bluuebunny/crossref_metadata_2025 huggingface dataset:
OGX-427, a 2'methoxyethyl antisense oligonucleotide (ASO), against HSP27: Results of a first-in-human trial
Authors: Hotte S. J. , Yu E. Y. , Hirte H. W. , Higano C. S. , Gleave M. , Chi K. N.
Published: August 2020

3506

Background: Heat shock protein 27 (Hsp27) is a chaperone protein expressed in many cancers and implicated as a therapeutic “hyper-node” affecting multiple pathways in cancer progression. Overexpression of Hsp27 confers a resistant phenotype. OGX-427 is a second generation ASO that inhibits Hsp27 expression which in preclinical models inhibited cell growth, induced apoptosis, and enhanced chemotherapy efficacy. The purpose of this phase 1 study was to determine the recommended phase 2 dose of OGX-427 alone and in combination with docetaxel. Methods: Eligible patients (pts) had to have metastatic breast, ovarian, prostate, NSCLC, or bladder cancer. OGX-427 was administered IV weekly on a 21-day cycle after 3 loading doses (LD) within 9 days. OGX-427 was escalated over 5 planned dose levels (DL) (200, 400, 600, 800, 1,000 mg), with 6 pts/DL. Plasma PK and serial ECGs were performed in cycle 1. Circulating tumor cells (CTC), Hsp27+ CTC and serum Hsp27 levels were evaluated serially. Results: 34 pts have been accrued and single agent dose escalation is complete. Median age was 62 (range: 33–86) yrs; 16 pts had prostate, 10 breast, 5 ovary and 3 lung ca. Median cycles administered were 2 (0–8) with 2 pts remaining on treatment. Most common related AEs: chills (53%), pruritis (29%), flushing (21%), elevated creatinine (18%), fatigue (15%), arthralgia (15%). More than 80% of pts had grade (Gr) 1/2 infusion reactions during the LDs or C1. One pt on 1,000 mg DL was hospitalized with Gr 3 infusion reaction. Gr 3 elevations of PTT (with normal INR) were seen in >50% of pts on 800 and 1,000 mg DL. At 600 mg DL, one pt had a Gr 3 epistaxis and one pt had a DLT with a Gr 3 cerebral bleed into a metastasis. No significant QTcF changes were observed. Three pts with prostate ca had PSA declines of 43%, 58%, 62% and 3 pts with ovarian cancer had CA-125 declines of 27%, 28%, and 41%. Five pts have had stable disease for >3 months. Preliminary mean PK data for 200–600 mg DLs: T1/2 = 2.8–3.1 hrs, peak concentration = 21,756 - 102,591 ng/mL and AUCinf ranged from 63,552 - 328,153 ng.h/mL, increasing with dose. Declines in CTC and Hsp27+ CTC have been observed at all DL. Conclusions: OGX-427 was well tolerated. Toxicity consisted mainly of infusion reactions and transient PTT changes. Changes in tumor markers suggest single-agent activity.

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A phase I and pharmacological study of MK-1775, a Wee1 tyrosine kinase inhibitor, in both monotherapy and in combination with gemcitabine, cisplatin, or carboplatin in patients with advanced solid tumors
Authors: Schellens J. H. , Leijen S. , Shapiro G. I. , Pavlick A. C. , Tibes R. , O'Day S. J. , Demuth T. , Viscusi J. , Xu Y. , Oza A. M.
Published: August 2020

3510

Background: MK-1775 is an inhibitor of Wee1, a kinase that phosphorylates CDC2 to inactivate the CDC2/cyclin B complex (regulating the G2 checkpoint). Since most human cancers harbor p53-dependent G1 checkpoint abnormalities, they are dependent on the G2 checkpoint. G2 checkpoint abrogation may therefore sensitize p53 deficient tumor cells to anti-cancer agents. Methods: This study is evaluating the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics (PD) of MK-1775 administered as both monotherapy (MT) and combination therapy (CT) with gemcitabine (G), cisplatin (P), or carboplatin (C). PART 1 consists of a single dose of MK-1775 followed by 14 days observation. If well tolerated, the same pt continues on to one of three treatment arms in PART 2: a single lower dose of MK-1775 in combination with: 1) 1000 mg/m2 G, 2) 75 mg/m2 P or 3) C AUC 5. Maximum Tolerated Doses (MTDs) will be established for MK-1775 as both monotherapy and in combination. PD biomarkers include IHC analysis for pCDC2/CDC2 in plucked hair and skin biopsies, peripheral blood, and tumor biopsies. Wee1 gene expression signature is measured in plucked hair and tumor biopsies by qPCR. Results: To date, 37 pts (median age 61; up to 4 prior therapies) have been treated with MK-1775. 4 pts experienced DLT. One pt on G + 200mg MK-1775 had gr3 leucopenia and neutropenia; one pt on P + 200mg MK-1775 had gr3, fatigue, diarrhea and hypokalemia and another pt gr2 nausea/vomiting > 48hrs requiring hospitalization. One pt on C + 325mg MK-1775 was hospitalized for gr3 bilirubin. Linear PK was demonstrated at 100, 200, 325, 650 and 1300 mg MK-1775. Terminal T½ of MK-1775 was 7.6–12.2 hrs and Tmax was 1.0–6.0 hrs. Preliminary MTDs of MK-1775 in combination with G, C and P were 200, 325 and 200mg, respectively. Significant changes in Wee1 signature gene expression were observed in plucked hair. Of 28 evaluable pts, >50% regression of axillary lymphadenopathy was seen in 1 pt with melanoma on the P arm, and stable disease in 14 other pts (median duration). Conclusions: MK-1775 is a first in class Wee1 inhibitor that is well tolerated and shows promising anti-tumor activity in previously treated pts.

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Phase II results of Study PX-171–007: A phase Ib/II study of carfilzomib (CFZ), a selective proteasome inhibitor, in patients with selected advanced metastatic solid tumors
Authors: Rosen P. J. , Gordon M. , Lee P. N. , Sausville E. , Papadopoulos K. P. , Wong A. F. , Vallone M. , Kunkel L. , Infante J. , Burris H. A.
Published: August 2020

3515

Background: CFZ is a novel proteasome inhibitor of the peptide epoxyketone class that exhibits a high level of selectivity for proteasome active sites. This phase 1/2 study assessed the maximum tolerated dose (MTD), safety, efficacy, pharmacokinetics (PK), and pharmacodynamics (PD) of CFZ in patients (pts) with advanced metastatic solid tumors. Methods: Pts failing ≥ 2 prior treatments were enrolled in the phase 1 3+3 dose escalation study. Pts received CFZ IV Day (D) 1, 2, 8, 9, 15 and 16 every 28 d for up to 12 cycles (C) Cycle 1 D1, D2 dosing in all cohorts was at 20 mg/m2. Subsequent doses remained at 20 mg/m2 or were escalated to 27 or 36 mg/m2 in a stepped up regimen on D8. At 20/36 mg/m2, 1 pt had a DLT (Grade 3 fatigue) and established the phase 2 dose. Phase 2 is designed as a Simon 2 stage of 70 pts split into 5 subgroups (small cell lung [SCLC], non-small cell lung [NSCLC], ovarian, renal, and other cancer). Tumor response was measured every 2 C. ORR, defined as CR+PR+SD, to 16 wks of CFZ. Stage 2 will open if a 1 PR or better at 16 wks occurs in a selected subgroup. Results: 14 pts in phase 1 and 51 pts in phase 2 (23M/28F, mean age 61 yrs) received a total of 154.5 cycles of CFZ. Median cycles administered was 1.7 (range 1 to 12). To date, there were 6 SCLC, 10 NSCLC, 11 ovarian, 6 renal, and 18 other cancer patients enrolled to the Simon stage 1. Efficacy of SD or better is detailed in the table. The most common AEs included fatigue headache, diarrhea, nausea and constipation. Notable was the absence of grade > 1 peripheral neuropathy and severe hematologic toxicities. Final results of the PK and PD will be reported. Conclusions: CFZ is active as a single agent in relapsed solid tumors demonstrating PR in both renal and SCLC; and SD >16 wks in mesothelioma, ovarian, renal and NSCLC. The 20/36 mg/m2 QDx2 dose schedule was well tolerated and lacks severe myelosuppression, hepatotoxicity and neuropathy which make CFZ an attractive agent to combine with traditional or novel targeted agents.

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Hypertension (HTN) in National Cancer Institute of Canada Clinical Trials Group study BR.24: A randomized, double-blind phase II trial of carboplatin (C) and paclitaxel (P) with either daily oral cediranib (CED), an inhibitor of vascular endothelial growth factor receptors, or placebo, in patients with advanced non-small cell lung cancer
Authors: Goodwin R. A. , Seymour L. , Ding K. , Gauthier I. , Le Maitre A. , Frymire E. , Arnold A. , Shepherd F. A. , Goss G. D. , Laurie S. A.
Published: August 2020

3527

Background: CED 30 mg/d with C+P increased response rate (RR: 38 vs 16% p < 0.0001) and median progression free survival (PFS: 5.6 vs 5 m, hazard ratio [HR] 0.77) over C+P alone. HTN is a known effect of angiogenesis inhibitors (AI). For BR.24, we describe the incidence of HTN, effects on drug delivery, predictors of its development/worsening, and assess the predictive effect of HTN on efficacy. Methods: Pts received C+P plus either placebo (n =146) or CED (n = 148). HTN as an adverse event (HTN AE: defined as either new onset HTN, or worsening grade HTN in a previously hypertensive pt), was managed with a protocol-defined algorithm. Exploratory analyses characterized the relationship between HTN AE and baseline characteristics and treatment arm. Kaplan Meier curves summarized time to event outcomes and Cox regression models with time dependent covariates correlated HTN AE to outcomes. Results: Rate of pts with a history of HTN were similar: CED 26 %, placebo 33 %. CED pts had significantly higher HTN AE (any: 38 vs 12%, p < 0.0001; grade 3 or 4: 19 vs 2 %). With the treatment algorithm, HTN AE had minimal impact on drug delivery (1 pt interrupted C+P, 11 pts [3.7%] reduced /discontinued CED / placebo). Headache was the only other AE that correlated with HTN AE. Predictors of HTN AE included: CED arm (p < 0.0001), good ECOG (p = 0.02), female (p = 0.006), history of HTN (p = 0.06). CED pts with HTN AE had significantly higher RR (51.8 vs 32.6%, p = 0.025) and PFS (8.5 vs 5.1 m; HR 0.45, 95% CI 0.29 to 0.72, p = 0.0007); similar but not significant findings were observed with placebo (RR 35.3 vs 17.2%, p= 0.098; PFS 5.6 vs 4.9 m; HR 0.84, 95 % CI 0.45–1.54); the interaction term by treatment arm was not significant. Conclusions: CED pts had greater HTN AE, but this did not impact drug delivery. Certain baseline characteristics predicted HTN AE in all pts. Unexpectedly, development of on-study HTN predicted improved outcome in all pts, although to a greater extent for those on CED. Additional evaluation of the role of HTN AE as a predictor of efficacy of both AI and cytotoxics is warranted.

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Final results of a phase I study of oral belinostat (PXD101) in patients with solid tumors
Authors: Kelly W. K. , DeBono J. , Blumenschein G. , Lassen U. , Zain J. , O'Connor O. , Foss F. , Tjornelund J. , Fagerberg J. , Petrylak D.
Published: August 2020

3531

Background: Belinostat (Bel) is a histone deacetylase inhibitor with broad preclinical activity. IV Bel is well-tolerated with clinical activity at 1 g/m2 daily x5, q3w. Methods: Patients (pts) were treated with multiple schedules (see table) to assess safety, pharmacokinetics (PK) and efficacy. PK was done on day (d) 1 (fasting) and d7 (non-fasting) along with serial ECGs. Results: 92 pts, median age 60 (range 32–89) have been included. Major cancer types included colorectal (22%), prostate (17%), bladder (11%). Most frequent related adverse events (AEs), any grade (gr), were fatigue (53%), nausea (49%), anorexia (36%), vomiting (27%), diarrhea (25%). Only related gr 3/4 AE noted by more than 1 pt was fatigue. Hematological tox included gr 2: anemia (6 pts), leucopenia (2 pts), and thrombocytopenia (1 pt). Two events of gr 2 QTc prolongation were reported. Recommended dose (RD) for continuous dosing was determined as 250 mg, QD or BID, based on dose limiting toxicity (DLT; gr 3 if not indicated) seen in 2 pts in cohort 2A: dehydration and fatigue. Based on overall tolerability and DLTs (cohort 2C fatigue; 3C gr 2 nausea/vomiting/diarrhea; 4C atypical chest pain, elevated creatinine; 2D atrial fibrillation, hypokalemia, fatigue) the RD for d1–14 dosing was determined as 750 mg QD, with option for intra-pt dose escalation if limited tox. For d1–5 dosing, evaluation of the highest dose-cohort is not finalized; 1 pt had gr 3 psychosis, but also experienced same event 16d after treatment stopped. Exposure of Bel in plasma correlates with dose; PK on d1/d7 indicate a possible effect of food. To date, 33 pts (41%) have SD; 5 pts ≥6 months (d on treatment: 710 adenoidcystic, +488 bladder, 485 renal, 196 rectal, 182 prostate), and 12 pts 3–6 months. Conclusions: Oral Bel can be delivered safely with multiple schedules. The safety profile and long stabilizations in multiple tumor types makes Bel an interesting option for further evaluation as a monotherapy and in combination with chemotherapy.

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A phase I dose-escalation study of the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of SCH 727965, a novel cyclin-dependent kinase inhibitor, administered weekly in subjects with advanced malignancies
Authors: Nemunaitis J. , Saltzman M. , Rosenberg M. A. , Khaira D. , Small K. , Kirschmeier P. , Statkevich P. , Abutarif M. , Yao S. , Bannerji R.
Published: August 2020

3535

Background: SCH 727965 is a potent and selective inhibitor of the cyclin-dependent kinases CDK1,2,5 and 9 with IC50's of < 5nM. SCH 727965 induces apoptosis in a broad array of tumor cell lines, causes tumor growth inhibition or regression in various xenograft models, and has a greater therapeutic index than flavopiridol in an in vivo screening model. SCH 727965 was advanced into clinical trials. Methods: SCH 727965 was administered by 2-hour IV infusion on days 1, 8 and 15 of a 28-day cycle. Doses were escalated with an accelerated titration algorithm to define the maximally administered dose (MAD) and the recommended phase 2 dose (RPTD). PD assessments included an ex vivo PHA lymphocyte stimulation assay, skin biopsies for IHC measurement of retinoblastoma protein phosphorylation, and functional imaging using FDG-PET/CT scans. PK and PD data were obtained during Cycle 1. Results: 43 subjects have been treated at doses ranging from 0.33 to 14 mg/m2. The most common treatment-emergent adverse events were nausea, anemia, and fatigue. The MAD was 14 mg/m2 defined by a DLT of grade 3 hypotension in one subject and transient grade 4 hyperuricemia in another subject. The RPTD was 12 mg/m2. Grade 3 or 4 treatment related adverse events were uncommon. Grade 3 or 4 neutropenia was seen in only 3 subjects. SCH 727965 inhibition of lymphocyte proliferation was dose-dependent, indicating a PD effect, and was sustained up to 8 hours post-dose at the RPTD. Drug exposure was dose-proportional. SCH 727965 was rapidly eliminated with a terminal half-life of 1.5 to 3 hours. No objective responses by RECIST criteria have yet been observed although PET SUV signal decreases as large as >30% have been observed in some subjects. Conclusions: SCH 727965 is safe and well tolerated at the recommended phase 2 dose of 12 mg/m2. The AE profile of weekly dosing differed from that seen in an every -21 day dosing schedule, and plasma concentrations at the RPTD or lower doses were above those required for in vivo efficacy in xenograft tumor models. PD activity was verified in an ex vivo lymphocyte proliferation assay, and preliminary changes on PET/CT suggest drug related modulation of tumor metabolic activity.

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Phase I first-in-human study of the polo-like kinase-1 selective inhibitor, GSK461364, in patients with advanced solid tumors
Authors: Olmos D. , Allred A. , Sharma R. , Brunetto A. , Smith D. , Murray S. , Barker D. , Taegtmeyer A. , de Bono J. , Blagden S.
Published: August 2020

3536

Background: Polo-like kinase-1 (Plk1), part of a family of highly conserved serine-threonine kinases, has multiple roles in mitotic progression, is over-expressed and also associated with poor prognosis in some tumor types. GSK461364 is a potent and selective ATP-competitive inhibitor of Plk1 (Ki 2.2nM) with demonstrated antiproliferative activity in vitro and in vivo. Methods: Adult patients (pts) with relapsed/refractory advanced solid tumors with performance status of 0–2 and adequate organ function were eligible. Sequential cohorts of 2–6 patients each received escalating doses of GSK461364 administered as a 4h intravenous infusion (Schedule [Sch] 1: D1,8,15 q28 or Sch 2: D1,2,8,9,15,16 q28). Primary objectives were to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of GSK461364. Secondary objectives included preliminary evaluation of anti-tumor activity. Results: 27 pts (20 male, 7 female) were evaluated. Four dose levels, 50mg (n = 2), 100 mg (n = 3), 150 mg (n = 3) and 225 mg (n = 8) were evaluated in Sch 1. Three dose levels, 25 mg (n = 2), 50 mg (n = 2) and 100 mg (n = 7) were evaluated in Sch 2. Dose-limiting toxicities (DLTs) observed were Gr 4 sepsis, in Sch 1 at 225 mg dose, Gr 4 pulmonary embolism (PE) and Gr 4 neutropenia >7d in Sch 2, both at 100 mg dose. Other Sch 1 adverse events (AEs) with a maximum grade ≥3 were fatigue and anemia (both, n = 2), pleuritic pain, pelvic pain, abdominal discomfort, constipation, vomiting, neutropenia, and deep vein thrombosis (all, n = 1). Other Sch 2 AEs with a maximum grade ≥3 were PE, renal failure, thrombocytopenia, and catheter-related infection (all n = 1). The most common adverse events (AEs) regardless of attribution, Sch and dose level were phlebitis (n = 9), fatigue (n = 9), nausea (n = 7), anemia (n = 6), anorexia (n = 6), diarrhea (n = 6), and infusion site reaction (n = 5). Preliminary PK data indicate that AUC and Cmax were proportional across doses; mean values were CLs ∼72–85L/hr, Vss ∼550–1200L and t1/2 ∼11.5hr. Phospho-histone H3, a marker of mitotic arrest, was detected, in circulating tumor cells, 24 hrs after first dose. Stable disease >5m has been observed in 2 esophageal cancer pts. Conclusions: Dose escalation continues in Sch1, Sch2 has been expanded at 75mg. An MTD has not yet been defined.

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Preliminary evidence of clinical activity in a phase I study of CAL-101, a selective inhibitor of the p1108 isoform of phosphatidylinositol 3-kinase (P13K), in patients with select hematologic malignancies
Authors: Flinn I. W. , Byrd J. C. , Furman R. R. , Brown J. R. , Lin T. S. , Bello C. , Giese N. A. , Yu A. S.
Published: August 2020

3543

Background: The class I PI3Ks regulate a variety of cellular functions relevant to oncogenesis, including metabolism, proliferation and survival. The PI3K p110δ isoform is highly expressed in cells of hematopoietic origin and plays a key role in B cell maturation and function. CAL-101 is a potent inhibitor of PI3K p110δ (IC50=65 nM) with 40 to 300-fold selectivity compared to other PI3K isoforms. In vitro studies of 0.1 to 10 μM CAL-101 showed inhibition of pAKT expression and/or apoptotic effects against primary chronic lymphocytic leukemia (CLL) and acute myeloid leukemia (AML) cells and against a range of leukemia and lymphoma cell lines. Methods: In an ongoing phase 1 dose escalation study in sequential cohorts of 3 patients with relapsed/refractory CLL or select B-cell non-Hodgkin's lymphoma, CAL-101 is administered orally twice daily for 28 days per cycle. Clinical response is evaluated according to NCI criteria at the end of Cycles 1 and 2 and every 2 cycles thereafter. Results: To date, 6 patients have been treated in the first 2 cohorts at dose levels of 50 mg and 100 mg and the 200 mg cohort is currently enrolling. No treatment-related adverse events greater than grade 1 have been seen, with 2 patients treated for >5 cycles. Mean trough drug levels in the 50 and 100 mg cohorts were 0.3 and 1 μM, respectively, which are in the range required to inhibit PI3K p110δ in vitro. Two of 6 patients attained partial response and 4 have stable disease. Partial responses were observed after 2 cycles of 50 mg in a patient with mantle cell lymphoma with 6 prior therapies, and after 1 cycle of 100 mg in a patient with follicular lymphoma with 6 prior therapies, including autologous stem cell transplant. Disease specific cohort expansion will occur at the maximally tolerated dose, and patients with AML will be added. Updated data will be presented at the meeting. Conclusions: Early results from a phase 1 study of the oral PI3K p110δ inhibitor CAL-101 show that it is well tolerated and has preliminary clinical activity in patients with B-cell malignancies.

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Different effects of insulin-like growth factor-1 receptor expression on prognosis of estrogen receptor positive versus triple-negative invasive ductal breast carcinoma
Authors: Wesseling J. , Hartog H. , Horlings H. , van der Vegt B. , Ajouaou A. , Kreike B. , van de Vijver M. , de Bock G. H. , Boezen M. , van der Graaf W. T.
Published: August 2020

3546

Background: The insulin-like growth factor type 1 receptor (IGF-1R) is involved in progression and sensitivity to systemic treatment of breast cancer. Moreover, targeted inhibition of IGF-1R is likely to be beneficial in systemic treatment. However, it is unknown how to select patients for IGF-1R targeted therapy. Therefore, we studied the relation between IGF-1R expression and prognosis in invasive ductal breast carcinomas. Methods: Immunohistochemistry was performed on tumor tissue of a consecutive cohort of 429 female patients treated for operable primary invasive ductal breast carcinoma. TMA sections were stained with antibodies against IGF1-R, insulin receptor (IR), ER, PR, HER-2, epidermal growth factor receptor (EGFR) and phosphorylated-Akt (p-Akt). Cytoplasmic and membranous IGF-1R staining were scored separately, as the relevance of IGF-1R cellular localization is yet unknown. Associations between IGF-1R expression with clinical and tumor characteristics were evaluated in a multivariate Cox regression model. To study in more detail the prognostic role of IGF-1R expression in triple negative invasive ductal carcinomas (TN IDCs), 51 TN IDCs from the series described above were combined with 64 TN IDCs from an independent dataset with similar patient and clinico-pathological characteristics. Results: Patients with tumors expressing both ER and cytoplasmic IGF-1R have a longer disease free survival (HR = 0.20; 95% CI 0.07 - 0.63; p-value = 0.006) and breast cancer specific survival (HR = 0.20, 95% CI 0.07 - 0.63, p-value = 0.002), independent of other known prognostic factors. Conversely, in the combined series of 105 TN IDCs, cytoplasmic IGF-1R expression was associated with a shorter disease free survival (HR = 2.29; 95% CI 1.08 - 4.48, p-value = 0.03). In a multivariate model including known prognostic factors, cytoplasmic IGF-1R expression was nearly significantly related to a shorter disease free survival (HR 2.06; 95% CI 0.95 - 4.47; p = 0.07). Conclusions: The favorable versus unfavorable association with prognosis of IGF-1R expression in ER positive versus TN IDCs may provide new opportunities to select patients for IGF-1R targeted therapy.

No significant financial relationships to disclose.
A phase Ib trial of IPI-504 (retaspimycin hydrochloride), a novel Hsp90 inhibitor, in combination with docetaxel
Authors: Riely G. J. , Stoller R. , Egorin M. , Solit D. , Dunbar J. , Savage A. , Walker J. , Grayzel D. , Ross R. , Weiss G. J.
Published: August 2020

3547

Background: IPI-504 is a water-soluble heat shock protein 90 (Hsp90) inhibitor. IPI-504 causes the degradation of a variety of mutated or amplified oncoproteins, including epidermal growth factor receptor (EGFR) and human epidermal growth factor receptor 2 (HER2). The combination of IPI-504 and docetaxel demonstrates additive efficacy in murine xenograft models. This Phase 1b trial was undertaken to identify the maximum tolerated dose (MTD) of IPI-504 in combination with docetaxel. Methods: Eligible patients (pts) had advanced solid tumors that were either refractory to available therapies or for which docetaxel alone was an appropriate therapy. Intravenous (IV) 75 mg/m2 docetaxel was given once every three weeks (q 3- weekly). IPI-504 was administered IV q 3-weekly, with 3 pts per cohort and inter-cohort dose escalation. All pts were evaluated for safety, pharmacokinetics (PK), and tumor response. Results: 16 pts have been enrolled at 3 dose levels of IPI-504 (7 at 300 mg/m2, 6 at 450 mg/m2, and 3 at 550 mg/m2). 6 pts had non-small cell lung cancer (NSCLC). Median age was 59 yrs (range 33–77). Median number of cycles received was 3 (1–11), with 5 pts currently on study. There have been 4 dose-limiting toxicities (DLTs): 1 at 300 mg/m2 (Grade 3 febrile neutropenia); 1 at 450 mg/m2 (Grade 3 fatigue); and 2 at 550 mg/m2 (Grade 1 asymptomatic sinus bradycardia requiring hospitalization for observation, and Grade 3 elevated AST with Grade 3 acute respiratory distress syndrome). All DLTs resolved on trial. No PK interactions between docetaxel and IPI-504 have been observed. The regimen of IPI-504 450 mg/m2 with docetaxel 75 mg/m2 has been identified as the recommended phase 2 dose on a q 3-weekly schedule. Conclusions: In this Phase 1b trial, the MTD of IPI-504 plus docetaxel q 3-weekly was identified. Toxicities were reversible and similar to those seen with docetaxel or IPI-504 alone in this patient population. Given the activity of single-agent IPI-504 against NSCLC and the standard use of docetaxel in that disease, an expanded evaluation of this regimen in pts with previously treated NSCLC is on-going. The combination of IPI-504 and docetaxel on a weekly schedule is also being explored.

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A dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of OSI-930 and erlotinib (E) in patients (pts) with advanced solid tumors
Authors: Macpherson I. , Stewart K. , Chick J. , Brock K. , Poondru S. , Gedrich R. , Stephens A. W. , Evans T. R.
Published: August 2020

3550

Background: EGFR and VEGFR are important targets in a number of human cancers with common downstream signalling pathways. Combined blockade of EGFR-VEGFR with E and OSI-930 has shown additional antitumor activity compared to either agent alone with long-term remissions in multiple xenograft models. Methods: Sequential cohorts of pts with advanced refractory solid tumors were treated with OSI-930 BID with addition of E QD from Day 8 and beyond to determine the maximum tolerated dose (MTD) and to evaluate safety, PK and efficacy of the combination. Escalation followed a standard 3+3 design until dose-limiting toxicity (DLT) was observed in ≥ 2/6 pts. PK of OSI-930, E and its metabolite OSI-420 were determined. Levels of soluble VEGFR2 (sVEGFR2) in plasma were also measured. Results: 16 pts have been entered (13M/3F); median age 63 years (range 41–78), PS ≤2 and 38% pts with mCRC. OSI-930/E were administered at 3 levels [mg(pts entered/evaluable)]; 200 BID/100 QD (7/6), 200 BID/150 QD (4/3), and 300 BID/150 QD (5/5). Median duration of therapy was 8 weeks (range 1–22). DLT was seen in 1/6 pts at 200 BID/100 QD (>5 day interruption due to G4 neutropenia); and 1/5 at 300 BID/150 QD (G3 Asthenia/lethargy). Other common related toxicities (% all grades:% g3/4) were: skin-related (rash, HFS etc) (85:23), Asthenia/lethargy/fatigue (69:15), diarrhea (77:8), anorexia (92:0), and transaminitis (31:15). Reduction and/or interruptions of one or both study drugs during or beyond the initial 28 days were required in 8/14 pts. Six of 11 pts evaluable for response achieved SD ≥12 weeks. Median plasma Cmax (and AUCTau) of OSI -930 for Cohort 3 (300 BID/150 QD) were: 0.826 (6.08), 0.947 (5.57), and 1.66 (14.3) μg/mL (μg.hr/mL) on Days 7, 8 and 22, respectively. Exposure of OSI-930 increased approximately 2-fold upon co-administration with E at steady-state. OSI-930 appeared not to alter the PK properties of E or the ratio of OSI-420 to E. Decreases in plasma sVEGFR2 were observed, indicating a PD effect of OSI-930. Conclusions: Additional patients are being added to confirm the MTD of the combination. PK data indicate a drug-drug interaction with doubling of the OSI-930 exposure on co-administration with E.

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Bevacizumab (B) plus everolimus (E) and panitumumab (P) in refractory advanced solid tumors
Authors: Howard L. A. , Bullock K. E. , Bendell J. C. , Uronis H. E. , Vlahovic G. , Blobe G. C. , Riedel R. F. , Nixon A. B. , Gockerman J. P. , Hurwitz H. I.
Published: August 2020

3551

Background: In preclinical models, VEGF, mTOR, and EGFR inhibitors have anti-tumor and anti-angiogenesis effects as monotherapies and in combination. B inhibits VEGF; E inhibits mTOR; P inhibits EGFR. There is also potential for interaction between the pathways. Previously BE and BE + erlotinib were evaluated and showed signs of clinical activity. Methods: Patients (pts) with refractory advanced solid tumors were accrued in a phase I dose escalation of B + E + P on a 28d cycle. Dose levels are shown in the table below. DLT was defined as any treatment-related grade 4 heme, grade 3/4 non-heme adverse event (AE), or receiving <85% any study drug in Cycle 1. Blood, skin, and tumor biopsies pre- and on-treatment were collected for correlative biomarkers of angiogenesis. Results: At this time, 12 pts (3M: 9F) are evaluable for toxicity; 9 for efficacy. Median age: 54 years (range 23–72). 9 of 12 pts had prior B exposure. Dose level 1 was expanded due to 1/3 DLT, with total of 3/6 DLT (Grade (Gr) 3 mucositis (n=2), Gr3 hypokalemia (n=1)). Dose level -1 had 3/3 DLT (Gr3, Gr4 mucositis (n=2), Gr3 non-acneform rash (n=1)). Dose level -2 had 0/3 pts DLT. Gr 3–4 related toxicities in cycle 2+: hypokalemia (n=4); hypophosphatemia (n = 1); hypomagnesemia (n = 1); diarrhea (n=1); hoarseness (n=1). Other events of interest were: Gr1–2 mucositis (n=7); Gr1 hyperlipidemia (n=5); Gr1–2 hyperglycemia (n=4); Gr2 hypertension (n=2); Gr1–2 neutropenia (n=5); Gr1–2 thrombocytopenia (n=5). 8/9 evaluable pts had SD as best response (median 26 wks, range 8+ to 32+ wks): 1 pt with pancreatic cancer and progression on 2 prior EGFR inhibitors had prolonged 32+ wk SD. There was 1 minor response (23.3%) in a pt with bevacizumab-refractory ovarian cancer (32+ wks). No CR or PR were seen. Conclusions: B + E + P at full doses has dose limiting toxicities of rash and mucositis. B 10 mg/kg q2wks + E 5 mg q48h + P 4.8 mg/kg q2wks is the maximum tolerated dose. This dose is currently being expanded in 20 patients with extensive pre- and on-treatment biomarker analyses. Updated clinical and biomarker data will be presented.

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A phase I study of sunitinib in combination with sirolimus in adults with advanced refractory malignancies
Authors: Li J. , Kluger H. , Saif M. W. , Murren J. R. , Lee J. J. , Kelly W. K. , Rink L. , Devine L. , Sznol M.
Published: August 2020

3554

Background: Sirolimus, a commercially available oral mTOR inhibitor, may complement the anti-angiogenic and anti-tumor activity of sunitinib, an oral small molecule inhibitor of multiple receptor tyrosine kinases (RTKs), by vertical disruption of VEGFr signaling, by reducing the compensatory production of VEGF in sunitinib-treated patients, and also by directly inhibiting tumor cell proliferation. Methods: Sunitinib was given at 50 mg daily (d) x 28 q6w. The dose of sirolimus was escalated in cohorts of 3–6 beginning at 4 mg weekly until the MTD was determined. The first cohort received sunitinib alone 50mg d x 14 followed by 14 days off in cycle #1. After the 4mg sirolimus dose cohorts, sunitinib dose was reduced in subsequent cohorts to 37.5mg, and dose escalation of sirolimus was re-initiated at 4mg. Results: 18 patients (pts) with ECOG PS <2 were enrolled, median age 57yo (r:24–76), M:F: 11:7. Median # of prior treatments (Rx): 2(r:0–5), 6 had no prior systemic Rx. Disease primary sites: GI-5 (28%), renal cell- 4 (22%), melanoma-2, soft tissue sarcoma (STS)-2, adenoca unknown 10-2, breast-1, H&N-1, NSCLC-1. At the 50/4 dose level, 4 of 8 required dose reduction (DR) or early discontinuation (ED) of Rx in cycle #1. At the 37.5/4 and 37.5/8 dose levels, 3/9 required DR or ED in cycle #1 or starting cycle #2. Several pts able to complete 1–2 cycles at full dose had significant toxicities including fatigue and hand-foot syndrome. 1 pt developed interstitial pneumonitis, 1 pt died on day 8 due to progressive disease. Four pts received >4 cycles (5-STS, 5-renal papillary, 13-neuroendocrine pancreas, 17-renal clear cell). Among 16 pts undergoing restaging, there was no CR or PR. 5 other pts demonstrated transient central necrosis or size reduction in some tumors. There was no apparent PK interaction at the 4mg sirolimus dose level, and no clear effect on sunitinib-induced increase in circulating VEGF levels. Conclusions: Toxicity precluded dose escalation of weekly sirolimus in combination with a standard sunitinib dose/schedule. These results suggest caution when combining targeted agents lacking specificity for tumor signaling or vasculature.

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A phase I dose finding study of the 3-day administration of BIBW 2992, an irreversible dual EGFR/HER-2 inhibitor, in combination with three-weekly docetaxel in patients with advanced solid tumors
Authors: Awada A. H. , Dumez H. , Wolter P. , Hendlisz A. , Besse-Hammer T. , Piccart M. , Uttenreuther-Fischer M. , Stopfer P. , Taton M. , Schöffski P.
Published: August 2020

3556

Background: BIBW 2992 (Tovok) is a potent, irreversible, new generation TKI, an inhibitor of EGFR and HER-2 (IC50 0.5 and 14 nM, respectively). A Phase I dose finding study of BIBW 2992 with docetaxel is reported. Methods: Patients (pts) had advanced solid malignancies and received docetaxel 75 mg/m2 i.v. on Day 1 and oral BIBW 2992 once daily on Days 2–4, in 3-week cycles. The BIBW 2992 dose was doubled in successive cohorts of 3–6 pts until ≥Grade 2 CTC, after which dose escalation occurred in increments of ≤50%. The MTD cohort expanded to 12 pts. PK profiles were taken on Days 1 and 2 of treatment cycles 1 and 2. Results: 40 evaluable pts (17 male) were treated at the following doses of BIBW 2992: 10 mg (6), 20mg (3), 40 mg (6), 60 mg (4), 90 mg (13), 120 mg (5) and 160 mg (3). Common adverse events (AEs) (% of patients) were fatigue (62.5%), diarrhea (57.5%), anorexia and stomatitis (52.5%), alopecia (50%), rash (42.5%), nausea and pyrexia (40%), vomiting (35%), general physical health deterioration (32.5%), and peripheral sensory neuropathy (30%). Two DLTs occurred: one pt had Grade 4 neutropenia (a DLT if complicated or lasting >5 or 7 days) and one had Grade 3 nausea, vomiting and diarrhea (BIBW 2992 120 mg). Both fully recovered upon treatment interruption/dose reduction (docetaxel 60 mg/m2/BIBW 2992 90 mg). The MTD was 90 mg BIBW 2992 with docetaxel 75 mg/m2. Four pts (breast cancer [2], thymoma [1], oesophageal carcinoma [1]) had a PR. One breast cancer pt had a confirmed CR. Two of these pts had prior taxane treatment. Ten pts had SD and received treatment for ≥6 courses with 4 receiving treatment for ≥9 courses. There was no deviation from dose-linearity of BIBW 2992 and docetaxel. Docetaxel (75 mg/m2) plasma concentration-time profiles, Cmax and AUC0-∞ before and after BIBW 2992 dosing were comparable. Conclusions: BIBW 2992 90mg administered for 3 days after docetaxel 75 mg/m2 is well tolerated and is the recommended dose for further trials. Objective responses or durable SD (≥6 months) were seen in 15 (39%) pts. No PK interaction was observed between BIBW 2992 and docetaxel.

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A phase I study of pazopanib in patients with advanced hepatocellular carcinoma
Authors: Yau C. C. , Chen P. J. , Curtis C. M. , Murphy P. S. , Suttle A. B. , Arumugham T. , Hodge J. P. , Dar M. M. , Poon R.
Published: August 2020

3561

Background: Patients (pts) with advanced hepatocellular carcinoma (HCC) have a poor prognosis. HCC is a highly vascular tumor with increased levels of angiogenic factors including VEGF and VEGFR. Pazopanib (GW786034) is an oral angiogenesis inhibitor targeting VEGFR, PDGFR, and c-Kit. A Phase I study was conducted to determine the maximum tolerated dose (MTD), safety, pharmacokinetics, pharmacodynamics and efficacy of pazopanib in patients with locally unresectable and/or advanced HCC. Methods: Eligibility criteria included unresectable and/or metastatic HCC with at least 1 target lesion, recovery from prior systemic regimens, ECOG PS 0 or 1, Child-Pugh A, and adequate organ function. Doses of pazopanib were escalated from 200 mg once daily (QD) to 800 mg QD in a 3 + 3 design. DCE- MRI was performed to assess changes in tumor permeability. Results: 27 Asian pts have been enrolled at QD doses of 200 (4 pts), 400 (10), 600 (8), 800 (5): median (range) age = 61 (38–76); M/F = 85%/15%; ECOG 0/1 = 59%/41%; 81% with metastatic disease; 67% with Stage IV; 22% with prior systemic therapy, 26% with prior TACE. Most common AEs were: diarrhea (59%; 4% Gr 3); hypertension (44%; 26% Gr 3), cough (19%); fatigue (19%; 4% Gr 3); and hair depigmentation (15%). Hepatobiliary lab abnormalities were: AST elevation (63%; 15% Gr 3), hyperbilirubinemia (63%; 4% Gr 3), ALT elevation (41%; 7% Gr 3), and Alk phos (37%; 4% Gr 3). DLTs were Gr 3 malaise (1 pt) and Gr 3 AST/ALT elevation (1 pt) at 800 mg. MTD was determined to be 600 mg QD. Median (range) days on study was 85 (4–663) overall; 106 days (4–274) at the MTD. Best response was PR in 2 pts (7%; 1 at 800mg, 1 at 600 mg) and SD > 4 mos in 11 pts (41%). Median TTP at the MTD was 137.5 days (4–280 days). Median % change in tumor permeability (Ktrans) following 3 weeks of pazopanib administration at the MTD (5 pts) was 45%. Predose and maximum plasma pazopanib concentrations at 800 mg QD were similar to values observed previously at the same dose. Conclusions: Pazopanib has a manageable safety profile in HCC at the MTD of 600mg QD. Preliminary evidence of antitumor activity was observed. Changes in tumor DCE-MRI parameters were seen following repeated dose pazopanib administration.

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Final results of a dose escalation (DE), pharmacokinetic (PK), and pharmacodynamic (PD) study of two schedules of OSI-930 in patients (pts) with advanced solid tumors
Authors: George S. , Lal R. , Camidge D. R. , Arkenau H. , Chick J. , Poondru S. , Yap T. A. , Eckhardt S. G. , Demetri G. D. , Scurr M.
Published: August 2020

3564

Background: OSI-930 is an oral TKI with potent activity against Kit, VEGFR2, and PDGFR. Preclinical studies demonstrate tumor regression with long-term remissions across multiple xenograft models. Methods: Sequential cohorts of pts with advanced solid tumors received continuous daily OSI-930 to determine the maximum tolerated dose (MTD) and to evaluate safety, PK/PD and efficacy of OSI-930 with both QD and BID dosing. An expansion cohort was enrolled for detailed PD analysis including sVEGFR2 plasma levels, PET imaging in GIST pts or DCE-MRI in selected pts. Results: A total of 58 pts were treated (20M/38F; median 60 years (range 19–83)). OSI-930 was dosed up to 1600 mg QD without reaching MTD. 46 pts received BID dosing [mg(# pts treated)]; 400(7), 500 (31) and 600(8). DLT's were seen in 3/8 pts at 600 mg BID; G3 rash (2 pts) and G4 GGT; and 3/31 at 500 mg BID; G3 myalgia, G3 fatigue and G3 lipase. G3 hypertension was noted in 3/46 pts but not dose-limiting. Common G1/2 toxicities were fatigue (37%), diarrhea (27%), nausea (31%), and rash (24%). Objective (CA125) responses were seen in platinum-resistant ovarian cancer (2 PR/8) while in heavily pretreated GIST (median 4 prior therapies including imatinib/sunitinib), 8/18 pts achieved SD ≥12 w. Median therapy duration in the BID arm was 9 w and 18/46 pts with SD ≥12 w. PK indicated that Css were achieved after ∼7d with BID dosing. PET scans showed reduction in glycolytic activity in 4/9 pts and DCE-MRI response was seen in 4/6 pts. A trend in decreased sVEGFR levels was seen at higher doses. Conclusions: At the MTD level of 500 mg BID OSI-930 is an active, well-tolerated compound with clinically relevant antitumor activity and exposure levels consistent with antitumor activity in preclinical models. PD data indicate mechanistic proof of concept for OSI-930. OSI-930/erlotinib combination phase I study is currently enrolling.

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Hypogonadism in male cancer patients treated with the tyrosine kinase inhibitors sunitinib (SUN) or sorafenib (SOR)
Authors: Wolter P. , Wildiers H. , Vanderschueren D. , Dumez H. , Clement P. , Schöffski P.
Published: August 2020

3565

Background: SUN and SOR are multi-targeted tyrosine kinase inhibitors (TKIs) inhibiting several kinases (VEGFR- 1,2; c-kit; PDGFR-α,β; flt-3; RET). SUN is approved for treatment of imatinib-resistant gastrointestinal stromal tumors (GIST) and metastatic renal cell carcinoma (RCC), SOR is used for RCC and hepatocellular carcinoma. We observed in some pts with fatigue under TKI treatment low testosterone (T) levels and started assessing the incidence and severity of gonadal dysfunction prospectively in male pts receiving these TKIs. Methods: Gonadal status (serum total testosterone (TT), free testosterone (FT), sex-hormone binding globulin (SHBG), luteinizing hormone (LH) and follicle-stimulating hormone (FSH) were evaluated in pts with RCC or GIST under SUN or SOR. SUN was given at a daily dose of 50 mg p.o. 4 weeks on, 2 weeks off, SOR at a daily oral dose of 800 mg. Results: We identified 27 pts (median age 63, range: 27–77), for which data on gonadal function were available, 23 RCC (85 %), 4 GIST (15%), with 22 (85.5%) receiving SUN and 5 (18.5%) SOR. Median treatment duration was 48 (2–202) weeks, 13 (48%) underwent dose reductions, in 4 (15%) pts due to grade 3 fatigue. All pts had at least once during TKI treatment T levels lower than normal (TT < 300 ng/dL and/or FT < 5 ng/dL), 17 (63%) had a low T with normal LH/FSH, 4 (15%) a low T with an elevated LH/FSH and 6 (22%) a low T and elevated FSH, but normal LH. The median TT level in the whole group was 194 ng/dL (21–477, normal range: 300–1,000 ng/dL), the median FT level in the whole group was 4.01 (0.45–9.07, normal range: 5–20 ng/dL). In the SUN cohort the median levels for TT and FT were slightly lower on day 28 in comparison to day 1 (184.5 vs 206 ng/dL for TT and 3.935 vs 4.225 ng/dl for FT). Pts with information available on testosterone at baseline (n = 8) tended to have slightly diminished baseline T levels (median: 222.5 [61–319] ng/dL), but 50% of these pts had been treated with other TKIs before. Two pts with grade 3 fatigue under SUN had very low T levels shortly after starting SUN (21 and 28 ng/dL, respectively). Conclusions: We observed a high incidence of hypogonadism in male RCC and GIST pts under treatment with SUN or SOR. Hypogonadism may likely contribute to the fatigue associated with these agents.

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Pharmacokinetic and pharmacodynamic results of a 4-hr IV administration phase I study with EPC2407, a novel vascular disrupting agent
Authors: Read W. L. , Rosen P. , Lee P. , Anthony S. , Korn R. , Raghunand N. , Tseng B. , Whisnant J. , Von Hoff D. , Tibes R.
Published: August 2020

3569

Background: EPC2407 is a 4-aryl-chromene single isomer microtubulin inhibitor with vascular disrupting and apoptotic activity at nanomolar concentrations. In an earlier phase I study dosing by 1 hr infusions daily x3 on a 21 day cycle, DLT at 21 mg/m2 was pain at tumor sites and vasoconstriction with increases of BP and QTc. MTD was 13 mg/m2 over 1 hr (ASCO 2008, Abst 2531). All drug-related toxicities resolved within an hour of stopping the infusion. Prolonged infusion of EPC2407 to extend exposure of tumor vasculature was designed with administration of EPC2407 over 4 hrs for 3 consecutive days of a 21 day cycle. Eleven patients have received this schedule and their cancers included leiomyosarcoma, colo-rectal, ovary, hepatocellular (2), NSCLC, pancreas, carcinoid, hemangiopericytoma, larynx and small bowel. Results: Doses escalated from 13 to 30 mg/m2 over 4 hours, with MTD determined to be 24 mg/m2. DLTs at 30 mg/m2 were similar to those seen in the 1 hr infusion, with pain at tumor sites in 1 participant and asymptomatic ST depression in a second. Other toxicities were also similar and included transient hypertension. QTc increases were not significant and no new toxicities were encountered. T1/2 with 4 hr infusion was ∼2hr, also seen with 1 hr infusion. AUC and Cmax values were similar to that predicted from the 1 hr data except AUC at 13 mg/m2 was lower than expected. DCE-MRI was done at baseline and after infusion on day 3, cycle 1. Analysis to date of DCE-MRI data of 4 patients showed a median decrease of 40% in both tumor permeability (Ktrans) and tumor perfusion volume (Vp). The two patients with hepatocellular carcinoma had notable stable disease and clear clinical benefit. Both patients received 18 mg/m2 dose, with one receiving 7 cycles over 5 months, and the other still on study (cycle 6) with stable disease for at least 4 cycles. Conclusions: EPC2407 shows clinical promise, with infusion-associated toxicities characteristic of the VDA drug class but without sustained or cumulative toxicity. Studies combining EPC2407 with conventional cytotoxic/cytostatic regimens are being designed.

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Phase Ib study of NGR-hTNF, a selective vascular targeting agent (VTA), in combination with cisplatin in patients with refractory solid tumors
Authors: Citterio G. , De Braud F. G. , Gregorc V. , De Pas T. M. , Scalamogna R. , Boselli S. , Giovannini M. , Caligaris-Cappio F. , Lambiase A. , Bordignon C.
Published: August 2020

3570

Background: NGR-hTNF is a VTA exploiting a tumor-homing-peptide (NGR) that selectively binds to an aminopeptidase N/CD13 overexpressed on tumor blood vessels. In preclinical models, significant synergy between low-dose NGR-hTNF and cisplatin was shown. Methods: Patients with resistant/refractory solid tumors were treated with NGR-hTNF given with a low-dose, doubling-dose scheme (0.2–0.4–0.8–1.6 μg/m2) as 1-hour intravenous infusion, in combination with cisplatin 80 mg/m2, both given every 3 weeks. A 3+3 escalation/de-escalation design was followed. PK sampling was performed after the first 3 cycles. DLT definition: any G3–4 toxicity related to NGR-hTNF. Results: 22 patients (median age: 60 years, range, 47–75; 14M/8F; ECOG PS 0/1 12/10) with different tumor types were evaluated over 77 cycles (range, 1–10). Median number of prior regimens was 3 (range, 1–6) and 12 patients (55%) were previously treated with platinum-based regimens. Both NGR-hTNF Cmax and AUC increased proportionally with dose. The combination was safe without PK interaction or exacerbation of platinum-associated toxicity profile. No shedding of soluble TNF receptors was observed up to 0.8 μg/m2. As expected for the low-dose range explored, MTD was not reached and no DLTs were registered at 0.2 μg/m2 (n = 4), 0.4 μg/m2 (n = 3) and 1.6 μg/m2 (n = 3). At 0.8 μg/m2, a patient had a G3 transient acute infusion reaction. This cohort was expanded up to 6 patients for safety reasons, with no DLTs registered, and up to 12 patients, for preliminary activity evaluation. At this dose level of 0.8 μg/m2, two lung cancer patients, both pre-treated with platinum, achieved a partial response (-79%) and a significant tumor shrinkage (-28%) lasting 7.2 and 6.7 months, respectively, and an additional 4 patients experienced stable disease for a median duration of 6.4 months. The median progression-free survival for all patients (n = 22), for patients enrolled at 0.8 μg/m2 (n = 12), and for patients pre-treated with platinum (n = 9) was 2.7, 4.7, and 4.3 months, respectively. Conclusions: The combination of NGR-hTNF 0.8 μg/m2 with cisplatin 80 mg/m2 shows a favourable toxicity profile and promising antitumor activity.

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