bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I and biodistribution study of ABT-806i, an 111indium-labeled conjugate of the tumor-specific anti-EGFR antibody ABT-806.
Authors: Gan Hui Kong , Burge Matthew E. , Solomon Benjamin J. , Holen Kyle D. , Zhang Yumin , Ciprotti Marika , Merdan Thomas , Munasinghe Wijith , Pedersen Michelle , Hintzman Patricia F. , Fox Gerard B. , Humerickhouse Rod A. , Scott Andrew Mark
Published: March 2020

2520

Background: ABT-806 is a humanized antibody targeting a conformationally exposed epitope only available when tumor Epidermal Growth Factor Receptor (EGFR) is overexpressed or (EGFRvIII) mutated. A prior trial treated 8 patients (pts) with a chimeric homologue (single-dose 5-40 mg/kg), with a minor response in one squamous cell carcinoma of skin pt. A prior phase 1A study of ABT-806 treated 26 pts (2-24 mg/kg IV q2w), with prolonged SD in one head and neck (H&N) cancer pt. No pt had a typical EGFR-inhibitor rash. The current study gathers further ABT-806 clinical data, assesses ABT-806i dosimetry in normal and malignant tissues and examines its relationship to clinical and PK/PD data. Methods: Pts with advanced tumors likely to express EGFR, ECOG 0-2, measurable disease and adequate organ function were enrolled. ABT-806i scans comprised ABT-806i 5-7mCi injection followed by whole body and regional SPECT scans over one week. Cohort (C) 1 pts (n=6) had ABT-806i scans alone. C2 pts (n=12) had ABT-806i scans at baseline and at week 6 (after 3 fortnightly doses of ABT-806; 6 pts at 18 mg/kg and 6 at 24 mg/kg). Subjects with PR/SD could receive ABT-806 on an extension study until progression. Results: 18 pts (M:F 11:7; median age 57 yrs) with tumors of H&N (6), colon (3), lung (2), brain (2), bladder (1), cervical (1) and other (3) were treated. An H&N pt had a confirmed PR whilst 5 pts had SD (lasting 37 and 24 wks in an adrenal carcinoma and H&N pt respectively). Two potential toxicities were seen at 24mg/kg on the extension study: equivocal rash (G1; three transient lesions on nose) and allergic reaction (Sweet’s syndrome, G2). Dosimetry in C1 pts confirmed safe radiation exposure levels to normal tissues. Many pts showed high, specific tumor uptake of ABT-806i, including 1 pt with an intracranial tumor. ABT-806i uptake was not significantly affected by concurrent ABT-806 treatment. Ongoing analyses of how ABT-806i uptake correlates with tumor EGFR and clinical response may inform the recommended phase 2 dose of ABT-806. Conclusions: The high therapeutic index and specificity of ABT-806 merits further investigation as monotherapy or an antibody-drug conjugate. ABT-806i may have utility as a bioimaging agent. Clinical trial information: NCT01472003.
A first-in-human trial of RG7116, a glycoengineered monoclonal antibody targeting HER3, in patients with advanced/metastatic tumors of epithelial cell origin expressing HER3 protein.
Authors: Meulendijks Didier , Lolkema Martijn P. J. K. , Voest Emile E. , De Jonge Maja J. , Sleijfer Stefan , Schellens Jan HM , Fleitas Tania , Cervantes-Ruiperez Andres , Martinez-Garcia Maria , Taus Alvaro , Soerensen Morten Mau , Thomas Marlene , Meneses-Lorente Georgina , Adessi Celine , Di Scala Lilla , Keelara Abiraj , Jacob Wolfgang , Weisser Martin , Lassen Ulrik Niels
Published: March 2020

2522

Background: The Human Epidermal Growth Factor Receptor 3 (HER3) is a key heterodimerization partner for other HER family members thereby acting as a downstream signal amplifier. This is a first in human study evaluating the safety of RG7116, a humanized anti-HER3 monoclonal antibody with potent HER3 signal inhibition. Due to a glycoengineered Fc-part this antibody displays enhanced antibody-dependent cellular cytotoxicity as compared to conventional antibodies. Methods: Patients (pts) with advanced or metastatic carcinomas with centrally confirmed HER3 protein expression were included. A “3+3” dose escalation design was performed starting at 100 mg flat dosing in a q2w regimen. In addition to single agent RG7116 (Part A), RG7116 plus cetuximab (Part B) and RG7116 plus erlotinib (Part C) combinations are evaluated. The results of Part A are presented. Results: Twenty-five pts have been enrolled in 6 cohorts (100 to 2000 mg). No DLTs were observed. Pts had a median (range) of 3 (2 to 6) prior chemotherapy lines. Nine infusion-related reactions (IRRs) Gr 1 to 3 occurred in 7 pts. Three drug-related AEs Gr 3 were reported, 1 IRR, 1 GGT increase, and 1 neutropenia. Only 1 patient was tested positive for human anti human antibodies (HAHA). The PK of RG7116 was non-linear from 100 mg up to 400 mg, possibly as a result of target-mediated drug disposition. Both Cmax and AUC showed a greater than doseEproportional increase over the same dose range, accompanied by a decline in total clearance. Dose proportionality was observed from 800 mg onwards. PD effects were observed from the first dose level onwards with HER3 membranous protein down-regulation in skin and from 200 mg onwards in ontreatment tumor samples. Five pts (1 NSCLC, 2 CRC, 1 SCCHN, 1 BC) had a best response of SD. Confirmed SD (>16 weeks) was observed in 2 pts. One BC patient achieved a PR in 18 FDG-PET and significant shrinkage of non-target tumor lesions on CT scan. Conclusions: RG7116 is the first glycoengineered monoclonal anti-HER3 antibody in clinical development. RG7116 monotherapy was well tolerated, and demonstrated preliminary signs of clinical activity. Clinical trial information: NCT01482377.
Combination of a MEK inhibitor, pimasertib (MSC1936369B), and a PI3K/mTOR inhibitor, SAR245409, in patients with advanced solid tumors: Results of a phase Ib dose-escalation trial.
Authors: Heist Rebecca Suk , Gandhi Leena , Shapiro Geoffrey , Rizvi Naiyer A. , Burris Howard A. , Bendell Johanna C. , Baselga Jose , Yerganian Scott B , Hsu Karl , Ogden Janet , Vincent Loïc , Richter Oliver von , Locatelli Giuseppe , Asatiani Ekatherine , Infante Jeffrey R.
Published: March 2020

2530

Background: PI3K/mTOR and MAPK signaling pathways are often deregulated in tumors. Simultaneous inhibition of these pathways with the MEK1/2 inhibitor, pimasertib, plus the dual PI3K/mTOR inhibitor, SAR245409, (ClinicalTrials.gov NCT01390818) was investigated. Methods: This was a phase Ib, modified 3+3, dose-escalation trial in patients (pts) with advanced solid tumors. Pts received pimasertib and SAR245409 at the following dose levels (DLs): DL1, 15/30; DL2a, 30/30; DL2b, 15/50; DL3, 30/50; DL4a, 60/50; DL4b, 30/70; DL5, 60/70; DL6a, 90/70; DL6b 60/90 and DL7, 90/90 mg (once-daily, qd). After the qd maximum tolerated dose (MTD) was established, twice-daily (bid) dosing was tested: DL1a, 60/30; DL1b, 45/50 and DL2 60/50 mg bid. A recommended phase II dose (RP2D) was determined. Enrollment continued at the RP2D in four expansion cohorts (18 pts each): dual KRAS/PIK3CA mutated (mt) colorectal cancer (CRC), triple-negative breast cancer, KRAS mt non-small cell lung cancer (NSCLC) and BRAFmt melanoma. Results: 53 pts were treated qd and 7 pts bid. The most common tumors were CRC (n=16), NSCLC (n=8), ovarian and pancreatic (n=7, each). At DL6b 2/3 pts had dose-limiting toxicities (DLTs; both grade [Gr] 3 nausea/vomiting). DL6a was confirmed as the MTD for the qd schedule. At bid DL1a 2/4 pts (both Gr 3 skin rash) and at DL1b 2/3 pts (Gr 3 skin rash and Gr 3 asthenia) had DLTs. DL5 was the RP2D based on tolerability after prolonged exposure. The most common adverse events in qd schedule were: rash (62%, 13% Gr 3), diarrhea (56%, 4% Gr 3), fatigue (51%, 2% Gr 3), nausea (49%, 2% Gr 3), vomiting (45%, 2% Gr 3), peripheral edema and pyrexia (34%, each) and visual impairment with underlying serous retinal detachment (21%). Preliminary pharmacokinetic results suggest no drug-drug interaction. There were 4 partial responses: KRAS mt CRC (n=1) and low-grade ovarian cancer (n=3, 1 KRAS mt/PIK3CA mt and 2 wild-type). Enrollment in expansion cohorts at DL5 is ongoing. Conclusions: Continuousqd dosing of pimasertib and SAR245409 is tolerated and has shown signs of activity. Phase II trials are being planned. Clinical trial information: NCT01390818.
Safety, pharmacokinetics, and preliminary activity of the α-specific PI3K inhibitor BYL719: Results from the first-in-human study.
Authors: Gonzalez-Angulo Ana M. , Juric Dejan , Argilés Guillem , Schellens Jan HM , Burris Howard A. , Berlin Jordan , Middleton Mark R. , Schuler Martin H. , Geel Robin Van , Helgason Thorunn , Bootle Douglas , Boehm Markus , Goggin Timothy K. , Demanse David , Quadt Cornelia , Baselga Jose
Published: March 2020

2531

Background: BYL719 is an oral small-molecule inhibitor of the p110α catalytic subunit of phosphatidylinositol 3-kinase (PI3K), which is encoded by the PIK3CA gene, one of the most commonly mutated genes in human cancers. BYL719 inhibits proliferation of PI3Kα-driven cancer cell lines in vitro and causes regression of PIK3CA-mutant tumor models in vivo. Methods: This Ph I study was performed in patients (pts) with advanced solid tumors carrying a somatic mutation of PIK3CA. Dose escalation used an adaptive Bayesian logistic regression model with overdose control. Following determination of the maximum tolerated dose (MTD), an expansion cohort was opened at the MTD to evaluate safety, pharmacokinetics (PK), and clinical activity in pts with PIK3CA-mutant advanced solid tumors, including estrogen receptor-positive (ER+) metastatic breast cancer (mBC). Results: During dose escalation 36 pts received doses up to 450 mg/d, where 4/9 pts had dose-limiting toxicities (DLTs). The MTD for once-daily dosing was declared as 400 mg/d. As of Nov 20 2012, DLTs were hyperglycemia, nausea, vomiting, and diarrhea. The most common BYL719-related adverse events (all grades, all cohorts, >25%) were hyperglycemia (49%), nausea (45%), diarrhea (40%), decreased appetite (38%), vomiting (30%), and fatigue (27%). 39 pts are enrolled in the MTD dose-expansion cohort. Investigation of a twice-daily regimen is also ongoing. BYL719 has a favorable, approximately dose-proportional PK profile with a Tmax of 2h and a T½ of 11h at the MTD. Partial responses were seen in 7 pts (in ER+ breast [2], cervical, trichilemmal, endometrial, ovarian, and head &neck cancer [1 each]); 17 pts stayed on study for >24 weeks. For 67 pts (76%) treated at doses of ≥270 mg/d, the median progression-free survival (mPFS) was 3.6 months (mo; 95% CI: 3.5–5.5 mo). mPFS in 15 ER+ HER2– mBC pts treated at ≥270 mg/d was 5.5 mo (95% CI: 3–7 mo). Conclusions: BYL719 displays dose-proportional and predictable PK. The safety profile is favorable, with mostly manageable on-target toxicities. At doses of ≥270 mg/d, tumor regression and prolonged disease control were observed in heavily pretreated pts with various tumor types carrying a PIK3CA mutation. Clinical trial information: NCT01219699.
First-in-human evaluation of the human monoclonal antibody vantictumab (OMP-18R5; anti-Frizzled) targeting the WNT pathway in a phase I study for patients with advanced solid tumors.
Authors: Smith David C. , Rosen Lee S. , Chugh Rashmi , Goldman Jonathan Wade , Xu Lu , Kapoun Ann , Brachmann Ranier K , Dupont Jakob , Stagg Robert J. , Tolcher Anthony W. , Papadopoulos Kyriakos P.
Published: March 2020

2540

Background: The WNT pathway is a key oncologic pathway in numerous tumor types. Vantictumab is a first-in-class anti-Cancer Stem Cell (CSC) antibody that interacts with the extracellular domain of 5 Frizzled receptors (1, 2, 5, 7, 8) and blocks canonical Wnt signaling (PNAS 109, 11717). In patient-derived xenograft models, vantictumab inhibits growth of many tumor types, reduces CSC frequency, promotes differentiation of tumor cells, and synergizes with many chemotherapeutic agents. Methods: Using a 3+3 design, vantictumab was given intravenously, first every 1 week (q1w) or q2w, and, ultimately, q3w. Objectives were determination of maximum tolerated dose, safety, pharmacokinetics (PK), pharmacodynamics (PD), and efficacy. Results: 18 patients have been treated in 5 dose-escalation cohorts (0.5 & 1 mg/kg q1w; 0.5 mg/kg q2w; 1 & 2.5 mg/kg q3w). Most common related adverse events (AEs) included Grade 1 and 2 fatigue, vomiting, abdominal pain, constipation, diarrhea and nausea. Only related Grade ≥3 AEs were dose-limiting toxicities of Grade 3 diarrhea and vomiting in 1 patient at 1 mg/kg q1w. Vantictumab clearance was dose-dependent, consistent with target-mediated drug disposition, with the half-life ranging from 1.5 (0.5 mg/kg) to 3 days (2.5 mg/kg). Exposure at highest dosed cohorts correlates with efficacy in preclinical tumor models. PD biomarkers indicate manipulation of WNT pathway in patient tumors and surrogate tissue. 1 patient at 0.5 mg/kg q1w had a bone fracture on Day 110 with an ~4-fold increase by Day 28 of β-C-terminal telopeptide (β-CTX), a marker for bone degradation. A revised safety plan and less frequent dosing enabled further dose escalation. Upon β-CTX doubling, 2 patients received zoledronic acid, and β-CTX returned to baseline. 3 patients with neuroendocrine tumors (NETs) had stable disease (SD) for 7+, 3.5, and 9+ months; ~2-, 4- and 7-fold longer, respectively, than on prior therapy. Conclusions: Vantictumab is well tolerated up to 2.5 mg/kg q3w. Bone toxicity appears manageable and reversible. Prolonged SD in 3 patients with NETs may represent single-agent activity. Dose escalation continues. Clinical trial information: NCT01345201.
A dose-escalation phase I study of a first-in-class cancer stemness inhibitor in patients with advanced malignancies.
Authors: Langleben Adrian , Supko Jeffrey G. , Hotte Sebastien J. , Batist Gerald , Hirte Hal W. , Rogoff Harry , Li Youzhi , Li Wei , Kerstein David , Leggett David , Hitron Matthew J. , Li Chiang
Published: March 2020

2542

Background: Cancer Stem Cells (CSC) are considered to be fundamentally responsible for malignant growth, relapse, metastasis, and resistance to conventional therapies. BBI608 is an orally-administered first-in-class cancer stemness inhibitor which blocks CSC self-renewal and induces cell death in CSC as well as non-stem cancer cells by inhibition of the Stat3, Nanog and b-catenin pathways, and has shown potent anti-tumor and anti-metastatic activities pre-clinically. Methods: A phase 1 dose escalation studyin adult patients with advanced cancer who had failed standard therapies was conducted to determine the safety, tolerability, recommended phase 2 dose (RP2D), pharmacokinetics and preliminary anti-tumor activity of BBI608. A modified Simon accelerated titration scheme was used for dose escalation, with a cycle consisting of twice-daily oral administration of BBI608 for 4 weeks. Cycles were repeated every 4 weeks (28 days) until progression of disease, unacceptable toxicity, or other discontinuation criteria were met. Results: Fourteen cohorts (N=41) were dosed from 20 mg to 2000 mg/day with adverse events being generally mild; the most common being grade 1-2 diarrhea, nausea, anorexia and fatigue. Four grade 3 events included diarrhea (n=3) and fatigue (n=1). MTD was not reached and further dose escalation was limited by pill burden. By the 400 mg/day dose level the plasma concentration of BBI608 was sustained for over 8 hours at a concentration above 1.5 uM (several fold above the IC50). 17/26 patients evaluable for tumor response achieved SD, for a DCR of 65%. Prolonged TTP was observed in 12/26 evaluable patients (46%), including patients with colorectal (CRC), head and neck, gastric, ovarian, melanoma, and breast cancer. In the subset of patients with CRC (N=18), SD was seen in 8/12 evaluable (67%). A median PFS of 14 weeks and median OS of 47 weeks were observed in evaluable CRC patients. Conclusions: Dose escalation of BBI608, a first-in-class cancer stem cell pathway inhibitor, has been achieved without dose limiting toxicity. BBI608 has shown an excellent safety profile, favorable pharmacokinetics, and encouraging signs of clinical activity particularly in CRC Clinical trial information: NCT01775423.
Influence of mild and moderate hepatic impairment on the pharmacokinetics (PK) of the pan-HER inhibitor dacomitinib.
Authors: Giri Nagdeep , Plotka Anna , Liang Yali , Boutros Tanya , Ni Grace , Masters Joanna , DeMicco Michael , Pardo Patricia , Bello Carlo , O'Connell Joseph
Published: March 2020

2568

Background: Dacomitinib (D) is a highly selective irreversible small molecule inhibitor of the HER family of tyrosine kinases in clinical development for NSCLC.Prior clinical studies of D, which has minimal renal excretion (~3%), enrolled pts with protocol-defined adequate liver function. Liver metastases, leading to abnormal liver function tests, are common in pts with advanced cancer. This study evaluated the effect of hepatic impairment on PK and safety of D following a single oral dose in subjects with mild or moderate hepatic impairment. Methods: In this phase I, open-label, parallel group study, 25 subjects with either normal hepatic function (n=8) or mild (Child-Pugh A; n=8) or moderate (Child-Pugh B; n=9) hepatic impairment were administered a single, oral dose of D (30 mg). PK samples were collected at intervals up to 264 h post-dose and safety was assessed by laboratory abnormalities, physical examination, vital signs, ECGs, and AE monitoring. Analysis of variance was performed on natural log-transformed AUC and Cmaxto estimate adjusted mean differences between groups and 90% CIs, which were exponentiated to produce the adjusted GMR and 90% CI of the ratios. Results: GMR and 90% CI for AUCinf and Cmax (preliminary analyses) are listed.Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Moderate hepatic impairment decreased D exposure by 15% and 20% for AUCinf and Cmax, respectively, vs normal hepatic function, but the 90% CI was relatively wide, and included 1. Plasma protein binding of D was similar in the 3 groups. No clinically significant treatment-related AEs were reported. Conclusions: Mean D exposure (AUCinf and Cmax) was similar in subjects with normal hepatic function and those with mild impairment. Mean D exposure appeared slightly lower in subjects with moderate impairment. Dose reduction of D in subjects with mild or moderate hepatic impairment may not be necessary. A single 30 mg dose of D was well tolerated in subjects with mild or moderate hepatic impairment. Clinical trial information: NCT01571388. [Table: see text]
A first-in-human phase I study of CZ48, a lactone ring protected oral camptothecin, in patients with advanced solid tumors.
Authors: Mahalingam Devalingam , Shaheen Montaser F. , Sarantopoulos John , Weitman Steven , Giovanella Beppino C. , Cao Zhisong , Coil Douglas , Markides Constantine , Liu Lucy , Verschraegen Claire F.
Published: March 2020

2578

Background: CZ48, the 20-O-propionate ester of camptothecin (CPT), is a prodrug of CPT first described by Cao et al. in 1998. The side-chain is enzymatically cleaved in tissues. This gives rise to CPT, a potent inhibitor of topoisomerase I. Methods: An open-label, single-arm, dose-escalation Phase I study was performed to determine the maximum tolerated dose (MTD) of CZ48 in patients with advanced solid tumors. Initial dosing started qd po 80mg/m2, advancing to 2560mg/m2 for 21 consecutive days, followed by 7 days rest. Dosing was restarted in cohorts of 3 patients tid po at 18mg/m2 and escalated to 1g/m2on a 5 days on, 2 days off schedule for 28 days. Patients were prescreened by measuring CPT levels in plasma following a single pilot dose of CZ48. Dose was doubled until occurrence of at least Grade 2 adverse event, at which time 3+3 patient cohorts with a dose escalation of 33%-100% were implemented. DLT in 2/6 patients defined the MTD as the preceding DLT dose. PK parameters were measured prior to dosing, days 1-5, and day 28 of Cycle 1. Results: Poor absorption led to initial qd dosing reaching 2560mg/m2 with no signs of DLT. Subsequent tid dosing showed improved plasma levels and arrival at DLT. 34 patients were treated across 8 dose levels from 18 to 1000 mg/m2. The most frequent study-related adverse effects were cystitis, vomiting, diarrhea and fatigue. Grade IV toxicities observed were febrile neutropenia, anemia, and thrombocytopenia. Preliminary PK data in the qd dosing showed poor correlation between dose and Cmax or AUC, while PK in tid patients showed slightly improved correlation between dose and both CZ48 AUC (Pearson's correlation coefficient ϱ=0.476, p<0.01) and CZ48 Cmax(ϱ =0.51, p<0.01). Evidence of clinical activity with stable disease ≥ 6 months was observed in 2 heavily pre-treated colon and one breast cancer patient. Conclusions: The MTD of tid po CZ48 administered 5 days on, 2 days off of 28-day cycle is between 750 mg/m2 and 576 mg/m2. Overall toxicity is relatively mild, with DLT being cystitis and myelosuppression. Even with tid dosing, PK values correlate poorly to dose. A new formulation with 3-5 fold higher preclinical absorption values is being considered for introduction into the trial. Clinical trial information: NCT00947739.
Final results of a phase I study of lapatinib (LAP) and cetuximab (CET) in patients with CET-sensitive solid tumors.
Authors: Deeken John F. , Wang Hongkun , Marshall John , Subramaniam Deepa Suresh , Hwang Jimmy J. , He Aiwu Ruth , Ramos Corinne , Hardesty Rosemarie A. , Steadman Kenneth , Weiner Louis M. , Pishvaian Michael J.
Published: March 2020

2616

Background: Acquired resistance to anti-EGFR MoAb therapy may be via EGFR-ErbB2 heterodimerization and pathway reactivation. Dual anti-EGFR treatment was recently found to be active in colon cancer. We performed a phase I trial of CET and LAP to determine the DLTs, MTD, and clinical activity of the combination. Methods: Pts received CET at 400mg/m2 then 250 mg/m2 weekly, combined with daily LAP in a 3+3 dose escalation trial. LAP dose levels (DL) were (1) 750mg, (2) 1000mg, and (3) 1250mg. Cycles lasted 3 weeks, toxicity was assessed through C2, and pts were restaged every 2 cycles. Baseline and post-C1 tumor biopsies were analyzed for phosphoprotein activation in 36 EGFR/ErbB2 pathway proteins. Germ-line pharmacogenetic (PGx) variations were correlated with efficacy and toxicity. Results: Between 10/2010 and 10/2012, 22 pts were enrolled - colon (8), lung (8), head and neck (4), and anal cancers (2) - and 59% had prior anti-EGFR therapy. 18 pts were evaluable for toxicity, and 18 for response. Mean treatment was 3.8 cycles (range 1 - 12); 3 patients are still on trial. One DLT occurred at DL1 (gr 3 rash) and DL2 (gr 3 diarrhea). No pt on DL3 experienced a DLT. No pt experienced a gr 4 toxicity; gr 3 toxicities anytime on therapy included rash (17%), diarrhea (6%), fatigue (6%), lymphopenia (6%), and hypomagnesemia (6%). Rash was experienced by 94% of pts (gr 1=50%, gr 2=28%, and gr 3=17%). Partial responses (PR) occurred in 4 pts (22%), stable disease (SD) in 8 (44%), and disease progression in 6 (33%), for a clinical benefit rate of 67%. Seven of 13 (54%) pts on prior EGFR therapy had SD or PR. Down-regulation of phosphorylated EGFR/ErbB2 pathway components correlated with response; distinct pathway components were up-regulated in non-responders, including PI3K, Jak/Stat, MAPK, and IGF. PGx variants in FcRII correlated with response (p=0.045); no variants correlated with toxicity. Conclusions: The RP2D is CET 250 mg/m2 weekly and LAP 1250mg daily. Treatment was well tolerated with few grade 3 toxicities and a significant 67% clinical benefit rate. Non-responders showed up-regulation of EGFR pathway components – components which are druggable, warranting further study. A trial in colorectal cancer is ongoing. Clinical trial information: NCT01184482.
First-in-human phase I study of CetuGEX, a novel anti-EGFR monoclonal antibody (mAb) with optimized glycosylation and antibody dependent cellular cytotoxicity.
Authors: Fiedler Walter , Sessa Cristiana , Gianni Luca , Cresta Sara , Schulze-Bergkamen Henning , Weidmann Jens , De Dosso Sara , Tessari Anna , Salzberg Marc Oliver , Baumeister Hans , Danielczyk Antje , Dietrich Bruno , Nippgen Johannes , Goletz Steffen
Published: March 2020

3008

Background: Epidermal growth factor receptor (EGFR) is a validated target in cancer. EGFR antagonists in clinical use do not exploit the full potential of this target. CetuGEX is an IgG1 mAb against EGFR. Fully human and optimized glycosylation lead to a 10- to 250-fold improvement of ADCC-mediated tumor cell killing in all FcγRIIIa allotypes and lack of immunogenic carbohydrate-chains, compared to cetuximab. Methods: Eligible patients with advanced solid tumors, progressing after standard treatment, were enrolled into this phase I, first-in-human, multicenter, single agent dose escalation trial. PK, PD and immunological parameters were assessed. Endpoints were safety and tolerability and secondarily pharmacokinetics, immunogenicity and anti-tumor activity. Results: 41 patients were treated on a q1w (8 dose levels from 12 to 1,370 mg flat dose), or q2w (990 mg flat) schedule. 25 pts had received at least 8 weekly doses (per protocol population [PP]).The most frequently observed drug-related AE were nausea (20%), vomiting (20%), hypertension (20%), almost all low grade and acneiform dermatitis (25%), only grade 1 or 2. Infusion-related reactions (IRR), virtually restricted to the first infusion, were associated with cytokine secretion: IL-6, IL-8, TNFα, IFNγ and IP-10 as marker of macrophage activation. Optimization of infusion scheme and premedication reduced IRRs in severity and frequency from 76% to 57% mainly of low grade. Blood NK cells were reduced as sign of redistribution. Activity was seen over all dose levels. One patient with NSCLC achieved a complete response. One patient with metastatic colorectal cancer had a partial response, another 2 patients with esophageal and gastric cancer without measurable disease at study entry had marked improvement of symptoms and normalization of tumor markers. Additional 15 pts had stable disease lasting from 8 weeks to over a year, including several minor responses, leading to a clinical benefit rate of 46% (19/41) in the overall and 76% (19/25) in the PP population. PK supports q1w and q2w dosing. Conclusions: CetuGEX shows clear signs of activity and acceptable toxicity. Phase II will soon be initiated. Clinical trial information: NCT01222637.
Highlighting the challenge of delayed overall survival (OS) curve separation in immunotherapy clinical trials.
Authors: Steele Savanna D. , Wang Song , Solinger Alan , Combest Austin J. , Bonneterre Marie-Edith Anne , Reitsma Dirk J.
Published: March 2020

3009

Background: Cancer immunotherapy holds great potential but can elicit delayed responses, unlike chemotherapy. A delay in the separation of OS curves (between the control and treatment arms) has led to difficulty in achieving adequate power for OS analysis (Hoos A, Ann Oncol. 2012). Since combining immunotherapies, such as an anti-CTLA4 and an anti-PD-1, may increase the percentage of subjects achieving durable responses (Curran MA, PNAS. 2010), we sought to determine how adding a complementary immunologic agent to the currently-approved ipilimumab would impact delay in OS curve separation. Arbitrarily assuming that treatment effect on OS was doubled, we determined how various delays in OS curve separation might impact sample sizes. Methods: We evaluated three dual-immunotherapy clinical trial scenarios in which the separation of OS curves either remained the same, decreased, or increased. Baseline OS estimates were from pivotal trial data for ipilimumab in melanoma (Robert C et al, NEJM. 2011). SAS PROC POWER with piecewise linear survival curve was then used to determine approximate corresponding sample sizes. Results: See Table. Conclusions: Demonstrating significance in order to gain regulatory approval is important for providing potentially life-saving medications. For trials evaluating dual-immunotherapies, despite doubling treatment effects, delays in OS curve separation of up to 6 months would require over 2700 subjects to reach statistical power. In an era where treatments are increasingly personalized, these numbers will be difficult to achieve, underscoring the importance of novel trial designs incorporating Bayesian hierarchical modeling, precompetitive collaborations, and/or the use of state-of-the-art predictive biomarkers. [Table: see text]
Mucin 1 (MUC1) expression in patients (pts) with early stage non-small cell lung cancer (NSCLC): Relationship between immunohistochemistry (IHC), tumor characteristics, and survival.
Authors: Mitchell Paul Leslie , Battye Shane , John Tom , Murone Carmel , Knight Simon , Bode Gerd , Schroeder Andreas , Asadi Khashayar
Published: March 2020

3011

Background: MUC1, a glycoprotein highly expressed in many malignancies, is being explored as an antigen for immunotherapy. How best to measure MUC1 expression as well as its prognostic value in NSCLC are still under discussion. Methods: TMAs were constructed using triplicate 1mm cores of FFPE tumour and stained with 214D4 (recognises protein core) and MA695 (recognises carbohydrate epitope) anti-MUC1 antibodies (abs). TMAs were assessed for polarisation, both cyto and mem staining intensity (scored 0-3) and proportion cells +ve (0-100%; scored 0–5), averaged for multiple cores. A composite score (intensity x cells +ve) was derived, ranging from 0–15 (3+ in >75% cells). Results: TMAs from 521 pts were analysed: male 362 (69.5%); never smoking 35 (7%); adeno 259 (49.7%), squamous 180 (34.5%), large cell 39 (7.5%); nodal N0 340 (65.3%), N1 71 (13.6%), N2 107 (20.5%). Results of IHC staining intensity, proportion positive cells and depolarisation were very similar for the two abs. There was high concordance in the composite score for the abs (R2=0.71, p<0.0001). Polarisation was discordant in 7.9% of cases. For 77 cases with paired primary/ N2 nodal tissue, mean 214D4 scores were 8.3 and 8.9 and MA695 10.6 and 9.9 respectively. Discordant staining in primary but not in node was seen in 5.2% and 10.4% with 214D4 and MA695 respectively. Increased expression as assessed by 214D4 (HR=1.26; 95% CI 1.014-1.565, p=0.04 log rank test) and MA695 (HR=1.20, 95% CI 1.042-1.605; p=0.02) was associated with improved survival. The prognostic value of depolarisation has yet to be analyzed. Conclusions: Over 93% of cases were MUC1 IHC positive. Composite scores for the 2 abs were highly correlated and depolarisation largely concordant. MUC1 expression was generally maintained in paired primary/nodal tumour. Increased expression of MUC1 was associated with improved survival however further investigation is needed to determine which abs best predict outcomes. [Table: see text]
Outcome with stereotactic radiosurgery (SRS) and ipilimumab (Ipi) for malignant melanoma brain metastases.
Authors: Shoukat Sana , Marcus David Mitchell , Rizzo Monica , Lawson David H. , Liu Yuan , Khan Mohammad Khurram
Published: March 2020

3032

Background: SRS with Ipi for brain metastases from malignant melanoma has been explored for overall survival (OS) (Knisely JP, Yu JB, Flanigan J, et al. Radiosurgery for melanoma brain metastases in the ipilimumab era and the possibility of longer survival. J Neurosurg. 2012;117:227-33). We present the first retrospective analysis to determine if this combination is safe and improves OS, while accounting for lactate dehydrogenase (LDH). Methods: Patients with melanoma brain metastases who underwent SRS between 1998-2010 (n=124) were compared with those who additionally received Ipi (n=11). The primary endpoint was median OS from time of SRS, calculated using Kaplan-Meier method. Cox proportional hazard model was carried out for univariate and multivariable survival analysis. The secondary endpoints were local control at initial site of SRS, anywhere intra-cranial failure, need for repeat SRS, and toxicity. Results: Median OS for the entire cohort was 6.9 months. Patients in the Ipi group had an improved median OS of 28.3 months vs. 6.8 months in the non-Ipi group (p = 0.013). No difference was noted in local control, anywhere intracranial failures, toxicity (radionecrosis, hemorrhage, patient reported memory deficits), or need for repeated SRS. MVA (Table) showed that Ipi independently predicted for improved OS even when taking into account LDH and ECOG performance status. The only confounding factor within the Ipi group was younger age of the Ipi cohort (43 vs. 55 yrs, p = 0.006). Conclusions: Use of SRS with Ipi appears to be safe and associated with an impressive increase in median OS in patients with brain metastases from malignant melanoma; this combination should be further investigated. [Table: see text]
Intraperitoneal radioimmunotherapy (RIT) for desmoplastic small round cell tumor (DSRCT): Initial results from a phase I trial.
Authors: Modak Shakeel , La Quaglia Michael P. , Carrasquillo Jorge A. , Zanzonico Pat , Enero Catherine , Pandit-Taskar Neeta , Kang Hye Jin , Cheung Nai-Kong V.
Published: March 2020

3033

Background: DSRCT, a rare sarcoma of adolescents and young adults usually arising from the peritoneum, is lethal in >80% of patients despite aggressive multimodality therapy. Recurrences often present as multifocal peritoneal implants, making it uniquely suited for intraperitoneal (IP) targeting. We hypothesized that targeted radiotherapy may improve local control and reduce relapses. IP RIT, by virtue of prolonged residence time and slow transfer to the circulation, may selectively target IP DSRCT while minimizing organ toxicity. The anti-4Ig-B7H3 murine monoclonal antibody 8H9 binds to 96% of primary DSRCT (Med Pediatr Oncol 39:547). 131I-8H9 injected intra-Ommaya is safe (J Neurooncol 97:409). Methods: We initiated a phase I study to test the safety of IP RIT with 131I-8H9. Cohorts of 3-6 patients were treated with 131I-8H9 at escalated doses from 30mCi/m2-60mCi/m2 as a single IP injection. A tracer dose of 2mCi124I-8H9 was given IP before 131I-8H9 to acquire PET images and biodistribution data. Pharmacokinetics (PK) was studied using serial blood draws. Results: 15 heavily prior-treated patients: 13 with DSRCT, 2 with rhabdomyosarcoma received 30, 40, 50mCi/m2 131I-8H9 (3 at each dose level) or 60mCi/m2 (n=6). Dose-limiting toxicity was not seen. Three patients (n=1 each) had transient, self-limiting, possibly therapy-related grade 3 toxicities: neutropenia, hepatic transaminase elevation and thrombocytopenia. No patient required hematopoietic stem cell rescue. Blood half life was 32.5±11.5h (n=12) and mean peritoneal residence time was 14.6h (n=3). Mean absorbed dose to blood based on blood sampling was 0.56±0.21 rad/mCi (n=14). Mean absorbed doses (rad/mCi) to kidney, liver, lung and spleen were 1.72, 1.92, 0.64 and 1.03 respectively (n=3). Dehalogenation was insignificant: >80% iodine remained protein-bound in blood (n=10). 6/7 DSRCT patients treated without evaluable disease remain in remission at a median of 11.1 months post 131I-8H9. Conclusions: IP 131I-8H9 was safe and 124I-8H9 provided valuable PK and dosimetry data. Since maximum tolerated dose was not reached we have expanded patient accrual to a planned dose of 90mCi/m2. Clinical trial information: NCT01099644.
HER2 evaluation process for neoadjuvant targeted therapies in breast cancer.
Authors: Mizuno Yoshio , Takeda Naoko , Yamada Junichi , Abe Hiroaki , Inoue Yuko , Seto Hiroshi , Sato Kazuhiko ,   Tokyo-West Tokushukai Hospital
Published: March 2020

3034

Background: Treatment with a combination of HER2-targeted therapies has emerged as an addition of trastuzumab to neoadjuvant chemotherapy regimens in breast cancer patients and it goes on increasing. For clinical HER2 determination, immunohistochemical (IHC) analysis is an attractive method and all IHC 2+ cases are categorized as equivocal and should be reflexed to fluorescence in situ hybridization (FISH) testing. However, research in recent years with respect to false-negative cases for HER2 testing have been reported, and it comes to the question of what considering the indication for trastuzumab in the neoadjuvant chemotherapy. To clarify these controversial points in applying the results of HER2 testing in the clinical setting, we performed a retrospective analysis of core needle biopsy (CNB) and surgical specimen results. Methods: 422 patients underwent primary operations for early breast cancer at Tokyo-West Tokushukai Hospital (Tokyo, Japan) from October 2008 to December 2012. Among these patients, 262 patients who received CNB prior to operation were enrolled. Those patients who received preoperative chemotherapy or had DCIS were excluded. With regard to diagnostic criteria, HER2 positivity was defined as either 3+ by IHC or FISH analysis amplification ratio of ≥2.2. In addition, if in any cases which CNB samples or surgical specimens showed HER2-positive had defined true HER2-positive cases, we assessed the false-negative results of the HER2 test via IHC using CNB samples and surgical specimens. Results: In a matched cohort of 262 patients, 59 cases showed HER2-positive (five cases were CNBs negative to surgical specimens positive, 14 cases were CNBs positive to surgical specimens negative, and 40 cases were both positive). If we decide for selection of trastuzumab target cases by CNBs only, we make mistakes in indications of trastuzumab for five (8.5%) of 59 HER2-positive cases who were CNBs negative to surgical specimens positive. Conclusions: There are quite a few cases show false negatives for HER2 testing in CNB samples. In cases of considering the indication for trastuzumab in the neoadjuvant chemotherapy, even if the CNB samples resulted in negative, we consider that retesting with FISH analysis should be carried out.
Serum lactate dehydrogenase (LDH) as a prognostic selection criterion for ipilimumab treatment in metastatic melanoma.
Authors: Blank Christian U. , Kelderman Sander , van Tinteren Harm , Heemskerk Bianca , van den Brom Rob , Hospers Geke A. , van den Eertwegh Alfons JM , Kapiteijn Ellen , De Groot Jan Willem , Jansen Rob L. , Fiets W. Edward , Krzystanek Marcin , Szallasi Zoltan , Furness Andrew James Scott , Renn Alex , Gore Martin Eric , Lorigan Paul , Schumacher Ton , Haanen John B. A. G. , Larkin James M. G.
Published: March 2020

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Background: Ipilimumab, a CTLA4 blocking antibody, has been shown to improve survival in metastatic melanoma patients in phase III trials. However, only a subset of patients experiences long-term survival benefit. Therefore, we analysed two independent retrospective sets of patients treated in ‘real world’ settings to identify prognostic factors that correlate with better outcome after ipilimumab therapy. Methods: Advanced melanoma patients, eligible for ipilimumab therapy, were treated in the Dutch and UK Expanded Access Programs (EAP) and after European licensing on the 3mg/kg schedule. Baseline characteristics and peripheral blood parameters were assessed and patients were monitored for the occurrence of adverse events and responses. Results: A total of 166 patients were enrolled in the Dutch EAP. Best overall response rate and disease control rate were (DCR) 17% and 35%. Median follow-up was 17.9 months, with a median progression free survival of 2.9 months. Median overall survival (OS) was 7.5 months, and OS at 1 year 37.8% and at 2 years 22.9%. Univariate analysis revealed that gender, age, Breslow thickness, baseline and week 6 lymphocyte count (ALC), and prior treatment had no influence on OS, while mWHO, M stage, baseline LDH, S100, erythrocyte sedimentation rate (ESR), and the slope of ALC did. In a multivariate model only baseline LDH and ESR remained as significant independent prognostic factors. The relevance of LDH was validated in an independent cohort of 68 patients from the UK. Stratifying the patients in the NL cohort according to LDH levels (≤upper limit normal (ULN), 54.4% of patients versus >2xULN, 16.9% of patients) separated into groups of patients observing DCR of 48% versus 14%, and median OS of 13.7 versus 3.1 months, while toxicity was similar in both groups (48% and 41%). None of the patients was alive at 15 months after treatment if baseline LDH was >2xULN in both the NL and UK cohorts. Conclusions: Overall survival upon ipilimumab treatment is lower in an expanded access population as compared to phase III trials. LDH >2xULN at baseline is a potential prognosticator in patients receiving ipilimumab and should be considered in guiding ipilimumab treatment initiation.
Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL).
Authors: Hijazi Youssef , Klinger Matthias , Schub Andrea , Wu Benjamin , Zhu Min , Kufer Peter , Wolf Andreas , Nagorsen Dirk
Published: March 2020

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Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.
Rituximab pharmacokinetics in children and adolescents with de novo intermediate and advanced mature B-cell lymphoma/leukemia: A Children’s Oncology Group (COG) report.
Authors: Barth Matthew John , Goldman Stanton , Smith Lynette , Perkins Sherrie L , Shiramizu Bruce , Gross Thomas G. , Harrison Lauren , Sanger Warren , Geyer Mark B , Giulino Lisa B. , Cairo Mitchell S.
Published: March 2020

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Background: The COG trial ANHL01P1 was undertaken to determine pharmacokinetics (PK) and safety following the addition of rituximab (R) to FAB/LMB 96 chemotherapy in children and adolescents with stage III/IV mature B-NHL and B-ALL±CNS disease. Methods: Patients received R (375mg/m2) on day -2 and 0 of two induction cycles and day 0 of two consolidation cycles. R levels were measured prior to any antibody infusion, during induction cycles (1 hour prior and 30-60 minutes after each R dose) and following consolidation cycles (1, 3, 6 and 9 months after last R dose). R was measured by ELISA with goat anti-rituximab antibody as the capture reagent and goat anti-mouse IgG-conjugated to horseradish peroxidase as the detection reagent. R terminal half-life (t½) was calculated if at least 3 time points after the last dose were measurable in an individual subject. Results: Serum R levels are reported in the Table. Highest peak levels were achieved following the second dose of each induction cycle with sustained troughs and a t½ of 26-29 days. Group C patients tended to have lower R levels than Group B. Patients with LDH ≥2xULN were noted to have lower R levels during induction 1 compared to those with LDH <2xULN. Children (<13 years) exhibited higher peak concentrations, similar trough levels and a shorter t½ than adolescents (≥13 years). None of these differences reached significance after adjusting for multiple comparisons. Conclusions: R can be safely added to FAB chemotherapy with high early R peak/trough levels and a long terminal half-life. The efficacy of R combined with FAB chemotherapy is currently being investigated in an ongoing international intergroup trial. Clinical trial information: NCT00057811. [Table: see text]
Immunomodulatory effects of a dipeptidyl peptidase inhibitor, ARI-4175, and NK cell activation in a colon cancer model.
Authors: Macfarlane Alexander , Bagnyukova Tetyana V , Campbell Kerry , Jones Barry , Bachovchin William , Borghaei Hossein
Published: March 2020

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Background: A possible mechanism of the antitumor effect of therapeutic antibodies is antibody-dependent cellular cytotoxicity (ADCC). We reported that an inhibitor of dipeptidyl peptidase (DPP)4-like serine proteases, Ari-4175, significantly slowed the growth of KRAS-mutated HCT-116 xenografts in nude mice, either as a single agent or with cetuximab (Ctx). Ari-4175 is not cytotoxic in vitro, and since it was able to overcome the resistance to Ctx due to the KRAS mutation in the HCT-116 line, we hypothesized that the antitumor activity involves the activation of NK cells and enhancement of ADCC. Methods: Ari-4175 was administered orally to nude mice at 200 µg q.d. x5 days/week. Peripheral blood or spleens were assayed for immune parameters, ex vivo, at various time points. Expression of surface markers on myeloid and NK cells were monitored by flow. Natural cytotoxicity and ADCC were assayed using HCT116 cells and Ctx using a flow based assay. Cytokines were measured using Luminex assays. Results: Ari-4175 induced upregulation of CD69 on NK cells on day 2, followed by upregulation of CD16 on day 7. Coordinate with these changes in peripheral blood, splenocytes from treated mice exhibited significantly increased in vitro cytotoxicity toward the HCT116 cells. Increased serum levels of inflammatory cytokines, including IL-1b, IL-6, MCP-1, GCSF, and IL-2 were seen. A significant expansion of a distinct CD45+CD14+Gr-1+MHC-II-CDllb+CD11cvariable myeloid cell population in both peripheral blood and spleens of mice was also seen after one week of treatment. Conclusions: Ari-4175 showed dramatic anti-tumor effect in KRAS-mutant CRC xengrafts when given alone or in combination with Ctx. In vitro data suggest that the therapeutic effect of 4175 might partially be due to the augmentation of ADCC through elevated expression of CD16 on NK cells. In addition, Ari-4175 appears, in vivo, to expand a unique myeloid cell population, which may be responsible for an inflammatory cytokine response and subsequent activation of NK cells. Our study provides a mechanistic rationale for testing Ari-4175 in a clinical trial and possible biomarker endpoints for evaluation in peripheral blood samples.