bluuebunny/crossref_metadata_2025 huggingface dataset:
The PI3-K/AKT/mTOR pathway as a target for breast cancer therapy
Authors: Di Cosimo S. , Scaltriti M. , Val D. , Rojo F. , Guzman M. , Jimenez J. , Seoane J. , Arribas J. , Baselga J.
Published: March 2020

3511

Background: The PI3K/Akt/mTOR pathway is found dysregulated in multiple tumours, including breast cancer (BC). RAD001 is a recently developed drug which blocks mTOR. To study this compound’s anti-tumour effect and interactions with the aforementioned pathway, we set up a translational research program which integrates basic and clinical research data. Methods: The preclinal studies performed in BC cell lines and xenografts included the use of proliferation assays, western blot (WB), small interfering RNA and immunohistochemistry (IHC) analysis. The clinical studies consisted in a phase I study with escalating doses and collection of tumour biospies at different time points Results: Our first achievement was validating the antibodies used in WB and IHC and directed towards different components of the PI3K/Akt/mTOR pathway. We first reported that sensitivity to RAD001 correlated to basal levels of p-Akt. We then observed that RAD001 inhibits mTOR downstream, pS6 and eIF4G, but increases the levels of p-Akt, both in vitro and in patients’tumour biopsies. We demonstrated that knock down of the pS6 kinase mimics the effect of RAD001. Indeed, by combining the PI3K inhibitors and the genomic approch of p85 dominant negative vector, we demonstrated that RAD001 induced p-Akt is through PI3K. Besides the p-Akt induction we also found a RAD001 induction of IRS-1, the pivot mediator of the Insulin like Growth factor-1 Receptor (IGF-1R). We reported that RAD001 resulted in a prolonged activation of IRS-1 and in a sustained association with the p85 subunit of PI3K. Thus RAD001 disrupts an inhibitory mechanism impinging on the PI3K signalling, resulting in sustained activation of the IGF-1R pathway. Accordingly we demonstrated that combination of RAD001 with coumpounds directed against the IGF-1R, i.e. both IGF-1R tyrosine kinase inhibitors and monoclonal antibodies, prevented RAD001 induced p-Akt and resulted in a supradditive growth inhibitory effects both in vitro and in MCF-7 human BC derived xenografts.We are now conducting a phase I study with a monoclonal antibody directed at the IGF-1R that blocks IGF-1R signalling. Conclusions: Dual inhibition of mTOR and IGF-1R completely blocks the PI3K/Akt/mTOR pathway and provide a mechanistic-based combined approach. Clinical studies in BC patients are being planned.

No significant financial relationships to disclose.
A phase I pharmacokinetic study of PR-104, a hypoxia-targeting agent, in patients with solid tumors
Authors: Jameson M. B. , Rischin D. , Pegram M. , Gutheil J. , Patterson A. , Denny W. , Wilson W.
Published: March 2020

3516

Background: PR-104 is a novel pre-prodrug (precursor of a prodrug) designed to form a cytotoxic nitrogen mustard (alkylating agent) in hypoxic regions of tumors. Following IV administration, PR-104 is converted by systemic phosphatases to the alcohol intermediate PR-104A, which, under hypoxic conditions, is reduced to form the active DNA-crosslinking mustard species PR-104H. This phase I trial defines a Maximally Tolerated Dose (MTD) and pharmacokinetics (PK) for this schedule. Methods: Patients (pts) with relapsed/recurrent solid tumors received PR-104 as a 1-hour IV infusion every 3 weeks with PK sampling on days 1–2 of cycle 1. Cohorts of ≥3 pts were treated starting at 135 mg/m2. Results: 23 pts have been enrolled: median age 51 years (range 29–72); 13 (57%) male. Most pts had received prior radiation or chemotherapy and had metastatic disease. Six dose levels (135, 216, 354, 550, 770, and 1,100 mg/m2) have been evaluated. Dose-limiting toxicity (DLT) was observed in one patient at 1,100 mg/m2 (grade 3 fatigue) and this dose level was expanded to 6 pts. In the first 4 cohorts, 54 adverse events (AEs) were considered drug-related by the investigator including nausea (26% of all AEs), fatigue (19%), vomiting (11%) and anorexia (6%); remaining AEs each constituted < 3% of the total. Of 16 grade 3 AEs, 3 were considered drug-related by the investigator (anemia, dehydration and vomiting). Prophylactic anti-emetics largely prevented nausea and vomiting at higher doses, at which dose-related decreases in neutrophils and platelets were seen. Conclusions: PR-104 has shown manageable toxicities similar to other cytotoxic agents, with no serious mucositis, diarrhea or alopecia. DLT is likely to be myelosuppression based on preclinical and current clinical data, with the MTD close to 1,100 mg/m2. The preclinical PK target for the alcohol intermediate has been exceeded at higher doses and, while no objective responses have been documented, reductions in tumor volume have been seen at these doses.

[Table: see text]

No significant financial relationships to disclose.
Phase 1 study of CP-868,596 an oral, highly specific PDGFR inhibitor
Authors: Lewis N. , Eder J. P. , Guo F. , Pierce K. J. , Olszanski A. J.
Published: March 2020

3524

Background: CP-868,596 is an orally available, highly specific inhibitor of platelet-derived growth factor receptors (PDGFR). PDGF and its receptor play an important role in angiogenesis, modulation of tumor interstitial fluid pressure (IFP), and influence cell growth, migration, and survival through signal-transduction pathways. Methods: The safety, tolerability and pharmacokinetics (PK) of daily oral CP-868,596 administered in 4-week cycles were assessed in patients with advanced solid malignancies. Original dose escalation cohorts were 100, 200, 280 and 340 mg QD administered on an empty stomach. Prevalence of persistent Grade 1 nausea and vomiting led to amendments that include “with food” cohorts. Safety assessments included adverse events (AEs), clinical laboratories, and ECG monitoring. PK blood samples were collected after a single dose and at steady state. PK parameters were estimated by non compartmental techniques. Results: Data is available for all 59 patients enrolled in the trial [(29 M/30F); mean age (range): 58.6 (18–80)]. The most common treatment related AEs were nausea (67.8%), vomiting (55.9%) and diarrhea (25.4%). The MTD with coadministration of anti-emetics on an empty stomach was 200 mg/day. Coadministration of CP-868,596 with food resulted in a decrease of nausea and vomiting. The recommended phase 2 dose is 100 mg BID given with food. CP-868,596 was rapidly absorbed after oral administration. Median Tmax ranged from 1 to 4 hours. Cmax and AUC of CP-868,596 increased with dose more-than proportionally. Moderate accumulation occurred with a mean AUC accumulation ratio of 1.4–4.0. The mean terminal t1/2 ranged from 11.6 to 16.8 hours and was similar across all dose levels. The effect of food on PK appeared to be dose-dependent in this parallel cohort design with a limited number of patients (n=3–8). Analysis of safety data showed increasing liver enzymes with increasing PK exposures. No objective responses were seen. Conclusion: Daily administration of CP-868,596 appears to be safe and well tolerated. DLTs were: N/V (2), elevated ALT/GGT (2/2), increased Mg (1), Hematuria (1), and Insomnia (1). Mean steady state serum concentrations in all dose cohorts exceeded the preclinically predicted minimal efficacious exposure (16 ng/mL).

No significant financial relationships to disclose.
Phase I trial of intravenous 17-allylaminogeldanamycin (A) and oral sorafenib (B) in pretreated advanced malignancy: Plasma Hsp90α induction correlates with clinical benefit
Authors: Vaishampayan U. N. , Sausville E. A. , Horiba M. N. , Quinn M. , Heilbrun L. K. , Burger A. , Ivy P. , Li J. , Lorusso P.
Published: March 2020

3531

Background: The combination of B with A was evaluated to recommend a phase II dose for using A in combination with B, since raf-kinase and VEGF inhibition by distinct pathways could result in synergy and prevent resistance to B. Patients and Methods: Eligibility included histologically confirmed advanced malignancy, at least 4 weeks since prior systemic cancer therapy and/or radiation, adequate organ function and performance status of 0–2. B was administered orally at fixed dose of 400 mg twice daily starting 2 weeks prior to A, which was added in escalating dose cohorts starting at 300mg/m2 intravenously over 3 hours on days 1, 8 and 15 in a 28 day cycle. Toxicity was assessed weekly and clinical response evaluated every 2 cycles. Results: 19 patients have been registered (6 clear cell renal, 1 papillary renal, 4 colorectal, 1 each with cervix, adrenal, oral, thyroid, pancreas cancer and 3 with melanoma). 16 have been treated for at least the first two cycles at 4 dose levels on this ongoing study. Dose limiting toxicity has not yet been reached at 400mg/m2 of A. Major toxicities were grade 3 fatigue in 1 patient and grade 2 nausea and diarrhea in 3 and 2 patients respectively. Grade 3 hand foot syndrome related to B was noted in 3 patients. Of 14 response evaluable patients, 1 demonstrated partial response (thyroid cancer) and 6 had stable disease;3 clear cell renal,1 each with papillary renal and cervix cancers, and 1 melanoma. Latter patient had stable disease for 10 cycles and was resected to render disease free. PK analysis reveals that steady-state was achieved after 1 week of B; addition of A did not alter PK of B. PK levels of A will be performed. Studies of Hsp90a in the plasma have been performed on 10 patients. Of the 10 patients evaluated for plasma Hsp90a (baseline values pre-A and at 4 and 18 days after A), 5 of the 6 clinically stable patients had 1.8 to 6.8- fold increase; 3 patients with clinical progression and 1 clinically inevaluable patient had induction of 0.8 to 1.7-fold. Conclusion: The combination of A and B is well tolerated and clinical benefit may correlate with induction of plasma Hsp90a. Supported by NIH# 5UO1CA062487- 14, 2MO1RR016500–006 and NCI CTEP.

No significant financial relationships to disclose.
Phase 1 dose-escalation study of 17-allylamino-17-demethoxygeldanamycin (17AAG) in combination with irinotecan in patients with solid tumors
Authors: Tse A. N. , Carvajal R. , Shah M. , Dials H. , Fogel M. , O’Reilly E. , Chung K. , Maki R. , Wu N. , Egorin M. , Schwartz G. K.
Published: March 2020

3533

Background: 17AAG is an inhibitor of the molecular chaperone Hsp90. Pre-clinical studies from our laboratory showed that treatment of cancer cells with 17AAG caused depletion of two critical checkpoint kinases, Chk1 and Wee1, resulting in abrogation of the G2/M checkpoint triggered by topoisomerase I poison, and selective induction of apoptosis in p53-defective cells. Methods: We initiated a phase 1 study of irinotecan (CPT) and 17AAG to determine the maximally tolerated doses (MTD) and tolerability, pharmacokinetics (PK) and pharmacodynamics (PD) of the combination. During the dose-escalating phase, patients (Pts) received CPT over 30 min followed by 17AAG over 2 hrs once weekly for two weeks in a 21-day cycle. At the MTD, Pts underwent post-treatment tumor biopsy for PD biomarker analysis after CPT only during week 1 and after the combination during week 2. Results: 22 Pts (median age 53; range 32–73; median KPS 80) with a wide spectrum of solid tumor types were enrolled. Four Pts developed dose-limiting toxicity in cohort 4 (100 mg/m2 CPT and 375 mg/m2 17AAG) including nausea, vomiting, diarrhea, and pulmonary embolism. The PKs of 17AAG and its metabolite 17AG were not affected by the co-administration of CPT. Although no CR/PR’s by RECIST criteria have been seen, minor responses were observed in CPT-naive Pts with pancreas (2), breast (1), and high grade neuroendocrine tumor (1). Pts are currently enrolled to the MTD expanded cohort for further assessment of tolerability and PD analysis. So far, paired tumor biopsies have been successfully obtained in 8/8 Pts and samples will be analyzed for p53 status, Hsp90 client protein depletion, G2/M checkpoint abrogation, and apoptosis. Conclusions: The combination of 17AAG and CPT can be given to Pts with acceptable toxicity. The recommended phase II dose of the combination is 100 mg/m2 CPT and 300 mg/m2 17AAG. (Supported by ASCO CDA and NCI K08 awards)

No significant financial relationships to disclose.
First-in-human study of AMG 655, a pro-apoptotic TRAIL receptor-2 agonist, in adult patients with advanced solid tumors
Authors: LoRusso P. , Hong D. , Heath E. , Kurzrock R. , Wang D. , Hsu M. , Goyal L. , Wiezorek J. , Storgard C. , Herbst R.
Published: March 2020

3534

Introduction: AMG 655 is a fully human monoclonal agonist antibody that binds human TRAIL receptor 2 (TR-2/DR5), activates caspases, and induces apoptosis in sensitive tumor cells. The primary objectives of this ongoing first-in-human study were to assess the safety, tolerability, and pharmacokinetics (PK) of AMG 655 in patients (pts) with advanced solid tumors. Methods: Three to 9 pts were enrolled into 1 of 5 sequential dose cohorts (0.3, 1, 3, 10, or 20 mg/kg) of AMG 655 administered intravenously Q2W. No AMG 655 was administered on day 43 to allow assessment of terminal PK parameters. RECIST and FDG-PET were analyzed by central radiology. Pts remained on study until tumor progression or unacceptable toxicities occurred. Results: As of October 19, 2006, 16 pts (4 in the 10 mg/kg cohort; 3 in each of the other cohorts) had received = 1 dose of AMG 655; 12 pts were men, mean (SD) age was 53 (±8.9) years. No DLTs or AMG 655-related serious AEs were reported. The MTD was not reached. Nine pts reported AMG 655-related AEs. Treatment-related AEs in 3 or more pts were: pyrexia (4 pts), fatigue (3 pts), and hypomagnesaemia (3 pts). Fatigue and elevated serum lipase were the only grade 3 or higher AMG 655-related AEs and both occurred in the same pt (0.3-mg/kg cohort). No anti-AMG 655 antibodies were detected. PK data were available from dose cohorts 1 to 3 (0.3, 1, and 3 mg/kg); AMG 655 demonstrated dose-linear kinetics with a half-life of ∼10 days. Tumor- response data were available for 13 pts. Partial response was observed in 1 pt with non-small cell lung cancer (NSCLC) who experienced a 46% reduction in tumor volume by RECIST and remains on study after 48 weeks. Stable disease was reported in 4 pts (range 6 to 35 weeks), and progressive disease in 8 pts. One pt with colorectal cancer and stable disease demonstrated a metabolic partial response with a 34% reduction in maximum standardized uptake value (SUVmax). Conclusions: AMG 655 administered up to 20 mg/kg Q2W appeared to be well tolerated in these pts. The anti-tumor activity of AMG 655 was confirmed with observation of a partial response in NSCLC and a metabolic partial response in colorectal cancer. Further studies evaluating AMG 655 in combination with chemotherapy and targeted agents are warranted.

No significant financial relationships to disclose.
Pharmacokinetic (PK) and phase I study of sorafenib (S) for solid tumors and hematologic malignancies in patients with hepatic or renal dysfunction (HD or RD): CALGB 60301
Authors: Miller A. A. , Murry D. J. , Owzar K. , Hollis D. R. , Abou-Alfa G. K. , Desai A. , Hwang J. , Villalona-Calero M. , Dees E. C. , Lewis L. D. , Ratain M. J.
Published: March 2020

3538

Background: We sought to characterize the PK and determine a tolerable dose of S in patients with HD or RD. Methods: Patients with performance status 0–2 and pathologically proven solid tumors, multiple myeloma, or non-Hodgkin’s lymphoma, for whom standard therapy was exhausted, were assigned to one of 9 cohorts: [1] Bilirubin (B) =ULN and SGOT =ULN and creatinine clearance (CC) =60 ml/min; [2] B > ULN but = 1.5 x ULN and/or SGOT > ULN; [3] CC between 40 and 59 mL/min; [4] B > 1.5 x ULN to = 3 x ULN (any SGOT); [5] CC between 20 and 39 mL/min; [6] B > 3 x ULN to 10 x ULN (any SGOT); [7] CC < 20 mL/min; [8] albumin < 2.5 mg/dL (any B/ SGOT); and [9] hemodialysis. S was administered po as a 400 mg test dose on day 1 with blood sampled before and 1, 2, 3, 4, 6, 24, and 168 hrs afterwards for PK. Total S concentrations were fit to a 2-compartment model and population parameters from previous studies were utilized. On day 8, continuous daily po S started with dose escalation in groups of at least 3 evaluable patients. Dose-limiting toxicity (DLT) by day 29 was defined as: grade 4 neutrophils or platelets; B = 1.5 x baseline in HD and = 2.5 x ULN in RD; CC reduction by > 20 mL/min in RD and >10 mL/min in HD; grade = 3 nausea/vomiting/diarrhea despite optimal supportive care; or any other grade = 3 non-hematologic toxicity. Results: Between 1/05 and 12/06, 146 patients (target 150) were registered but 12 never started therapy. With the exception of cohorts 6 and 7, at least 12 patients per cohort were evaluable. The dose level in each cohort with DLT in less than one third of patients was: [1] 400 mg bid; [2] 400 mg bid; [3] 400 mg bid; [4] 200 mg bid; [5] 200 mg bid; [6] not even 200 mg every third day tolerable; [7] n/a; [8] 200 mg qd; and [9] 200 mg qd. All DLT was non-hematologic: 9 of 12 events in patients with HD were increase in B; other DLT included abdominal pain, rash, fatigue, nausea/vomiting, hand-foot syndrome, congestive heart failure, diarrhea, hemorrhage, and hypertension. PK data are available for 51 patients. Apparent S clearance was: highly variable, median 5.69 (range 1.27 - 19.98) L/hr; not related to age, body weight, or sex; and not different among cohorts. Conclusions: Apparent S clearance does not depend on cohort. We propose the above empiric starting doses by cohort.

No significant financial relationships to disclose.
A phase I study of bevacizumab (BV) plus ABT-510 in patients with advanced solid tumors
Authors: Uronis H. E. , Bendell J. , Blobe G. , Morse M. , Geier D. , Nixon A. , Howard L. , Evans D. , Li H. , Hurwitz H.
Published: March 2020

3541

Background: BV is a potent inhibitor of vascular endothelial growth factor (VEGF) with broad clinical activity both alone and in combination. ABT-510 is a 9 amino acid synthetic analog of the N-terminal region of thrombospondin (TSP-1), an endogenous inhibitor of angiogenesis. ABT-510 exhibits anti-angiogenic effects in preclinical models and has been well-tolerated as a single agent in previous Phase I & 2 studies. As a combination anti-angiogenesis therapy, we evaluated BV + ABT-510 in a phase I biomarker study. Methods: In cohorts of 3–6 patients, BV and ABT-510 were evaluated. BV was dosed in mg/kg IV q2weeks and ABT-510 was given daily in mg SC BID; cycle length was 28 days. Dose levels were as follows: (1) BV 5/ ABT-510 50; (2) BV 10/ ABT-510 50; (3) BV 10/ ABT-510 100. At the recommended phase II dose, 20 patients are being enrolled for detailed biomarker studies. DLT was defined as any hematological toxicity = grade 4 or grade = 3 non- hematological event in Cycle 1 related to treatment, with the exception of grade 3 hypertension adequately controlled by medication. Eligible patients had advanced solid tumors, adequate organ and marrow function, and no co-morbidities suggesting increased risk for class-related toxicities. Dermal wound angiogenesis assays were analyzed for visualization as well as phospho-VEGFR2, TGFβ, phospho-AKT, and thrombospondin-1 and -2, both pre- and on-treatment. Plasma was assayed for multiple angiogenic factors. Results: 22 patients have been enrolled; 17 are currently evaluable for toxicity and 14 for efficacy. No DLT were seen in any cohort. Possible treatment related adverse events occurring in later cycles included: gr3 GI bleed (n=1) and gr3 headache (n=1). 7 patients had stable disease as best response (range 8- 64+ weeks); 2 remain on therapy, one at 64+ weeks and one at 24+ weeks. Conclusions: BV + ABT-510 is well-tolerated and has hints of activity in refractory tumors. The recommended phase II dose is BV 10mg/kg IV q14d and ABT-510 100mg SC BID. Updated clinical and biomarker data will be presented.

No significant financial relationships to disclose.
Phase I study of tipifarnib and sorafenib in patients with biopsiable advanced cancers (NCI protocol 7156 supported by NCI grant UO1 CA062461)
Authors: Hong D. S. , Camacho L. , Ng C. , Wright J. , Newman R. A. , Moulder S. , Tannir N. , Wheler J. , Khan R. , Kurzrock R.
Published: March 2020

3549

Background: The Ras and Raf kinases are sequential signaling proteins in the MAPK pathway and inhibition of both targets may confer synergistic effects, particularly in tumors with activation of either kinase through mutation or other mechanisms. Therefore, we sought to combine sorafenib, a multikinase inhibitor (Raf, VEGFR, PDGFR) and tipifarnib an inhibitor of farnesyltransferase that is critical for Ras activity in a phase I study to determine the safety, pharmacokinetics (PK), and tumor response. Methods: The trial was a phase I trial of advanced cancer patients(pts) with a conventional dose escalation design. Each cycle consisted of 28 days of sorafenib and 21 days of tipifarnib. Dose levels are listed in the table . Results: To date, a total of 27 pts have been enrolled (median age 54.5 yrs, M:F 1:1. 3 RCC, 3 breast, 4 sarcoma, 4 melanoma, 3 CRC, 4 thyroid, 2 H&N, one thymic, one adrenal cortical, one SCC of the lung, and one unknown primary SCC). Two pts developed grade 3 DLT-skin rash on the first dosing level (tipifarnib at 100 mg po BID and sorafenib at 400 mg po BID). Dose escalation was modified as per table below. At dose level 4, 2/5 pts entered experienced a DLT of grade 3 rash and grade 3 drug fever, therefore MTD has been determined to be tipifarnib 100 mg BID, sorafenib 400 mg qam, 200 mg qpm. The most common treatment related toxicities included lymphopenia (18), hyperglycemia (17), and skin rash (14). Currently, 19 of the 27 pts are evaluable; 13 pts had SD (8–44 weeks); 2 RCC pts for 32 weeks, an adrenal cortical ca pt for 32 weeks, one melanoma pt for 44 weeks. PK analysis suggested findings similar to single agent PK profiles, no PK interactions were apparent. Conclusions: Significant toxicity with the combination of these two agents, even doses well below single agent maximum levels were observed. The MTD was determined to be tipifarnib at 100 mg BID, sorafenib at 400 mg qam, 200 mg qpm. PK analysis, to date show,no pharmacokinetic interaction between tipifarnib and sorafenib.

[Table: see text]

[Table: see text]
Sorafenib (S) and dacarbazine (D) combination in patients (pts) with advanced malignant solid tumors: Phase I study with tumor biopsy genomic analysis and dynamic contrast enhanced ultrasonography (DCE-US)
Authors: Soria J. , Lazar V. , Lassau N. , Pena C. , Massard C. , Robert C. , Koscielny S. , Deutsch E. , Zafarana E. , Armand J. P.
Published: March 2020

3556

Background: S is a multikinase inhibitor targeting VEGFR-1, -2, -3, PDGFR-a and -β and Raf kinase. The combination of S (400 mg bid) and D (1,000 mg/m2, 21-day [d] cycle [C]) was previously defined as maximum tolerated dose. Objectives were to define the pharmacokinetic (PK) profile of D ± S, assess safety of the combination and collect antitumor activity data by genomic analysis and by DCE-US. Methods: All pts received D (1,000 mg/m2 by 1-hr infusion) with continuous oral S 400 mg bid (except Day1C1). PK was performed during 1st and 2nd infusions. RNA expression profiling was performed on sequential tumor biopsies at baseline (BL) and Day 21. DCE-US was assessed at BL and Day 8, 21 of C1. Results: 23 pts treated (median age 59 y) had melanoma (4), leiomyosarcoma (4), adenocarcinoma (5), mesothelioma (3), neuro-endocrine tumor (3) and other (4). 22 had = 1 prior chemotherapy (range, 1–7). Median (range) number of D cycles was 4 (1–9), median (range) duration of S treatment was 15 wks (3–48). Toxicities were manageable and included diarrhea (48% any grade [G], no G3/4), hand-foot skin reaction (48% any G, 4% G3), fatigue (26% G3), thrombopenia (22% G4), and neutropenia (13% G4). Of 22 evaluable pts, 1 (melanoma) had confirmed PR, 13 pts had SD as best response, with a median (range) duration of 161 d (75–258). 7 pts continue with SD. PK (n=15) showed increased mean AUC by 41% and mean Cmax of AIC (an inactive D metabolite that is formed in an equal proportion to the active moiety, diazomethane, that cannot be analytically measured) by 45%. Genomic analysis in 10 pts with PFS =3 mos and in 7 with PFS <3 mos identified a subset of 4 genes whose modulation differentiates these groups with 100% accuracy. 99 DCE-US performed in 17 pts showed 3/7 with short PFS had increased volume on Day 21 and in 3 an increase in maximal intensity >50% on Day 8. Of 10 pts with long PFS, maximal intensity decreased by >50% on Day 21 in 8 pts. Conclusion: Combination of D and S is manageable with clear evidence of antitumor activity. Preliminary data strongly suggest a new paradigm based on sequential tumor genomic analysis allowing early identification of responders. Early stage DCE-US may predict PFS duration.

No significant financial relationships to disclose.
A phase I study of vorinostat in combination with bortezomib in refractory solid tumors
Authors: Schelman W. R. , Kolesar J. , Schell K. , Marnocha R. , Eickhoff J. , Alberti D. , Wilding G. , Bailey H.
Published: March 2020

3573

Background: Vorinostat (suberoylanilide hydroxamic acid, SAHA) is a histone deacetylase (HDAC) inhibitor that has anti- tumor activity in hematologic malignancies and advanced solid tumors. Based on studies showing that HDAC inhibitors increase the activity of the 26S proteasome, vorinostat has been postulated to act synergistically with bortezomib. This study was conducted to determine the toxicities and efficacy of vorinostat with bortezomib. Correlative studies included pharmacokinetics and the effects of vorinostat/bortezomib on cell cycle, proteasome inhibition, histone acetylation, gene expression and apoptosis. Methods: This study used standard eligibility criteria except pts must have had no prior bortezomib. The treatment plan consisted of vorinostat given orally on days 1–14 with bortezomib IV on days 1, 4, 8 and 11 of a 21-day cycle. Starting dose (Step A, level 1) was once-daily vorinostat (400 mg) and bortezomib (0.7 mg/m2). Step B consisted of twice-daily dosing of vorinostat (200mg) with bortezomib at MTD established in Step A. RECIST was used to measure response. Effects on G2/M-phase arrest in buccal mucosa cells (BMC) were measured using flow cytometry. Samples were collected on days 1 and 9, at 0, 2 and 4 hr following treatment. Results: 22 pts have been enrolled; 14 men, 8 women. Tumor types: 5 sarcoma, 5 colorectal, 3 pancreatic, 2 lung, 1 breast, 1 ovarian, 1 bladder, 1 gastric, 1 germ cell, 1 mesothelioma, 1 GIST. Grade 3–4 toxicities at least possibly related to vorinostat at any dose level were as follows: fatigue (3), n/v (1), thrombocytopenia (1), and hyponatremia (1). One pt was unevaluable. DLTs included fatigue (3), hyponatremia (1) and elevated ALT (1). The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. One pt with refractory soft tissue sarcoma had a PR > 9 mo. There was no effect on cell cycle arrest observed with vorinostat in BMCs. Conclusions: The MTD for Step A was established at vorinostat 400mg daily and bortezomib 1.3 mg/m2. Accrual continues at Step B, dose level 1. Subjective and objective evidence of clinical activity has been observed in pts with refractory solid tumors. (Supported by NCI grant UO1 CA062491, NCI SAIC contract 25XS097 and GCRC M01 RR03186.)

No significant financial relationships to disclose.
A first-in-man phase I study of R306465, a histone deacetylase (HDAC) inhibitor exploring pharmacokinetics (PK) and pharmacodynamics (PD) utilizing an electrochemiluminescent immunoassay in patients (p) with advanced tumours
Authors: Fong P. C. , Settatree S. , Sinha R. , Hardcastle A. , Hellemans P. W. , Arts J. , Brown K. H. , Janicot M. , Aherne W. , De Bono J. S.
Published: March 2020

3578

Background: R306565 is an aromatic hydroxamic acid with predominant inhibitory effects on Class 1 HDAC enzymes (with IC50 ∼10 nM). HDAC inhibitors (HDACi) affect gene expression at the transcriptional level, leading to cell cycle arrest and induction of apoptosis. Methods: P with solid tumours or lymphoma were given R306465 orally daily for 3 weeks (w) out of 4 in an escalating schedule. Objectives include safety, tolerability, PK (including food effect exploration), PD evaluation and circulating tumour cell (CTC) quantitation. Results: Four dose levels (100, 200, 300 and 400 mg) have been evaluated involving 15 p (7 male), age range 29–72 (median 59 y) and ECOG PS 0–2. A total of 37 cycles have been administered. Most common adverse events (AE) were Grade (G) 1–3 fatigue (87%), G1–2 nausea (66%), G1–2 vomiting (33%), G1–2 diarrhoea (40%), and G1–2 anorexia (40%). Dose limiting toxicity of G3 fatigue was seen in 1/6 p in the 400mg cohort. PK parameters were approximately dose proportional. Plasma concentrations increased in the fed state. PD effect of histone H3 acetylation (AcH3) in peripheral blood mononuclear cells (PBMC) was determined quantitatively with a novel validated electrochemiluminescent immunoassay developed in-house (applying Mesoscale Discovery technology). Although some interpatient variability exists, increased AcH3 was observed in 2/6 p in the 400 mg cohort, while the percentage rise in AcH3 was minimal for cohorts 1–3. Peak AcH3 achieved in 2 p dosed at 400 mg was approximately 5–10 fold increase over baseline. Using CellSearch technology for quantitation of CTCs, 8/14 p had detectable CTCs at baseline; the CTC trend will be presented. 4 p had stable disease (SD) for = 4 months. Conclusions: R306465 could be safely administered on a daily dosing schedule for 3 of 4 w up to 400 mg. Common toxicities seen were gastrointestinal and fatigue. Maximum tolerated dose has not been reached. PK suggests dose proportionality. Promising PD data showing increased acetylation in PBMC at 400 mg, further supports the utilization of the immunoassay platform in HDACi clinical trials.

No significant financial relationships to disclose.
Pharmacogenetic prediction for tumor response, toxicity, and survival of NSCLC patients treated with irinotecan and cisplatin chemotherapy
Authors: Han J. , Lee S. , Lee D. , Kim H. , Lee J.
Published: March 2020

3581

Background: Inherited genetic polymorphisms of the genes involved in the activation and metabolism of irinotecan can affect toxicity and clinical outcome of patients after treatment with irinotecan. We examined 14 polymorphisms within six genes putative influence on irinotecan metabolism to define a pharmacogenetic model for predicting tumor response, toxicity, and survival in NSCLC patients treated with irinotecan/cisplatin chemotherapy. Methods: Blood samples from 81 NSCLC patients treated with irinotecan (80 mg/m2 D1 & D8) and cisplatin (60 mg/m2 D1) chemotherapy were used for genotyping UGT1A1 211G>A (*6), UGT1A1*28, UGT1A9 -118(T)9>10 (*22), ABCB1 1236C>T, 2677G>T/A, 3435C>T, ABCC2 -24C>T, 1249G>A, 3972C>T, ABCG2 34G>A, 421C>A, and SLCO1B1 -11187G>A, 388A>G, and 521T>C polymorphisms. Genotypes were correlated with tumor response, toxicity, and survival by multivariate logistic or Cox regression analysis with adjustment for clinical and histopathologic features. Results: The overall response rate was 47% (36/77), the median progression-free survival was 5.1 months, and the median overall survival (OS) was 14.3 months. The most common severe toxicity was NCI-CTC grade 4 neutropenia, which occurred in 22 (27%) patients. Grade 3 diarrhea was developed in 8 (10%) patients. The presence of ABCC2 3972T allele was predictive for tumor response (odds ratio=3.244, 95% CI 1.219–8.629, p=0.018). The UGT1A1 211AA (*6/*6) genotype was a significant risk factor for grade 4 neutropenia (odds ratio=6.111, 95% CI 1.032–36.197, p=0.046). The UGT1A9*22 allele showed a trend for less grade 3 diarrhea (odds ratio=0.205, 95% CI 1.032–36.197, p=0.054). In multivariate Cox regression analysis, the UGT1A1*6/*6, UGT1A9*22/*22, and squamous cell histology were predictive for worse PFS (p=0.015, 0.049, and 0.026, respectively). Whereas, ABCC2 1249A allele, ECOG PS 2, male gender, and stage IV were predictive for worse OS (p=0.017, 0.014, 0.045, and 0.015, respectively). Conclusions: Patients’ selection based on pretreatment genotyping can minimize irinotecan-related severe toxicity and maximize the clinical benefit of irinotecan-based chemotherapy for patients with advanced NSCLC.

No significant financial relationships to disclose.
Extended phase I trial of the oral pan-Bcl-2 inhibitor AT-101 by multiple dosing schedules in patients with advanced cancers
Authors: Pitot H. C. , Saleh M. , Holmlund J. , Maleski J. , Forero A.
Published: March 2020

3583

Background: Over-expression of Bcl-2 family proteins is common in human cancers. Initial trials of the oral pan-Bcl-2 inhibitor AT-101 showed acute dose limiting toxicity of Gr 3–4 AST/ALT (MTD 40 mg/d), and ileus with prolonged dosing daily (QD) for 21/28 days per cycle (Saleh, NCI_EORTC, 2005; James, ASCO, 2006). Our ongoing Phase 1 study tests different dosing schedules of AT-101 in adults with advanced cancers. Methods: Serial patient (pt) cohorts received AT-101 at escalating doses twice a day for three days every other week (BIDx3dEOW) or once weekly (QW). Adverse events (AEs) were graded by the NCI CTCAE v. 3.0. Results: 24 pts have received pulse dosing; safety data are available for 20 pts (30–70 mg BIDx3dEOW, N=13; 80–160 mg QW, N=7). For comparison, 38 pts received 5–60 mg QD. Median number of cycles (range): BIDx3dEOW_2(1–9); QW_3(1–3), QD_2(1–12). AST/ALT is not yet dose limiting, nor the MTD reached, at 70 mg BIDx3dEOW or 160 mg QW. Ileus occurred in 4/38 pts dosed daily but in no pts on either pulse schedule. Other potentially related Gr 3–4 AEs were: BIDx3dEOW (6 pts)–AST (1 pt), abdominal pain (2 pts), elevated CK/right ventricular dysfunction (1 pt w/history of COPD/doxil therapy), hypokalemia (1 pt);QW: none; QD: AST/ALT (5 pts), nausea/vomiting/diarrhea (3 pts each) fatigue (2 pts), hypocalcemia (2 pts), hypokalaemia/anorexia/dehydration/hypophosphatemia (1 pt), elevated GGT (1 pt). The most common Gr 1–2 AEs_nausea/vomiting/fatigue_occurred in over 50% of QD and BIDx3dEOW pts but only 1/7 QW pts. Plasma Cmax (mean ± SD, μM): 70 mg BIDx3d EOW, 2.4 ± 0.9; 160 mg QW, 3.5 ± 1.3; 40 mg/d (MTD, 21/28 d), 2.6 ± 2.0. T ½ was approx. 3 hours on all schedules. Conclusions: Pulse dosing of AT-101 appears associated with reduced toxicity than more continuous daily dosing, and may be preferable in combination regimens.

No significant financial relationships to disclose.
Phase I dose escalation study of the anti-IGF-1R monoclonal antibody CP-751,871 in patients with refractory solid tumors
Authors: Haluska P. , Shaw H. , Batzel G. N. , Molife L. R. , Adjei A. A. , Yap T. A. , Roberts M. L. , Gualberto A. , de Bono J. S.
Published: March 2020

3586

Background: The insulin-like growth factor 1 receptor (IGF-IR), a tyrosine kinase, and its ligands (IGF-I & -2) are upregulated in many human tumors (e.g., breast, prostate, colon and non-small cell lung cancer) and enhance proliferative and prosurvival signaling. Inhibition of IGF-IR activation in tumor models suppresses tumor growth and increases tumor sensitivity to chemotherapy, supporting the development of agents targeting IGF-IR. CP-751,871 is a potent, highly specific, fully humanized, monoclonal antibody that inhibits IGF-IR autophosphorylation and induces receptor internalization. Methods: A Phase I dose escalation study was initiated to define the safety and tolerability, and to characterize the pharmacokinetic properties of CP-751,871 in patients with advanced solid tumors refractory to standard therapies. Results: Following informed consent and screening, a total of 24 patients with refractory solid tumors (e.g. colorectal, NSCLC, sarcoma and prostate cancer; 1–6 previous regimens) were enrolled. Patients received 3 to 20 mg/kg of CP-751,871 by IV infusion on Day 1 of 3-week cycles in four dose-escalation cohorts of 3 patients. No dose limiting toxicities were identified and the maximum feasible dose (MFD) cohort of 20 mg/kg was extended with 12 additional patients. No higher than grade 3 CTCAE v3.0 toxicities, attributed to study drug, have been so far reported. Grade 3 toxicities, all reported in patients dosed with 20 mg/kg of CP-751,871, are increased GGT (4%) and fatigue (4%). Grade 2 toxicities include: anorexia (7%), diarrhea (7%), increased GGT (4%), hyperglycemia (4%), fatigue (4%), increased urinary frequency (4%), nausea (4%), increased ALT (4%) and increased AST (4%). Pharmacokinetic analysis is currently ongoing. No objective responses were observed. At the MFD, patients received a median of 4 cycles (1–16). Three patients were stable for > 6 months and one patient, currently at cycle 16, remains on study. An additional cohort of 12 adrenocortical cancer patients is under evaluation. Conclusions: These data indicate that CP-751,871 is safe and well tolerated. Due to its good safety profile, CP-751,871 may constitute a suitable targeted agent to use in combination with approved therapies in multiple tumor types.

No significant financial relationships to disclose.
Targeting syk kinase for the treatment of B-cell lymphoma
Authors: Sharman J. P. , Irish J. , Coffey G. , Czerwinski D. , Hitoshi Y. , Levy R.
Published: March 2020

3600

Background: B-Cells require constitutive signaling from the B-Cell Receptor (BCR). Elimination of the BCR induces cell death. Since the BCR lacks enzymatic activity and relies upon the non-receptor tyrosine kinase Syk to initiate a signal transduction cascade, we hypothesized that R406; a small molecule Syk kinase inhibitor might eliminate the constitutive BCR signal and therefore have selective cytotoxicity for B-cells. Methods: Signal transduction changes were evaluated in cell lines and primary normal B-Cells via western blotting and phosphoflow cytometry. Effects on B-Cell, T-Cell, and Myeloid lineage cell lines were evaluated by 3H-thymidine proliferation assays, BRDU cell cycle analysis, and Annexin-V staining. Primary tumor samples were evaluated for B-Cell selective toxicity by evaluation of active caspase activity. Results: In cell culture R406 significantly alters the basal phosphorylation status of multiple proteins. Proliferation of B-Cell lines is reduced with an IC50 range of 625nM to 2.5uM without effect on T-Cell or Myeloid lineage cell lines. Cell cycle analysis reveals a reduction in B-Cell S-Phase with increase in G1/G0. Apoptosis is also increased in the B-cell lines without significant increase in the non-B cell lines. Primary normal B-Cells show reduced phosphorylation of BTK, Erk, and p38 in response to BCR cross linking. Primary tumor samples reveal activity against B-Cell neoplasms. In samples containing both malignant B-Cells and normal T-Cells, the induction of active caspase-3 is restricted to the malignant B-Cell population. Conclusions: 1) R406 alters signal transduction in B-Cells. 2) R406 demonstrates selective anti-B-Cell activity among cell lines. 3) Primary tumor samples reveal cytotoxic activity against malignant B-Cells without toxicity to T-Cells within the same specimen. 4) This compound has been safely tested in humans for non-malignant diseases with an appropriate pharmacokinetic profile; therefore these results support the initiation of an upcoming multicenter phase I/II clinical trial in patients with lymphoma.

No significant financial relationships to disclose.
Two phase 1 studies of MPC-6827, a novel vascular disrupting agent (VDA), in patients with advanced solid tumors and CNS metastases
Authors: Kurzrock R. , Akerley W. , Hong D. , Ng C. , Warren T. , Zavitz K. , McCage C. , Laughlin M. , Camacho L.
Published: March 2020

3604

Background: MPC-6827 is a novel competitive inhibitor of tubulin polymerization via the colchicine binding site and functions as a highly potent (1–10nM) cytotoxic agent and as a VDA. MPC-6827 inhibits tumor cell growth and survival in vitro and in vivo, with activity in xenograft models of mouse melanoma and human cancers of the ovary, breast, prostate, colon and pancreas. The compound is not a substrate for multidrug resistance pumps and reaches high CSF concentrations. Methods: Two 3+3 designed dose-escalating Phase 1 studies were conducted to define the safety, tolerability, maximum tolerated dose (MTD) and PK of weekly IV administrations of MPC-6827 for pts with advanced solid malignancies (trial 1; N=46 pts) and measurable CNS involvement (trial 2; N=17 pts). In trial 2, there was intrasubject dose escalation for the first cycle and subsequent cycles were dosed at the highest dose achieved in Cycle 1. Antitumor activity was evaluated by RECIST guidelines in both studies. Results: Dose escalation proceeded until MTD was determined at 3.3 mg/m2. The dose limiting toxicity was acute coronary syndrome. Common mild to moderate toxicities included fatigue, headache, flushing, diarrhea, nausea, vomiting and arthralgias. There were no neurological deficits observed and no evidence of myelosuppression. No objective responses were observed. Radiographic changes consistent with vascular disruption in tumors were documented in a number of subjects at higher doses. Conclusions: MPC-6827 is safe and overall well tolerated. MTD is 3.3 mg/m2. Vascular flow modulation analyses are ongoing. MPC-6827 is currently in Phase 2 development.

No significant financial relationships to disclose.
Oxaliplatin/5FU/LV in adjuvant colon cancer: Updated efficacy results of the MOSAIC trial, including survival, with a median follow-up of six years
Authors: de Gramont A. , Boni C. , Navarro M. , Tabernero J. , Hickish T. , Topham C. , Bonetti A. , Clingan P. , Lorenzato C. , André T.
Published: March 2020

4007

Background: The MOSAIC study was designed to evaluate the effects of the FOLFOX4 regimen (5-FU/LV + oxaliplatin) on 3- year disease free survival (DFS) probability in patients with stage II and III colon cancer. Methods: Patients (n=2246) with completely resected stage II (40%) or III (60%) colon cancer were randomly assigned to receive 5-FU/LV (LV5FU2) or FOLFOX4 every 2 weeks for 12 cycles. Results: Results for the primary endpoint of the study (for the overall population, with a median follow-up [FU] of 3 years), showed a significant benefit in DFS for the FOLFOX4-treated patients (78.2% vs 72.9%; HR: 0.77, p=0.002) (André et al, NEJM, 2004). Patients were followed beyond the 3-year cut-off for DFS and overall survival (OS) updates. Final DFS, at 5 years FU, are consistent with earlier results (HR: 0.80, p = 0.003). In addition, at a median FU of 6 years, the study demonstrates a significant benefit in OS for the stage III patients. Summary of OS results (median FU 6 years) Long-term safety update shows no increase in the rate of secondary cancer (5.0% in both treatment arms). Conclusions: These results confirm the benefit of the FOLFOX4 regimen in adjuvant colon cancer patients.

[Table: see text]

No significant financial relationships to disclose.
Sequential compared to combination chemotherapy with capecitabine, irinotecan, and oxaliplatin in advanced colorectal cancer (ACC): A Dutch Colorectal Cancer Group (DCCG) phase III study
Authors: Punt C. J. , Koopman M. , Douma J. , Wals J. , Honkoop A. H. , Erdkamp F. L. , de Jong R. S. , Rodenburg C. J. , Mol L. , Antonini N. F.
Published: March 2020

4012

Background: Overall survival (OS) in phase III studies with 1st line combination therapy in ACC may be influenced by imbalances in salvage treatments. This is the first study that prospectively investigates the sequential vs the combined use of all available effective cytotoxic drugs. Methods: Previously untreated patients (pts), WHO PS 0–2 were randomized between 1st line capecitabine (Cap), 2nd line irinotecan (Iri), and 3rd line Cap + oxaliplatin (CapOx) (Arm A, sequential) vs 1st line CapIri and 2nd line CapOx (Arm B, combination). The dose of Cap was 1250 mg/m2 (mono) or 1,000 mg/m2 (combination) b.i.d. day 1–14, Iri 350 mg/m2 (mono) or 250 mg/m2 (combination), and Ox 130 mg/m2. All cycles were q 3 weeks with Iri/Ox given i.v. on day 1. Response was assessed q 3 cycles. Primary endpoint was OS. The study was designed to detect a 20% reduction in the hazard of death (HR=0.80) for an increase in median OS from 14 to 17.5 months (a=0.05, 2-tailed test). Results: 820 pts were randomized between Jan ‘03 and Dec ‘04 in 74 Dutch hospitals. Of 804 eligible pts, 796 received = 1 cycle. Median age was 63 (27–84) yrs, median WHO PS 0 (0–2), median follow-up 32 months. Pts (n) in arm A: 398 (1st line), 248 (2nd line), 141 (3rd line); arm B: 398 (1st line), 210 (2nd line). Median OS in arm A was 16.3 months (95%CI 14.3–18.2) and in arm B 17.7 months (95%CI 15.2–19.4), logrank p=0.2. Overall gr 3–4 toxicity over all lines did not differ significantly except for gr 3 hand-foot syndrome (HFS) (13% in A and 6% in B, p=0.0009). Death was probably related to treatment in 11 pts (neutropenic sepsis and/or diarrhea, 8 arm A, 3 arm B) and involved protocol violations in some. In 1st line significant differences in gr 3–4 toxicity in arm A vs arm B were diarrhea (10% vs 25%, p<0.0001), febrile neutropenia (1% vs 6%, p=0.0001) and HFS (12% vs 5%, p=0.0004). All-cause 60-day mortality was 3.0% (n=12) in arm A and 4.5% (n=18) in arm B. Updated results will be presented at the meeting, including data on QoL (EORTC QLQ C30). Conclusions: Combination therapy does not significantly improve OS compared with sequential therapy. Both treatment strategies are valid options for pts with ACC.

No significant financial relationships to disclose.
Final results of OPTIMOX2, a large randomized phase II study of maintenance therapy or chemotherapy-free intervals (CFI) after FOLFOX in patients with metastatic colorectal cancer (MRC): A GERCOR study
Authors: Maindrault-Goebel F. , Lledo G. , Chibaudel B. , Mineur L. , Andre T. , Bennamoun M. , Mabro M. , Artru P. , Louvet C. , de Gramont A.
Published: March 2020

4013

Background: The OPTIMOX2 study was designed to evaluate a complete stop of chemotherapy after 6 bimonthly cycles of FOLFOX. Methods: OPTIMOX2 is a large phase II study performed before the availability of bevacizumab. Patients (pts) were randomized between an OPTIMOX1 arm: 6 cycles of FOLFOX7 followed by LV5FU2 until progression then reintroduction of FOLFOX7, and the OPTIMOX2 arm: 6 cycles of FOLFOX7, complete stop of chemotherapy and reintroduction of FOLFOX7 before the tumor progression reached the baseline measures. Results: 202 pts were included between Feb 2004 and Apr 2006. Response rates were (OPTIMOX1/OPTIMOX2): CR+PR 63%/61%. Median PFS were OPTIMOX1/OPTIMOX2) 8.3/6.7 months (p=.04). Median duration of disease control (DDC), addition of PFS of first FOLFOX7 administration plus PFS of FOLFOX reintroduction if no progression at first evaluation, was 10.8m in the OPTIMOX1 arm and 9.0m in the OPTIMOX2 arm, p=.32. Median duration of chemotherapy-free interval (CFI) in the OPTIMOX2 arm was 4.6 months. Patients with poor prognostic factors had a shorter CFI, p=.01. Median overall survival was 24.6m in the OPTIMOX1 arm and 18.9m in the OPTIMOX2 arm, p=.05. Median survivals (OPTIMOX1/OPTIMOX2) were not reached/28.7m in patients with good prognostic and 20.9/14.5m in patients with poor prognostic. Conclusions: Maintenance LV5FU therapy prolongs PFS and OS, especially in patients with poor prognosis. CFI can be recommended only in selected patients without adverse prognostic factors. Our next study, DREAM, is evaluating maintenance therapy with targeted agents alone.

No significant financial relationships to disclose.