bluuebunny/crossref_metadata_2025 huggingface dataset:
A single-dose, placebo- and moxifloxacin-controlled 3-period study of the effects of temsirolimus on cardiac repolarization in healthy subjects
Authors: Hug B. , Boni J. , Leister C. , Burns J. , Sonnichsen D.
Published: August 2020

2551

Background: Temsirolimus (CCI-779) is a novel selective inhibitor of the mammalian target of rapamycin (mTOR) approved by the US FDA for the treatment of patients with advanced renal cell carcinoma. This study was designed to assess the effect of a single dose of 25 mg IV temsirolimus on the corrected QT interval (QTc) in healthy subjects. Methods: Fifty-eight (58) healthy subjects were enrolled in this 3-period crossover study. In periods 1 and 2, subjects were administered IV placebo either alone or with open-label oral moxifloxacin. In period 3, subjects were administered 25 mg IV temsirolimus. Serial ECGs were digitally captured in triplicate and manually over read by a central vendor. The primary statistical objective was to estimate the effect of temsirolimus compared with placebo on change from time-matched baseline QTc at the end of infusion (0.5 hour time point). Secondary endpoints and objectives included estimates of effect at 12 additional time points, population PKPD analyses, and categorical summaries of interval data. Assay sensitivity was evaluated by the effect of moxifloxacin on change from time-matched baseline QTc as compared with placebo. Results: Temsirolimus had no effect on the QTc interval in the primary analysis. At 11 of 12 secondary time points, the upper bound for the temsirolimus QTc 90% CIs for the time-matched change from baseline difference from placebo was less than 10 msec without evidence of QTc trends or relationship to temsirolimus or sirolimus whole blood concentrations. Mean concentrations were comparable to those observed in patients with renal cell carcinoma following administration of 25 mg IV temsirolimus. Moxifloxacin produced a statistically significant increase in the QTc interval as compared with placebo. No relevant PKPD relationship was seen using linear or Emax models. No subject in this study had a QTc interval exceeding 450 msec and no subjects had a change from baseline >30 msec. Conclusions: We conclude that therapeutic exposures of temsirolimus are not associated with changes in QTc interval that reach the level of regulatory significance, according to ICH E14 guidance. The findings are consistent with the lack of QTc interval prolongation observed in studies of cancer patients.

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EZN-2968, a novel hypoxia-inducible factor-1α (HIF-1α) messenger ribonucleic acid (mRNA) antagonist: Results of a phase I, pharmacokinetic (PK), dose-escalation study of daily administration in patients (pts) with advanced malignancies
Authors: Patnaik A. , Chiorean E. G. , Tolcher A. , Papadopoulos K. , Beeram M. , Kee D. , Waddell M. , Gilles E. , Buchbinder A.
Published: August 2020

2564

Background: HIF-1 is a transcription factor that regulates expression of many key genes, notably those switching cell metabolism to anaerobic glycolysis and inducing neovascularization in response to hypoxia. Increased HIF-1α levels are associated with poor prognosis in several neoplasms. EZN-2968 is a potent locked nucleic acid antisense oligonucleotide suppressing HIF-1α mRNA translation in vitro (IC50 ∼1–5 nM). Methods: This study was designed to determine the safety, tolerability, PK, maximum tolerated dose, recommended dose, and preliminary evidence of antitumor activity of EZN-2968. Pts with advanced malignancies were treated with EZN-2968 administered as a daily 2-hr IV infusion x 5 days every 4 weeks using a 3+3 dose-escalating design. Dose escalation was based on toxicities observed during Cycle 1. Results: 19 pts (11 men; median age = 60 y [47–79 y]) were treated with EZN-2968 doses of 0.5 (3 pts), 0.8 (3 pts), 1.2 (3 pts), 1.8 (4 pts), 2.7 (3 pts), and 4.1 (3 pts) mg/kg/day. Tumor types included colorectal cancer (7 pts); renal cancer (4 pts); soft-tissue sarcoma (STS; 2 pts); angiosarcoma (1 pt); melanoma (1 pt); and breast, ovarian, pancreatic, and prostate cancers (1 pt each). No dose-limiting toxicities were observed. The most common adverse events (Aes) were vomiting (32%); fatigue (26%); and anemia, diarrhea, nausea, and tumor pain (each 21%). Most Aes were Grade 1 or 2. Plasma PK for Day 1 is tabulated below. Stable disease was observed for 1 pt with angiosarcoma (28 wks) and 1 pt with renal cancer (12 wks). Conclusions: EZN-2968 was well tolerated in previously treated pts with advanced malignancies. PK data do not show accumulation of EZN-2968. Dose escalation is ongoing; final results will be presented at the meeting. Durable stable disease has been observed.

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Ixabepilone and lapatinib for HER2-positive advanced breast cancer: Preclinical rationale and phase I trial
Authors: Mainwaring P. N. , Nguyen T. , Price G. , Venter D.
Published: August 2020

2582

Trastuzumab with or without taxanes are the cytotoxic therapies of choice for advanced Her-2 positive breast cancer. Ixabepilone and lapatinib have demonstrated clinical efficacy in advanced breast cancer that is resistant to taxanes and trastuzumab. We have compared the therapeutic potential of ixabepilone, lapatinib, paclitaxel and trastuzumab, in vitro, prior to commencing a phase I clinical trial. Three different breast cancer cell lines SK-BR3, BT-474 and MCF-7 (control; non-Her-2 amplified), were seeded 96-well plates, cultured for 24 hours and different concentrations of ixabepilone or paclitaxel and trastuzumab or lapatinib were added. Experiments were performed in triplicate. A MTT viability assay was used to measure the activity of live cells after 0, 3, 24, 48 and 120 hours. The cells and vehicle control wells were averaged and normalized to 100% for comparison to the average value of the 6 replicate wells graphed over time for each cell line, drug concentration and cell density. Student-t test was used to determine the level of significance comparing the 0 hour time point in a pair-wise, pooled variance manner to each other time point. Paclitaxel + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Paclitaxel + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + trastuzumab significantly reduced proliferation p < 0.001 at 120 hrs; Ixabepilone + lapatinib significantly reduced proliferation p < 0.001 at 120 hrs; Dose response curves were clearly evident for all combinations. Of note proliferation was reduced earlier and at lower drug concentrations with lapatinib combinations than with trastuzumab combinations. The drugs whose efficacy was proven in MCF-7 cells were studied in detail on the xCELLigence cell analysis system. These data recapitulated the MTT data and provided in depth detail of the rate of drug action. An international multicentre phase I trial of Ixabepilone with lapatinib ± capecitabine has commenced in patients with Her-2 positive taxane and trastuzumab resistant advanced breast cancer. Toxicity has been as previously described with fatigue, arthralgias, onycholysis and rash occurring. No DLTs have occurred. RECIST responses have been confirmed in 2 of the first 3 patients enrolled.

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A phase I trial of adoptive transfer of allogeneic natural killer (NK) cells in patients (pts) with advanced non-small cell lung cancer (NSCLC)
Authors: Iliopoulou E. G. , Kountourakis P. , Karamouzis M. V. , Doufexis D. , Ardavanis A. , Baxevanis C. N. , Rigatos G. , Papamichail M. , Perez S. A.
Published: August 2020

3001

Background: HLA-mismatched NK cells have been found effective in acute myeloid leukemia pts. Preclinical studies revealed that activated NK cells massively infiltrate lung tissue and improve recipient survival, suggesting a potential role in lung cancer therapeutics. We performed this phase I trial to evaluate safety and antitumor responses of allogeneic, in vitro activated and expanded NK cells in combination with chemotherapy (C) in pts with advanced NSCLC. Methods: Pts with unresectable locally advanced/metastatic NSCLC receiving 1st/2nd line C were eligible. Two relative donors for each pt were selected based on their HLA and KIR typing. CD56+ cells were isolated from 150ml of donor peripheral blood and cultured for 20–23 days with 20ng/ml interleukin-15 and 10-5M hydrocortisone. Activated and expanded NK cells, after sterility, phenotype, and function testing, were diluted in 500ml N/S 0.9% with 2% human serum albumin and administered i.v. for 1 hour 2 days after previous and 1 week prior next C. Premedication with corticosteroids and/or H1 inhibitors was allowed. The number of NK cells to be injected was up to 2x1011/dose for up to 4 doses. Pts and donors signed detailed informed consent. Results: Between 11/2007 and 11/2008 16 pts (performance status 0–1) were enrolled; 1 pt had rapid disease progression before treatment. Pts characteristics: M/F 12/4; histology: adenocarcinoma/squamous cell carcinoma 13/3; stage IIIb/IV 2/14; 1st/2nd line treatment 13/3; median age 64 years (range, 50–71). The number of doses administered was 2 (N=9 pts), 3 (N=2 pts), or 4 (N=4 pts). The number of cells injected varied from 0.2–29x106/Kg (mean 7.4x106±7.7x106). During and after injection of NK cells no side effect (local or systemic) was observed. With a median follow-up of 6 months (range, 1–14) 3 pts with partial response and 7 pts with disease stabilization were recorded. Conclusions: Adoptive transfer of allogeneic, in vitro activated and expanded NK cells in combination with chemotherapy is safe, even at the highest dose administered. Based on these encouraging results a randomized phase II trial is further justified.

No significant financial relationships to disclose.
Overcoming tumor antigen anergy in human malignancies using the novel indeolamine 2,3-dioxygenase (IDO) enzyme inhibitor, 1-methyl-D-tryptophan (1MT)
Authors: Soliman H. H. , Antonia S. , Sullivan D. , Vanahanian N. , Link C.
Published: August 2020

3004

Background: The limited effect of cancer immunotherapy is due to the tumor's ability to induce host anergy towards its antigens. The enzyme indoleamine 2,3-dioxygenase (IDO) is thought to play a key role in anergy induction. IDO metabolizes tryptophan (trp) into immunosuppressive metabolites such as kynurenine (kyn). The oral IDO inhibitor, 1-methyl-D-tryptophan (1MT), was studied in preclinical models. The preclinical data support the activity of 1-MT in preventing T-cell anergy in TDLN, slowing growth of LLC mouse xenografts, and synergizing with chemotherapy in regression of autochthonous breast tumors in MMTV-Neu mice. This led to a phase I first-in-man trial using 1-MT in solid tumors. Methods: This is a phase I study treating adults with refractory solid malignancies. Patients are treated with up to 6 consecutive 28-day cycles starting at 200mg once daily. A 3+3 dose escalation to MTD is used. PK analysis, weekly labs, and CT scans every 2 cycles were done. Correlative studies include serum kyn/trp levels, T-reg cell quantification by flow, tumor IDO expression by IHC, and humoral immune response using a proprietary tumor antigen microarray. Results: Ten pts have recieved 1-MT at 200mg daily. Tumors treated included 1 esophageal, 1 peritoneal, 3 melanomas, 2 sarcomas, and 3 NSCLC. PK results show good bioavailability and a t1/2 of 2–4 hrs. Of the 7 evaluable pts, 4 had SD and 3 had PD. Attributable toxicities were 1 case of grade 1 fatigue and 2 cases of grade 2 hypophysitis. Both cases occurred in pts who received prior immunotherapies. Six new pts without prior immunotherapy were enrolled at the 200mg dose level. Five pts remain on treatment currently. Three pts had decreased T-reg cells after treatment with 1MT and 4 pts showed marked CRP increases. One pt had increased autoantibody titers against 3 tumor antigens compared to baseline. Conclusions: 1-MT appears to be an active, orally bioavailable, and reasonably well tolerated immunomodulator at 200mg daily. Development of hypophysitis in 2 patients indicates the drug can break tolerance resulting in autoimmunity. Enrollment to the trial continues. Future trials will combine 1-MT with other immunotherapies and chemotherapies for solid tumors.

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Phase I adjuvant trial of multi-epitope p53 vaccine for patients with squamous cell carcinoma of the head and neck (SCCHN): A preliminary report
Authors: Andrade P. , Deleo A. , Visus C. , Butterfield L. , Argiris A. , Ferris R. L.
Published: August 2020

3012

Background: Alteration in the tumor suppressor protein, p53, is one of the most common events in human cancers. Since most mutations of p53 are associated with accumulation of p53, the nonmutated portions of protein are readily accessible to degradation into wild type (wt) sequence peptides for immune recognition by T lymphocytes. Methods: A phase I trial was conducted in stage I-IVa patients (pts) with SCCHN with no active disease using autologous dendritic cells (DC) loaded with two HLA-A*0201-restricted T cell-defined p53 peptides alone (Arm 1, 5 pts), plus either a wt p53 helper peptide (Arm 2, 5 pts) or nonspecific helper peptide (dervied from tetanus toxoid, Arm 3, 6 pts). The accrual goal is 24 patients, divided into the 3 arms. Each pt received 3 intranodal vaccinations at 2-week intervals. The primary endpoint was immunological response using ELISPOT, tetramer or delayed type hypersensitivity (DTH)reactions to p53 peptides. Results: 16 pts have been vaccinated so far. Erythema or hematoma were observed at vaccine injection sites in two pts. At 15-mo median follow-up, 11/16 pts are alive without evidence of disease, 2 developed disease recurrence, and 1 pt developed a second primary lung cancer. Two have died of unrelated causes. Immunological analyses of the SCCHN patients’ responses to immunization indicate responses to both HLA-A2 binding peptides. Tetramer frequencies for p53-specific CTL or IFN-gamma ELISPOT assays indicated a 5/16 responders. Ongoing correlative analyses include characterization of human papillomavirus (HPV) infection, HLA, antigen processing machinery, and staining with soluble T cell receptor for HLA-A2-p53 peptide complexes on tumor cells. Conclusions: Adjuvant p53 peptide-loaded DC-based vaccination is feasible and safe in pts with SCCHN. A phase II wt p53-based vaccine trial will be proposed based on the most efficacious regimen used in this trial.

No significant financial relationships to disclose.
Elimination of cancer stem cells (CD133+/EpCAM+) from malignant ascites by the trifunctional antibody catumaxomab: Results from a pivotal phase II/III study
Authors: Lindhofer H. , Schoberth A. , Pelster D. , Hess J. , Herold J. , Jäger M.
Published: August 2020

3014

Background: Putative cancer stems cells (CSCs) are defined as “tumor-initiating cells” that have the capacity to self-renew and to give rise to the variety of differentiated cells found in the malignancy. The CD133 membrane glycoprotein represents a CSC marker that has been previously demonstrated to be capable of identifying a cancer-initiating subpopulation in brain tumors, melanoma, and EpCAM+ solid tumors. The trifunctional anti-EpCAM x anti-CD3 antibody catumaxomab efficiently eliminates tumor cells from the peritoneal fluid of malignant ascites (MA) patients as demonstrated in a pivotal phase II/III trial (Parsons et al., ASCO 2008). Here we report on the presence of CD133+/EpCAM+ putative CSCs in MA and, more importantly, on the elimination of this cell population from the peritoneal fluid of MA patients by means of catumaxomab therapy. Methods: 18 CTX-refractory patients with MA caused by a variety of primary carcinoma diseases (i.e., ovarian, pancreas, and gastric cancer) were analyzed for the presence CD133+/EpCAM+ cells in peritoneal fluids by means of CD133+/EpCAM+ double staining on cytospin preparations. Analyses were performed before, 2 days after the first, and 1 day after the last catumaxomab infusion, respectively. Double-stained cytospin preparations were evaluated with a computerized image analysis system. Results: Before therapeutic intervention, CD133+/EpCAM+ cells were detected in the peritoneal fluids of 14 from 18 patients suffering from MA. After the 1st infusion of catumaxomab (10μg), 9 of these 14 patients showed complete elimination of the CD133+/EpCAM+ cells. After 4 i.p. catumaxomab infusions (10μg day 0, 20μg day 3, 50μg day 7 and 150μg day 10) the CD133+/EpCAM+ cells were completely eliminated from the peritoneal fluids of all 14 MA patients. Conclusions: In a preliminary monitoring study, putative CSCs (CD133+/EpCAM+) were present in peritoneal fluids of 78 % of analyzed MA patients with different underlying primary tumor entities. Catumaxomab efficiently destroyed CD133+/EpCAM+ cells within peritoneal fluids of MA patients. Consequently, catumaxomab-based therapeutic measures may offer an additional treatment opportunity to eliminate CSCs in EpCAM+ malignancies.

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Phase II experience with MDX-1106 (Ono-4538), an anti-PD-1 monoclonal antibody, in patients with selected refractory or relapsed malignancies
Authors: Brahmer J. R. , Topalian S. L. , Powderly J. , Wollner I. , Picus J. , Drake C. G. , Stankevich E. , Korman A. , Pardoll D. , Lowy I.
Published: August 2020

3018

Background: Programmed death-1 (PD-1), an inhibitory receptor expressed on activated T cells, may suppress antitumor immunity. This expansion cohort in a phase I/II trial of MDX-1106, a fully human IgG4 antibody blocking PD-1, sought to further evaluate the safety and activity of the 10 mg/kg dose. Other objectives included evaluation of pharmacokinetics (PK) and immunological effects. Methods: Patients (pts) with treatment refractory metastatic non-small cell lung cancer (NSCLC), renal cell carcinoma (RCC), colon cancer (CC), melanoma (MEL), or prostate cancer (CRPC), and no history of autoimmune disease received a single infusion of MDX-1106 at 10 mg/kg. Disease status was evaluated at week (wk) 8 by RECIST criteria. Pts with stable disease or lesional responses could receive additional MDX-1106 at wks 12 and 16. Those with PR/CR were observed without retreatment. Results: 21 pts (5 CC, 2 NSCLC, 8 MEL, 5 HRPC, 1 RCC) were treated from 10/07 to present, and 6 were retreated. No MDX-1106 related SAEs occurred. One pt developed arthritic symptoms requiring treatment, and 2 pts had asymptomatic TSH elevation. One pt with RCC had a PR after 3 doses, lasting 5+ months (mo). Lesional regressions (“mixed response”) were seen in 2 MEL pts; to date, one has received 7 doses of MDX-1106 over 15 mo without serious toxicity. Biopsy of a regressing MEL lymph node metastasis showed a moderately increased and selective CD8+ T cell infiltrate post treatment. The median serum t 1/2 of MDX-1106 was 20.6 days, which was roughly 50% longer than observed for lower doses. There was no evidence of immunogenicity based on HAHA development. Interestingly, in contrast to PK results, flow cytometric analysis demonstrated sustained occupancy of 60–80% PD-1 molecules on T cells for at least 3 mo following a single dose. Analyses of circulating lymphocyte subsets and tumor B7-H1 expression are in progress. Conclusions: Intermittent dosing of MDX-1106 at 10 mg/kg demonstrated clinical activity against RCC and MEL without serious toxicity. Therapy with MDX-1106 to enhance endogenous antitumor immunity, either alone or combined with other immunological therapies, warrants further study.

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Cellular immune suppression in cancer patients and its implication for dendritic cell therapy
Authors: Nesselhut J. , Lorenzen D. R. , Marx D. , Chang R. Y. , Matthes C. , Hildenbrand B. , Schneider E. M. , Nesselhut T.
Published: August 2020

3028

Background: The treatment of human cancer with monocyte-derived dendritic cells (MoDC) is a promising and innovative approach. However, many of the treated patients fail to respond to therapy. The reduced clinical antitumor response may be due to an inflammatory immune-suppressive tumor microenvironment. Regulatory T-cells (T-reg) and other cells with suppressive potential can promote an immune suppressive tumor microenvironment and thus play an important role in regulation of the immune response. Methods: Whole blood from n=100 cancer patients with various tumor types and from n=30 healthy donors were analysed by flow cytometry. CD4+ lymphocytes with immune suppressive potential were characterized by analysing the expression of CD25, CD39, CD127. Results: We found a significantly higher proportion of CD25+/CD39+ and of CD25+/CD127low T-helper cells in the blood of cancer patients as compared to healthy donors. This may indicate two different types of T-reg involved in immune suppression in cancer patients. Treatment of patients with metronomic chemotherapy induced a down-regulation of these cells. Interestingly, we found a subpopulation of cells within the lymphocyte gate characterized by CD2high and CD86 expression in cancer patients with very advanced stage, similar to such normally found in hemaphagocytic lymphohistiocytosis (HLH) patients characterized by exceeding high plasma concentration of IFN-g and IL-10 (Schneider et al. 2002). These cells can be down-regulated by treatment with a tetradecapeptide (Ezrin) known to act as an immune modulator with anti-viral activity leading to reduction of inflammatory cytokines. Conclusions: An efficient induction of a clinical antitumor response requires both a polarization of MoDC in a TH1 direction as well as changing an immune suppressive tumor microenvironment. For the first time, we identified HLH associated cells in advanced cancer patients. As HLH is characterized by hyperinflammation, these cells may indicate an inflammatory tumor microenvironment. Thus, anti-inflammatory therapy should be considered as co-treatment with immunotherapy with dendritic cells for down-regulation of immune suppressive cells (T-reg, CD2high/CD86+ cells) to promote a clinical antitumor response.

No significant financial relationships to disclose.
Pharmacodynamic (PD) evaluation of LY2181308 in patients with metastatic malignancies
Authors: Talbot D. C. , Davies J. , Olsen A. , Andre V. , Lahn M. , Powell E. , Kadam S. , de Bono J. , McHugh P. , Ranson M.
Published: August 2020

3507

Background: Survivin is an inhibitor of apoptosis and its overexpression in cancer has been associated with poor survival. LY2181308 (LY), a novel modified antisense oligonucleotide is a specific inhibitor of survivin. The safety and PK profile of LY from this first-in-human study was presented at ASCO 2008. We now present the PD data from this trial. Methods: Patients with advanced or metastatic malignancies who had failed previous anti-tumor treatments were enrolled. Three consecutive IV loading doses given over 3 hours were followed by weekly maintenance doses. Pre- and post-dosing biopsies were mandated to test for evidence of modification of the target at doses where a PD effect was expected. Biopsies were taken 48 hours after the last loading dose by CT-guided fine needle biopsy. Tumor tissue was paraffin-embedded for immunohistochemistry (IHC) and survivin gene expression. Given the finite amount of biopsy material, the quantification of survivin protein was prioritized. In addition, at one site, pre- and post-dosing endobronchial sampling was conducted in NSCLC patients, with the aim of quantifying levels of native survivin protein, and assessing changes in cell cycle profile in freshly isolated tumor cells using FACS analysis. Results: Out of the 34 patients enrolled, 22 patients had a pre- and posttreatment biopsy. Results from IHC indicated that survivin expression was reduced in the nucleus and cytoplasm in 11/17 and 5/14 evaluable pairs, respectively. LY was detected in neoplastic and non-neoplastic tumor cells in 5/16 and 15/16 evaluable pairs respectively. Gene expression analysis indicated a reduction in survivin expression by 20% to 50% in 11/15 evaluable pairs. Analysis of the fresh tumor material from endobronchial sampling revealed that 2 out of 3 patients with NSCLC had a near-complete elimination of survivin-positive cells accompanied by an increase in the fraction of cells with a sub-G1 DNA content, consistent with cell death. Conclusions: In this study, we were able to demonstrate the presence of the ASO in tumor tissue and confirm a reduction in survivin protein and gene expression. These findings demonstrate the proof of principle of antitumor activity of LY and provide the rationale for phase II studies.

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Clinical activity observed in a phase I dose escalation trial of an oral c-met and ALK inhibitor, PF-02341066
Authors: Kwak E. L. , Camidge D. R. , Clark J. , Shapiro G. I. , Maki R. G. , Ratain M. J. , Solomon B. , Bang Y. , Ou S. , Salgia R.
Published: August 2020

3509

Background: PF-02341066 (PF) is a selective, ATP-competitive, small molecule oral inhibitor of the c-Met/HGFR and ALK receptor tyrosine kinases that has not previously been tested in humans. A Phase 1 dose-escalation trial evaluating PF as an oral single agent was conducted to investigate safety, PK and PD in patients (pts) with advanced cancer (excluding leukemias). Methods: PF was administered under fasting conditions QD or BID on a continuous schedule to pts in successive dose-escalating cohorts at doses ranging from 50 mg QD to 300 mg BID. Pts with advanced cancer were enrolled in the study. Results: Thirty-seven pts were enrolled into the dose escalation part of the study. Tumor types included colorectal, pancreatic, sarcoma, ALCL and NSCLC. The MTD was 250 mg BID. Three DLTs were observed: grade 3 increase in ALT (1 pt at 200 mg QD) and grade 3 fatigue (2 pts at 300 mg BID). The most common AEs were nausea, emesis, fatigue and diarrhea. Nausea and emesis were independent of dose or duration of treatment. Mean AUC (30–57% CV) and Cmax (36–69% CV) increased proportionally with dose from 100 mg QD to 300 mg BID. The median terminal half-life was 46 hours. A 2- to 4-fold increase in the oral midazolam (MDZ) AUC was observed following 28-days of PF dosing at 100 mg QD (n = 3) and 300 mg BID (n = 2), respectively, suggesting PF to be an inhibitor of CYP3A. Ten pts have entered an enriched RP2D cohort of pts with tumors harboring c-Met amplification/gene mutation or ALK fusion genes. There has been 1 confirmed PR in a sarcoma pt with ALK rearrangement (inflammatory myofibroblastic tumor). Among 10 NSCLC pts whose tumors harbor EML4-ALK rearrangement, 1 pt has had a PR, 2 pts have achieved unconfirmed PR and 4 pts have had SD (3 have experienced reduction in tumor burden by ∼20% in measurable lesions and 1 has been treated for 28 weeks). Conclusions: The MTD of PF is 250 mg BID. The major AEs were fatigue or GI-related, and all AEs were manageable and reversible. There was no evidence of non-linear PK at PF doses >100 QD. Treatment with PF-02341066 resulted in promising clinical activity against tumors carrying activating ALK gene rearrangements. Further study of PF in pts with ALK-dependent tumors is warranted.

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A phase I study of XL228, a potent IGF1R/AURORA/SRC inhibitor, in patients with solid tumors or hematologic malignancies
Authors: Smith D. C. , Britten C. , Clary D. O. , Nguyen L. T. , Woodard P. , Hurwitz H. I.
Published: August 2020

3512

Background: XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1–3, ABL and SRC family kinases. It is being evaluated in a phase 1 trial in patients (pts) with advanced malignancies. Methods: XL228 is administered as weekly 1-hour IV infusions. Cohorts of pts with refractory solid tumors or lymphoma are evaluated for determination of the maximum tolerated dose, pharmacokinetics, and pharmacodynamic effects using FDG-PET, signal pathway analysis in tumor and normal tissue biopsies, and plasma marker analysis. MTD expansion cohorts will include pts with multiple myeloma and colorectal cancer. Results: Thirty-six pts have been treated at doses ranging from 0.45 to 8.0mg/kg. The maximum administered dose was defined as 8.0mg/kg as a result of the dose limiting toxicities of Grade (Gr) 4 neutropenia, and Gr 3 neutropenia requiring dose skipping. XL228 is generally well tolerated; one serious adverse event of drug-related Gr 3 vomiting has been observed. Common drug-related adverse events include Gr 1 nausea, fatigue, decreased appetite, and flushing, and Grade 1–2 hyperglycemia (fasting) lasting up to 4 hours post- infusion. XL228 exposure was approximately dose-proportional; the mean terminal half-life (t1/2, z) ranged from 27 to 54 hours. Low accumulation was observed after weekly administration. Protein phosphorylation measurements in skin, hair, and blood samples demonstrate inhibition of IGF1R, SRC and FGFR1 signaling by XL228, including reductions in hair follicle phospho-IGF1R and phospho-FAK1 of 39% and 42%, respectively, in a pt dosed at 5.4mg/kg. Evidence of clinical activity includes one non-small cell lung cancer pt with an unconfirmed partial response (confirmation pending) and 9 additional pts (of 30 evaluable) with stable disease (SD) lasting >3 months, including a small cell lung cancer pt on study for 13.3+ months after failing carboplatin/etoposide. For pts with SD, the median time on study is currently 5.9 months (range 3.3+ to 13.3+). Conclusions: XL228 is generally well tolerated and has shown encouraging preliminary clinical and pharmacodynamic activity.

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First-in-human phase I study of the novel structure proteasome inhibitor NPI-0052
Authors: Hamlin P. A. , Aghajanian C. , Younes A. , Hong D. S. , Palladino M. A. , Longenecker A. M. , Lloyd G. K. , Hannah A. L. , Spear M. A. , Kurzrock R.
Published: August 2020

3516

Background: NPI-0052 is a second-generation proteasome inhibitor that has a novel structure with preclinical studies suggesting unique proteasome inhibition (PI), signal transduction, efficacy and toxicology profiles, and activities in a broad range of models including bortezomib (BZ) resistant models. Methods: Patients were treated with NPI-0052 IV weekly x 3 in 4-week cycles in a 3+3 design dose escalation to a Recommended Phase 2 Dose (RP2D). PI was assayed in whole blood (PWB) and in PBMCs. Up to 10 patients each (lymphoma and solid tumors) are treated at the RP2D. Results: 39 patients have been treated between 0.0125 mg/m2 to 0.8 mg/m2 for up to 12 cycles. The RP2D was 0.8 mg/m2 and has been well tolerated in this study, with the most notable drug-related adverse events being N/V, fatigue, diarrhea, dizziness, headache, decreases in hemoglobin, and insomnia. Thrombocytopenia or neuropathy did not appear to be induced by NPI-0052. Escalation was halted at 0.8 mg/m2, as DLT of transient “hallucinations” (visual imprints when eyes closed) and dizziness/unsteady gait were reported in another study at 0.9 mg/m2. PK data indicate T1/2 ∼4–10 minutes, with clearance at 3–15 L/min and Vz of 35–85L. PI (chymotrypsin-like activity) in PWB and PBMC were dose dependent (mean D1 and D15 PI in PWB at 0.8 mg/m2 was 75 and 100%) (efficacious doses of BZ have been reported to result in a range of ∼40–70% PI). PI in PBMC returned to ∼baseline within one week of each dose, while inhibition remained in PWB. Stable disease was observed in patients with cervical carcinoma (11 months; maximum response was 24%; PI increased with dose escalation), colorectal, hepatocellular, adenoid cystic, melanoma, granulosis cell and ovarian. Conclusions: NPI-0052 produces dose-dependent pharmacologic effects, with equal to greater PI seen than reported with therapeutic doses of BZ. At the RP2D toxicity is mild-to-moderate, without the toxicity profile associated with BZ. Together with preclinical data this suggests NPI-0052 may have utility in treating patients who are not candidates for BZ as well as in indications and combinations that have not supported BZ use. Additional trials have been initiated including combinations with other targeted agents.

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Phase I study of enzastaurin (ENZ) and bevacizumab (BV) in patients with advanced cancer: Safety, pharmacokinetics (PK), and response assessment
Authors: Carducci M. A. , Armstrong D. K. , Collins C. , Wang T. , Schaefer S. , Ermisch S. , Musib L. C. , Nicol S. , Thornton D. E. , Zhang Z.
Published: August 2020

3517

Background: ENZ, an oral kinase inhibitor, suppresses tumor growth through PKC and PI-3 kinase/AKT. BV binds VEGF and inhibits angiogenesis. Since ENZ and BV are complementary in inhibiting angiogenesis, we conducted a Phase I study of ENZ / BV. Methods: Eligible patients (pts) had advanced cancer, adequate organ function and no co-morbidities for increased risk of drug-related toxicities. Six pts were enrolled per cohort; if ≤1 DLT the next cohort opened. A loading dose of ENZ 1125 mg was given on Day 1, C1. After 1 cohort combining ENZ 500 mg/QD and BV at 5mg/kg IV q 2 wks, subsequent cohorts alternated pts between BV 10 mg/kg IV q 2 wks and BV 15 mg/kg IV q 3wks with escalating doses of ENZ (500 mg/QD, 250 mg/BID, and 375 mg/BID) for a total of 7 cohorts. DLT was defined as C1: Grade (G)4 neutropenia ≥7 days, febrile neutropenia, G3 thrombocytopenia with bleeding or G4 thrombocytopenia; G3/G4 non-hematological toxicities, and toxicities associated with BV. ENZ PK was performed at steady-state on Day 1, C2. Results: 43 pts (21 with ovarian cancer) are evaluable for toxicity. Two DLTs (G3 elevated aminotransferase and intraparenchymal hemorrhage) occurred at different dose levels. No apparent increase in ENZ or BV toxicity was seen. Two SAEs (DVT and myocardial ischemia) in two pts occurred at DL 3 after 3 cycles and 13 cycles, respectively. Common toxicities included fatigue, chromaturia, dry/sore mouth, nausea and diarrhea. Nine of 43 pts (21%) had a response (CR, PR), 6 responses were in the ovarian subset (29%). Median time to progression was 3.9 mos (range 0–19.2 mos) and 7.7 mos for ovarian pts (range 0.3–19.2 mos). Overall, 43% remained on study without disease progression for >6 mos (51% of ovarian pts remained on study for >6 mos). Mean steady-state ENZ concentrations (%CV) at 500 mg/QD, 250mg/BID and 375mg/BID were 1080 nmol/L (82.8 %), 516 nmol/L (102%) and 1120 nmol/L (93.3%), respectively. Conclusions: The addition of ENZ to BV in any of the currently approved BV dosing schedules is well tolerated and clinically active in advanced cancer pts. ENZ exposures are highly variable and comparable across the three dose groups. The combination of ENZ / BV demonstrates encouraging activity, specifically in our population of ovarian cancer pts.

[Table: see text]
Phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of PF-00337210, a highly selective VEGFR inhibitor
Authors: Liu G. , LoRusso P. M. , Goncalves P. , Holen K. , Traynor A. , Zhang J. , Hee B. , Tortorici M. , Shalinsky D. R. , Ricart A. D.
Published: August 2020

3519

Background: PF-00337210 potently inhibits VEGFR2 phosphorylation and is >10-fold more selective, based on IC50, for VEGFR2 than other kinases (eg, KIT and PDGFRs). In vitro, PF-00337210 inhibits VEGF-mediated HUVEC survival (IC50 = 0.53 nM). In vivo, it inhibits tumor angiogenesis and human xenograft growth. Methods: The primary objectives were to determine the safety profile and MTD of PF-00337210. PK and PD (DCE-MRI at baseline and cycle [C] 1, day [D] 2) were also evaluated. The volume rate transfer constant (Ktrans) assessed VEGFR inhibitory effects on vascular permeability and perfusion. Results: To date, 29 patients (pts) with advanced solid tumors were treated with PF-00337210 at doses of 0.67–9 mg QD, 13 of whom (45%) had received prior VEGF/VEGFR inhibitors. No dose-limiting toxicities (DLTs) occurred at 0.67–8 mg QD. Two DLTs occurred at 9 mg QD: one pt had chest pain, G3 troponin I, and G3 myocardial ischemia; a second pt had significant hypertension (HTN) at the anticipated Tmax after the first dose (systolic ≥180 mmHg over 3 hrs). HTN and fatigue were the most common treatment-related adverse events (AEs). HTN occurred in 8 pts (28%); incidence and intensity corresponded with dose, but was well controlled with antihypertensive agents. Fatigue was reported in 9 pts (31%) and occurred most frequently in pts receiving ≥6 mg QD. Other AEs included nausea, anorexia, proteinuria, and diarrhea. PK data indicated that mean (%CV) t1/2 at 8 mg QD was 8.60 (81) h (n=4) and AUC0–24 was 309 (45) ng.h/mL at steady-state (SS) on C1D15. Exposures (AUC0–24) were generally linear and variability ranged from 21 to 44% across doses. The observed accumulation ratio (Rac) at SS was 1.22 (15) (n=21), which was predicted by t1/2. PF-00337210 decreased mean Ktrans (1/min) values by 22.5±11.8 (n=2), 15.2 (n=1), 5.4±4.8 (n=3), and 25.3±8.5% (n=4) at 4, 6, 8, and 9 mg QD, respectively. No objective responses were observed but 7/29 pts (24%) had stable disease. Conclusions: PF-00337210 was well tolerated with the DLTs being HTN and myocardial ischemia. The QD MTD was determined to be 8 mg. Preliminary evidence of VEGFR inhibition was shown by DCE-MRI at ≥4 mg QD. The trial is now evaluating BID dosing which may allow increased drug exposures and fewer hypertensive effects that may be related to Cmax.

[Table: see text]
Phase II trial of pazopanib in progressive, metastatic, iodine-insensitive differentiated thyroid cancers
Authors: Bible K. C. , Smallridge R. C. , Maples W. J. , Molina J. R. , Menefee M. E. , Suman V. J. , Burton J. K. , Bieber C. C. , Ivy S. P. , Erlichman C.
Published: August 2020

3521

Background: Systemic therapies have had little impact on the outcomes of patients with advanced differentiated thyroid cancers. Methods: A three-outcome one-stage Phase II trial was conducted to assess the anti-tumor activity and toxicities of the orally bioavailable VEGF/tyrosine kinase inhibitor pazopanib (800 mg daily) in patients with advanced and progressive radioiodine-insensitive differentiated thyroid cancers. Up to 2 prior therapies were allowed, with measurable disease required. Design: at the 0.10 significance level, there would be a 90% chance of detecting a RECIST response rate of >20% given a true response rate of >5%; with the regimen considered promising if >4 confirmed responses observed. Results: From February to November 2008, 32 patients (53% male) aged 23–79 years (median: 63 years) were enrolled. Common sites of metastases were: lung (100%), nodes (52%), and bone (39%). Measurement data are available for 26 patients, with the median number of cycles administered thus far 4 (range: 1–8, total: 101). Overall, therapy has been well tolerated. Six patients (23%) required dose reduction due to: grade 2+ ALT (3 pts), grade 3 mucositis (1 pt); grade 3 diarrhea and dehydration (1 pt), and grade 3 abdominal pain (1 pt.). Other serious toxicities included grade 3 colon perforation and grade 3 chest pain (1 pt). No thyroglobulin antibody (TGA) negative patient has become TGA positive, and 11 of 16 patients (69%) with initially elevated thyroglobulin levels experienced a decline in thyroglobulin of >50%. Five RECIST partial responses have been confirmed to date (19%). Two patients are alive with disease progression and another has died from disease progression. Conclusions: Pazopanib appears to have both a favorable toxicity profile and promising clinical activity in patients with advanced and progressive differentiated thyroid cancers. Supported in part by NCI CA15083 and CM62205.

No significant financial relationships to disclose.
Circulating tumor and endothelial cells as pharmacodynamic biomarkers in a phase I clinical trial of intravenous bevacizumab in combination with escalating doses of oral cediranib for patients with advanced malignancies
Authors: Davis D. W. , Liu W. , Kurzrock R. , Naing A. , Wheler J. , Ricks L. W. , Ivy S. , Hong D.
Published: August 2020

3525

Background: Rare circulating tumor cells (CTCs) and endothelial cells (CECs) offer a feasible approach for studying the pharmacodynamic effects of investigational agents. We investigated the effects of bevacizumab (B) and cediranib (C) on inhibition of the VEGFR pathway and correlated these changes with dose and clinical response. Methods: Peripheral blood was obtained at baseline, 24hrs and at C2D26–30 post-treatment from patients (n=14) undergoing dose escalation of intravenous B and oral C. CTCs and CECs (CD31+ or CD105+) were isolated and immunofluorescently stained. Laser scanning cytometry (LSC) was used to quantify phosphorylated and total-VEGFR2 (pVEGFR2/VEGFR2), pERK/ERK, and apoptosis in each phenotype. Changes in each biomarker were correlated with partial response (PR) or stable disease and progression > 2 months, evaluated using RECIST. Results: Overall, immature CECs (CD105+) enumerated by CellSearch™ revealed a dose-dependent significant decrease (p=0.0001). A 3-fold induction in apoptosis was observed at 24 hrs compared to baseline in the CD105+ CECs. Mature CD31+ cells assessed for VEGFR2 activity revealed an 83% and 1.9% significant (p=0.019) inhibition in pVEGFR2 expression at low (B;3mg/kg) and high (B;5mg/kg) doses, respectively. In the non-responders, mature CECs revealed a dose-dependent significant increase (-6.8% to 63%;p=0.031) in pERK/ERK expression levels. No significant changes were observed in CTC enumeration by CellSearch™. LSC-mediated CTC enumeration revealed a 4.77 % and 2.33% increase in CTCs following treatment in the non- responders and responder (p=0.809), respectively. Analysis of pVEGFR2 in CTCs revealed a 58% inhibition in the responder versus a 163% increase in expression in the non-responders (p=0.63). Conclusions: Inhibition of pVEGFR2 and induction of apoptosis in CECs confirmed the target therapy. An increase in CD105+ CECs is consistent with the hypothesis that anti-angiogenic efficacy induces endothelial cell shedding. Assessment of CECs indicates that B and C are more biologically active at lower doses, and resistance may be attributed to ERK activity. Support: UO1 CA062461 (RK)

No significant financial relationships to disclose.
Pharmacodynamics and pharmacokinetics of AUY922 in a phase I study of solid tumor patients
Authors: Ide S. , Motwani M. , Jensen M. R. , Wang J. , Huseinovic N. , Stiegler P. , Wang X. , Quadt C.
Published: August 2020

3533

Background: AUY922 is a synthetic inhibitor of Heat Shock Protein 90. Disruption of the HSP90 chaperone hetero- complex results in the loss of repression of heat shock factor-1 (HSF1), and subsequent induction of HSP70. We evaluated HSP70 as a pharmacodynamic (PD) marker of AUY922 activity in a phase I/II clinical trial in patients (pts) with solid tumors. Methods: Single agent AUY922 was administered by IV infusion once a week to pts with advanced solid malignancies. HSP70 levels in PBMC were quantitated by ELISA in samples taken at baseline and multiple time-points post the 1st and 5th treatments over two cycles. Fold change of HSP70 induction was calculated and compared to dose level and AUY922 blood exposure obtained within the first week of treatment (single dose) at 6, 24, 48, and 168 hours post-treatment. Results: Of the 40 pts treated to date, HSP70 levels in PBMC has been evaluated in 36, encompassing seven dose levels ranging from 2 mg/m2 to 40mg/m2. Baseline levels of HSP70 in PBMC ranged from 26.0 to 95.1 ng/mg protein, with a median of 42.5ng/mg. The highest level of HSP70 induction obtained over two cycles was increasing with dose from 2 to 40 mg/m2, with a range of 1.4 to 12.1 fold, and the amount of HSP70 induction was frequently higher in the second cycle of treatment. In the first cycle of treatment, HSP70 induction is correlated to blood AUC. The degree of HSP70 upregulation in PBMCs at 40 mg/m2 exceeds the 8-fold upregulation seen in BT474 xenograft tumor tissue when treated with efficacious doses of AUY922. Conclusions: PK/PD analyses show that the highest level of HSP70 achieved post-treatment increases with dose, and at the highest dose tested thus far (40mg/m2), this pharmacodynamic effect has not yet reached a maximum response. Additionally, our analysis suggests that in humans, the PD effect of AUY922 is reaching the level corresponding to that required for anti-tumor effect in the BT474 xenograft model.

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Target-specific, histology-independent, randomized discontinuation study of lapatinib in patients with HER2-amplified solid tumors
Authors: Galsky M. D. , Von Hoff D. D. , Neubauer M. , Anderson T. , Fleming M. , Sweetman R. W. , Mahoney J. , Midwinter D. , Vocila L. , Zaks T. Z.
Published: August 2020

3541

Background: The current paradigm of histology-specific drug development may not be optimal in the era of targeted therapeutics. We sought to explore the activity of lapatinib, an oral tyrosine kinase inhibitor of HER2, with a trial design focused on the target rather than on tumor-type. Methods: Patients (pts) with HER2-amplified treatment-refractory metastatic gastro- esophageal (G/E), bladder (B), ovarian (O), or uterine (U) tumors were enrolled into a double-blinded randomized discontinuation study of lapatinib 1500 mg PO daily (malignancies selected based on reported frequencies of HER2 amplification). The planned sample size was 250 HER2+ pts, with the goal of then randomizing 100 pts with SD at week (wk) 12 to either lapatinib or placebo until progressive disease (PD). Pts who responded at wk 12 (CR or PR) continued on lapatinib; those who progressed were discontinued from study. Primary objectives were response rate at 12 wks and percentage of pts who remain progression free at 24 wks. Secondary objectives were duration of response, progression free survival (PFS) after randomization, and determination of the incidence of HER2 amplification in multiple tumor types. Futility analyses were preplanned to ensure feasibility of screening and of randomization (i.e. a sufficient rate of non- progression at 12 wks). Results: A total of 145 pts were screened (G/E=47, B=35, O=58, U=5); 42 were HER2-amplified (G/E=16, B=13, O=13, U=0) and 32 (G/E=13, B=9, O=10) were enrolled. At wk 12, 1 (3%) patient had a CR, 10 (31%) had SD, 19 (59%) had PD, and 2 (6%) were unknown. Median time to progression during open-label lapatinib was 78 days, 95% CI (42, 92). Only 7 pts with SD underwent randomization. Two pts with esophageal cancer remain on study; one (CR at wk 12) remains a CR at wk 60 and the other (SD at wk 12) remains with SD at wk 36. Low response rate coupled with slow screening and enrollment led to early study closure. Conclusions: Basing trial eligibility on a target, versus histologic classification, is challenging. While HER2 amplifications appear to be prevalent in select non-breast tumors, lapatinib monotherapy in refractory disease is associated with a low level of objective responses.

[Table: see text]