PIPA: A phase Ib study of selective ß-isoform sparing phosphatidylinositol 3-kinase (PI3K) inhibitor taselisib (T) plus palbociclib (P) in patients (pts) with advanced solid cancers—Safety, tolerability, pharmacokinetic (PK), and pharmacodynamic (PD) analysis of the doublet combination.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 3087-3087
Author(s):  
Juanita Suzanne Lopez ◽  
Manuel SelviMiralles ◽  
Malaka Ameratunga ◽  
Anna Minchom ◽  
Javier Pascual ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Platelet Rich Plasma ◽  
Pi3k Pathway ◽  
Pi3k Inhibitors ◽  
Activating Mutations ◽  
Pathway Activation ◽  
Biomarker Analysis ◽  
Paired Tumour ◽  
Mixed Histology

3087 Background: Oncogenic hyperactivation of the PI3K pathway is common in multiple cancers, with preclinical data showing that CDK4/6 inhibitors sensitise PIK3CA mutant cancers to PI3K inhibitors. We report the activity of the P+T in solid tumors with PI3K pathway activation, along with the PD biomarker analysis. Methods: We previously reported the dose escalation phase identifying 125mg P given 3-weeks-on, 1-week-off in combination with T 2mg as the recommended phase 2 dose (R2PD, Lim, ASCO 2017). We report the results in solid tumors with confirmed activating mutations (mts) in the PI3K pathway, from dose escalation and expansion, with no prior exposure to CDK4/6 or PI3K pathway inhibitors. PD studies include analyses of platelet-rich plasma (PRP) and paired tumour biopsies. Results: 20 pts (median age 61, range 34-72) were treated at the doublet RP2D, M/F 7/13, with a median 4 prior treatments (range 2-11). Tumour types included colorectal, breast, lung, endometrial,oligodendroglioma and head and neck cancers. Durable disease control occurred in 3 patients with ER+ advanced breast cancer with responses lasting >6 months including 1 pt with a H1047R PIK3CAmt with an ongoing RECIST PR>36 cycles, 2 pts with PIK3CAmt colorectal cancer had RECIST SD for >5 months, and 1 patient with a PIK3CGmt anaplastic oligodendroglioma had clinical and radiological benefit lasting 5.5 months. Treatment was well tolerated with predictable G1-2 adverse events (AEs). G3 toxicities of neutropenia (n=6), thrombocytopenia (2), rash (2), mucositis (1) and raised transaminases (1 each) were all transient with no G4/5 AEs. Significant decreases in tumour pRb, and pAKT and pGSK3ß in PRP, confirmed modulation of both CDK4/6 and PI3K pathways at R2PD. Conclusions: Doublet P+T is well tolerated at the combination RP2D, with PD evidence of PI3K and CDK4/6 modulation in both plasma and tumor. Promising preliminary anti-tumor activity is seen in a mixed histology cohort selected for activating PIK3 mutations. Clinical trial information: NCT02389842.

An open label, multicenter, phase I/II study of RP1 as a single agent and in combination with PD1 blockade in patients with solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2671-TPS2671
Author(s):  
Mark R. Middleton ◽  
Joseph J. Sacco ◽  
Jaime R. Merchan ◽  
Brendan D. Curti ◽  
Ari M. Vanderwalde ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Objective Response ◽  
Phase 2 ◽  
Biomarker Analysis ◽  
Tumor Types

TPS2671 Background: RP1 is an attenuated oncolytic HSV-1 that expresses a fusogenic glycoprotein from gibbon ape leukemia virus (GALV-GP R-) and GM-CSF. RP1 induces potent GALV-GP R- enhanced immunogenic cell death and host anti-tumor immunity in murine tumor models and increases PD-L1 expression. This clinical trial (NCT03767348) was designed to test the hypotheses that RP1 is safe when given alone and together with nivolumab (phase 1) and has efficacy together with nivolumab in four tumor types (phase 2). Methods: The primary goals of this clinical trial in a total of ~150 patients are to define the safety profile of RP1 alone and together with nivolumab, determine the recommended phase 2 dose (phase 1), and then in four phase 2 cohorts, to determine objective response rate in patients with melanoma, non-melanoma skin cancer, urothelial carcinoma and MSI-H solid tumors. Secondary objectives include duration of response, CR rate, PFS, viral shedding, and immune biomarker analysis. Patients with advanced cancer who failed prior therapy were eligible for the phase I component. In Phase 2 patients with histologic diagnoses of the four tumor types (N=30 for each) and who meet safety criteria for nivolumab treatment are eligible. Prior treatment with checkpoint blockade is not allowed except for the melanoma cohort. In the phase 1 portion patients are treated by intra-patient dose escalation of virus (range, 104 - 108 PFU) by intratumoral injection every two weeks for 5 total doses followed by 12 patients dosed 8 times at the RP2D in combination with nivolumab. Phase 1 patients were divided into two groups based on presence of clinically accessible lesions amenable to direct injection or those with visceral/deep lesions requiring image guidance for injection. In the phase 2 portion patients will receive the RP2D for eight injections and nivolumab will be given starting with the second RP1 injection. For the phase 1 portion, a modified 3+3 dose escalation design is used to assess safety and in the phase 2 portion, statistical analysis will be performed using a two-stage three-outcome optimum design with objective responses determined by RECIST criteria. As of February 11, 2019, 27 patients have been enrolled. Clinical trial information: NCT03767348.

Dual epidermal growth factor receptor (EGFR) inhibition: Phase I study combining cetuximab (C225) and erlotinib (E) in advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3552-3552
Author(s):  
R. Sangha ◽  
C. Ho ◽  
L. Beckett ◽  
D. H. Lau ◽  
P. N. Lara ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Level ◽  
Phase Ii ◽  
Dose Escalation ◽  
Gene Copy ◽  
Hematologic Toxicity ◽  
Advanced Solid Tumors ◽  
Egfr Inhibition ◽  
Biomarker Analysis

3552 Background: The EGFR pathway is implicated in lung tumorigenesis by aberrantly regulating cell proliferation, apoptosis, and invasion. Maximal blockade of the EGFR can be achieved by dually inhibiting the extracellular and intracellular domain with the monoclonal antibody C225 and the tyrosine kinase inhibitor, E. Given preclinical synergy of C225 and E, we hypothesized this combination would be feasible and result in improved therapeutic benefit. Methods: Patients (pts) with advanced solid tumors were enrolled using a standard phase I dose escalation design. C225 was administered IV weekly, with no loading dose, and E given orally daily on a 28-day cycle. Four dose levels were studied: C225 150 mg/m2, E 100 mg; C225 200 mg/m2, E 100 mg; C225 250 mg/m2, E 100 mg; and C225 250 mg/m2, E 150 mg. Dose limiting toxicity (DLT) was defined as: grade (Gr) 4 platelets, Gr 3 platelets with bleeding, febrile neutropenia, ≥ Gr 3 ANC with documented infection, or clinically significant > Gr 3 non-hematologic toxicity. Gr 3 rash based solely on pain or Gr 3 hypersensitivity infusion reactions were not considered DLTs. Results: 18 pts were treated: 13 NSCLC, 3 H&N, 1 pancreas, and 1 invasive thymoma. Characteristics: Age range 41–80, median 62.5; Gender: 7 M; ECOG PS ≤1 = 17; Prior chemo ≤1 = 10. Planned dose escalation was completed without reaching the MTD. The highest dose level was expanded to 6 pts. A single DLT for Gr 3 diarrhea was observed at the second dose level (C225 200 mg/m2, E 100 mg). Gr 3/4 toxicities were: lymphopenia (3), acneiform rash (3), nausea/vomiting (3), pruritis (1), fatigue (1), diarrhea (1), confusion (1), hypomagnesemia (1), hypocalcemia (1), hyponatremia (1), hyperkalemia (1), and anemia (1). Of 13 evaluable pts, 1 PR (NSCLC) and 4 with SD (2 NSCLC, 2 H&N). Median cycles: 2 (1–14) with one NSCLC pt on therapy for 8 cycles and one H&N pt receiving 14 cycles. Biomarker analysis of EGFR polymorphisms, gene copy number via FISH, and protein expression will be presented, along with the mutation status of EGFR and KRAS. Conclusions: 1) Dual EGFR inhibition with C225 250 mg/m2 weekly and E 150 mg daily is feasible, well tolerated, and the recommended phase II dose. 2) Efficacy of this combination in NSCLC is being evaluated in a phase II trial. [Table: see text]

Phase 1 dose-escalation study of ACT001 in patients with recurrent glioblastoma and other advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2037-2037
Author(s):  
Jason D. Lickliter ◽  
Ross Jennens ◽  
Charlotte Rose Lemech ◽  
Ganessan Kichenadasse ◽  
Dongpo Cai ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Radiation Treatment ◽  
Phase 1 ◽  
Dose Range ◽  
Malignant Gliomas ◽  
Advanced Solid Tumors ◽  
Biomarker Analysis ◽  
Dose Levels

2037 Background: ACT001, an orally-available parthenolide derivative targeting NF-κB and STAT3 signaling pathways, has immunomodulatory effects and showed promising activity in preclinical models of glioblastoma (GBM). The updated data in this report summarizes clinical findings from this first-in-human clinical trial of ACT001 in patients with advanced solid tumors, including GBM. Methods: Eligible patients were adults with ECOG PS 0-1 and satisfactory hematologic, renal and hepatic function. Additionally, GBM patients had progressive disease despite initial radiation and temozolomide, measurable tumor and no radiation treatment within 3 months prior to enrollment. ACT001 was given orally BID until intolerance or disease progression. Dose escalation followed a standard 3+3 design. Gliomas were imaged with MRI every 8 weeks and responses assessed using RANO criteria. Results: A total of 24 patients were enrolled as of this report: 14 with primary GBM, 2 with secondary GBM, 2 with anaplastic astrocytoma, 2 with colorectal cancer and 1 with each of anaplastic oligioastrocytoma, diffuse intrinsic pontine glioma, non-small cell lung cancer and pleural epithelioid mesothelioma. Median age was 49 years old (range 32-72). ACT001 dose levels were 100 mg BID, 200 mg BID, 400 mg BID, 600 mg BID, 900 mg BID and 1200 mg BID. Study drug treatment was well tolerated with no dose-limiting toxicity or ACT001-related SAE observed. The originally-planned maximum dose of 600 mg BID and the 1200 mg BID dose were expanded to 7 and 5 patients, respectively. The plasma half life of ACT001 was approximately 3-4 hours and no accumulation was observed after multiple dosing. Cmax and AUC0-last were approximately dose linear across the evaluated dose range. Of the 19 patients with recurrent malignant gliomas, a complete remission was observed in 1 patient with GBM (ongoing 27 months from starting ACT001) and stable disease lasting ≥ 6 months was seen in 3 patients. Preliminary biomarker analysis of PBMC samples revealed a post-treatment reduction in CD4+ Treg cells at some dose levels. Conclusions: In this first-in-human phase 1 study, ACT001 was well tolerated and showed satisfactory bioavailability and preliminary evidence of anti-tumor activity in malignant glioma patients dosed at 400 mg BID or lower. A phase 1b trial in recurrent GBM patients of ACT001 at 200-400 mg BID in combination with anti-PD-1 therapy is planned. Clinical trial information: ACTRN12616000228482.

Phase I dose escalation study and biomarker analysis of E7080 in patients with advanced solid tumors

2008 ◽  
Vol 26 (15_suppl) ◽  
pp. 3527-3527 ◽  
Author(s):  
K. Yamada ◽  
T. Hirata ◽  
Y. Fujiwara ◽  
H. Nokihara ◽  
N. Yamamoto ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study ◽  
Biomarker Analysis

Phase I dose-escalation study of XL147, a PI3K inhibitor administered orally to patients with solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3500-3500 ◽  
Author(s):  
G. Shapiro ◽  
E. Kwak ◽  
J. Baselga ◽  
J. Rodon ◽  
C. Scheffold ◽  
...  
Keyword(s):  
Steady State ◽  
Solid Tumors ◽  
Skin Rash ◽  
Dose Escalation ◽  
Plasma Concentrations ◽  
Safety Data ◽  
Pi3k Pathway ◽  
Dependent Manner ◽  
Dose Escalation Study ◽  
Grade 3

3500 Background: XL147 is a selective inhibitor of Class I PI3K isoforms. In preclinical cancer models XL147 is cytostatic or cytoreductive as monotherapy and enhances the efficacy of targeted agents and chemotherapeutics. This open label, Phase 1 dose escalation study assesses the safety, pharmacokinetics, pharmacodynamics, and efficacy of XL147 in advanced solid tumors. Methods: For each 28 day cycle, patients (pts) receive XL147 on Days 1–21 (21/7) or as a continuous daily dose (CDD). Cycle 1 safety data determine dose-limiting toxicities (DLTs). Tumor response is assessed every 8 weeks. Results: As of December 2008, 39 pts have been treated: 36 on 21/7 across 7 dose levels (30–900 mg) and 3 on CDD at 100 mg. At 900 mg, 2 of 3 pts experienced a DLT of reversible grade 3 rash, and the MTD was established as 600 mg based on 15 pts. Drug-related toxicities included grade 3 skin rash (3 pts), grade 3 arterial thrombosis (1 pt), grade 2 transaminase elevation (1 pt), and grade 1 hyperglycemia (4 pts). XL147 exposure increased with dose from 30–400 mg and was similar from 400–900 mg. XL147 reached steady-state plasma concentrations by Day 15–20. Mean t1/2, z at steady-state ranged from 3.7–6.3 days. Doses ≥400 mg yielded exposures that exceeded the EC90 in xenograft models. A trend suggesting augmented food-induced changes in insulin was evident; however, glucose was minimally affected. XL147 reduced levels of phosphorylated PI3K pathway components in PBMCs, hair, skin, and tumor tissues in an exposure-dependent manner. In 2 pts dosed at the MTD, reductions of ≥70% in PI3K pathway signaling were observed in tumor tissue without compensatory upregulation of MEK/ERK phosphorylation. As of December 2008, 6 pts (3 NSCLC, 1 BCC, 1 NHL, 1 PC) continued on study >6 months including 3 >10 months (NHL, NSCLC, BCC). One pt with hormone refractory PC has sustained a normalization of PSA levels through 5 months. Conclusions: XL147 was generally well tolerated with the MTD for the 21/7 schedule defined as 600 mg. The most common drug-related toxicity was skin rash. Inhibition of PI3K pathway signaling has been demonstrated in tumor and surrogate tissues. Prolonged stable disease has been observed. [Table: see text]

A pharmacokinetic (PK) pharmacodynamic (PD) driven first-in-human study of the oral class I PI3K inhibitor CH5132799, in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3022-3022 ◽  
Author(s):  
Aurelius Gabriel Omlin ◽  
James F. Spicer ◽  
Debashis Sarker ◽  
David James Pinato ◽  
Roshan Agarwal ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Platelet Rich Plasma ◽  
Pik3ca Mutation ◽  
Human Study ◽  
Maximum Tolerated Dose ◽  
Pi3k Inhibitor ◽  
Class I ◽  
Ca 125 ◽  
Clinical Activity

3022 Background: The phosphatidylinositol 3-kinase (PI3K) pathway is a promising target in cancer. CH5132799 is a novel PI3K inhibitor, selectively inhibiting class I PI3Ks (α, β, δ and γ) with no inhibition of class II and III or mTOR, and with potent antitumor activity in preclinical studies (Tanaka et al, Clin Cancer Res; 17; 3272-81, 2011). First-in-human study objectives were determination of maximum tolerated dose (MTD), safety/tolerability, PK/PD and clinical activity (RECIST). Methods: A 3+3 dose escalation design was used. The initial dosing schedule of CH5132799(schedule A) was once a day (QD). Due to a relatively short half-life, a twice a day (BID) schedule (schedule B) was introduced. PK profiles were studied over 72 hours. PD analyses included quantification of various phosphoproteins in platelet rich plasma (PRP). Tumor assessments were performed at baseline and cycle 3 day 1 (C3D1) and FDG-PET scans at baseline, C1D8 and C3D1. Results: 29 patients (pts) with a variety of solid tumors have been treated (A 23 pts, B 6 pts, the most common tumors were breast, oesophageal, colorectal and ovarian). The starting doses were 2 mg (A) and 48 mg (B). The current doses being explored are 96 mg (A) and 72 mg (B). The most frequently reported drug-related AEs were Grade 1/2 diarrhea, nausea, fatigue, anorexia and anemia. 1 DLT (Grade 3 elevated LFT) was observed in a hepatocellular carcinoma pt at 48 mg BID. MTD has not yet been determined. The preliminary mean ±SD Cmax and AUC at 96 mg QD were 202±129 ng/ml and 1407±935 ng·hr/ml respectively, which is consistent with an efficacious exposure based on preclinical models. Some patients achieved the expected exposure at over 32 mg. From single dose of 48mg there was a reduction of phosphorylation of AKT in PRP after treatment, consistent with pathway modulation. A patient with clear cell ovarian cancer and a PIK3CA mutation treated at 48 mg BID showed >50% decrease in SUV on a PET scan at C1D8 and a 75% decrease in CA-125 at C2D1. 5 pts exhibited SD (>8 weeks). Conclusions: CH5132799 is well tolerated either QD ≤96 mg or BID ≤48 mg. Dose-escalation continues and updated safety/efficacy/PK/PD data will be presented.

scholarly journals AKT Inhibition in Solid Tumors With AKT1 Mutations

2017 ◽  
Vol 35 (20) ◽  
pp. 2251-2259 ◽  
Author(s):  
David M. Hyman ◽  
Lillian M. Smyth ◽  
Mark T.A. Donoghue ◽  
Shannon N. Westin ◽  
Philippe L. Bedard ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Kinase Inhibitor ◽  
Human Cancer ◽  
Neutral Loss ◽  
Evaluation Criteria ◽  
Predictive Biomarkers ◽  
Progression Free Survival ◽  
Pi3k Pathway ◽  
Genomic Context ◽  
Biomarker Analysis

Purpose AKT1 E17K mutations are oncogenic and occur in many cancers at a low prevalence. We performed a multihistology basket study of AZD5363, an ATP-competitive pan-AKT kinase inhibitor, to determine the preliminary activity of AKT inhibition in AKT-mutant cancers. Patients and Methods Fifty-eight patients with advanced solid tumors were treated. The primary end point was safety; secondary end points were progression-free survival (PFS) and response according to Response Evaluation Criteria in Solid Tumors (RECIST). Tumor biopsies and plasma cell-free DNA (cfDNA) were collected in the majority of patients to identify predictive biomarkers of response. Results In patients with AKT1 E17K–mutant tumors (n = 52) and a median of five lines of prior therapy, the median PFS was 5.5 months (95% CI, 2.9 to 6.9 months), 6.6 months (95% CI, 1.5 to 8.3 months), and 4.2 months (95% CI, 2.1 to 12.8 months) in patients with estrogen receptor–positive breast, gynecologic, and other solid tumors, respectively. In an exploratory biomarker analysis, imbalance of the AKT1 E17K–mutant allele, most frequently caused by copy-neutral loss-of-heterozygosity targeting the wild-type allele, was associated with longer PFS (hazard ratio [HR], 0.41; P = .04), as was the presence of coincident PI3K pathway hotspot mutations (HR, 0.21; P = .045). Persistent declines in AKT1 E17K in cfDNA were associated with improved PFS (HR, 0.18; P = .004) and response ( P = .025). Responses were not restricted to patients with detectable AKT1 E17K in pretreatment cfDNA. The most common grade ≥ 3 adverse events were hyperglycemia (24%), diarrhea (17%), and rash (15.5%). Conclusion This study provides the first clinical data that AKT1 E17K is a therapeutic target in human cancer. The genomic context of the AKT1 E17K mutation further conditioned response to AZD5363.

388 Preliminary results from KEYNOTE-A36, a study of GB1275, a first-in-class oral CD11b modulator, alone and with pembrolizumab or chemotherapy in specified advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A413-A413
Author(s):  
Johanna Bendell ◽  
Wells Messersmith ◽  
Drew Rasco ◽  
Andrea Wang-Gillam ◽  
Wungki Park ◽  
...  
Keyword(s):  
Adverse Events ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Tumor Tissue ◽  
Phase 1 ◽  
Cancer Center ◽  
List Type ◽  
Advanced Solid Tumors ◽  
Serial Blood ◽  
Biomarker Analysis

BackgroundGB1275 is a first-in-class CD11b modulator that reduced myeloid-derived suppressor cells (MDSCs) and tumor associated macrophages (TAMs), repolarized M2 immunosuppressive TAMs to an M1 phenotype, and increased tumor infiltration of activated CD8+ T cells in preclinical models. Preclinical anti-tumor activity was observed with single-agent therapy and in combination with chemotherapy or immuno-oncology therapies.1 We report results from the dose escalation portion of an ongoing, first-in-human study of GB1275 monotherapy and combined with pembrolizumab in patients with specific advanced solid tumors. (NCT04060342)MethodsThis study comprises phase 1 dose escalation followed by phase 2 expansion in specific tumor types. In phase 1, cohorts of 3 to 6 patients with histologically confirmed, locally advanced/metastatic pancreatic, esophageal, gastric, MSS colorectal, metastatic castrate-resistant prostate cancer, or triple negative breast cancer are sequentially assigned to one of the ascending dose levels of GB1275 orally twice daily (BID) in 1 of 3 regimens: A (GB1275 monotherapy); B (GB1275 + pembrolizumab) commenced after completion of two cohorts of A; and C (GB1275 + nab-paclitaxel + gemcitabine) will be initiated after A. Patients in Regimens A and B had previously exhausted standard of care treatment options. Dose escalation was based on safety, including dose-limiting toxicity (DLT). Serial blood samples were collected for pharmacokinetic (PK) and biomarker analyses; tumor tissue was also collected for biomarker analysis.ResultsAs of July 28, 2020, 36 patients were treated, 23 in Regimen A (GB1275 100 mg to 1200 mg BID) and 13 in Regimen B (GB1275 100 mg to 800 mg BID + pembrolizumab). No DLTs or adverse events requiring steroid treatment were reported. GB1275-related adverse events were reported in 19 (52.8%) patients; most were Grade 1 and most frequent events (≥10%) were dysesthesia (13.9%) and photosensitivity reaction (11.1%). Stable disease was reported in 4 (17%) patients in Regimen A and 6 (46%) in Regimen B with a median (range) exposure of 84 days (35–172). A dose-dependent increase in GB1275 exposure was observed. An increase in tumor infiltrating lymphocyte (TIL) counts was noted in both Regimens A and B. Other biomarker analyses in serial blood and tumor tissue are ongoing.ConclusionsDose escalation of GB1275, up to 1200 mg and 800 mg BID in Regimens A and B, respectively, demonstrated tolerability as monotherapy and combined with pembrolizumab. The maximum tolerated dose has not been reached. Preliminary observation of an increase in TILs after treatment is encouraging.Ethics ApprovalThis ongoing study is being conducted in accordance with the Declaration of Helsinki and Council for International Organizations of Medical Sciences (CIOMS) International Ethical Guidelines. The study was approved by the Ethics Boards of the University of Colorado Hospital, Washington University School of Medicine - Siteman Cancer Center, Memorial Sloan Kettering Cancer Center, The Sarah Cannon Research Institute/Tennessee Oncology, South Texas Accelerated Research Therapeutics, and The Royal Marsden NHS Foundation Trust.ReferencePanni RZ, Herndon JM, Zuo C, et al. Agonism of CD11b reprograms innate immunity to sensitize pancreatic cancer to immunotherapies. Sci Transl Med 2019 Jul 3;11(499).

scholarly journals Synergistic interactions with PI3K inhibition that induce apoptosis

eLife ◽  
2017 ◽  
Vol 6 ◽  
Author(s):  
Yaara Zwang ◽  
Oliver Jonas ◽  
Casandra Chen ◽  
Mikael L Rinne ◽  
John G Doench ◽  
...  
Keyword(s):  
Small Molecule ◽  
Small Molecule Inhibitors ◽  
Tumor Regression ◽  
Pi3k Pathway ◽  
Induce Cell Cycle Arrest ◽  
Pi3k Inhibitors ◽  
Activating Mutations ◽  
Pi3k Inhibition ◽  
A Genome

Activating mutations involving the PI3K pathway occur frequently in human cancers. However, PI3K inhibitors primarily induce cell cycle arrest, leaving a significant reservoir of tumor cells that may acquire or exhibit resistance. We searched for genes that are required for the survival of PI3K mutant cancer cells in the presence of PI3K inhibition by conducting a genome scale shRNA-based apoptosis screen in a PIK3CA mutant human breast cancer cell. We identified 5 genes (PIM2, ZAK, TACC1, ZFR, ZNF565) whose suppression induced cell death upon PI3K inhibition. We showed that small molecule inhibitors of the PIM2 and ZAK kinases synergize with PI3K inhibition. In addition, using a microscale implementable device to deliver either siRNAs or small molecule inhibitors in vivo, we showed that suppressing these 5 genes with PI3K inhibition induced tumor regression. These observations identify targets whose inhibition synergizes with PI3K inhibitors and nominate potential combination therapies involving PI3K inhibition.

Rationally designed treatment for solid tumors with MAPK pathway activation

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2532-2532
Author(s):  
V. Karantza-Wadsworth ◽  
M. Stein ◽  
A. Tan ◽  
J. Mehnert ◽  
E. Poplin ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Dose Escalation ◽  
Maximum Dose ◽  
Tumor Regression ◽  
Mapk Pathway ◽  
Mitogen Activated Protein Kinase ◽  
Hematologic Toxicity ◽  
Pathway Activation ◽  
Combinatorial Treatment

2532 Background: Preclinical studies shed light to the mechanism conferring paclitaxel resistance in solid tumors with active Ras/Raf/Mitogen-Activated Protein Kinase (MAPK) pathway, and determined a molecular mechanism by which addition of the proteasome inhibitor bortezomib abrogated this resistance, enabling tumor regression in animals in vivo. Methods: A Phase I study was contacted to determine the MTD of paclitaxel and bortezomib combinatorial treatment. Sixteen patients with refractory solid tumors were treated with weekly paclitaxel and bortezomib. Six patients had NSCLC; 4, colon cancer; 2, pancreatic; 2, melanoma; 1, breast; 1, ovarian. Patients with baseline neuropathy greater than or equal to Grade 1 were excluded. The starting dose was 40 mg/m2 for paclitaxel and 0.7 mg/m2 for bortezomib. A modified continual reassessment method (MCRM) was used for dose escalation with 3-patient cohorts treated at each dose level. The Target Toxicity Level (probability of DLT at the MTD) was set at 25%. Maximum dose escalation was no more than 75% of the previous SED level, if no Grade 3 hematologic toxicity or DLT were observed. Otherwise, the maximum dose escalation was no more than 50% of the previous SED level. The process continued until SED changes were no more than 10% for two consecutive cohorts. Results: The MTD for the combinatorial treatment was reached at 60 mg/m2 paclitaxel and 1.0 mg/m2 bortezomib. Of 15 evaluable patients, 1 patient with paclitaxel-resistant NSCLC had PR and 5 patients (2, NSCLC; 1, pancreatic; 1, colon; 1, ovarian) had stable disease. Median TTP was 2.3 months (0.8 to 6 months). Three NSCLC patients achieved TTP longer than 5 months. The combination of paclitaxel and bortezomib was relatively well tolerated. Paclitaxel PK parameters are being determined, and paraffin-embedded tumor specimens are being evaluated for MAPK pathway activation by IHC for phospho-ERK. Results will be correlated with clinical response. Conclusions: The MTD for the proposed combinatorial treatment is 60 mg/m2 for paclitaxel and 1.0 mg/m2 for bortezomib, and is relatively well tolerated. Combination of paclitaxel with bortezomib is effective in taxane-resistant NSCLC, and worthy of further investigation. No significant financial relationships to disclose.

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