004 is a two-antibody mixture targeting nonoverlapping EGFR epitopes. In preclinical models, Sym004 causes significant EGFR internalization and degradation, which translates into superior growth inhibition in the presence of ligands. In this phase I trial, we observed grade 3 skin toxicity and hypomagnesemia as mechanism-based dose-limiting events during dose escalation. In dose-expansion cohorts of 9 and 12 mg/kg of Sym004 weekly, patients with metastatic colorectal cancer and acquired EGFR inhibitor resistance were enrolled; 17 of 39 patients (44%) had tumor shrinkage, with 5 patients (13%) achieving partial response. Pharmacodynamic studies confirmed marked Sym004-induced EGFR downmodulation. MET gene amplification emerged in 1 patient during Sym004 treatment, and a partial response was seen in a patient with EGFRS492R mutation that is predictive of cetuximab resistance.Significance: Potent EGFR downmodulation with Sym004 in patients with metastatic colorectal cancer and acquired resistance to cetuximab/panitumumab translates into significant antitumor activity and validates the preclinical hypothesis that a proportion of tumors remains dependent on EGFR signaling. Further clinical development and expanded correlative analyses of response patterns with secondary RAS/EGFR mutations are warranted. Cancer Discov; 5(6);598–609. ©2015 AACR.See related commentary by Stintzing and Heinemann, p. 578This article is highlighted in the In This Issue feature, p. 565

Supplementary Table 1. Summary of 33 Patients Treated with Abemaciclib in Dose Escalation. Supplementary Table 2. Baseline patient and disease characteristics. Supplementary Table 3. Possibly related treatment-emergent adverse events (>10% all grades) for hormone receptorpositive breast cancer cohort (n=19) receiving combination therapy with abemaciclib plus fulvestrant. Supplementary Table 4. Summary of abemaciclib pharmacokinetic parameters following a single oral administration. Supplementary Table 5. Summary of abemaciclib pharmacokinetic parameters following repeated once-daily (Q24H) or twice-daily (Q12H) oral administration. Supplementary Table 6. Efficacy for NSCLC cohort, overall and by KRAS status. Supplementary Table 7. Efficacy for other tumor-specific cohorts.

Purpose To report 3 cases of reversible epitheliopathy induced by A166—a human epidermal growth factor receptor (HER2)-targeted antibody-drug conjugate (ADC) therapy for resistant HER2 tumours. Methods Advanced HER2 tumour patients were enrolled in A166 phase I/II clinical trial using Bayesian logistic regression model dose escalation. Key exclusion criteria were ≥grade 2 (G2) corneal pathology, severe organ disease, and other cancer therapy within 4 weeks. Eye exams were performed at baseline, regularly scheduled intervals, and additionally upon A166-induced ocular symptoms. Topical therapy with autologous serum tears (ASTs) was implemented based on visual acuity, symptoms, and slit lamp exam. A166 was withheld if ≥G2 ocular toxicity developed; if status improved to ≤G1, A166 therapy was resumed. Visual acuity, corneal exam, and subjective comfort were recorded. Results After ≥2 cycles of A166, 6 eyes of 3/23 enrolled patients developed whorl pattern epitheliopathy suggestive of limbal stem cell (LSC) dysfunction requiring cessation of A166 despite positive tumour response. Patients 1 and 3 received 3.6 mg/kg A166 dose, and patient 2 received 3.0 mg/kg. Topical steroids (2/4 eyes) failed to improve epitheliopathy. Adding ASTs improved vision, ocular comfort, and whorl pattern epitheliopathy in 6/6 eyes within 3 weeks. Patient 1 continues to improve on ASTs; patient 2 withdrew from the study; and patient 3 resumed A166 therapy. Conclusion A166 precipitates LSC dysfunction-like epitheliopathy. Combination therapy including aggressive lubrication, withholding drug, and ASTs help reverse toxicity. Recognizing that ADC-induced epitheliopathy can respond to ocular management may enable cancer patients to continue lifesaving therapy.

Supplemental Table

PDF file, 57K, Ratio of plasma PlGF or cNRP1 to baseline for each subject at all time points evaluated (Days 14, 21) from the Phase Ia study.

Study Design

Purpose: Multiple cancers harbor genetic aberrations that impact AKT signaling. MK-2206 is a potent pan-AKT inhibitor with a maximum tolerated dose (MTD) previously established at 60 mg on alternate days (QOD). Due to a long half-life (60–80 hours), a weekly (QW) MK-2206 schedule was pursued to compare intermittent QW and continuous QOD dosing.Experimental Design: Patients with advanced cancers were enrolled in a QW dose-escalation phase I study to investigate the safety and pharmacokinetic–pharmacodynamic profiles of tumor and platelet-rich plasma (PRP). The QOD MTD of MK-2206 was also assessed in patients with ovarian and castration-resistant prostate cancers and patients with advanced cancers undergoing multiparametric functional magnetic resonance imaging (MRI) studies, including dynamic contrast-enhanced MRI, diffusion-weighted imaging, magnetic resonance spectroscopy, and intrinsic susceptibility-weighted MRI.Results: A total of 71 patients were enrolled; 38 patients had 60 mg MK-2206 QOD, whereas 33 received MK-2206 at 90, 135, 150, 200, 250, and 300 mg QW. The QW MK-2206 MTD was established at 200 mg following dose-limiting rash at 250 and 300 mg. QW dosing appeared to be similarly tolerated to QOD, with toxicities including rash, gastrointestinal symptoms, fatigue, and hyperglycemia. Significant AKT pathway blockade was observed with both continuous QOD and intermittent QW dosing of MK-2206 in serially obtained tumor and PRP specimens. The functional imaging studies demonstrated that complex multiparametric MRI protocols may be effectively implemented in a phase I trial.Conclusions: Treatment with MK-2206 safely results in significant AKT pathway blockade in QOD and QW schedules. The intermittent dose of 200 mg QW is currently used in phase II MK-2206 monotherapy and combination studies (NCT00670488). Clin Cancer Res; 20(22); 5672–85. ©2014 AACR.

Supplemental Tables

PDF file - 490KB, Supplementary Figure 2. Effects of SAR245409 on Plasma Fasting Insulin and Fasting Glucose.

This Supplementary Methods section provides details for assays that allowed elucidation of the pharmacokinetic and pharmacodynamic results described in the Results and Discussion sections of the article. These supplemental methods descriptions are to be published with the manuscript

Supplemental Figure

Swimmer plots of abemaciclib + PD-L1 inhibitor and merestinib + PD-L1 inhibitor combination cohorts

Supplementary Tables S1-2, Figure 1. Supplementary Table S1. Matrix view of Part A-2 dose titration and PK sampling scheme. Supplementary Table S2. Efficacy outcomes by investigator review per RECIST v1.1. Supplementary Figure 1. Seventeen patients were tested with IFN-γ ELISPOT assay.

Supplementary Figure 1 Total Nesvacumab (REGN910) and Total Ang2 vs Time (cycle 1) following IV infusion in Patients. Supplementary Figure 2 Serum levels of ESM1, SDF-1, PLGF-1 and sVCAM-1 following Nesvacumab (REGN910) treatment. Supplementary Figure 3 Correlative analysis of baseline serum Ang2, ESM-1, SDF-1 ,PIGF and cVCAM-1 and treatment duration. Supplementary Figure 4 Correlative analysis of baseline Ang2 in tumor vessels and treatment duration/response. Supplementary Figure 5 Ang2 and VEGF-A protein levels in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 6 Biomarker analysis of archival tumor tissue. Supplementary Figure 7 Microvascular density in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 8 Tumor cell proliferation in tumor tissue pre and post treatment with Nesvacumab (REGN910). Supplementary Figure 9 TIE-2 protein levels associated with tumor vessels pre and post treatment with Nesvacumab (REGN910)

PDF file - 4775KB, Supplementary Figure 3. Reduction in Extracellular Signal-Regulated Kinase (ERK) Pathway Signaling by SAR245409 in Paired Tumor Biopsies.

Table S1:Summary of baseline pathological diagnosis; Table S2:Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Capsule Formulation; Table S3: Noncompartmental Pharmacokinetic Summary Following Oral Administration of ralimetinib on Day 1 and on Day 14 (Cycle 1) - Tablet Formulation

Purpose: Study objectives included evaluating the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of VX15/2503 in advanced solid tumor patients.Experimental Design: Weekly i.v. doses were administered on a 28-day cycle. Safety, immunogenicity, PK, efficacy, T-cell membrane–associated SEMA4D (cSEMA4D) expression and saturation, soluble SEMA4D (sSEMA4D) serum levels, and serum biomarker levels were evaluated.Results: Forty-two patients were enrolled into seven sequential cohorts and an expansion cohort (20 mg/kg). VX15/2503 was well tolerated. Treatment-related adverse events were primarily grade 1 or 2 and included nausea (14.3%) and fatigue (11.9%); arthralgia, decreased appetite, infusion-related reaction, and pyrexia were each 7.3%. One pancreatic cancer patient (15 mg/kg) experienced a Grade 3 dose-limiting toxicity; elevated γ-glutamyl transferase. Complete cSEMA4D saturation was generally observed at serum antibody concentrations ≥0.3 μg/mL, resulting in decreased cSEMA4D expression. Soluble SEMA4D levels increased with dose and infusion number. Neutralizing anti-VX15/2503 antibodies led to treatment discontinuation for 1 patient. VX15/2503 Cmax and AUC generally increased with dose and dose number. One patient (20 mg/kg) experienced a partial response, 19 patients (45.2%) exhibited SD for ≥8 weeks, and 8 (19%) had SD for ≥16 weeks. Subjects with elevated B/T lymphocytes exhibited longer progression-free survival.Conclusions: VX15/2503 was well tolerated and produced expected PD effects. The correlation between immune cell levels at baseline and progression-free survival is consistent with an immune-mediated mechanism of action. Future investigations will be in combination with immunomodulatory agents. Clin Cancer Res; 22(4); 827–36. ©2015 AACR.

Purpose: To determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics, immunogenicity, and preliminary antitumor activity of CT-322 (BMS-844203), a VEGFR-2 inhibitor and the first human fibronectin domain–based targeted biologic (Adnectin) to enter clinical studies.Experimental Design: Patients with advanced solid malignancies were treated with escalating doses of CT-322 intravenously (i.v.) weekly (qw), or biweekly (q2w). Plasma samples were assayed for CT-322 concentrations, plasma VEGF-A concentrations, and antidrug antibodies.Results: Thirty-nine patients completed 105 cycles of 0.1 to 3.0 mg/kg CT-322 i.v. either qw or q2w. The most common treatment-emergent grade 1/2 toxicities were fatigue, nausea, proteinuria, vomiting, anorexia, and hypertension. Grade 3/4 toxicities were rare. Reversible proteinuria, retinal artery, and vein thrombosis, left ventricular dysfunction, and reversible posterior leukoencephalopathy syndrome were dose limiting at 3.0 mg/kg. The MTD was 2 mg/kg qw or q2w. CT-322 plasma concentrations increased dose proportionally. Plasma VEGF-A levels increased with dose and plateaued at 2 mg/kg qw. Anti–CT-322 antibodies developed without effects on pharmacokinetics, VEGF-A levels, or safety. Minor decreases in tumor measurements occurred in 4 of 34 evaluable patients and 24 patients had stable disease.Conclusions: CT-322 can be safely administered at 2 mg/kg i.v. qw or q2w and exhibits promising antitumor activity in patients with advanced solid tumors. The absence of severe toxicities at the MTD, demonstration of plasma drug concentrations active in preclinical models, and clinical pharmacodynamic evidence of VEGFR-2 inhibition warrant further development of CT-322 and suggest strong potential for Adnectin-based targeted biologics. Cancer Res; 17(2); 363–71. ©2011 AACR. Clin Cancer Res; 17(2); 363–71. ©2011 AACR.

This supplementary information file contains the Figure Legend for the Supplementary Figure S1. This figure legend and Supplementary Figure Fig S1 are intended for publication with the manuscript; Fig S1 shows the effect of VX15/2503 administration on serum levels of soluble SEMA4D. Article text related to Fig S1 is contained in the Results and Discussion sections, pages 19 and 22, respectively.

Supplementary Tables S1-S4 and Figures S1-S3. Tables S1/S2: % tumor response in mice with HCT116 and A2058 tumor xenografts following treatment; Table S3: Diagram showing dose-decision guidelines utilized in the MK-2206 clinical study based on observed toxicities; Table S4: number of patients with drug-related AEs in all courses of treatment; Figure S1/S2: Line graph showing the relative tumor volume and body weight observed in patients over time expressed in terms of days following treatment; Figure S3: Patient presenting with Grade III rash

Sup Figure 3. A 59-year-old male with metastatic colorectal cancer treated with 60mg QOD of MK-2206.

Supplementary Table 1. Summary of the Most Common (>10%) Treatment-Emergent Adverse Events

PDF file - 1005KB, Supplementary Figure 1. Mean (+ or - SE) SAR245409 Plasma Concentration-Time Profiles on Days 1 and 27 of Cycle 1.

Purpose: This study evaluated the clinical relevance of the dual-targeting strategy involving PI3K/AKT/mTOR and RAF/MEK/ERK pathways.Experimental Design: We investigated safety, efficacy, and correlations between tumor genetic alterations and clinical benefit in 236 patients with advanced cancers treated with phase I study drugs targeting phosphoinositide 3-kinase (PI3K) and/or mitogen-activated protein kinase (MAPK) pathways in our Phase I Clinical Trials Program.Results: Seventy-six (32.2%) patients received a PI3K pathway inhibitor in combination with a MAPK pathway inhibitor (D), whereas 124 (52.5%) and 36 (15.3%), respectively, received an inhibitor of either the PI3K or MAPK pathways (S). The rates of drug-related grade >III adverse events were 18.1% for (S) and 53.9% for (D; P < 0.001); the rates of dose-limiting toxicities were 9.4% for (S) and 18.4% for (D; P = 0.06). The most frequent grade >III adverse events were transaminase elevations, skin rash, and mucositis. In our comprehensive tumor genomic analysis, of 9 patients who harbored coactivation of both pathways (colorectal cancer, n = 7; melanoma, n = 2), all 5 patients treated with (D) had tumor regression ranging from 2% to 64%.Conclusions: These results suggest that dual inhibition of both pathways may potentially exhibit favorable efficacy compared with inhibition of either pathway, at the expense of greater toxicity. Furthermore, this parallel pathway targeting strategy may be especially important in patients with coexisting PI3K pathway genetic alterations and KRAS or BRAF mutations and suggests that molecular profiling and matching patients with combinations of these targeted drugs will need to be investigated in depth. Clin Cancer Res; 18(8); 2316–25. ©2012 AACR.

Trial Profile