bluuebunny/crossref_metadata_2025 huggingface dataset:
Sorafenib but not sunitinib affects the induction of immune responses
Authors: Hipp M. M. , Hilf N. , Walter S. , Werth D. , Kanz L. , Weinschenk T. , Singh H. , Brossart P.
Published: March 2020

3504

Background: The tyrosine kinase inhibitors (TKIs) sorafenib and sunitinib are approved for the treatment of patients with metastatic renal cell cancer. To analyze the possible use of these compounds in combination with immunotherapeutic approaches we investigated the effects of both TKIs on function of human dendritic cells (DCs) and induction of primary immune responses in vitro and in vivo. Methods: Human monocytes-derived DCs were treated with DMSO, sorafenib or sunitinib. Functional and phenotypic analyses as well as the possible impact on signal transduction pathways were performed. Furthermore, induction of immune responses in vivo was analyzed in animals treated with both compounds. Results: Sorafenib but not sunitinib inhibits function of DCs. Exposure of DCs to sorafenib reduces expression of CD1a, MHC and costimulatory molecules in response to stimuli via TLR ligands. Sorafenib reduces cytokine production by DCs as well as their ability to migrate and stimulate T cell (TC) responses. We found that these inhibitory effects of sorafenib are mediated via inhibition of PI3K, MAP kinases and NFκB signaling. The TKIs have no influence on phenotype and proliferation of TCs. To analyze the effects of TKIs on the generation of immune responses in vivo, induction of TC responses was assessed by peptide vaccination with the model antigen OVA-001 in C57BL/6 mice. When mice were pretreated with both TKIs which were also given during vaccination, it was observed that sorafenib, but not sunitinib significantly reduces the generation of vaccine-specific CD8+ TCs. Numbers of CD4+ CD25+ regulatory TCs are reduced in sunitinib-treated mice, but not in sorafenib-treated animals. All effects of the TKIs are reversible, and the immune responses go back to normal levels if mice are immunized after discontinuation of treatment. Conclusions: In summary, sunitinib represents an interesting compound to be used in combination with immunotherapeutic approaches to treat cancer patients.

No significant financial relationships to disclose.
Phase 1 study of ARQ 197, a selective inhibitor of the c-Met RTK in patients with metastatic solid tumors reaches recommended phase 2 dose
Authors: Garcia A. , Rosen L. , Cunningham C. C. , Nemunaitis J. , Li C. , Rulewski N. , Dovholuk A. , Savage R. , Chan T. , Bukowksi R. , Mekhail T.
Published: March 2020

3525

Background: ARQ 197 is a selective inhibitor of the c-Met receptor tyrosine kinase, an oncogene implicated in tumor invasiveness, metastasis, cancer cell proliferation, resistance to apoptosis, chemoresistance and angiogenesis. The c-Met RTK is a high-affinity receptor for hepatocyte growth factor (HGF). c-Met and HGF are dysregulated in a broad spectrum of cancers, thus inhibitors of c-Met could be promising targeted agents deserving clinical investigation. Methods: A phase 1 dose escalation study in metastatic pts who failed standard therapy was initiated to determine safety, tolerability, RP2D, pharmacokinetics, pharmacodynamics and preliminary antitumor activity of ARQ 197. Cycles consisted of twice-daily oral dosing of ARQ197 for two out of 3 weeks. Results: Thirty-eight pts were enrolled with data available for 36 pts (21M/15F; median age 61). Ten cohorts were assessed ranging from 10 to 360 mg/day. ARQ 197 was well tolerated and no DLT was observed. All treated pts achieved plasma drug concentrations significantly above the in vitro IC50. Doses through 70 mg b.i.d. revealed Cmax and AUC(0–12hr) increased linearly. There was no further increase in systemic exposure in pts treated with 90 through 180 mg b.i.d. There was notable inter-patient variability in Cmax and AUC(0–12hr), typical of oral dosing. The effects of cytochrome P450 polymorphism will be discussed. Adverse events (N=29) were generally mild with the most common being: fatigue (24 %), diarrhea (21%), and constipation (21%). Grade 3 or greater events possibly or probably related to ARQ 197 include: elevated ALP (3%), ALT (3%) and AST (3%). Of the 38 pts enrolled, 36 received at least one complete cycle of ARQ 197 with 33 evaluable for efficacy. Two pts achieved a PR (1 confirmed) and 19 had stable disease (SD) 21 10+ to 34+ weeks. Conclusions: Based on pharmacokinetic data, a RP2D for ARQ 197 was determined to be 120 mg b.i.d. Higher oral doses did not result in increased systemic systemic exposure to the drug. Eleven pts remain on study and continue to receive ARQ 197 treatment. A favorable adverse event profile and encouraging signs of anti-tumor activity was observed and continuous daily dosing of ARQ 197 is now being explored to better define clinical toxicity and efficacy.

[Table: see text]
First in human phase I pharmacokinetic (PK) and pharmacodynamic (PD) study of KU-0059436 (Ku), a small molecule inhibitor of poly ADP-ribose polymerase (PARP) in cancer patients (p), including BRCA1/2 mutation carriers
Authors: Yap T. A. , Boss D. S. , Fong P. C. , Roelvink M. , Tutt A. , Carmichael J. , O’Connor M. J. , Kaye S. B. , Schellens J. H. , de Bono J. S.
Published: March 2020

3529

Background: Ku is a novel, potent, orally active PARP-1 and 2 inhibitor. It induces selective cytotoxicity in cells with defective homologous recombination repair such as BRCA1/2 deficient tumor cells. Methods: Starting at 10 mg daily (qd) for 2 out of 3 weeks (w), Ku dose escalation was guided by toxicity and PK data. Cohorts of 3–6 p with advanced solid tumors were treated, with provisions for enrichment with BRCA1/2 mutation carriers. PD studies evaluated PARP functional activity in surrogate tissue, including peripheral blood mononuclear cells (PBMC), and tumor tissue when available. Results: 44 p were treated; 17 M/ 27 F; mean age 56 (range 19–82). ECOG PS =2. 11 p had BRCA1/2 mutations and 2 p had strong family histories suggesting BRCA1/2 mutations. Dose levels tested were 10, 20, 40 and 80 mg qd, then 60 and 100 mg twice daily (bid) - all for 2 out of 3 w; followed by 100, 200, 400 and 600 mg bid continuously. Dose limiting toxicity was seen in 1 of 6 p at 400 mg bid. This p had grade (G) 3 neurocognitive toxicity, nausea and vomiting, all of which resolved within 24 hours of drug discontinuation. Other Ku toxicities included G1–2 fatigue, anorexia, constipation and diarrhea. PK data supports dose proportionality up to 200mg bid; mean elimination half-life was 6 hours (range 4.6–7), mean clearance/bioavailability (F) was 4.55 L/h (range 1.8–9.1), and mean volume of distribution/F was 39.9L (range 17–92.1). PD studies indicate a significant (>50%) inhibition of PARP functional activity in PBMC and tumor at doses >40 mg qd. Encouraging anti-tumor activity was seen. 4 p had significant tumor marker declines, 3 of whom also had radiological evidence of response (including 1 partial response by RECIST criteria for 6 months). 7 other p had stable disease for 3 to 6 months. Several of these p had BRCA1/2 mutations and were chemotherapy resistant. Conclusions: Ku leads to significant PARP inhibition with minimal toxicity. The final dose level (600 mg bid continuously) is being tested to maximize tumor PARP inhibition. Both radiological and biochemical evidence of antitumor activity have been seen in BRCA1/2 cancer p. Exploration of Ku in phase II and combination studies is warranted.

[Table: see text]
Inhibition and flare patterns of metabolic response to the heat shock protein 90 (Hsp90) inhibitor IPI-504 visualized by FDG-PET in patients (pts) with advanced gastrointestinal stromal tumors (GIST) resistant to tyrosine kinase inhibitor (TKI) therapy
Authors: Van den Abbeele A. D. , Yap J. T. , Grayzel D. S. , Walker J. , Demetri G. D.
Published: March 2020

3530

Background: We have previously demonstrated the inhibition and rebound of GIST glycolytic metabolism with FDG-PET while pts were on or off TKI in prior trials of imatinib and sunitinib. We tested the same principle in a phase I trial of IPI-504, a novel potent inhibitor of Hsp90 (a chaperone for protein homeostasis) that results in selective destruction of the mutated KIT kinase in human GIST cell lines regardless of TKI-resistance mutations. Methods: Twenty-one patients with metatastic and/or unresectable GIST following failure of prior therapy with TKI were treated with IPI-504. Serial FDG-PET imaging was performed at baseline, during the 1st cycle after at least 2 doses (C1, days 4–11, “ON”, n = 18), and at the end of the 10-day off-treatment period prior to the start of the 2nd cycle (C1, “OFF”, n = 20). A subset of 5 pts also had FDG-PET at the end of the 3rd cycle (C3, day 11, “ON”). Maximum standardized uptake values (SUVmax) were measured in up to 3 lesions/pt with the greatest FDG uptake, and the SUVmax of all lesions was summed at each time point. Percent change in the summed mean SUVmax was calculated at each time point relative to the previous scan. Temporal changes were evaluated in those pts showing more than a 10% decrease in SUVmax during C1 “ON” compared to baseline. Results: We observed a >10% reduction in SUVmax (mean = - 28%) during the 1st cycle (C1, “ON”) in 8/18 pts. All these pts showed an increase in SUVmax (mean = +29%) when off therapy (C1, “OFF”). Three of these 8 pts had a scan during cycle 3. All demonstrated a decrease in SUVmax (mean = -30%) while on the drug (C3, “ON”). Conclusion: These preliminary findings suggest that: (1) tumor metabolic response as measured with FDG-PET parallels the intermittent pattern of IPI-504 administration in this study as early as after the 2nd dose administration; and, (2) IPI-504 has a rapid downstream effect on glucose metabolism similar to that observed with TKIs despite the very different mechanism of action of IPI-504. The pattern of response to Hsp90 inhibition seen in this heavily pretreated population strongly supports further clinical investigation.

No significant financial relationships to disclose.
First in-human phase 1 trial of a novel amino-peptidase inhibitor, CHR-2797
Authors: Protheroe A. , Reid A. , Attard G. , Davies A. , Spicer J. , Vidal L. , Bone E. , Hooftman L. , Harris A. , De-Bono J.
Published: March 2020

3537

Background: CHR-2797 is a novel, orally bioavailable agent which displays potent, tumor cell-selective, anti-proliferative properties. It is an inhibitor of Zn++-dependent aminopeptidases and generates signs of amino acid deprivation in sensitive cells, decreased protein synthesis and an increase in the level of the pro-apoptotic protein, Noxa. CHR-79888 is an active metabolite of CHR-2797. Patients and Methods: This study was conducted according to an accelerated titration design to define the MTD, DLT, toxicity profile and PK of CHR-2797 when administered orally for 28 days or longer. Patients (ECOG PS = 2) with histologically confirmed advanced solid tumors resistant or refractory to standard therapy were eligible. Results: 37 pts (median age 61.5 years [range 22.4–80.1]; 30M/7F; median ECOG PS 1; median prior regimens 2, range 0–6) enrolled in 12 cohorts (doses between 10 and 320mg). The first four patients received a 10 mg dose for 7, 14, 21 or 28 days respectively. Subsequent cohorts received 28 days continuous dosing, with dose doubling in single patient cohorts until drug-related toxicity = Grade 2. Thereafter the study followed a 3+3 design with = 40% dose increments. Common (gr 1–2) toxicity included fatigue (47%), diarrhea (47%), dizziness (24%), constipation, vomiting, abdominal pain (all 21%), and thrombocytopenia (18%). Toxicities show dose dependency for thrombocytopenia and fatigue. MTD was declared at 320 mg after 2 DLT’s were reported: 2 patients were unable to complete 28 days of daily dosing due to syncope/anemia, and dizziness/visual disturbances/thrombocytopenia, respectively. Patients recovered fully after cessation of the drug. The dose level below (240 mg) was expanded to 13 patients. Plasma PK was determined for both CHR-2797 and -79888, on days 1 and 28, which showed dose proportional increases in AUC and Cmax. Intracellular and intratumoral levels of both the parent and metabolite were also measured. So far 4 patients continued therapy for 7–9 months: one patient (RCC [130 mg]) achieved a PR, and 3 patients (ovarian ca [40 mg], NSCLC [130 mg], and breast ca [180 mg] had confirmed SD (> 3 months). Conclusion: Once daily oral CHR-2797 can be administered safely for 28 days in doses up to 240 mg and exhibits favorable PK.

No significant financial relationships to disclose.
Safety and anticancer activity of low dose regimen of NGRhTNF, a new vascular targeting agent, in solid advanced malignancies (NGR002 phase I trial)
Authors: Gallo-Stampino C. , Rizzardi G. , Toma S. , Corti A. , Scifo P. , Citterio G. , Gregorc V. , Del Maschio A. , Caligaris-Capio F. , Bordignon C.
Published: March 2020

3540

Background: NGRhTNF is a vascular targeting agent (VTA) exploiting a tumour homing peptide (CNGRCG) selectively binding angiogenic vessels in solid tumours where NGRhTNF specific binding relies on dynamic interactions with TNF-receptors and aminopeptidase N (CD13). NGRhTNF combines activity on tumour vascular permeability and direct anticancer activity. Consistently, mouse preclinical data indicate significant synergy between low dose NGRhTNF and cytotoxic agents. Methods: 4 dose levels of NGRhTNF (0.2 up to 1.6 mcg/sqm) have been administered q 3 w in 16 patients. Main end-points included safety, anticancer activity and pharmacokinetic.Measurement of circulating tumor and endothelial cells (CTC and CEC), sTNFRI and s TNFRII, along with plasma cyto-chemokine profile have been performed. Results: 16 patients were enrolled (6F/10M);median age 60,range 43–73). Toxicity was limited to constitutional symptoms, and chills were the most frequent event (40%). Over a median follow-up of 15 weeks, stable disease was achieved in 44% of patients, with long lasting disease control in 2 cases (27 and 75 weeks, with establishment of indication to radical surgery after 75 weeks, presently tumor free after removal of the residual tumor mass). In these 2 patients, VEGF, MMP-9, CA125, significantly decreased over time. DCE-MRI indicates that NGRhTNF increases vascular permeability after first drug exposure, particularly at the dose of 0.4 mcg/sqm, while following multiple infusions it exerts an antivascular effect, as demonstrated by the decrease of Ktrans values. Moreover NGRhTNF is able to elicit inflammatory and immune responses over time, as indicated by the modulation of expression of multiple cyto-chemokines. Finally, changes in CTC levels over time consistently matched the clinical outcome. Conclusions: Low dose NGRhTNF has an optimal safety profile along with anticancer activity acting on tumour vasculature and inducing relevant biological effects, thus rendering the agent suitable for a development both as monotherapy and in combination with chemotherapeutics. The phase II program is due to start in early 2007.

[Table: see text]
A phase I dose-escalation and pharmacokinetic (PK) study of sunitinib (SU) plus docetaxel (D) in patients (pts) with advanced solid tumors (STs)
Authors: Robert F. , Sandler A. , Schiller J. H. , Ilagan J. , VerMeulen W. , Harper K. , Liu G. , Tye L. , Chao R. , Traynor A.
Published: March 2020

3543

Background: SU is an oral, multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, RET and FLT3, approved multinationally for the treatment of advanced RCC and imatinib-resistant or -intolerant GIST. In mouse xenograft models of breast cancer, SU enhanced the antitumor activity of D. This study was designed to assess the safety/maximum tolerated doses (MTDs), PK profile and preliminary efficacy of SU+D in pts with advanced STs. Methods: This is a phase I, dose-finding study in pts with advanced STs. The primary objective is to determine the MTD and safety of SU and D administered in combination. Successive cohorts of pts with advanced STs were to receive oral SU at 25, 37.5 or 50 mg daily for 4 wks of a 6-wk cycle (4/2 schedule) or for 2 wks of a 3-wk cycle (2/1 schedule) in combination with IV D at 60 or 75 mg/m2 every 21 days (q21d). The MTD was defined as the highest dose at which 0 of 3 or 1 of 6 pts encountered dose-limiting toxicities (DLTs) during cycle 1. Antitumor activity was assessed by CT or MRI scan. Results: 37 pts (most common primary tumor types: mRCC [n=10], NSCLC [n=13]) have been enrolled as of Nov. 2006: 10 pts on the 4/2 schedule and 27 pts on the 2/1 schedule (see table ). The most commonly observed DLT was neutropenia (with or without fever; maximum grade 4), which occurred in 5 pts and was manageable/reversible. There was 1 grade 5 event on the 2/1 schedule (C1D3), of pulseless electrical activity and pulmonary hemorrhage. The MTDs on the 4/2 schedule were SU 25 mg and D 60 mg/m2. The MTDs on the 2/1 schedule were SU 37.5 mg and D 75 mg/m2; PK analysis at this dose level is ongoing. Stable disease has been observed in 5 of 9 evaluable pts (56%) on the 4/2 schedule and 20 of 25 evaluable pts (80%) on the 2/1 schedule at the MTD. Conclusions: The combination of oral SU 37.5 mg/day on the 2/1 schedule with D 75 mg/m2 IV q21d has a manageable safety profile in pts with advanced STs. PK and preliminary efficacy analyses are ongoing to support these dosing combinations for further study.

[Table: see text]

No significant financial relationships to disclose.
Dyamic contrast enhanced MRI (DCE-MRI) pharmacodynamic (PD) study of sorafenib in metastatic renal cell carcinoma (RCC): Results of a randomized, phase II trial
Authors: hahn O. M. , Yeng C. , Medved M. , Karczmar G. , Kistner E. , Manchen B. , Mitchell M. , Karrison T. , Ratain M. , Stadler W. M.
Published: March 2020

3545

Background: SOR is an antiangiogenic drug for metastatic RCC. We conducted a randomized, dose ranging trial to investigate if DCE-MRI is a PD marker for SOR. Methods: Patients (pts) were randomized to placebo, 200 or 400 mg bid SOR. DCE-MRI was performed at baseline and after 4 weeks (wks) of therapy at which time placebo pts were rerandomized to 200 or 400 mg bid of SOR. RECIST based response was determined by CT every 12 wks. DCE-MRI parameters, area under the contrast concentration vs. time curve for 90 seconds after contrast injection (IAUC90) and Ktrans, were calculated for a tumor region-of-interest selected in a blinded manner. Ktrans was calculated with the Tofts model using a tumor local arterial input function from a multiple reference tissue method. Blood pressure (BP) was obtained from clinic charts. Primary endpoint: change in Ktrans or IAUC90 over 4 wks with a planned 66 pts to detect 20% and 40% decrease in 200, 400 mg groups. Results: Due to SOR approval 57 pts were enrolled, 48 with two MRIs (5 early progression, 3 withdrew, 1 toxicity); 44 are evaluable for study endpoints. Analyses were conducted with log ratio of IAUC90 and Ktrans at 4 wks relative to baseline. Mean IAUC90 log ratio (± SD) in the placebo, 200 and 400 mg cohorts were 0.041 (± 0.197), -0.040 (± 0.132), -0.356 (± 0.411) respectively (p = 0.0003 for linear trend), corresponding to changes of +4%, -4% and -30%. Ktrans log ratios were 0.131 (± 0.315), -0.148 (± 0.382), -0.271 (± 0.499) respectively (p = 0.0077 for trend) corresponding to changes of +14%, -14% and -24%. In 27 pts with plasma SOR levels, change in IAUC90 and Ktrans did not correlate with steady state levels on day 28. Using a Cox proportional hazards model, IAUC90 and Ktrans change are not predictors of progression-free survival (median f/u 24 wks). The mean BP increased with SOR dose (0.8 ± 8.0, 8.3 ± 10.4, and 10.5 ± 11.1 for the placebo, 200, and 400 mg doses) but no correlation with IAUC90 or Ktrans change was seen. Conclusions: DCE-MRI parameters IAUC90 and Ktrans have high variability and are PD markers for SOR, but the magnitude of effect in this prospective blinded study is less than previously reported. With this small study, no correlations with PK or clinical outcome are detectable.

No significant financial relationships to disclose.
Bosutinib (SKI-606), a dual Src/Abl tyrosine kinase inhibitor: Preliminary results from a phase 1 study in patients with advanced malignant solid tumors
Authors: Messersmith W. A. , Krishnamurthi S. , Hewes B. A. , Zacharchuk C. M. , Abbas R. , Martins P. , Dowling E. , Volkert A. , Martin E. , Daud A. I.
Published: March 2020

3552

Background: Bosutinib (SKI-606) is a potent, low molecular weight, orally active, competitive inhibitor of both Src and Abl tyrosine kinases. Elevations of Src kinase activity occur in a variety of human tumor types and are correlated with aggressiveness. We conducted a phase 1 study in patients (pts) with advanced solid tumors to assess tolerability, safety, pharmacokinetics (PK), and preliminary antitumor activity of bosutinib. Methods: Patients in cohorts of 3–6 received 50, 100, 200, 300, 400, 500 or 600 mg bosutinib orally on study day 1 and then once daily beginning on day 3. Timed blood samples were collected on days 1–3, 15 and 16 for PK analysis. Tumor assessments (modified RECIST criteria) were made at baseline and the end of every third cycle (21 days/cycle). Collection of tissue samples for analysis of Src biomarkers was optional. Results: Preliminary data are presented for 51 pts (median 57 years, 57% women). Three pts who received 600 mg bosutinib/day had drug-related dose-limiting toxicity of grade 3 diarrhea (2 pts) and grade 3 rash (1 pt). Gastrointestinal (GI) toxicity was reported among 6 pts in the 500-mg maximum tolerated dose (MTD) lead-in cohort so that 400 mg was selected as the MTD. Drug-related adverse events (AEs), any grade, occurring in =25% of pts were nausea (67%), diarrhea (55%), anorexia (45%), vomiting (43%), asthenia (41%). The only grade 3 drug-related AE occurring in =5% of pts was diarrhea (14%). After oral administration, bosutinib exposure increased in a dose-dependent manner. Multiple-dose exposure was nearly 2- to 3-fold higher than single-dose exposure. Mean elimination half-life was approximately 17 to 21 hours, supporting a once-daily dosing regimen. Six pts had stable disease >15 weeks (2 pts each with breast, colorectal cancer, non-small cell lung cancer [NSCLC]) and 1 pt had stable disease >52 weeks (pancreatic cancer). Conclusions: Bosutinib was generally well tolerated with predominantly gastrointestinal AEs. Accrual and evaluation of an expanded cohort restricted to patients with colorectal, pancreatic, and NSCLC tumors is ongoing. The patient with pancreatic cancer has had stable disease >52 weeks.

No significant financial relationships to disclose.
Phase I trial of daily lenalidomide and docetaxel given every three weeks in patients with advanced solid tumors
Authors: Sanborn S. L. , Cooney M. , Gibbons J. , Brell J. , Savvides P. , Krishnamurthi S. , Bokar J. , Horvath N. , Ness A. , Remick S.
Published: March 2020

3570

Background: Lenalidomide is a potent anti-angiogenic and immune modulating agent. This phase I trial of docetaxel and lenalidomide was undertaken to evaluate the maximal tolerated dose (MTD), dose-limiting toxicity (DLT), and secondarily, any tumor response for this novel combination. Methods: Patients with advanced solid tumors with adequate organ function were eligible. Lenalidomide was given orally days 1–14, and docetaxel was administered intravenously on day 1 of each 21-day cycle. DLT was defined as grade 3 or higher non-hematologic toxicity, grade 4 neutropenia with fever, and grade 4 anemia or thrombocytopenia. Results: Nineteen patients, 14 male and 5 female, with tumor types including prostate (7), sarcoma (3), head and neck (2), pancreatic, colon, melanoma, adenocarcinoma of unknown primary, gastric, bladder, and GIST have been enrolled. ECOG performance status was zero (10 patients) or one (9 patients). The median age was 59 years (range 35 to 86). Fourteen patients had zero or one prior treatment regimens (range 0 to 6). A total of 64 cycles have been administered (range 1 to 12). In the first nine evaluable patients, eight (89%) had grade 3 or 4 neutropenia. Docetaxel 75 mg/m2 given every 3 weeks with lenalidomide 5 mg on days 1–14 exceeded the MTD due to one grade 3 nausea/vomiting and one grade 4 neutropenia with fever. After the addition of pegfilgrastim on day 2, there has not been any neutropenia in the subsequent seven evaluable patients. Other grade 3 and 4 toxicities included leukopenia (31%), lymphopenia (19%), as well as nausea, vomiting, fatigue, anemia, infection, hyponatremia, and hypokalemia (6% each). Seven patients (44%) have had stable disease (range 3 to 12 cycles). One prostate cancer patient experienced a >95% reduction of PSA. Enrollment is ongoing and the current dose level is docetaxel 75 mg/m2, lenalidomide 10 mg days 1–14, and pegfilgrastim on day 2. Conclusions: The toxicity evaluation is ongoing. This trial will provide the MTD of docetaxel 75 mg/m2 given every 3 weeks with lenalidomide on days 1–14 in combination with pegfilgrastim support to avoid neutropenia.

No significant financial relationships to disclose.
Identification of predictive and surrogate molecular markers for dasatinib in prostate cancer: Rationale for patient selection and efficacy monitoring
Authors: Wang X. , Reeves K. , Luo R. , Wu S. , Xu L. , Ayers M. , Lee F. , Clark E. , Huang F.
Published: March 2020

3579

Background: Dasatinib is a potent, multi-targeted kinase inhibitor that was recently approved for treatment of chronic myelogenous leukemia resistant to imatinib. To aid its clinical development in prostate cancer, we used a panel of prostate cancer cell lines to identify molecular markers that could be used to predict sensitivity to dasatinib and to monitor its activity. Methods: Baseline gene expression profiles of 16 cell lines were used to identify predictive biomarkers based on the correlation of gene expression with in vitro sensitivity of cells to dasatinib. Selected cell lines were treated with dasatinib to identify surrogate biomarkers based upon changes in gene expression following dasatinib treatment. Results: We identified 174 genes whose baseline expression levels were highly correlated with sensitivity or resistance to dasatinib. These include cell lineage markers cytokeratin 5 (CK5), androgen receptor (AR), and prostate specific antigen (PSA). Our results indicate that “basal type” cell lines (those with high expression of CK5 and low expression of AR and PSA) are sensitive to dasatinib. Dasatinib treatment studies further identified genes whose expression levels were significantly modulated by the drug. Ten genes, including urokinase-type plasminogen activator (uPA), were not only significantly correlated with sensitivity to dasatinib but also reduced in their expression upon drug treatment. In addition, the down-regulation of uPA was specific to dasatinib and the effect was not seen in taxol-treated cells. The extent of down-regulation was correlated with the sensitivity of cell lines to dasatinib. EphA2, a specific kinase target of dasatinib, was identified as a biomarker common to prostate and breast cancers. Finally, the expression of 5 genes including CK5, AR, PSA, uPA and EphA2 in prostate tumors was examined and the dasatinib sensitivity signature was validated using a published data set derived from a clinical population. Conclusions: Candidate markers correlated with dasatinib sensitivity were identified. A five-gene model consisting of predictive markers as well as potential surrogate markers has been formulated and will be evaluated in ongoing dasatinib prostate cancer trials.

No significant financial relationships to disclose.
Treatment of metastatic colorectal cancer with aimpila, a glycoside/alpha-fetoprotein complex
Authors: Pak V. , Molchanov O. , Vincent M.
Published: March 2020

3589

Background: Aimpila is a non-covalent complex of two natural compounds: porcine alpha-fetoprotein (PAFP) and a glycosidic apoptosis inducer (AI). PAFP is able to bind selectively to the AFP receptor-positive cancer cells and deliver the AI intracellularly due to AFP receptor-mediated endocytosis. The AI opens mitochondrial permeability transition pores, resulting in apoptosis. Preclinically, the complex is cytotoxic. We investigated the single agent activity of aimpila in patients (pts) with liver metastatic colorectal cancer (mCRC). Methods: Eligibility Criteria: Age >18 yrs, mCRC, any prior treatment, having documented progressive metastatic liver disease. Treatment consisted of oral capsules at a fixed sub-maximal dose (0.3 mg of active substance in an oral capsule, twice a day for 8 weeks). 12 pts were accrued, 6 chemonaïve; median ECOG performance status was 0, median age 56 years (range 45–65), and median time from previous treatment failure was 9.0 months (range 1–20). CT scans were performed before and after. Results: Of the 12 patients, 9 are evaluable for response by RECIST. Two achieved a complete response (CR), 1 a partial response (PR); subsequent confirmatory CT scans are pending. Three achieved stabilization (SD), in 2 cases = 2 months; 3 experienced disease progression. Of 3 non-evaluable pts, 1 experienced clinical deterioration without a CT scan, 1 experienced stable disease >2 months but with both lesions <10 mm in diameter, and a third developed nausea and vomiting leading to interruption of treatment, the only recorded significant adverse event. CEA estimations before and after treatment are available from 2 pts; 1 pt (radiological CR) going from 816 ng/ml to 268 ng/ml; the other (radiological SD) going from 1,243 ng/ml to 638 ng/ml. In this latter patient, one of the liver lesions disappeared, radiologically. The PR pt and 1 of the SD pts had progressed after previous oxaliplatin-based chemotherapy. Median survival has not yet been reached, with a median follow-up of 4 months. Conclusion: Single agent aimpila was well-tolerated in this patient population and produced major objective responses in some patients with liver mCRC. Further study is warranted.

[Table: see text]
A phase I dose escalation pharmacokinetic (PK) and pharmacodynamic (PD) study of weekly and twice weekly erlotinib in advanced stage solid malignancies
Authors: Chia S. K. , Chi K. N. , Kollmannsberger C. , Paton K. , Bhagat K. , D’Aloisio S. , Das-Gupta A. , Kletzl H. , Zwanziger E. , Gelmon K.
Published: March 2020

3594

Background: Erlotinib is a potent oral TKI of the epidermal growth factor receptor (EGFR). At the current recommended daily dose of 150 mg/day there is activity in advanced stage NSCLC, but with frequent grade 1/2 rash and diarrhea. We performed a phase I dose escalation study of erlotinib with a once and twice weekly schedule to assess the PKs, PDs, and to determine if toxicities would be less on an intermittent but high dose schedule. Methods: A standard dose escalation schedule starting at 1,400 mg once/week and 600 mg twice/week with increments of 200 mg to 4 dose cohorts/schedule was utilized with three patients per cohort. A cycle consisted of 3 weeks of therapy. PKs were performed on cycle 1 and 2. PDs on normal skin punch biopsies were performed at baseline and after cycle 1. Tumour evaluation was done following every 2nd cycle. Subjects were treated until progression or unacceptable toxicity. Results: 32 patients were enrolled from Oct 2004-April 2006. Median age 58 years (28–74 years); median PS 1 (0–2); and median prior palliative systemic regimens 2 (0–6). In the once weekly schedule the maximum tolerated dose (MTD) was not reached with the top dose of 2,000 mg/week. A median of 2 cycles were delivered (1–14), with 3/13 patients achieving stable disease = 3 months. 4/13 patients had G1 rash and 6/13 patients G1 diarrhea during the first 2 cycles. In the twice weekly schedule the MTD was reached at 1,200 mg twice/week with 2/6 subjects experiencing G3 rash. The recommended dose level is 1,000 mg twice/week. A median of 4 cycles were delivered (1–28) with 2 partial responses, 1 minor response and 6 stable disease = 3 months out of 19 patients in total. G1/2 rash or diarrhea occurred in 13 and 9 patients respectively. No corneal toxicity was seen. The PK data demonstrated a variable but linear pattern. At 1,000 mg twice/week the median Cmax, Tmax and AUC0–24 hr was 6.28 μg/ml, 2 hours and 135 μg.h/ml respectively. PD analysis is ongoing. Conclusions: A once weekly and twice weekly high dose schedule of erlotinib is feasible, with MTD not reached in the once weekly schedule. A recommended dose of 1,000 mg twice/week has clinical activity, is generally well tolerated, and results in significantly higher systemic exposure than the 150 mg once daily dose.

No significant financial relationships to disclose.
Preliminary results of a phase I clinical trial of CYT-6091: A pegylated colloidal gold-TNF nanomedicine
Authors: Libutti S. K. , Paciotti G. F. , Myer L. , Haynes R. , Gannon W. E. , Eugeni M. , Seidel G. , Shutack Y. , Yuldasheva N. , Tamarkin L.
Published: March 2020

3603

Background: CYT-6091, a nanotherapeutic manufactured by covalently linking tumor necrosis factor-a (TNF) onto the surface of 30 nm particles of pegylated colloidal gold, avoids uptake by the reticuloendothelial system (RES) and distributes primarily to solid tumors. In tumor bearing mice, CYT-6091 shows little to no uptake by the RES and increases intra-tumor TNF levels 10-fold. Electron micrographs show the accumulation of gold nanoparticles in tumors, with few particles in healthy tissue. In dogs with naturally occurring cancers and healthy rabbits, CYT-6091 caused fever but no hypotension, the known DLT for TNF. Methods: CYT-6091 is being tested in a phase I open label trial in solid tumor, advanced stage disease patients. Patients (n=3/dose), admitted to the NIH Clinical Center ICU, receive two IV injections of CYT-6091 on day 0 and 14. Doses start at 50 μg/m2 of TNF and increase by 50 μg/m2 increments to 300 μg/m2. Vital signs are monitored and blood samples are drawn over 48 hours. The primary endpoint of the study is to determine the MTD for CYT-6091. Secondary endpoints include PK, disease response (staged 45 days post treatment), and the detection of gold nanoparticles in tumors and in adjacent healthy tissue. Results: Seven patients have been treated to date. The three treated with the lowest dose (50 μg/m2) exhibited a febrile response, which was mitigated by acetaminophen and indomethacin pretreatment. None of the seven patients treated with 50, 100 or 150 μg/m2 showed a DLT hypotensive response, and blood chemistries and urinalysis were not significantly different following treatment. PK estimates for the TNF T1/2, administered as CYT-6091, are 117, 145 and 127 minutes for 50, 100 and 150 μg/m2, respectively. Electron micrographs of tumor biopsies and adjacent healthy tissue show as much as a 10-fold increase in the number of gold nanoparticles in tumors from 5 of 6 patients compared to adjacent healthy tissue. Conclusion: These observations are the first definitive demonstration in man of the tumor targeting of a systemically administered, colloidal gold-based nanomedicine.

No significant financial relationships to disclose.
VEGF and VEGF receptor-2 (VEGFR2) gene polymorphisms predict tumor recurrence in stage II and III colon cancer
Authors: Lurje G. , Schultheis A. M. , Hendifar A. E. , Ashouri S. , Zhang W. , Gordon M. A. , Nagashima F. , Chang H. M. , Yang D. , Lenz H. J.
Published: March 2020

4004

Background: Despite recent advances in the treatment of metastatic colorectal cancer, tailoring adjuvant treatment of stage II and III colon cancer patients remains controversial. Identifying a reliable panel of prognostic and predictive markers for tumor recurrence is critical in selecting an individualized and tailored chemotherapy. Tumor angiogenesis plays an important role in tumor development, progression and metastasis. In this retrospective study, we tested whether a specific pattern of 40 functionally significant polymorphisms in 37 genes involved in angiogenesis and tumor microenvironment will predict the risk of tumor recurrence in stage II and III colon cancer patients treated with adjuvant chemotherapy. Methods: Between 1999 and 2006 blood specimens from 140 patients (69 females and 71 males with a median age of 59 years; range=28–86) were obtained at the University of Southern California/Norris Comprehensive Cancer Center (USC/NCCC). Sixty-three patients had stage II and 77 had stage III colon cancer. The median follow-up was 5.4 years (range=2.0–16.8). 51 of 140 patients (36.4%) developed tumor recurrence with a 5-year probability of 0.28 ± 0.06 for stage II and 0.40 ± 0.06 for stage III colon cancer patients. Genomic DNA was extracted from peripheral blood and genotypes were determined using PCR based RFLP. Results: Polymorphisms in VEGF (C936T; p=0.009, log-rank) and VEGFR2 (+4422 AC- repeat; p=0.04, log-rank and +1416 T/A; p=0.0009, log-rank) were associated with risk of tumor recurrence in stage III colon cancer patients (n=77). VEGFR2 AC-repeat polymorphisms were additionally associated with risk of recurrence in Stage II colon cancer patients (n=63, p=0.02, log-rank). Conclusion: VEGF C936T and VEGFR2 (+4422 AC-repeat and +1416 T/A) polymorphisms may help to identify Stage II and III colon cancer patients who are at increased risk for developing tumor recurrence. Angiogenesis seems to play a crucial role in tumor recurrence, thus targeting VEGF and VEGFR2 may be of clinical benefit for stage II and stage III colon cancer patients. Large prospective trials are needed to validate these preliminary data.

No significant financial relationships to disclose.
Time-dependent patterns of failure and treatment benefit from adjuvant therapy for resectable colon cancer: Lessons from the 20,800-patient (pt) ACCENT dataset
Authors: Sargent D. J.
Published: March 2020

4008

Background: To explore and inform 3 critical issues facing trialists and practicing oncologists testing adjuvant therapy (AT) for stage II and III colon cancer: 1) The nature and duration of AT benefit, 2) detailed information on survival and recurrence (rec) rates, including long-term event rates (> 10 years (yrs)), and 3) adequacy of statistical models for power and sample size calculations based on a disease-free survival (DFS) endpoint. Methods: The dataset assembled by the Adjuvant Colon Cancer Endpoints (ACCENT) Group, a collection of individual pt data from 18 trials and over 20,800 pts testing 5-FU based AT for pts with stage II and III colon cancer, was analyzed. Results: 1) Significant DFS benefit from AT were manifest in the first two years post randomization; after 2 years DFS rates in the AT and control groups were not significantly different. Significant Overall Survival (OS) benefit of AT was consistent over the 8 year follow-up period. 2) After 5 yrs, rec rates were <1.5%/yr, and after 8 yrs, < 0.5%/yr. 3) For DFS, a Weibull model provided superior model fit compared to the standard exponential model. In the range of Weibull values seen in trials in the dataset, however, the use of the Weibull model did not meaningfully impact power and sample size (<2% impact on power for the same sample size), assuming a constant effect of AT on DFS. Additionally, modeling a non-constant AT effect (as observed for DFS) had a similar negligible impact on statistical power compared to the standard exponential model, for the same sample size. Conclusions: AT provides significant benefit for DFS, primarily within the first 2 years, translating into long-term OS benefit. Long term follow-up for rec yields few events. Despite some increased complexity, existing methods remain appropriate for power and sample size determination for the DFS endpoint, pending further confirmation.

No significant financial relationships to disclose.
Effect of alvimopan (ALV) on gastrointestinal (GI) recovery, length of hospital stay (LOS), and postoperative ileus (POI)-related morbidity in patients (PTS) undergoing bowel resection (BR) for colon or rectal cancer (CRC)
Authors: Weese J. L. , Du W. , Techner L.
Published: March 2020

4014

Background: POI, an interruption of bowel motility, occurs universally after BR and is exacerbated by exogenous opioid analgesia. ALV, a peripherally acting mu-opioid receptor (PAM-OR) antagonist, accelerated GI recovery after BR in multicenter, randomized phase III efficacy trials. CRC is the most common reason for BR in the US, and in the ALV trials CRC was the primary reason for BR for 723 of 1,409 (51%) PTS. This abstract examines GI recovery, LOS, POI-related morbidity, and safety in only this subset of PTS. Methods: This pooled ad hoc analysis assessed the subset of PTS in phase III ALV trials who underwent BR via laparotomy because of CRC and received ALV 12 mg or placebo (PLA) (N = 723). All PTS were scheduled for postoperative intravenous patient-controlled opioid analgesia and received oral ALV or PLA preoperatively and BID postoperatively until hospital discharge or for = 7 postoperative days. Efficacy endpoints included GI-2 recovery (first bowel movement and tolerance of solid food) and postoperative LOS (calendar day after surgery to hospital discharge order written). Treatment effect on GI-2 recovery was analyzed using Cox proportional hazards models, and magnitude of effect was expressed with Kaplan-Meier means. POI-related morbidity included nasogastric tube insertion or complications of POI resulting in prolonged hospital stay or readmission. Safety was monitored by adverse event reports. Conclusions: ALV significantly accelerated GI recovery, reduced postoperative LOS, and reduced the proportion of PTS with POI-related morbidity compared with PLA in PTS undergoing BR for CRC. ALV was well tolerated with a lower incidence of nausea and vomiting in the ALV group than in the PLA group.

[Table: see text]

No significant financial relationships to disclose.
The impact of dietary patterns on cancer recurrence and survival in patients with stage III colon cancer: Findings from CALGB 89803
Authors: Meyerhardt J. A. , Niedzwiecki D. , Hollis D. , Saltz L. , Willett W. , Mayer R. J. , Fuchs C. S.
Published: March 2020

4019

Background: Dietary factors have been associated with the risk of developing colon cancer; the influence of diet on pts with established disease is unknown. Methods: We conducted a prospective observational study of 1,009 patients with stage III colon cancer enrolled in a phase III adjuvant chemotherapy trial. Patients reported on dietary intake using a food frequency questionnaire during and 6 months after adjuvant chemotherapy. We identified two major dietary patterns, prudent and Western, by factor analysis. The prudent pattern was characterized by higher intake of fruits, vegetables, poultry and fish; the Western pattern by higher intake of red meat, fat, refined grains and desserts. Since there was no difference in efficacy between the 2 treatments, data for all pts were combined and analyzed according to quintiles of each dietary pattern. Patients were followed for cancer recurrence or death. Results: A higher intake of a Western pattern diet after cancer diagnosis was associated with a significantly worsened disease-free survival (DFS). After adjustment for gender, age, T and N stage, body mass index, physical activity level, weight change, baseline performance status, and treatment arm, patients in the highest quintile of Western pattern diet intake experienced a hazard ratio for DFS of 3.15 (95% confidence interval [CI], 1.76–5.63; p trend = <0.0001), compared to those in the lowest quintile. Western pattern diet was associated with a similar detriment in recurrence-free survival (adjusted p trend = 0.001) and overall survival (adjusted p trend = 0.0002). In contrast, prudent pattern diet did not significantly influence cancer recurrence or mortality. Conclusions: Higher intake of a Western pattern diet may increase the risk of recurrence and mortality among patients with stage III colon cancer patients treated with surgery and adjuvant chemotherapy. Further studies are needed to delineate which components of such a diet are most influential.

[Table: see text]

No significant financial relationships to disclose.
RTOG 0315: A randomized, double-blind, placebo-controlled phase III study to determine the efficacy of octreotide acetate in preventing or reducing the severity of chemoradiation-induced diarrhea in patients with anal or rectal cancer
Authors: Zachariah B. , James J. , Gwede C. K. , Ajani J. , Chin L. , Donath D. , Kane B. L. , Rotman M. , Berk L.
Published: March 2020

4032

Background: Diarrhea is a common side effect of chemoradiation for pelvic malignancies. Octreotide acetate has been shown to control grade 3–4 chemotherapy-induced diarrhea in >90% of patients. The primary objective of this randomized placebo-controlled phase III study was to determine the efficacy of long acting octreotide acetate in preventing the onset of grade 2–4 diarrhea. Secondary objectives were to assess the impact of diarrhea on chemoradiation delivery and medical resource utilization. Methods: Eligible patients (pts) with primary anal or rectal cancer, and scheduled to receive concurrent chemoradiation to a minimum dose of 45 Gy using pelvic field sizes greater than 10x10cm, were enrolled. Pts with history of pelvic radiotherapy, chronic bowel disease, diarrhea of grade ≥2, or colostomy were excluded from the study. Pts were stratified by RT dose (<50 Gy and ≥50 Gy), chemotherapy (bolus and continuous) and gender. Pts were randomized to receive two 30 mg intramuscular injections of octreotide acetate (Sandostatin LAR® Depot) or placebo. Injections were given between day -7 and day -4 and on day 22 (± 3 days) of RT. The primary endpoint was incidence of grade 2, 3, or 4 diarrhea (CTCAE v3.0). Assuming a 45% placebo incidence rate, a one-sided chi-square test (alpha 0.05) would require 226 pts to detect a 42% reduction in incidence due to octreotide acetate. Results: The study accrued 233 pts (215 analyzable), 106 pts in the placebo arm and 109 pts in the octreotide acetate arm. The majority of pts (80%) on each arm had rectal cancer. There was no statistically significant difference in incidence of grade 2+ diarrhea (p=0.21) with 52 (49%) and 48 (44%) in the placebo and octreotide acetate treatment arms, respectively. There was also no statistically significant difference between the treatment arms in chemoradiation delivery or medical resource utilization. Conclusions: Prophylactic use of octreotide acetate was not shown to significantly reduce the incidence of mild, moderate or severe diarrhea.

No significant financial relationships to disclose.