bluuebunny/crossref_metadata_2025 huggingface dataset:
Survival of patients considered for participation to contemporary dose-seeking phase trial: Matter of tumour burden, nature of treatment or of dose-levels?
Authors: Bouchet Juliette , Isambert Nicolas , Cassier Philippe Alexandre , Gomez-Roca Carlos Alberto , Clisant Stephanie , Delord Jean-Pierre , Favre Veronique , Philippe Peggy , Desmoulins Isabelle , Levart Alice , Meniai Fatima-Zhora , Penel Nicolas
Published: March 2020

2549

Background: We have analyzed the survival of pts considered for participation to contemporary phase 1 trial. Methods: All consecutive pts having signed the PIS/IC have been analyzed. OS have been measured using Kalan-Meier method. RMS had been calculated, RMS (0 to 3) is sum of the following prognostic factors: LDH>ULN, met. sites>2 and albumin <35 g/L. Comparisons have been done with Log-rank tests and Cox model. Results: OS of the entire cohort was 448 days. 73.4% of pts having been enrolled. Among not enrolled pts, 74.1% of pts received another treatment. The OS was 497, 247 and 110 days, in pts enrolled in phase I trial, in pts not enrolled but receiving another treatment and in non-treated pts (p=0.001). After adjustment to RMS and with pts not enrolled but receiving other treatment as reference, the HR was 0.47 (95-CI:0.34-0.66; p=0.0001) in pts enrolled in phase 1 compared and 3.54 (1.92-6.52; p=0.0001) in non-treated pts. We have then more specifically analyzed the pts enrolled in single-agent dose-escalating phase I. The OS was 894, 272 and 395 days in pts receiving the 2 first dose-levels, in those receiving intermediate dose-levels and those receiving the phase 2-recommended dose, respectively (p=0.001). The OS was 328 in pts receiving molecular targeted agent and 539 in those receiving cytotoxic agents (p=0.004). In a multivariate analysis, the nature of investigational agent and the dose-level were not associated with better outcome. The sole prognostic factor for OS in multivariate analysis was the RMS (0+1 vs 2+3: HR=3.80 [1.76-8.20], p=0.01). Conclusions: Inclusion in phase 1 trial was associated with better outcome in both crude analysis and after adjustment to RMS. Among enrolled pts, in multivariate analysis RMS reflecting the tumor burden was the sole prognostic factor, the nature of the drug and the dose-level were not associated with the outcome.
CTEP #8342 autophagy modulation with antiangiogenic therapy: A phase I trial of sunitinib (Su) and hydroxychloroquine (HCQ).
Authors: Melnyk Nataliya , Xie Xiaoqi , Koh Danny Ju Yong , Rajpal Megha , Moss Rebecca Anne , Gibbon Darlene , Cleary James M. , Tran Minh-Thu , Scott Pamela , Stein Mark N. , Tan Antoinette R. , Adams Shari , Lindquist Diana C. , Harris Pamela Jo , Takebe Naoko , Lin Hongxia , Aisner Joseph , White Eileen , DiPaola Robert S. , Mehnert Janice M.
Published: March 2020

2553

Background: Angiogenesis inhibitors promote autophagy, a response to nutrient deprivation in which autophagosomes (AP) and lysosomes fuse to recycle intracellular constituents, leading to sustained tumor viability. We hypothesized that the VEGF-R2, c-kit, PDGFR inhibitor Su induces autophagy. The autophagy inhibitor HCQ may then interfere with autophagy dependent tumor survival, possibly improving patient (pt) outcomes. Methods: This trial determined the MTD of Su+HCQ in pts with advanced malignancies using a 3+3 design. Su 50 mg qd was given in 4 week on/2 week off cycles (C) with daily HCQ in escalating dose cohorts. A MTD expansion cohort of 12 pts was also enrolled. Modulation of autophagy was measured by changes in the AP marker light chain-3 (LC3)II/I ratio in paired PBMC samples from C1 and C2. Results: 21 pts, median age 59, PS 0 (7), 1 (13) or 2 (1) enrolled, including 5 colon, 2 renal and 5 sarcomatous tumors. 4 DLTs were observed: 3 DLTs (gr 3 confusion, gr 3 colon fistula, gr 3 thrombocytopenia) in DL2 (50 mg Su, 200 mg bid HCQ), and 1 DLT (gr 3 dehydration) in DL1 (50 mg Su, 200 mg HCQ). DL1 was thus declared the MTD. Gr 3/ 4 toxicities included: related to Su, thrombocytopenia (14%), fatigue (19%), neutropenia (14%), hypertension (14%), intestinal perforation (10%); related to HCQ, fatigue (14%). PK data of Su alone, its active metabolite SU012662 and the total were evaluated using noncompartmental analysis. Cmax and AUCs of the active metabolite SU012662 significantly increased (p<0.005) during C2 relative to C1, indicating drug-drug interactions between HCQ and Su. 9 of 21 (43%) had stable disease for > 3 cycles (median 73 days). Inconsistent autophagy modulation was seen in PBMCs. LC3 immunohistochemistry on baseline tumor blocks to assess individual tumor autophagy levels is in progress. Conclusions: pK interaction between Su and HCQ resulting in accumulation of Su metabolites may be responsible for the predominantly Su-associated toxicities observed which prohibited further HCQ dose escalation. Lack of evidence for autophagy modulation is likely due to the inability to escalate HCQ to doses necessary to induce autophagy inhibition. Further study of this combination seems unwarranted. Clinical trial information: NCT00813423.
Phase I trial of ADI-peg 20 plus docetaxel (DOC) in patients (pts) with advanced solid tumors.
Authors: Tomlinson Ben Kent , Bomalaski John S. , Diaz Monica , Akande Taiwo , Mahaffey Nichole , Li Tianhong , Dutia Mrinal P. , Kelly Karen , Gong I-Yeh , Gandara David R. , Pan Chong-xian , Lara Primo
Published: March 2020

2569

Background: ADI-PEG20 is an enzyme that degrades arginine (Arg), an amino acid relevant to biosynthetic pathways of normal and malignant cells. It has shown tolerability and activity in several solid tumors. Preclinical studies have shown that Arg deprivation by ADI-PEG 20 in cancer cells induces autophagy, caspase-independent apoptosis, and potentiates DOC-induced cytotoxicity in prostate cancer (PC) models. A phase I trial (standard 3+3 design) of ADI-PEG20 (IM weekly) plus DOC (IV on day 1 q 3 weeks) was conducted to assess feasibility and safety of the combination. Methods: Eligible pts were >18 years of age, had advanced malignant solid tumors, adequate end organ function, and performance status (PS) 0-2. ADI-PEG 20 was escalated over 4 dose levels (4.5, 9, 18, 36 mg/m2). DOC dose was 75 mg/m2. Dose limiting toxicity (DLT) was defined as any of the following in cycle 1: thrombocytopenia [grade (Gr) 3 with bleeding/transfusion, or Gr 4]; neutropenia with fever or documented infection attributable to ADI PEG20; or any ≥ Gr 3 non-heme toxicity related to study drug except alopecia. Allergic reaction associated with DOC was not considered a DLT. Serum levels of Arg were serially measured. Results: 18 pts were accrued: median age, 64.5 yrs; male, 83%; PS 0, 72%. Most common tumors were NSCLC (8), PC (3), and tongue cancer (TC) (2). Median number of prior systemic therapies was 3. One DLT was seen in dose level 1 (urticarial rash) requiring expansion of that dose level to 6 pts. No additional DLTs attributable to ADI PEG20 were seen. Serious adverse events (all expected and attributed to DOC) were recorded in 11/18 pts, including Gr IV neutropenia (6, 33%) and Gr IV anemia (2, 11%). There were 2 on-study deaths unrelated to protocol therapy. In 11 pts with evaluable disease, 1 with TC had a partial response (PR), 6 had stable disease (SD) (3 NSCLC, 2 PC, 1 TC). Arg levels decreased in the 1st cycle for 6/11 pts with available data, including 2 with SD, and 1 with PR. Conclusions: The combination of ADI PEG20 and DOC is feasible with reasonable tolerability in this heavily pre-treated cohort. Full doses of both agents were achievable: ADI-PEG 20 at 36mg/m2 with DOC 75 mg/m2. An expansion cohort of castration resistant PC pts is now accruing at this recommended dose. Clinical trial information: NCT01497925.
Novel toxicity endpoint for dose-finding designs evaluating molecularly targeted agents (MTA).
Authors: Ezzalfani Monia , Zohar Sarah , Mandrekar Sumithra J. , Vassal Gilles , Le Deley Marie-Cécile
Published: March 2020

2577

Background: The emergence of MTA in oncology has revolutionized the phase I design paradigm. The usual dose-limiting toxicity (DLT) endpoint is an oversimplification of the complex toxicity profile resulting in loss of information. Moreover, MTAs can induce less DLTs but more multiple moderate toxicities that may lead to dose reduction in long lasting treatment. We thus sought to develop a new toxicity endpoint, the Total Toxicity Profile (TTP), to incorporate multiple toxicities. Methods: We reanalysed the phase I trial that evaluated erlotinib (75, 100, 125, 150 mg/m2) in children with brain stem glioma (NCT00418327). Only 2/21 patients experienced protocol defined DLTs, but multiple moderate toxicities were observed. The TTP endpoint is a weighted combination of all toxicities experienced by the patient (Euclidean norm of the weights), where the weights (ranging from 0 to 10) reflect the clinical importance of each grade and type of toxicity. The weights and the acceptable toxicity target (target TTP) were elicited from 3 clinicians using hypothetical patient cohorts with various toxicity outcomes. They were asked to make a decision of where the next cohort of patients would be treated: higher, lower or same dose level. The target TTP was defined as the mean of TTPs of the cohorts associated with a decision to repeat the dose. We used the TTP-driven Quasi-Likelihood Continual Reassessment Method (QL-CRM) to re-estimate the recommended dose. Results: Clinicians identified 5 main dermatological toxicity types possibly attributable to erlotinib. The consensus weights (table below) as well as the target TTP (set at 4.66) were easily obtained, confirming the feasibility of the process. The weights differed from the CTCAE grades, confirming the interest of the approach. The recommended dose based on the retrospective analysis of all grades toxicity was lower than that identified by the DLT-driven CRM (100 instead of 125mg/m2). Conclusions: By neglecting multiple moderate toxicities, DLT-driven designs may over-estimate the recommended dose when investigating MTA. Our proposal is an appealing alternative design for MTA. [Table: see text]
Can estimated glomerular filtration rate (eGFR) replace isotopic measurement of GFR for carboplatin dosing in stage 1 seminoma?
Authors: Shepherd Scott T.C. , Gillen Gerry , Morrison Paula , Forte Carla , MacPherson Iain R. , Mark Patrick , White Jeff D.
Published: March 2020

2589

Background: Accurate determination of GFR is essential for correct dosing of carboplatin, the standard adjuvant therapy for stage 1 seminoma. Isotopic methods (e.g. 51Cr-EDTA) remain the gold standard for determination of GFR. However, the use of eGFR could reduce the need for such isotope studies. As novel formulae to estimate GFR such as CKD-EPI and MDRD4 have improved the assessment of renal function in non-oncological settings, we investigated their utility for carboplatin dosing. Methods: 115 patients (pts) (mean age 40.3, std dev. 10.1) who received adjuvant carboplatin for stage 1 seminoma at our institution between 2007-2012 were identified. All pts underwent 51Cr-EDTA measurement of GFR with carboplatin dose calculated using the Calvert formula, based on GFR uncorrected for body surface area (BSA). Theoretical carboplatin doses were then calculated using eGFR values obtained using the CKD-EPI and MDRD4 formulae with additional calculation to uncorrect for BSA. Creatinine clearance was calculated by Cockcroft-Gault (CG) formula. For each pt the carboplatin doses calculated by eGFR were compared with the actual dose calculated by the gold-standard method; a difference of less than 10% was considered acceptable. Results: The Table shows the percentage of pts who would have received an equivalent carboplatin dose using each eGFR formula compared to the dose calculated using 51Cr-EDTA. The CKD-EPI formula performed best with 58.9% of pts receiving within 10% of the correct dose. Pts predicted to be underdosed by CKD-EPI eGFR were more likely to be obese (BMI >30) (p=0.01); there were no predictors of the 18.8% who would have received an excess dose. Conclusions: Our data support further evaluation of the CKD-EPI formula but highlight the clinically significant variances in carboplatin dosing when using non-isotopic methods of GFR estimation. [Table: see text]
Copper transporter CTR1 expression and tissue platinum concentration in NSCLC.
Authors: Kilari Deepak , Tang XiMing , Chow Chi-Wan , Fujimoto Junya , Kalhor Neda , Swisher Stephen , Wistuba Ignacio Ivan , Stewart David J. , Siddik Zahid Hussain , Kim Eric S.
Published: March 2020

2601

Background: Platinum (Pt) resistance is a major limitation in the treatment of advanced non-small cell lung cancer (NSCLC). We previously demonstrated that low tissue Pt concentration in NSCLC tumor specimens was significantly associated with reduced tumor response and worse survival. Furthermore, low expression of the copper transporter CTR1, a transporter of Pt uptake is reported to be associated with poor clinical outcome following Pt-based therapy in NSCLC patients. However, a defect in CTR1expression as a causative factor in reduced Pt accumulation in NSCLC tissues is not well-established. We investigated the relationship between tissue Pt concentrations and CTR1 expression in NSCLC specimens. Methods: We identified paraffin-embedded NSCLC tissue blocks from 30 patients who underwent neoadjuvant Pt-based chemotherapy with known tissue Pt concentrations at MD Anderson Cancer Center. Expression of CTR1 was determined by immunohistochemistry with adequate controls; 0 = undetectable; 1+ = barely detectable staining; 2+ = readily appreciable staining; and 3+ = dark brown staining. Pt concentration was compared between different CTR1 expression groups. Results: Tissue Pt concentration significantly correlated with tumor response in 30 patients who received neoadjuvant Pt-based chemotherapy (P<0.001). There was an uneven distribution of CTR1 expression scores with a majority of specimens demonstrating scores of 2+ (N=15, 50%). There were 2 specimens with no detectable CTR1 expression (score of 0) and 6 patients with a score of 3+. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentrations compared to those with scores of 3+ (P=0.014). Furthermore, those with undetectable CTR1 expression had reduced tumor response compared to those with scores of 3+ following Pt-based chemotherapy (P=0.039). Conclusions: To the best of our knowledge, this is the first study to correlate CTR1 expression in clinical specimens to both tumor Pt uptake and response. Patients with undetectable CTR1 expression in their tumors had significantly lower Pt concentration and reduced tumor response. Further evaluation with a larger sample size is required. (Supported by 2012 ASCO Young Investigator Award)
Phase I expansion trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid tumors.
Authors: Varga Andrea , Mita Monica M. , Wu Jennifer J. , Nemunaitis John J. , Cloughesy Timothy Francis , Mischel Paul S. , Bendell Johanna C. , Shih Kent C. , Paz-Ares Luis G. , Mahipal Amit , Delord Jean-Pierre , Kelley Robin Katie , Soria Jean-Charles , Wong Lilly , Xu Shuichan , James Angela , Wu Xiaoling , Chopra Rajesh , Hege Kristen , Munster Pamela N.
Published: March 2020

2606

Background: CC-223 is an ATP-competitive inhibitor of the mTOR kinase, including both TORC1 and TORC2. CC-223 was selected to address resistance of rapamycin analogues mediated by TORC2 activation. Methods: Following establishment of the MTD (reported at ASCO 2012), subjects with select advanced, refractory solid tumors, including NSCLC, HCC, NET, GBM and breast were enrolled in expansion cohorts of up to 20 evaluable subjects. CC-223 was dosed at 45 mg once daily in 28 day cycles until disease progression. Results: As of 09 January, 2013, 101 solid tumor subjects have been treated, including NSCLC (26), HCC (25), NET (23), breast (14), and GBM (13). Results from the NSCLC, HCC, and GBM cohorts are reported here; NET results are reported separately. The most common (> 20%) related adverse events (all grades) were fatigue, rash, stomatitis, hyperglycemia, anorexia, nausea, vomiting and diarrhea. In addition, related serious adverse events included infection (1), pneumonitis (4), renal insufficiency (2) and pancreatitis (2). CC-223 dose reduction was required in > 50% of subjects with NSCLC and HCC, usually during cycle 1 or 2. Exposure-dependent TORC1 (p4EBP1) and TORC2 (pAKT) inhibition was observed across cohorts. mTOR pathway inhibition and/or decreased proliferation was demonstrated in paired tumor biopsies, but results were inconsistent. Reduction in glucose uptake (> 25% decrease in SUV) on PET imaging at day 15 was observed in 78% (14/18) of NSCLC and 69% (11/16) of HCC subjects. Partial tumor responses were observed in evaluable subjects with NSCLC (1/17; confirmed, treatment duration 36 weeks) and HCC (3/15; 1 confirmed, treatment duration 15 – 26 weeks). Disease control rate in the overall NSCLC cohort was 42% (11/26) and in the HCC cohort, 40% (10/25). GBM subjects underwent salvage resections on study and none were progression-free at 6 months. CC-223 was present in all (11/11) resected GBM tumors with plasma:tumor ratios of 16 - 77%, confirming transit across the blood-brain barrier. Conclusions: Encouraging signals of biomarker and clinical activity were observed in HCC and NSCLC. Due to the frequency of dose reductions, select additional cohorts will be enrolled at a starting dose of 30 mg QD. Clinical trial information: NCT01177397.
A phase I study of MK-2206 in combination with lapatinib in patients (pts) with advanced solid tumors.
Authors: Wisinski Kari Braun , Tevaarwerk Amye , Bell Maria , Burkard Mark E. , Eickhoff Jens C. , Wilding George , LoConte Noelle K. , Traynor Anne M. , Hoang Tien , Heideman Jennifer , Kolesar Jill , Liu Glenn
Published: March 2020

2607

Background: The AKT protein kinase is a key mediator of signaling in the human epidermal growth factor receptor-2 (HER2) pathway. HER2 inhibition can result in feedback regulation of signaling, leading to high AKT activity. Preclinical studies demonstrate activity of combined HER2 and AKT inhibition. Lapatinib is an oral tyrosine kinase inhibitor of HER2. MK-2206 is an oral selective inhibitor of AKT with a maximum tolerated dose (MTD) of 60mg qod. Both agents cause rash and diarrhea. This study was designed to determine the MTD, dose limiting toxicities (DLTs), adverse events (AEs), clinical activity and pharmacokinetic (PK) parameters of the combination. Methods: This phase I study evaluated the safety of MK-2206 (30-60 mg qod) and lapatinib (1000-1500 mg qd) continuously. Cycles were 28 days, except cycle 1 (35 days), due to a 1 week MK-2206 lead-in to evaluate for PK interactions. Because of the continuous nature of therapy, protocol-specified intolerable grade 2 AEs were considered DLTs during cycle 1. Results: 23 pts (median age 59 [range 22-72];15 female:8 male) were enrolled. The most common malignancies were colorectal (8 pts), lung (4 pts), and breast (3 pts). 4 pts were unevaluable per protocol; 19 evaluable pts were on study a median of 8 weeks (range 3-35). 3 pts experienced DLTs. At dose level one, 1 pt had grade (gr) 3 hyponatremia and fatigue. At dose level four, 1 pt had gr 4 hyponatremia, gr 3 rash and hypocalcemia and 1 pt had intolerable gr 2 mucositis with delivery of <75% of drug. The most common AEs at least possibly related to therapy included diarrhea (gr 3-4 in 3 pts; gr 1-2 in 16 pts), nausea (gr 3 in 2 pts; gr 1-2 in 14 pts) and rash (gr 3 in 2 pts; gr 1-2 in 12 pts). The MTD was 45mg po qod of MK-2206 with 1500 mg po qd of lapatinib, exceeding biologically active doses for each agent. One pt with adrenal cortical carcinoma was on study for 6 months with stable disease (SD) and 1 pt with colorectal cancer was on study for 5 months with significant tumor marker decline and SD. PK analyses are ongoing. Conclusions: MK-2206 in combination with lapatinib is well-tolerated at biologically active single agent doses. Anti-tumor activity will be evaluated further in a dose expansion cohort in pts with advanced HER2-positive breast cancer. Clinical trial information: NCT01245205.
A first-in-human phase I trial of AR-12, a PDK-1 inhibitor, in patients with advanced solid tumors.
Authors: Mateo Joaquin , De Bono Johann Sebastian , Ramanathan Ramesh K. , Lustberg Maryam B. , Zivi Andrea , Basset Dawn , Ng Matthew , Young Anna-Mary , Garrett Michelle , Decordova Shaun , Raynaud Florence I. , Yap Timothy Anthony , Zukiwski Alexander A. , Proniuk Stefan , Shapiro Charles L.
Published: March 2020

2608

Background: AR-12 (OSU-03012) is an oral celecoxib analogue lacking COX-2 inhibitory activity that inhibits pyruvate dehydrogenase kinase isoenzyme 1 (PDK-1), AKT and impacts the endoplastic reticulum stress pathway. Preclinical studies indicate antitumor activity of AR-12 in various models and enhanced activity in combination. We completed a first in human clinical trial to determine its safety and tolerability, maximum tolerated dose (MTD) and recommended phase II dose (RD). Secondary objectives included assessment of tumor response, pharmacokinetics (PK) and pharmacodynamics (PD) including food effect. Methods: Patients (pts) with advanced solid tumors, ECOG PS 0-1, and adequate organ function were recruited in a modified 3+3 dose-escalation study. Pts received a run-in dose of AR-12 to analyze PK-PD and food effect, followed by continuous daily (QD) dosing in 28-day cycles. A twice daily (BID) cohort was initiated based on safety data. PD analysis was performed in platelet-rich plasma (PRP) and paired tumor biopsies when feasible. Results: 35 pts received at least one dose of study drug; 30 were evaluable for dose limiting toxicities (DLT) at dose ranges 100-3200mg QD and 800-1600mg BID. No DLT were observed in the QD cohort; DLT in the BID cohort are listed in table 1. Drug-related events (NCI-CTCAE v3) included rash (G2-2pts; G3-1pt), fatigue (G2-2pts; G3-4pts), nausea (G2-7pts; G3-1pt) and bloating (G2-1pt). Cmax after single dose was dose-proportional but high PK variability was observed, likely due to inadequate disintegration and dissolution of the formulation in the stomach. At RD, partial GSK3ß inhibition in PRP after 4 hours suggests AKT-pathway modulation. Best response (RECIST v1.0) was stable disease >6 cycles for 2 pts. Conclusions: The RD based on safety data is 800mg BID. Signs of pathway modulation were observed in concordance with the expected mechanism of action but were short-lasting. Considering limited drug absorption and PK variability, a new formulation of the drug will be developed to overcome these limitations. Clinical trial information: NCT00978523. [Table: see text]
Protein pathway activation mapping guided biomarker development to identify optimal combinations of MEK inhibitor with PI3K/mTOR pathway inhibitors for the treatment of triple-negative breast cancer.
Authors: Schweber Sarah J. , Rodriguez-LaRocca Alicia G. , Calvert Valerie , Petricoin Emanuel , Horwitz Susan Band , Andreopoulou Eleni , McDaid Hayley M.
Published: March 2020

2612

Background: Activated MAPK and PI3K pathway signaling are associated with poor prognosis in triple negative breast cancer (TNBC). Although some TNBC cell models are sensitive to MEK inhibition, feedback activation of the PI3K pathway mediates resistance. Thus, suppression of both arms of the MAPK/PI3K/mTOR network is a rational approach to targeting TNBC. Here we explore the anti-tumor efficacy of combinations of MEK inhibitor with PI3K, AKT, or mTOR inhibitors with a focus on biomarker development. Methods: Combinations of the MEK inhibitor PD-0325901 with the PI3K inhibitor GDC-0941, AKT inhibitor MK-2206, dual mTORC 1/2 inhibitor Torin 1, or the rapalog temsirolimus were evaluated in TNBC cell lines. Synergy was assessed using the combination index method of Chou and Talalay. We utilized reverse-phase protein array to map the signaling architecture of the treated lines to verify target suppression and identify pharmacodynamic biomarkers. Results: All combinations demonstrated synergy that was mediated by both suppression of proliferation and cell death in a dose-dependent manner. Cell death was delayed, peaking at least 96 hours post-dosing, and was associated with sustained suppression of target proteins in both pathways, including pERKT202/Y204, pS6rpS235/236, p4EBP-1S65, and pPRAS40T246. However, suppression of pAKT (at T308 or S473) was variable and not consistently required for cell death. Pathway mapping identified a protein network ‘signature’ specific to all combination therapies that emerged at 72 hours and was associated with cell death. Thus, all combinations appear to share common downstream effectors. All combinations showed promising efficacy and will be evaluated in a human-in-mouse model of TNBC. Conclusions: These data support therapeutic strategies for TNBC that simultaneously inhibit both arms of the MAPK/PI3K/mTOR signaling network. For continued biomarker development, we stress the importance of studying the delayed effects of combination therapy. This strategy coupled with a protein network based approach uncovered a unique functional signaling ‘signature’.
A combination of dual PI3K-mTOR inhibitor, GDC-0980, with PARP inhibitor plus carboplatin blocked tumor growth of BRCA-competent triple-negative breast cancer cells.
Authors: Dey Nandini , Sun Yuliang , Carlson Jennifer , Friedman Lori , De Pradip , Leyland-Jones Brian
Published: March 2020

2613

Background: PARP is a promising target in the TNBC. The PI3K pathway, in addition to its pro-proliferative effects on tumor cells, also controls the repair of DSB (Kumar, 2010; Friedman, 2009; Juvekar, 2012; Ibrahim, 2012). We hypothesize that the growth of TNBC tumor will be blocked due to the inhibition of (1) HR / NHEJ, and (2) PI3K-mTOR pathway mediated survival signals following GDC-0980 (G), when combined with PARP inhibitor (impaired DNA-SSB-repair), and carboplatin (C) (increased DNA-DSB). Methods: We tested the in vivo efficacy of a combination of G with ABT888 (A) plus C in BRCA-competent TNBC cells, and compared the triple combination arm (A+C+G) with a combination arm of A+C+ pan PI3K inhibitor GDC-0941 in mice xenograft (MDA-MB231) model. Mechanistically, we tested, (1) cell survival/ proliferation (5-7 BRCA-wt and mutant cell lines) using MTT assay, CelltiterGLO, and cell cycle analyses, (2) anchorage independent and dependent clonogenic growth (3D ON-TOP and soft-agar assay), (3) apoptosis, and (4) cell signaling marker(s). Results: (1) G alone decreased the tumor growth by 40-50%. (2) The G + A + C combination blocked the growth of established tumors by 90% as compared to control(s). (3) Interestingly, G + A + C combination had markedly higher percentage of inhibition of tumor growth than the inhibition observed in the A+C+GDC-0941 arm (36%). (4) G treatment time-dependently increased cl-caspase 3, 9, and cl-PARP and increased AnnexinV positivity both time (24 and 48 hrs) and dose dependently (50 and 200 nM) in cells. (5) G when combined with A+C was most effective in inducing apoptosis in PIK3CA-mutated BT20 cells. (6) The triple combination (50 nM G+10 μM A + 10 μM C) inhibited clonogenic growth of MDA-MB231, MDA-MB468 and BT20 cells. (7)Treatment of G decreased downstream effectors of PI3K-mTOR pathway, pAKTS473, pP70S6K and pS6RP. Conclusions: Tumor growth of BRCA-competent TNBC cells is blocked by a combination treatment of G with A+C. The profound anti-tumor effect of this triple combination can be explained by the anti-proliferative and pro-apoptotic actions of the drugs. The combination of G with A+C merits further investigation in TNBC.
A first-in-human phase I study of ER-α36 modifier icaritin in patients with advanced solid tumors.
Authors: Fan Ying , Xu Binghe , Ding Xiaoyan , Ma Fei , Wang Jiayu , Yuan Peng , Luo Yang , Li Qing , Zhang Pin , Cai Ruigang
Published: March 2020

2614

Background: ER-α36 was recently identified to be expressed in varieties of cancers and may play important roles in carcinogenesis and tumor progression. Icaritin, a natural prenylflavonoid derived from the Chinese herb Epimedium, is a first of its kind ER-α36 modifier, which demonstrated potent anti-tumor effect in multiple cancer cell lines and their xenograft models. This study aims to determine its safety, tolerability, pharmacokinetics (PK), and potential antitumor activity. Methods: This phase I study comprises phase Ia and Ib. In phase Ia part, patients with advanced breast cancer (ABC) were treated with escalating doses of Icaritin orally once daily on a continuous 28-day dosing schedule. In phase Ib part, dosing was fixed to 600 or 800mg twice daily and expansion was made to other selected malignancies including hepatocellular cancer (HCC), colorectal cancer (CRC) and intrahepatic cholangiocarcinoma (ICC) to further explore PK parameters and efficacy. Results: 24 patients were enrolled to receive Icaritin at six dose levels ranging from 50mg to 1600mg per day in phase Ia. No dose limited toxicity (DLT) was found even in the highest dose defined in the protocol, thus the maximum tolerated dose (MTD) was not reached. Only grade 1 drug-related adverse events were observed including neutropenia, ALT elevation, hypercholesteremia, fatigue, anorexia, hypertriglyceridemia, proteinuria, myalgia, hot flash and rash. PK data from the fed dosing showed 3-fold increase of Cmax and AUC compared with the fast dosing. Half life was around 2-7 hours. Among 22 evaluable subjects, no complete or partial response (CR or PR) was detected, 5 patients had stable disease(SD)for 3 months or longer. For phase Ib study, 24 patients had been enrolled. One ABC, 2 CRC and 3 ICC patients progressed after 2 months of medication. Among 7 HCC patients already evaluated, 1 obtained PR and progressed after one year of treatment and 2 remained in the study, stable for 5 months. Similar drug related toxicity profile was noted in phase Ib. Conclusions: Icaritin was generally well-tolerated without DLT across tested dose levels. Evidence of promising antitumor activity was observed in ABC and HCC. Final results will be presented at the meeting. Clinical trial information: NCT01278810.
Peripheral and tumor immune correlates in patients with advanced melanoma treated with combination nivolumab (anti-PD-1, BMS-936558, ONO-4538) and ipilimumab.
Authors: Callahan Margaret K. , Horak Christine E. , Curran Michael A. , Hollman Travis , Schaer David A. , Yuan Jianda , Lesokhin Alexander M. , Kitano Shigehisa , Hong Quan , Ariyan Charlotte Eielson , Busam Klaus J. , Feely William , Jure-Kunkel Maria , Grosso Joseph , Simon Jason S. , Korman Alan J. , Wigginton Jon M. , Gupta Ashok Kumar , Sznol Mario , Wolchok Jedd D.
Published: March 2020

3003^

Background: Nivolumab and ipilimumab are fully human monoclonal antibodies that block the immune checkpoint receptors PD-1 and CTLA-4, respectively. In a multi-cohort, phase I study of nivolumab/ipilimumab combination therapy in melanoma patients (pts), objective response rates up to 47% were observed (NCT01024231). Putative predictive biomarkers from peripheral blood (PB) or tumor, including tumor PD-L1 expression, absolute lymphocyte count (ALC) and PB myeloid derived suppressor cells (MDSC) were evaluated. Pharmacodynamic changes in activated and effector T cells were also assessed. Methods: Tumor PD-L1 membrane expression was assessed in archival FFPE specimens by immunohistochemistry (28-8 PD-L1 antibody). ALC was measured in serial PB samples; changes in the percentage, number and phenotype of activated CD4+ and CD8+T cells and MDSC were characterized by flow cytometry. Results: PD-L1 expression was seen in 37% (10/27) of pts, using a cut-off of 5% tumor cell membrane staining. Objective responses (OR) were seen in pts with both PD-L1 negative (8/17) and PD-L1 positive (4/10) tumors. Relative to baseline, a rise in ALC was not detected, but phenotypic changes in PB T-cell subsets, including increases in the percentage of CD4 and CD8 expressing HLA-DR, ICOS and/or Ki67 were seen with combination therapy. Low ALC (<1.0 at wk 6-7) did not preclude OR as 3 of 12 pts with low ALC responded. Of pts evaluated, OR with ≥80% reduction in tumor burden at 12 wk were seen in pts with a low frequency of pretreatment PB MDSC (3/7) but no OR were seen in pts with high MDSC (0/6). Conclusions: In this small subset of pts,OR were seen independent of PD-L1 or ALC status in contrast to prior observations with nivolumab or ipilimumab, respectively. Thus, the immune response generated by combination therapy may have unique features compared to either monotherapy. The relationship between frequency of PB MDSC and reduction in tumor burden will be further explored. Further efforts in this study and in future phase III randomized studies will investigate these and other phenotypic changes in immune cell populations and their relationship to patterns of clinical activity. Clinical trial information: NCT01024231.
EGF-based cancer vaccine: Optimizing predictive and surrogate biomarkers.
Authors: Crombet Ramos Tania , Neninger Elia , Gonzalez Jorge , Rodriguez Pedro Camilo , Garcia Beatriz , Popa Xitlally , Mazorra Zaima , Viada Carmen , Luaces Patricia Lorenzo , Gonzalez Gisela , Lage Agustin
Published: March 2020

3013

Background: EGFR is overexpressed in many epithelial tumors. EGF is one of the most important growth factors that stimulates EGFR, in a paracrine way. CIMAvax-EGF is a therapeutic cancer vaccine intended to induce antibodies against EGF. It is composed by recombinant EGF conjugated to P64 from N.Meningitides as a carrier and Montanide, as adjuvant. Methods: Two controlled trials were done in advanced NSCLC and castration-resistant prostate cancer patients (CRPC). A multicentric, randomized Phase III trial was designed to assess the efficacy, immunogenicity, and safety of CIMAVAx-EGF in advanced NSCLC patients. Patients with histology- or cytology-proven NSCLC at stage IIIB/ IV were enrolled. All subjects received 4 platinum-based cycles before entering the study. On the other hand, a multicentric, randomized Phase II trial was designed to assess the immunogenicity and safety of the vaccine in CRPC patients. The EGF cancer vaccine was administered in combination with mitoxantrone and prednisone. Results: 405 patients bearing NSCLC and 200 men with CRPC were enrolled in the 2 trials. In both studies the vaccine was immunogenic. Antibody titers against EGF increased with vaccination and EGF concentration in sera showed a fast reduction after immunization. The anti-EGF antibody response was directly correlated with overall survival. CIMAVax-EGF was safe and most prevalent adverse events were grade 1-2 injection site pain, fever, headache, nausea, vomiting, and chills. The vaccine significantly increased the survival of the NSCLC patients while it did not augment significantly the overall survival of the CRPC patients. In both studies, EGF concentration was measured at baseline and it was found to be much higher than in normal subjects. High EGF concentration predicted greater benefit after vaccination. On the contrary, NSCLC and prostate control patients with high levels of EGF had a poorer outcome. Conclusions: Antibody response against EGF is a surrogate marker of survival. High EGF concentration might be a predictive marker of vaccine efficacy and a poor prognostic biomarker for non-vaccinated NSCLC and CRPC patients. The predictive and prognostic value of the EGF concentration will be validated prospectively. Clinical trial information: IIC EC 081.
Association of tumor PD-L1 expression and immune biomarkers with clinical activity in patients (pts) with advanced solid tumors treated with nivolumab (anti-PD-1; BMS-936558; ONO-4538).
Authors: Grosso Joseph , Horak Christine E. , Inzunza David , Cardona Diana M. , Simon Jason S. , Gupta Ashok Kumar , Sankar Vindira , Park Jong-Soon , Kollia Georgia , Taube Janis M. , Anders Robert , Jure-Kunkel Maria , Novotny Jim , Taylor Clive R. , Zhang Xiaoling , Phillips Therese , Simmons Pauline , Cogswell John
Published: March 2020

3016

Background: The immune checkpoint receptor programmed death-1 (PD-1) negatively regulates T-cell activation. In a phase I study, nivolumab, a PD-1 receptor blocking antibody, demonstrated durable clinical activity. Evaluation of the expression of the PD-1 ligand, PD-L1, by IHC with the 5H1 Ab suggested a correlation between pretreatment tumor PD-L1 expression and clinical response (Topalian et al, NEJM 2012). Methods: 304 pts with non-small cell lung cancer (NSCLC, n=127), melanoma (MEL, n=107), renal cell (RCC, n=34), colorectal (n=19) or prostate cancer (n=17) received nivolumab between 2008-2012 (0.1−10 mg/kg IV Q2W) during dose escalation and/or cohort expansion. Formalin-fixed paraffin-embedded tumor tissue and peripheral blood mononuclear cells (PBMC) were analyzed to explore potential pharmacodynamic/ predictive biomarkers associated with nivolumab therapy. Tumor surface PD-L1 expression was evaluated by IHC using an automated assay based on a sensitive and specific PD-L1 mAb (28-8) distinct from 5H1. PD-L1 positivity (PD-L1+) was defined as ≥5% cell membrane staining of any intensity. Lymphocyte subsets in PBMC were measured using flow cytometry. Results: Tumor membrane PD-L1 was measured in 101 MEL and NSCLC pts. 17/38 (45%) of MEL and 31/63 (49%) of NSCLC biopsies were PD-L1+. A numerically higher objective response rate (ORR), longer progression-free survival (PFS), and overall survival (OS) was seen with PD-L1+ in MEL pts (Table).Analysis of the association of PD-L1 expression with ORR, PFS and OS in NSCLC is ongoing. A correlative analysis of pt response with pre-/post-dose levels of lymphocytes will be presented. Conclusions: These data, using a novel, automated PD-L1 IHC assay and mAb, support the hypothesis of tumor PDL1+ predicting activity of nivolumab in advanced cancer, which is being prospectively assessed in phase III trials. Clinical trial information: NCT00730639. [Table: see text]
Deletion and mutation of IL10RA gene on chromosome 11q23 to avert CpG-B oligodeoxynucleotides-induced apoptosis of human chronic lymphocytic leukemia B cells.
Authors: Liang Xueqing , Bachanova Veronika , Chen Wei
Published: March 2020

3023

Background: Targeting TLR9 expressed on human CLL cells with CpG-B oligodeoxynucleotides leads to IL-10-induced tyrosine phosphorylation of STATs and apoptosis of B-CLL cells. However, B-CLL cells from a small subset of patients were resistant to CpG-B ODN treatment. Here, we investigated the molecular mechanism by which B-CLL cells are sensitive or resistant to CpG-B ODN treatment. Methods: Purified CD19+CD23+CD5+primary B-CLL cells were cultured for 5 days with/without CpG-B ODN (CpG 2006, CpG 685) or rh-IL-10. B-CLL cell apoptosis were determined by viable cell counts, Annexin V/PI and TMRE staining, Western blot and intracellular staining of the activation/cleavage of caspases, PARP, Bax translocation and cytochrome c release, IL-10R1 expression and IL-10 binding by flow cytometry, IL10RA gene deletion by FISH, IL10R1 S138G mutation by Bi-PASA, The tyrosine or serine phosphorylation of STATs by Western blot. Results: Fifteen CpG-sensitive and 11 CpG-resistant primary CLL samples were comparatively studied. B-CLL cells from 15/15 CpG-sensitive samples were induced into apoptosis by either CpG-B ODNs or IL-10 in a treatment time and dose-dependent manner. Both CpG-B ODNs and IL-10 significantly increased pTyr701-STAT1/pTyr705-STAT3 expression and induced apoptosis via the mitochondrial apoptotic pathway in 15 primary B-CLL cells. No IL-10RA gene deletions were detected, 13/15 patients were IL10R1 S138G AA wildtypes and 2/15 patients were AG heterozygotes. In contrast, CpG-B ODNs or IL-10 failed to induce apoptosis in 11/11 CpG-resistant B-CLL cells. Interesting, 2/11 CLL samples had IL10RA genes deletion and 7/11 had IL10R1 S138G GG homozygote mutation. IL10RA gene deletion significantly decreased the IL10R1 expression; both IL10RA gene deletion and mutation significantly decreased the IL-10 binding, abolished or reduced CpG-B ODNs or IL10-induced pTyr701-STAT1/pTyr705-STAT3 expression in B-CLL cells. Conclusion: Deletion and mutation of IL10RA gene on chromosome 11q23 averts CpG-B ODN-induced apoptosis of human B-CLL cells, which may serve as biomarker to predict sensitivity or resistance of CLL to CpG-B ODN treatment.
Investigating genes and micro-RNAs that may predict clinical benefits of anti-CTLA-4 therapy.
Authors: Gao Jianjun , Chen Hong , Ng Tang Derek , Sharma Padmanee
Published: March 2020

3043

Background: Blockade of T cell co-inhibitory receptor CTLA-4 with a monoclonal antibody, ipilimumab, has led to augmented anti-tumor immune responses, clinical benefit, and FDA approval of ipilimumab for the treatment of metastatic melanoma. Only a subset of patients benefit from anti-CTLA-4 therapy. In order to identify genes, microRNAs, and signaling pathways that are modulated by anti-CTLA-4, which may be used for potential correlation with clinical outcomes or provide additional targets for therapy, we purified and analyzed CD4+T cells from patients treated with anti-CTLA-4 for changes in gene and microRNA expression profiles. Methods: On an IRB-approved phase Ia presurgical clinical trial, 6 patients with localized bladder cancer were treated with two doses of ipilimumab at 10 mg/kg at weeks 1 and 4. Pre-therapy and post-therapy blood samples were collected for CD4+ T cell enrichment by using the T cell isolation kit from Miltenyi Biotec (Auburn, CA). RNA and microRNA were isolated from purified CD4+T cells using Qiagen RNA isolation kits for Affymetrix microarray and micoRNA array analyses. Microarray data were then analyzed using Ingenuity iReport (Redwood City, CA). RT-PCR and Western blot were used to confirm significant changes in genes or pathways identified in microarray analyses. Results: Anti-CTLA-4 treatment resulted in modulation of differentially expressed genes (DEGs). After two doses of treatment, anti-CTLA-4 significantly changed expression of a total of 289 DEGs. Further pathway analyses indicated that anti-CTLA-4 induced a variety of pathways involved in cell proliferation and immune modulation, including PI3K/AKT, MAP/ERK, and IFN/JAK-STAT pathways. We have also identified 9 microRNAs that potentially regulate the expression of genes changed by anti-CTLA-4 therapy. Conclusions: Anti-CTLA-4 treatment results in modulation of multiple genes, microRNAs, and pathways, which likely play important roles in anti-tumor immune responses. We are currently testing a number of these identified genes and microRNAs as potential predictive biomarkers for anti-CTLA-4 therapy in a small cohort of patients who had complete response vs. progression of disease after anti-CTLA-4 therapy.
Therapeutic superiority of a TCR-like antibody to an intracellular WT1 oncogene peptide compared with the tyrosine kinase inhibitor imatinib in a mouse model of Philadelphia chromosome positive (Ph+) ALL.
Authors: Dubrovsky Leonid , Brea Elliott Joseph , Veomett Nicholas J , Dao Tao , Yan Su , Liu Cheng , Scheinberg David A.
Published: March 2020

3047

Background: Acute and chronic leukemias demonstrate significantly increased expression of the Wilms tumor gene 1 (WT1) product, including CD34+ CML stem cells, making WT1 an attractive therapeutic target. However, WT1 protein is intracellular and currently un-druggable. ESKM is a fully human IgG1 antibody that targets a 9 amino acid sequence (RMF) of the protein WT1 in the context of HLA-A0201. Methods: BV173 is an HLA-A0201 positive Ph+ ALL cell line. It over-expresses WT1 and binds strongly to ESKM. We evaluated the in vitro and in vivo efficacy of ESKM in combination with TKIs. Antibody-dependent cell-mediated cytotoxicity (ADCC) was evaluated in vitro by chromium release assay, utilizing human PBMC effectors. In vivo tumor growth was assessed in NSG mice bearing disseminated luciferase tagged BV173 with bioluminescence imaging and flow cytometry of the bone marrow after sacrifice. Imatinib was used at maximum tolerated doses for these mice as determined in pilot studies. Results: The addition of imatinib in vitro did not affect the ability of ESKM to perform ADCC. The BV173 engrafted NSG mice treated with ESKM with and without TKIs showed tumor regression one week after beginning therapy, clearing leukemia from the liver and spleen. Mice relapsed primarily in the bone marrow, with increasing luciferase signal after two weeks of therapy. Compared to untreated control animals, after 5 weeks of therapy, imatinib alone only reduced tumor growth by 45%; ESKM alone reduced growth by 81%, and the combination of ESKM and imatinib reduced growth by more than 95%. Flow cytometry of cells remaining after treatment showed binding of ESKM, suggesting escape was not due to down regulation of the epitope. Conclusions: In this mouse model of Ph+ ALL, ESKM antibody therapy is superior to imatinib and the combination of both modalities is additive. This antibody is efficacious in vitro and in vivo against WT1 overexpressing leukemias, in context of HLA-A0201. This combination holds promise as a therapy for leukemias in patients who are HLA-A0201 positive, with the potential of improved cytoreduction in patients with Ph+ leukemias.
Phase II study of dendritic cell vaccination combined with recombinant adenovirus-p53 in treatment for patients with advanced pancreatic carcinoma.
Authors: Chai K , Ai Yq , Jiang Lw
Published: March 2020

3049

Background: There are few choices of treatments for advanced pancreatic carcinoma (PC) due to the resistances to chemo- or radio-therapy. Immunotherapy based on dendritic cell (DC) vaccines and p53-based gene therapy are two promising therapeutic modalities. They also demonstrated favorable safety profiles. In this study, we compared the immunological and clinical response between DC vaccine therapy and DC vaccine combined with recombinant adenovirus-p53 (rAd-p53) gene therapy. Methods: Thirty-six patients with a stage IV pancreatic cancer, 21 men and 15 women with an average age of 56.2 years old, were included in this study and randomly assigned to two groups: 16 patients in DC group (DCG) and 20 in DC plus rAd-p53 group (DPG). The DCG patients received autologous antigen-loaded DC (antigen from isolated pancreatic cancer cells) and the DPG patients received both DC and rAd-p53. DC vaccines were injected intra-dermally once every week for 4 injections and rAd-p53 were given by intravenous injections once per 3 days for 5 times at a dose of 3 x 1012viral particles. The response, safety and peripheral blood lymphocyte subsets were investigated. Results: The post-treatment CD3+, CD3+CD4+, CD4+/CD8+ ratio of patients’ peripheral blood in both groups were increased. But the percent of CD4+CD25+ regulatory T cells were significantly decreases. In DPG, 5 patients had a partial response (PR) and 4 patients had stable disease (SD) according to the RECIST standard. The 3 and 3 DCG patients achieved a PR and SD, respectively. The disease control rates (PR+SD) were 45.0% and 37.5% for DPG and DCG, respectively. The 6-month overall survival rates were 50.0% and 43.8% for DPG and DCG, respectively. The median survival times were 6.8 and 5.5 months for DPG and DCG, respectively. Mild to medium grade fever was observed in most of the patients in the two groups. No serious adverse events were found. Conclusions: DC-based immunotherapy and p53 gene therapy are safe and appropriate treatments for patients with advanced pancreatic carcinoma. The combined treatments showed more beneficial results than the DC immunotherapy alone.