bluuebunny/crossref_metadata_2025_split huggingface dataset:
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. [Table: see text]
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. [Table: see text]
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. [Table: see text]
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. [Table: see text] [Table: see text]
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. [Table: see text]
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. [Table: see text]
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. [Table: see text]
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. [Table: see text]