bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase II trial of vaccination with full length NY-ESO-1/IMX in patients with advanced malignant melanoma
Authors: Nicholaou T. , Davis I. D. , Marakovsky E. , Miloradovic L. , Hopkins W. , Chen W. , McArthur G. , Pan L. , Hoffman E. W. , Old L. J. , Cebon J.
Published: March 2020

2571

Background: NY-ESO-1 is an immunogenic “cancer-testis” (CT) antigen, expressed in many cancers including melanoma. Iscomatrix adjuvant (IMX), a saponin-based adjuvant, was formulated with NY-ESO-1 (ESO) protein (ESO/IMX). ESO/IMX was highly immunogenic as defined by ESO specific antibody (Ab), delayed type hypersensitivity (DTH) & T-cell responses in patients (pts) with resected ESO+ve cancer. Disease free survival in vaccine recipients with resected melanoma appeared longer than in controls. A prospective evaluation was subsequently undertaken to determine whether ESO/IMX could mediate antitumor responses in pts with advanced NY ESO-1+ve melanoma. Methods: 27 pts were vaccinated in a trial designed to assess objective clinical responses, safety, & immunogenicity. Vaccination consisted of 100 μg ESO/IMX administered q 4 wk × 3; this cycle was repeated in pts without symptomatic progression unless they required other treatment. Pts were then eligible to continue vaccination q12 weeks so long as they were responding or stable. Results: ESO/IMX was well tolerated. 13 pts progressed when evaluated after the first cycle at week 11. No objective clinical responses were seen. Vaccine-induced antibody titers to NY-ESO-1 were comparable to those seen in the earlier minimal residual disease trial (ranging to > 1: 390,000). DTH & T-cell responses were less marked. This occurred despite many pts with advanced measurable disease having pre-existing spontaneous ESO immunity ( Table ). DTH responses were seen in 11 pts; 5 had pre-existing responses (2 were boosted) and 6 were induced. The DTH responses were lost by week 33. Conclusion: No objective responses were seen. Vaccine-induced immunity appeared to be attenuated in the presence of advanced metastatic disease. Ongoing laboratory studies are investigating the role of regulatory T cells in the suppression of ESO-specific immunity in these pts with a view to adopting strategies to counter regulatory responses e.g. low-dose cyclophosphamide prior to vaccination.

[Table: see text]

[Table: see text]
Dendritic cell based vaccination in combination with IL-2 as a treatment for advanced renal cell carcinoma patients: Results from a phase I/II trial
Authors: Berntsen A. , Geertsen P. , Trepiakas R. , Wenandy L. , Andersen M. H. , Straten P. T. , Lorentzen T. , Johansen J. S. , Johnsen H. E. , Svane I. M.
Published: March 2020

2575

Background: Autologous dendritic cells (DC) pulsed with tumor-associated antigens as peptides or tumor lysate derived proteins can induce generation of cytotoxic T-cells in cancer patients. Survivin and telomerase are tumor-associated antigens overexpressed in renal cell carcinoma, and telomerase and survivin derived HLA-A2 binding peptides are able to induce effector T-cells cytotoxic to tumor cells. Tumor lysate can be generated from allogeneic renal carcinoma cell lines and has a natural high amount of antigens potentially enabling the induction of a polyclonal immune response against multiple targets on tumor cells. Methods: Twenty-two patients with progressive metastatic renal cell carcinoma were included and toxicity and efficacy of DC-based immunotherapy were evaluated. HLA-A2 positive patients were treated with mature autologous DCs pulsed with a broad panel of HLA binding telomerase and survivin peptides and PADRE; HLA-A2 negative patients received DCs pulsed with allogeneic tumor lysate and KLH. The vaccines were administered intradermally or intranodally weekly/biweekly ten times and repeated monthly until tumor progression. Patients received low dose IL-2 as an adjuvant. Immune response was monitored using ELISPOT assay. IL-6 and the biomarker YKL-40 were measured in serum using ELISA assay. Results: Vaccinations were well tolerated. 17/22 patients were evaluable and 10 patients had stable disease (SD) for up to 11+ months (range 2–11+ months). Interestingly, serum IL-6 increased in patients with progressive disease compared with a decrease in patients with SD. After vaccination mean values of YKL-40 were 91ng/ml in patients with SD and 208ng/ml in patients with PD. Immune monitoring is ongoing and preliminary data demonstrate that peptide specific CTLs are induced by the treatment. Conclusions: This pilot study demonstrates, that vaccination with autologous DCs pulsed with tumour antigens is safe and without severe toxicity. Disease stabilization was observed in half of the treated patients. Serum IL-6 and YKL-40 values might be useful parameters to predict clinical response during vaccination therapy.

No significant financial relationships to disclose.
Dendritic cells loaded with wild-type p53 peptides induce T cell immunity and disease stabilization in patients with advanced breast cancer
Authors: Svane I. M. , Pedersen A. E. , Johnsen H. E. , Nielsen D. , Kamby C. , Nikolajsen K. , Ottesen S. , Zocca M. , Johansen J. S. , Claesson M. H.
Published: March 2020

2577

Background: p53 mutations and over-expression are found in up to 30% of breast cancers and are associated with poor prognosis following conventional therapy. Peptides derived from over-expressed p53 protein are presented by class I MHC molecules and may act as tumor-associated epitopes and thereby as target for vaccination. Due to the diversity of p53 mutations, immunogenic peptides representing wild-type sequences are preferable as basis for a broad-spectrum p53-targeting cancer vaccine. Furthermore, single amino acid modified p53 peptides can increase HLA-A2 binding capacity and induction of p53-specific cytotoxic T cells. Methods: In a phase I-II trial a total of 32 HLA-A2+ patients with progressive advanced breast cancer were treated with autologous dendritic cells (DC) loaded with six HLA-A2 binding peptides: 3 wild-type [p5365–73 RMPEAAPPV, p53264–272 LLGRNSFEV, p53187–197 GLAPPQHLIRV], 3 modified [p53149–157 SLPPPGTRV, p53139–147 KLCPVQLWV, p53103–111 YLGSYGFRL]. Each patient received up to 10 sc vaccinations with 5x106 p53-peptide loaded DC with 1–2 weeks interval. Concomitantly, 6 MIU/m2 IL-2 was administered s.c. Results: Clinical benefit, mainly as SD or minor regression was obtained in 12 out of 32 patients. Using ELISPOT assay vaccine induced p53 peptide specific T cells were demonstrated in 7/11 of the analyzed response patients but only in 4/14 patients with continued progression, in contrast, 2 patients in this group had reduction of pre-existing reactivity. In most cases T cells specific for several of the six p53 peptides were found and no single p53-epitope was predominant. SD was associated with cessation of serum LDH rise and reduction in serum IL-6 level. In addition more response patients had significant p53 tumor expression. T cell immunity was further explored by dextramer technology and CD107 cytotoxicity assay, and serum YKL-40 was measured and compared to clinical response. Conclusions: A significant fraction of breast cancer patients with progressive disease obtained disease stabilization during treatment with p53-peptide loaded DCs. Induction of p53 specific immunity and changes in disease markers support the clinical results.

No significant financial relationships to disclose.
A phase I study of BIBF 1120, an orally active triple angiokinase inhibitor (VEGFR, PDGFR, FGFR) given continuously to patients with advanced solid tumours, incorporating dynamic contrast enhanced magnetic resonance imaging (DCE-MRI)
Authors: Lee C. P. , Taylor N. J. , Attard G. , Nathan P. D. , De Bono J. S. , Temple G. , Tang A. , Padhani A. R. , Judson I. R. , Rustin G. J.
Published: March 2020

3015

Background: BIBF 1120 is a potent inhibitor of VEGFR, PDGFR, FGFR kinases, and of members of the Src family of tyrosine kinases (Src, Lck, Lyn). Methods: Patients (Pts) with advanced solid tumours were enrolled. BIBF 1120 was administered orally once daily (q.d.) continuously, starting at 100 mg/day. Dosing was later amended to twice daily (b.i.d.) in view of transaminitis seen with q.d. dosing. DCE-MRI studies were performed at baseline, days 2 and 28. All pts underwent pharmacokinetic (PK) sampling. Results: 51 pts (26M/25F; median age 57 y, range 22–78 y; ECOG PS 0/1 = 22/27) were treated at: 100 mg q.d. (n = 6), 200 mg q.d. (n = 6), 300 mg q.d. (n = 7), 400 mg q.d. (n = 16), 450 mg q.d. (n = 5); 250 mg b.i.d. (n = 11). Median treatment duration was 57 days (range: 1 day– 22 m). The most common toxicities were nausea, vomiting, diarrhoea, abdominal pain and fatigue, all ≤ grade (G)2. Asymptomatic, reversible elevation of liver enzymes which was dose limiting in 2/5 pts at 450 mg q.d. defined the MTD at 400 mg q.d. At 250 mg b.i.d., 2/11 pts had DLT (G3 elevation in liver enzymes: n = 1; G3 abdominal pain: n = 1). 44 pts treated for ≥2 m were assessable for response: 13 pts had SD for ≥3 m (median 7m, range 3–22 m; renal, prostate, colorectal, chondrosarcoma, leiomyomatosis, fibromatosis). 3 pts with renal cancer had SD for 8, 14+ and 22 m respectively. PK evaluations generally showed increasing gMean Cmax and AUC values with increasing doses, with high inter-patient variability. Tmax was ∼2h post-dosing. gMean t1/2 values ranged from 6.8–26.4h. DCE-MRI of target lesions in 35 pts showed significant antivascular/antiangiogenic effects in some patients and dose cohorts, particularly at 200 mg q.d. and ≥400 mg q.d. DCE-MRI effects were most pronounced at 28 days, especially in metastatic liver lesions. Conclusions: BIBF 1120 is well-tolerated in patients with advanced solid malignancies and induces in vivo antiangiogenic effects detectable by DCE-MRI. Some patients experienced clinically meaningful disease stabilisation. The recommended dose for future Phase II studies was determined to be 250 mg b.i.d.

[Table: see text]
Final clinical and pharmacokinetic (PK) results from a phase 1 study of the novel N-cadherin (N-cad) antagonist, Exherin (ADH-1), in patients with refractory solid tumors stratified according to N-cad expression
Authors: Stewart D. J. , Jonker D. J. , Goel R. , Goss G. , Maroun J. A. , Cripps C. M. , Wells J. , Wargin W. , Malik R. K. , Peters W. P.
Published: March 2020

3016

Background: Malignant transformation and invasiveness correlate with upregulation of N-cad, a cell adhesion molecule expressed on tumor cells and vascular endothelium. N-cad antagonism by ADH-1, a cyclic pentapeptide (CHAVC), causes rapid tumor vascular disruption and apoptosis in preclinical models. We report the final clinical and PK results from the first human study (AHX-01–001). Methods: 46 subjects with incurable solid tumors stratified according to tumor N-cad expression were enrolled. 99 doses of ADH-1 were given by IV bolus or short infusion (31 in a Special Access Program). Doses ranged from 50–1000 mg/m2, with 3–6 subjects/cohort. Blood and urine were collected for PK on Day 1, assayed by LC/MS/MS, and a 2 compartment analysis was performed. Results: ADH-1 was generally well tolerated and the maximum tolerated dose was not defined. The most commonly reported adverse events were grade 1–2 fatigue (59%), nausea (32%), dysgeusia (25%), and flushing (20%). 4 subjects in the N-cad positive group (n=28, including 3 N-cad unknown) demonstrated anti-tumor activity; a PR of 6 month duration in refractory esophageal carcinoma; a minor response in lung metastases from an unknown primary following a single dose; and >7 months SD in refractory adrenocortical and colorectal carcinoma. No anti-tumor activity was noted in the N-cad negative group (n=18). The mean initial ADH-1 half-life (t½) was 20 min and the mean terminal phase t½ was 2.2 hr. Mean systemic clearance (CL) was 6.5 L/hr/m2. Both t½ and CL were independent of dose. Cmax increased dose proportionally, ranging from 7 to148 μg/mL, and AUC0-∞ tended to increase dose proportionally. The volume of distribution at steady-state (Vss) averaged 14.3 L/m2, indicating modest tissue distribution. Approximately 30% of the dose was excreted unchanged in the urine. Conclusions: ADH-1 was generally well tolerated and demonstrated evidence of anti-tumor activity in subjects with N-cad positive tumors. The PK profile was biphasic and the t½ averaged 2.2 hr. Cmax and AUC0-∞ increased dose proportionally, and CL was independent of dose.

No significant financial relationships to disclose.
Phase I trial involving the pharmacodynamic (PD) study of circulating tumour cells, of CP-751,871 (C), a monoclonal antibody against the insulin-like growth factor 1 receptor (IGF-1R), with docetaxel (D) in patients (p) with advanced cancer
Authors: Attard G. , Fong P. C. , Molife R. , Reade S. , Shaw H. , Reid A. , Spicer J. , Hamlin J. , Gualberto A. , De Bono J. S.
Published: March 2020

3023

Background: C is the first specific, fully human, monoclonal antibody to target IGF-1R in clinical trials. It potently inhibits IGF-1R signaling, enhancing D antitumour activity. This trial investigated the safety, feasibility, dose limiting toxicity (DLT), PK and antitumor activity of D administered with C every 3 weeks. PD studies evaluated circulating tumor cell (CTC) IGF-1R expression and CTC counts pre- and post-treatment. Methods: The C doses tested were 0.1, 0.4, 0.8, 1.5, 3.0, 6.0 and 10 mg/kg in sequential cohorts of 3–6 p. D was fixed at 75mg/m2. P achieving disease control continued on C alone if experiencing D toxicity. Results: 21 p (20 male) have received 100 courses of C with D. 7 p received 8 or more courses of the combination. A further 21 courses of C alone have been administered. No toxicity has been attributed to C to date with the observed toxicities being attributable to D. Grade 3/4 toxicities were neutropenia (16/21 p) and neutropenic fever in 2/21 p. Grade 3 diarrhea was reported in 3 p, but this was easily controlled with antidiarrheals. Transient grade 1 hyperglycaemia was noted largely on day 1, following steroid premedication (14 p), but no significant C related hyperglycemia has been observed. An MTD has not been reached. Serial echocardiograms demonstrated no cardiac toxicity. Of 18 castration resistant prostate cancer (CRPC) p treated, 4 have had a confirmed PR, with 2 unconfirmed PR and 2 having disease stabilization for > 6 months (median number of courses: 10; range: 3–12). 5 p have maintained SD with C alone for 2–7 courses. CTC were detected in 16 of 18 p (CTC numbers ranged from 1 to 202 in 7.5ml of blood). IGF-1R expression was detected in 12 p. CTC IGF-1R was undetectable following treatment with C at doses above 3 mg/kg. Conclusions: This combination is safe and feasible with no toxicity attributed to C and encouraging antitumor activity in CRPC.

[Table: see text]
Two immunoglobulin G fragment C receptor polymorphisms associated with clinical outcome of EGFR-expressing metastatic colorectal cancer patients treated with single agent cetuximab
Authors: Zhang W. , Gordon M. , Schultheis A. M. , Nagashima F. , Azuma M. , Yang D. , Iqbal S. , Lenz H.
Published: March 2020

3028

Background: Cetuximab is a chimeric immunoglobulin G1 anti-EGFR monoclonal antibody with efficacy in metastatic colorectal cancer patients refractory to irinotican chemotherapy. Recent studies show that Antibody-dependent cellular cytotoxicity (ADCC) mediated through Fc receptors plays an important role in the antitumor effect of IgG1 antibody. There are three classes of FcγRs involved in the regulation of ADCC. FcγRIIa(CD32) and FcγRIIIa(CD16) activates and FcγRIIb inhibits activation. Clinical studies show FcγRIIIa 158 V/F polymorphism was associated with tumor response and progression-free survival in the follicular lymphoma patients treated with rituximab as first line treatment. Also, a H/R polymorphism at position 131 of FcγRIIa has been found to affects its affinity to human IgG and independently predict response to Rituximab. Since Cetuximab and Rituximab belong to the same chimeric IgG1 monoclonal antibody, we test hypothesis whether these two FcγR polymorphisms associated with clinical outcome in colorectal cancer patients treated with single agent Cetuximab. Methods: we tested both FcγRIIIa 158 V/F and FcγRIIa 131 H/R gene polymorphisms using PCR-RFLP method in genomic DNA extracted from peripheral blood from 39 EGFR-expressing metastatic colorectal cancer patients enrolled in a phase II single agent Cetuximab treatment clinical trial (IMCL-0144). Results: We found patients with FcγRIIa 131 HH or HR genotype show better time to progression and overall survival compare to patients with R/R genotype (p=0.037, p=0.22, respectively, log-rank test). Also, there is trend significance in tumor response when we compare patients with RR genotype and patients with HH or HR genotype (p=0.08, fisher’s exact test). FcγRIIIa 158 V/F also show trend significance in tumor response (p=0.067, fisher’s exact test). Conclusions: These data suggest Two Immunoglobulin G Fragment C Receptor polymorphismsFcγRIIIa158V/F andFcγRIIa 131 H/R may be potential molecular markers for clinical outcome of refractory metastatic colorectal caner patients treated with single agent EGFR inhibitor Cetuximab. Prospective studies are needed to confirm these preliminary findings.

[Table: see text]
A phase I/II trial of sorafenib (S) with bevacizumab (B) in metastatic renal cell cancer (mRCC) patients (Pts)
Authors: Sosman J. A. , Flaherty K. , Atkins M. B. , Puzanov I. , McDermott D. F. , Vermeulen W. , Harlacker K. , Hsu A. , Rothenberg M.
Published: March 2020

3031

Background: In an effort to enhance the efficacy of vascular endothelial growth factor (VEGF) pathway blockade in mRCC we initiated a Phase I-II trial of combination S and B to block VEGFR signaling and VEGF binding, as well as, platelet derived growth factor receptor β (PDGFR) signaling. Methods: Pts with measurable (RECIST) mRCC, adequate organ function, and PS 0–1 were eligible for this trial. Cohorts of 6 pts were enrolled at 3 sites to define the MTD and DLT of the combination of S and B. The schedule was B IV q 14 days and S daily with cycles of 28 days. Response and toxicity were assessed at the end of 2 cycles. Dose levels began with S at 200mg BID and B at 5 mg/kg (level 1) with the hope to reach phase II doses of both agents (S at 400mg BID and B at 10mg/kg). The MTD or the phase II dose of each agent would then be administered to up to 45 pts with mRCC, clear cell histology, and prior nephrectomy. Results: A total of 18 patients have been enrolled to date, with 15 completing their first response evaluation. Pts were median age 61 years (46–74 range); M/F: 15/3; PS: 0/1= 12/6; 17 clear cell, 1 chromophobe, 11 prior nephrectomy; 4 with prior cytokine therapy. Two pts in level 1 experienced DLT with recurrent and intolerable (grade 3) hand-foot syndrome (HFS). An additional 6 patients were treated at dose level -1 (S at 200mmg QD and B at 3mg/kg) with no DLTs. Six more pts have been treated at dose level 1 with Vit B6 at 300mg/d in an attempt to minimize HFS. Toxicity data in this cohort is incomplete. Additional toxicities among the 18 pts included grade 3 hypertension (4), grade 3 proteinuria (2), and grade 2 stomatitis (3). Responses including 4 objective PRs, and 4 pts with 20–30% regression have been seen in the 14 evaluated pts. Only 2 patients have had disease progression. Conclusions: The phase II doses for this combination have not yet been established, but will likely be lower than the full phase II doses of the individual agents. The toxicities from HFS (primarily) and hypertension and stomatitis appear to be limiting. Even at the initial low doses of S and B, significant anti-tumor activity has been observed. The completion of this phase I trial will be reported. The phase II studies in mRCC are highly anticipated. Support by phase I contract UO-1 CA099177

[Table: see text]
A phase I dose-escalation study of weekly IMC-1121B, a fully human anti-vascular endothelial growth factor receptor 2 (VEGFR2) IgG1 monoclonal antibody (Mab), in patients (pts) with advanced cancer
Authors: Camidge D. R. , Eckhardt S. G. , Diab S. , Gore L. , Chow L. , O’Bryant C. , Temmer E. , Ervin-Haynes A. , Katz T. , Fox F. , Cohen R. B.
Published: March 2020

3032

Background: Anti-VEGFR2 antibodies are effective in a variety of preclinical leukemia and solid tumor models. IMC-1121B is a fully human anti-VEGFR2 IgG1 Mab. Methods: Cohorts of 3–6 pts (ECOG PS ≤ 2) with advanced cancer and no significant cardiovascular, thrombotic or bleeding disorders received escalating doses of IMC-1121B. A single initial dose with extended PK sampling was followed by 4 x weekly infusions per treatment cycle starting at 2mg/kg. 7 dose levels up to a maximum of 16 mg/kg are planned. Human anti-human antibodies (HAHA) directed against IMC-1121B were assessed at baseline and before each Week 4 dose. Tumor response was assessed every 2 cycles. PD analyses include DCE-MRI, serum VEGF and sVEGFR1/2 levels, and peripheral blood mononucleocyte gene expression profiling at baseline and post-dosing. Results: 12 pts (8 M; 4 F), median age 58 years (range: 36–76), have entered the study: cohort 1 (2mg/kg) n=6, cohort 2 (4mg/kg) n=4 and cohort 3 (6mg/kg) n=2. No toxicities ≥ grade 2, considered definitely or probably related to study drug, have occurred. Toxicities ≥ grade 2 possibly drug-related include anorexia, vomiting, anemia, depression, fatigue, and insomnia. To date, there has been one unconfirmed partial response (melanoma) and 5 pts with stable disease for >3 months (colon: 2, breast, gastric, thyroid). Preliminary non-compartmental PK analysis reveals dose-dependent elimination and non-linear exposure, consistent with saturable clearance mechanism(s): mean t1/2 = 63.62, 93.46, 99.63 hrs, mean Cmax = 43.67, 80.25, 264 ug/mL, and AUC0-Inf = 3860, 9242, 27437 hr*ug/mL, at the 2, 4, and 6 mg/kg dose levels, respectively. Conclusions: Weekly administration of IMC-1121B is well tolerated at doses up to 6mg/kg/week. There is early evidence of a non-linear dose-PK relationship. Dose escalation continues. Updated safety, PK, PD, HAHA, and efficacy data will be presented.

[Table: see text]
An enriched phase I, pharmacokinetic and pharmacodynamic study of the N-cadherin (NCAD) cyclic competitive binder exherin (ADH-1) in patients with solid tumors
Authors: Sessa C. , Perotti A. , Maur M. , Fasolo A. , Scaramuzza D. , Braghetti A. , Marsoni S. , Malik R. K. , Peters W. P. , Gianni L.
Published: March 2020

3042

Background: N-cad is a cell adhesion molecule expressed by vascular endothelium and tumor cells of invasive tumors. ADH-1, a cyclic pentapeptide, antagonizes N-cad, causing rapid tumor vascular disruption and apoptosis in preclinical models. We report results from a Phase I study of weekly doses of intravenous ADH-1 given to patients with N-cad+ solid tumors, to evaluate safety, PK, antitumor activity, and effect of ADH-1 on tumor vasculature assessed by DCE-MRI. Methods: ADH-1 starting dose was 150 mg/m2 administered weekly for 3 W in 28 D cycles. DCE-MRI was performed to assess changes in tumor perfusion 90 mins after the first dose of ADH-1, and repeated on D 15 if no changes were noted. Following the 3rd dose level (DL 3, 600 mg/m2 ), the schedule was amended to weekly ADH-1 without interruption, in 21 D cycles. Results: 55 pts with refractory solid tumors were screened, 56% were N-cad+ [screened/N-cad+: GYN 16/21 (Ovarian 13/17), GI 5/14, breast 2/6, renal 5/5, head & neck 2/3, others 2/6]. 13 pts (5 males, median age 53 yrs.) received 20 cycles of ADH-1 by bolus injection at 150, 300 and 600 mg/m2/weekly ×3 W Q21–28 D. No DLTs have occurred to date. No pts have experienced > grade 2 study drug related AEs. One pt, with fallopian tube ca. had a mixed response. There was a 30% reduction in retroperitoneal nodal disease at the end of cycle 3, and a 37% reduction at the end of Cy 4. However, new bone lesions were also noted at the end of cycle 4 assessment. Tumor blood flow reduction of ≥40% was noted in this patient, and she also reported pain in the region of the tumor following multiple doses of ADH-1. PK parameters are available for the first 3 DLs (150, 300, and 600 mg/m2): mean Cmax 22.1, 37.0, and 50.8μg/mL, respectively; AUCinf 24.3, 60.6, and 110.3 h·μg/mL; Vss 12.6, 15.1, and 16.3 L/m2; and T1/2 1.8, 2.7, and 2.4hr. Conclusions: ADH-1 has been well tolerated in 4 dose levels tested to date, dose escalation is proceeding. No DLTs have occurred and the MTD has not been reached. Anti-tumor activity has been noted. Updated clinical, PK and PD results will be presented.

[Table: see text]
A phase I and pharmacokinetic study of continuous infusion EMD 121974 (EMD), an antiangiogenic αvβ3 and αvβ5 integrin antagonist, in patients with advanced solid malignancy
Authors: Undevia S. D. , Janisch L. , Stadler W. M. , Wittemer S. M. , Ratain M. J.
Published: March 2020

3052

Background: Integrins αvβ3 and αvβ5 are cell-surface receptors that play a significant role in angiogenesis by mediating the ligation signal that allows endothelial cells to attach to the extracellular matrix. These integrins share the binding epitope Arg-Gly-Asp (RGD). EMD is an RGD-containing cyclic pentapeptide. In clinical studies to date, EMD has been administered in an intermittent fashion. However, EMD has a short half-life of 3–5 hours with no evidence of drug accumulation. These data prompted the initiation of this phase I study of continuous infusion EMD. Methods: EMD was administered as a continuous infusion without break in 4-week cycles. Plasma samples for pharmacokinetic studies were obtained weekly in cycle 1 immediately prior to and 2 hours after infusion bag change. Results: To date 21 patients (15 male/6 female, median age 56, median Karnofsky performance status 90%) have been treated at the following dose levels: 1, 2, 4, 8, 12, 18, and 27 mg/h. Hematologic toxicities have been limited to grade 2 anemia and grade 3 lymphopenia. Non-hematologic toxicities have been limited to grade ≤ 2 and include alopecia, anorexia, diarrhea, fatigue, hypokalemia, hyponatremia, hypophosphatemia, insomnia, mucositis, nail changes, nausea, and transaminase elevation. One patient treated at 27 m/h experienced an unobserved death of unknown cause after two weeks of therapy. Pharmacokinetic analysis has been completed for patients treated at the 12 mg/h dose level and below. Mean values for half-life, clearance, and volume of distribution were comparable across dose levels, and steady-state concentration increased proportionally to dose. Conclusions: EMD can be safely administered as a continuous infusion at doses of up to at least 18 mg/h. No single toxicity has been consistently observed. A patient death in cycle 1 has resulted in the expansion of the 27 mg/h dose level. The pharmacokinetics of continuous infusion EMD were predictable and in general agreement with the published data of twice weekly infusion. Study enrollment is ongoing.

[Table: see text]
Final results of a phase I study of daily oral AZD2171, an inhibitor of vascular endothelial growth factor receptors (VEGFR), in combination with carboplatin (C) + paclitaxel (T) in patients with advanced non-small cell lung cancer (NSCLC): A study of the National Cancer Institute of Canada Clinical Trials Group (NCIC CTG)
Authors: Laurie S. A. , Arnold A. , Gauthier I. , Chen E. , Goss G. , Ellis P. , Shepherd F. A. , Matthews S. , Robertson J. , Seymour L.
Published: March 2020

3054

Background: AZD2171 is a potent oral inhibitor of the tyrosine kinase activity of all VEGFR subtypes. This study was undertaken to determine the recommended phase II dose of AZD2171 in conjunction with standard doses of C and T, and to assess the tolerability, safety, PK profile and anti-tumor activity of this combination. Methods: Patients with stage IIIB / IV NSCLC (any histology); PS 0–2; no prior chemotherapy for metastatic disease and no significant hemoptysis / bleeding, were eligible. Treated, clinically stable brain metastases were permitted. C - AUC 6, and T - 200 mg/m2 over 3 hours, q3weekly. AZD2171 commenced day 2 cycle 1 at a starting dose of 30 mg po daily. PK profile of all was drugs performed during cycles 1 and 2. Response was assessed by RECIST every second cycle. Results: 20 patients were enrolled: AZD2171 30 mg (9 pts) and 45 mg (11 pts). Median age 58; 19 PS 0 / 1; 8 females. At 30 mg, one confirmed DLT was observed (grade 3 ALT); hypertension ≥ grade 2 was seen in 6 pts, prompting the institution of a standardized algorithm for management of this predictable toxicity. Of the first 3 pts enrolled to the 45 mg dose level, one DLT was observed (grade 3 febrile neutropenia with grade 3 mucositis); no further DLT was observed in the expanded cohort. Other common toxicities: fatigue, anorexia, mucositis and diarrhea. Hematologic toxicity was not greater than that expected with CT alone. No hemoptysis was seen. To date, 15 pts are evaluable for response: 6 PR, 8 SD and 1 PD. Many SD pts had evidence of tumor shrinkage, including central cavitation. Conclusions: Toxicities of this combination appear manageable and predictable. Full single-agent dose of AZD2171 may be administered with standard C+T. Hypertension, a typical toxicity of inhibitors of VEGF signaling, was observed but manageable. Encouraging anti-tumor activity of the combination has been observed. NCIC CTG BR.24, a phase II/III trial of C+T with AZD2171/placebo is underway.

[Table: see text]
Phase I study of rapamycin (R) in combination with CYP3A4 modifier, ketoconazole (K), in patients with advanced malignancies
Authors: Cohen E. E. , Moshier K. , Innocenti F. , Kocherginsky M. , House L. , Ramirez J. , Undevia S. D. , Fleming G. F. , Ratain M. J.
Published: March 2020

3061

Background: R is currently FDA approved for the treatment of renal allograft rejection but mTOR is a relevant target in several cancer types. K, a CYP3A4 inhibitor, increases the area under the concentration curve (AUC) of R and co-administration of R and K can overcome poor R bioavailability and decrease costs substantially. The aims of this study were to find the maximum tolerated dose (MTD) and dose-limiting toxicities (DLT) of R administered weekly in combination with K and describe the pharmacokinetics (PK) of the combination in patients with advanced malignancies. Methods: R and K were administered concurrently to successive cohorts of patients. R starting dose was 1 mg once weekly and was escalated by 1 mg per dose level. K was administered at a constant dose of 200mg BID 1 day prior to each R dose then 200 mg QD on the next 3 consecutive days. Results: 34 subjects (median age 60 years) have been enrolled. The highest dose of R administered thus far was 5mg without DLT. Most frequent toxicities observed of any grade included hyperglycemia (41%), lymphopenia (35%), hyperlipidemia (35%), fatigue (29%), anemia (26%), anorexia (24%), and nausea (24%). Observed grade 3 toxicities included 2 patients with lymphopenia, 2 patients with elevated transaminases, and 1 patient each with emesis and hyperglycemia. One patient experienced grade 3 confusion likely due to a drug-drug interaction of K with concomitant psychotropic medications. PK analysis of the first 2 dose levels confirms that K significantly increases Cmax and AUC of R ( Table ). R Cmax (with K) averaged 22.5 (11.7) and 27.4 (7.9) (mean/SD) ng/ml at the 1 and 2 mg dose levels, respectively. R AUC (with K) averaged 408.9 (225.4) and 663.8 (201.8) (mean/SD) ng*h/ml at the 1 and 2 mg dose levels, respectively. Conclusions: Low dose weekly R plus K results in potentially efficacious concentrations, as demonstrated by classic mTOR inhibitor toxicity. Higher doses on this schedule without K are probably also feasible, but would have higher costs.

[Table: see text]

No significant financial relationships to disclose.
International multicenter phase II study of the HDAC inhibitor (HDACi) depsipeptide (FK228) in cutaneous T-cell lymphoma (CTCL): Interim report
Authors: Whittaker S. , McCulloch W. , Robak T. , Baran E.
Published: March 2020

3063

Background: Depsipeptide, a unique bicyclic peptide histone deacetylase inhibitor (HDACi), has shown activity in a range of in vitro and in vivo tumor models and clinical activity in T-cell lymphomas and prostate cancer. This study seeks to confirm the CTCL activity previously reported by the NCI (Piekarz, et al., ASCO, 2004). Methods: Single-arm, open label study, in 25 centers in the UK, Germany, Poland and the US. Patients aged ≥18 years with biopsy-confirmed CTCL (centrally reviewed) who have failed at least one prior systemic treatment receive up to 6 cycles of depsipeptide as a 4-hour IV infusion on Days 1, 8 and 15 q 28 days. Eligibility criteria include: mycosis fungoides and Sézary syndrome plus variants, Stages IB - IVA, adequate organ function, ECOG PS ≤ 1. Patients with significant cardiovascular abnormalities are excluded in addition to those taking QTc-prolonging or CYP3A4-inhibiting drugs. The primary endpoint is overall reponse rate measured by a combination of imaging, circulating cell counts and a weighted skin average instrument, confirmed by standardized photography. A subset undergoes pharmacokinetic assessments. Correlative studies include acetylation status, apoptotic markers and proteomic analyses where possible. Target accrual is 76 to yield 64 evaluable patients. Results: 30 patients have received treatment with 17 evaluable for efficacy. Responses seen are 1 cCR, 4 PRs (duration 2+ to 6 months) 9 SD and 3 PD. 3 patients withdrew early for PD and 2 for other reasons. The remaining patients on study are too early to assess. Most frequent toxicities are: nausea/vomiting, fatigue, myelosuppression and asymptomatic ECG changes. No patient has withdrawn for toxicity and there have been no treatment-related deaths. Conclusions: The previously reported efficacy of depsipeptide in CTCL has also been seen in the present study. Duration of response is encouraging. Toxicity is manageable and the study continues to accrue.

[Table: see text]
Molecular basis of altered uracil catabolism in individuals with 5-FU toxicity and normal DPD enzyme activity
Authors: Reed H. A. , Ezzeldin H. H. , Mattison L. K. , Diasio R. B.
Published: March 2020

3070

Background: Dihydropyrimidine dehydrogenase (DPD) deficiency accounts for approximately 43% of grade 3–4 toxicity to 5-Fluorouracil (5-FU). However, a significant number of patients with normal DPD enzyme activity remain with unexplained molecular basis of 5-FU toxicity. It has been suggested by the few cases previously reported that deficiency of dihydropyrimidinase (DHP)enzyme encoded by the DPYS gene and/or beta-ureidopropionase enzyme, encoded by the BUP-1 gene, could also be implicated in 5-FU toxicity. Methods: This study included 40 volunteers with known 13C-UraBT and DPD enzyme activity, 25 cancer patients with 5-FU toxicity despite normal DPD enzyme activity, and 25 liver biopsies from cancer patients with different grades of toxicity. All samples were analyzed for molecular defects in the DPYS and BUP-1 genes, using DHPLC and RT-PCR techniques. Results: Molecular analysis of the DPYS gene revealed the presence of two non-conservative amino acid changes, one frame-shift mutation that leads to a stop codon and premature termination of the DHP protein, five silent mutations, nine intronic sequence variations, two sequence variations in the 5’UTR and one in the non-coding region of exon 10. Molecular analysis of the BUP-1 gene revealed the presence of two non-conservative amino acid changes, one of which (314C>A: A85E) has already been reported to abolish enzyme activity; six silent mutations, four intronic sequence variations, one polymorphism in the 5’upstream sequence, and one sequence variation in each of the 5’UTR and the 3’UTR. Conclusions: The molecular basis of 5-FU toxicity is not limited to DPD deficiency; since molecular defects in genes downstream of DPD can potentially also impair 5-FU catabolism. Genetic testing for molecular defects in DPYS and BUP-1 may predict patients at risk of developing 5-FU toxicity despite having normal DPD enzyme activity. Assessing the integrity of the entire uracil catabolic pathway might be crucial to avoid toxicity in a significant group of patients receiving 5-FU or a related drug (CA62164).

No significant financial relationships to disclose.
Pharmacogenetic pathway analysis of irinotecan
Authors: Rosner G. L. , Panetta J. C. , Xiao L. , Innocenti F. , Ratain M. J.
Published: March 2020

3073

Background: Irinotecan (IRN), a chemotherapeutic agent for various solid tumors, is the parent compound for SN-38, the active metabolite. The pharmacokinetics (PK) of IRN are complex and associated with variability in clinical outcomes. We sought to learn about the pharmacogenetics (PGx) of IRN by relating the drug’s PK to polymorphisms (SNPs) in drug-metabolizing enzyme and transporter genes potentially relevant to IRN. Methods: We measured concentrations of IRN and 3 metabolites in 86 patients. We fit a novel 7-compartment (15 parameter) model (including enterohepatic circulation) to the concentration data for IRN and metabolites. We applied principal components (PCs) analysis to the patient-specific PK model parameters to reduce the number of outcome variables and to identify appropriate linear combinations of the parameters that relate to IRN’s metabolic pathways. We then analyzed associations between SNPs and PCs to learn about functional polymorphisms. Associations are significant if p < 0.05. Results: We found that 8 PCs accounted for 90% of the total variation in the 15 fitted parameters. PC #1 corresponded to SN-38 in plasma and was associated with SNPs in the CYP3A4, MRP2, and ABCG2 genes. PC #2, the IRN compartments’ PC, was associated with a SNP in OATP-C*1b. The APC PC was associated with a CYP3A5 SNP. The SN-38 glucuronidation PC was associated with UGT1A1 and UGT1A9 polymorphisms. Conclusions: PC analysis is a useful way to reduce the dimension of multiple PK parameters and to produce pathway-specific and interpretable measures relating to PK. The use of PCs in PGx analysis allows identification of potential functional polymorphisms, which can be further evaluated in other data sets.

[Table: see text]
A phase I study of the pan-Bcl2 family inhibitor GX15–070, administered as a 3-hour weekly infusion in patients with refractory solid tumors or lymphomas
Authors: Firozvi K. , Hwang J. , Hansen N. , Malik S. , Maclean M. , Siu L. , Marshall J. L. , Mendelson D. , Kuruvilla J.
Published: March 2020

3081

Background: GX15–070 is an antagonist of the BH3-binding groove of the bcl-2 family of anti apoptotic proteins. GX15–070 activates apoptosis in vitro and exhibits clinical activity in chronic lymphocytic leukemia (O’Brien et al, ASH 2005) with a recommended phase II dose of 28 mg/m2 every 3 weeks with DLT of grade 3 infusional CNS toxicities. Methods: In a standard titration design, 4 cohorts of 3 patients (pt) were treated with 5mg/m2 - 14 mg/m2 IV infused over 3 hours, weekly. Each cycle of therapy consisted of 4 weekly infusions. Pharmacokinetics (PK) and pharmacodynamic (PD) response based on plasma oligonucleosomal DNA levels were evaluated. Results: N=15 pts were treated. Median age was 58 (range 24–71). Median number of prior regimens was 4 (range 1–11). A total of 105 infusions (26 cycles) was administered. GX15–070 underwent first order elimination kinetics with a short initial distribution phase (α t1/2=0.6 h), followed by a longer elimination γphase (t1/2=43.8 h). At the 14 mg/m2 dose level, median C max and AUC values were 98 ng/ml and 276 ng.hr/ml, respectively. The coefficient of variation was low at 38%. Adverse events have mostly been observed during or shortly after the infusion and have been transient. The most common pertain to the central nervous and gastro-intestinal system (drowsiness, euphoria, ataxia, and abdominal pain). Most toxicities were mild to moderate, with the exception of grade 3 pain experienced by 2/2 pts with Hodgkin’s disease, that resolved rapidly but resulted in treatment discontinuation in 1 patient. One episode of Grade 3 infusional CNS toxicity was reported at 14 mg/m2 requiring the inclusion of 6 patients with no further DLT. No neutropenia, thrombocytopenia or lymphopenia have been reported. The MTD has not been reached. Mean increase in plasma oligonucleosomal DNA was 36 fold (range 0–182 fold) over baseline. Best response to treatment to date : SD ≥ 8 weeks (4); PD (5); too early (6). Conclusion: Weekly GX15–070 as been well tolerated at doses showing biological activity. Dose escalation will be pursued up to 28 mg/m2 weekly.

No significant financial relationships to disclose.
Therapeutic implications for acquired resistance and heart toxicity using targeted therapy to erbB2
Authors: Bacus S. S. , Hill J. , Spector N.
Published: March 2020

3084

Background: ErbB2 overexpression predicts for a poor prognosis in breast cancer making it an attractive therapeutic target. Molecules such as EGFR/ErbB2 tyrosine kinase inhibitors (TKI’s), lapatinib/GW2974 and antibodies such as trastuzumab are currently used in clinical trials. Clinical responses to TKI’s have been observed, but are short-lived. Our data elucidates the pathway of acquired resistance to TKI’s and the underlying pathway associated with cardiac toxicity after trastuzumab treatment. Finally, we show the clinical implications and the therapeutic approaches to overcome this. Methods: Immunostaining and Western Blot were performed for HER2, EGFR, ER, PR, Bcl-2, FOXO3a, ERRα, ERR, PGC-1α, p-AKT and pERK. AU565, MCF7, BT-474, MCF7/HER2 and AU/BCL2 were treated with ß-estradiol, tamoxifen citrate, GW2974 and trastuzumab. Results: We show that upregulation of ERα and ER-regulated genes contribute to the resistance to HER1/HER2 inhibitors. Although the ErbB2 pathway is inhibited by lapatinib, the dependence of tumor cell survival in resistant cancer cells switches from ErbB2 to ER pathway. By inhibiting ErbB2/P13/AKT signaling, the inhibitors upregulate FOXO3a, which upregulates ER and ER-regulated genes, such as BCL2, contributing to cellular resistance. We also show that this occurs in patients with ErbB2/EGFR overexpressing ER positive cancers treated with lapatinib. By combining EGFR/HER2 inhibitors or antibodies with interventions that down regulate ER activity or estrogen deprivation, we were able to delay ER-mediated resistance. In addition, we have shown that the genes associated with the fatty acid metabolic pathway are upregulated by trastuzumab, but not lapatinib. Conclusion: Our results show that activation of ER and ER-regulated genes (BCL2) that contributed to the development of resistance to ErbB inhibitors in AU and BT474 cells also occurred in patients treated by lapatinib whose breast cancers expressed a similar phenotype. Identifying the mechanisms involved in the development of resistance and toxicities to ErbB inhibitors will lead to rational therapeutic strategies and improve their efficacy. In addition, less cardiac toxicity is anticipated in patients treated with lapatinib.

No significant financial relationships to disclose.
Alternating versus continuous “FOLFIRI” in advanced colorectal cancer (ACC): A randomized “GISCAD” trial
Authors: Labianca R. , Floriani I. , Cortesi E. , Isa L. , Zaniboni A. , Marangolo M. , Frontini L. , Barni S. , Beretta G. D. , Sobrero A.
Published: March 2020

3505

Background: In ACC “FOLFIRI” is one of the standard regimens and is able to obtain about 40% response rate (RR) with an overall survival (OS) of 17–18 months. Experimental studies (Sobrero, 2000) indicate that an alternating chemotherapy could delay the appearance of cell resistance and reduce the therapeutic load for patients (pts). Methods: In order to evaluate whether intermittent “FOLFIRI” (CPT-11: 180 mg/sqm d1 + l-folinic acid -FA: 100 mg/sqm in 2 hr + 5fluorouracil-5FU: 400 mg/sqm bolus + 600 mg/sqm 22 hr infusion, d 1 and 2 every 2 weeks, for 2 months on and 2 months off) (arm A) was at least as effective as continuous “FOLFIRI” (same regimen, every month) (arm B), until progression in both arms, 336 pts from 27 Centers were randomised from 7/2001 to 6/2005. The characteristics of pts were: median age 64 years (r 29–75), males 214 (63%), PS 0: 222 (66%), liver mets only 166 (49%), multiple mts including liver 80 (24%). Results: RR was 29% in arm A and 35% in arm B, with a median progression-free survival (PFS) of 8.8 and 7.3 months respectively (HR = 1.00, 95% CI: 0.74 - 1.36). At a median follow-up of 27 months, median overall survival (OS), the primary endpoint of the trial, was 16.9 months in arm A and 17.6 in arm B (HR = 1.11, 95% CI: 0.83 - 1.48). Toxicity was acceptable and similar in the 2 arms (WHO grade 3–4 toxicity: neutropenia in 12% pts, diarrhoea in 11%, nausea/vomiting in 4% and fatigue in 3%). Conclusions: Our results demonstrate that alternating “FOLFIRI” obtains the same survival as a continuous treatment, thus reducing the discomfort to pts and the economic costs.

No significant financial relationships to disclose.
Randomized double blind (DB) placebo (Plcb) controlled phase III study assessing the efficacy of xaliproden (X) in reducing the cumulative peripheral sensory neuropathy (PSN) induced by the oxaliplatin (Ox) and 5-FU/LV combination (FOLFOX4) in first-line treatment of patients (pts) with metastatic colorectal cancer (MCRC)
Authors: Cassidy J. , Bjarnason G. A. , Hickish T. , Topham C. , Provencio M. , Bodoky G. , Landherr L. , Koralewski P. , Lopez-Vivanco G. , Said G.
Published: March 2020

3507

Background: X, an orally administered non-peptide neurotrophic agent developed by sanofi-aventis, was shown in vitro to minimize neuritic damage induced by Ox (co-culture of Schwann cells and dorsal roots ganglia explant). The probability of occurrence of Grade (Gr) 3–4 PSN at a cumulative dose of Ox of 1000 mg/m2, was consistently reported to be of 18–20%. Methods: First line MCRC pts were randomized to receive, in a DB fashion, FOLFOX4 and either Plcb or X 1mg daily. X was administered from the 1st day of chemotherapy till 15 days post last Ox cycle. Co-primary objectives were reduction in the risk of occurrence of Gr 3–4 PSN relative to cumulative dose of Ox (Kaplan-Meier method) and non-inferiority in response rate (RR). Secondary endpoints included evaluation of sensory action potential (SAP) and safety. Results: From July 2002 to May 2004, 649 pts were randomized (324 Plcb, 325 X). Pts characteristics were well balanced across arms, median number of Ox cycles was 12 in both arms, median relative dose intensity (%) was 83.8 (Plcb) and 85.2 (X). A significant risk reduction of 39% in the probability of Grade 3–4 PSN in favor of X was reported (hazard ratio [95% CI] = 0.61 [0.40; 0.93], p= 0.0203). Overall RR [95 % CI] was: Plcb 42.6% [37.1; 48.2] and X 44.9% [39.4; 50.6]. As prospectively defined in the protocol, the lower bound of the CI of the RR ratio above 0.8 confirms noninferiority in RR (1.055 [0.88; 1.26]). In both arms the mean % of change in SAP worsens as a function of PSN severity. 17.3 (Plcb) and 13.5% (X) of the pts discontinued Ox because of PSN. Severe toxicities (% Gr 3–4), reported with a ≥2% difference between arms, were (plcb vs X): diarrhea 10.9 vs 13.0, pulmonary embolism 0.9 vs 3.1, fatigue 3.7 vs 1.5, neutropenia 43.0 vs 37.8. Conclusion: X was shown to be efficient in reducing the risk of Grade 3–4 oxaliplatin-induced PSN without impacting FOLFOX4 antitumor activity.

No significant financial relationships to disclose.