bluuebunny/crossref_metadata_2025 huggingface dataset:
Phase I study of docetaxel injection concentrate for nano-dispersion (DICN), a novel polysorbate 80-free formulation of docetaxel.
Authors: Jain Minish Mahendra , Deshmukh Chetan Dilip , Bondarde Shailesh Arjun , Bhatt Niraj , Divekar Ganesh
Published: March 2020

2592

Background: A polysorbate 80-free formulation of docetaxel may preclude the need for dexamethasone pre-medication and may also reduce toxic effects associated with polysorbate 80. DICN is a novel polysorbate 80-free formulation of docetaxel stabilized with lipid and polymer using NanotectonTM technology. We studied safety, tolerability, and the pharmacokinetics (PK) of DICN in patients with advanced solid malignancies. Methods: Entry criteria included: age 18-65 years, histologically/cytologically confirmed advanced malignancy, performance status ≤ ECOG 2, estimated survival ≥ 12 weeks, and adequate organ function. A standard phase I 3+3 dose escalation schema was employed with an increase of 12.5 to 50% over previous DICN dose level as per safety profile. The infusion was 60 min for 1 cycle and major objectives were to determine maximum tolerated dose (MTD), and PK and safety profiles. Premedication to prevent hypersensitivity was not administered to patients receiving DICN. Three patients were treated with docetaxel 75 mg/m2 to gather PK data. Plasma was analyzed for docetaxel level using a validated assay. Results: Twenty-seven patients treated with DICN had a mean age of 48.8 yrs (range 29-65); 21 were females; and entered with metastatic breast cancer (MBC; n=14), non-small cell lung carcinoma (NSCLC; n=6), ovarian (n=2), and other (n=5). Doses (mg/m2) studied were 60 (n=7), 75 (n=5), 100 (n=3), 125 (n=3), 150 (n=6), and 170 (n=3). Despite lack of dexamethasone premedication, no patient receiving DICN reported a hypersensitivity reaction. Two DLTs (febrile neutropenia) were reported at DICN 170 mg/m2. DICN PK (AUC0-24, AUC0-∞, and Cmax) increased in a dose proportionate manner from 60 to 170 mg/m2. Compared with docetaxel 75 mg/m2, Cmax and AUC0-24 of DICN 75 mg/m2 was 1.4 and 1.2 times higher, respectively, and 1.9 and 1.8 times higher, respectively for DICN 150 mg/m2. The median Tmax of DICN 75 mg/m2 and docetaxel 75 mg/m2 were 1.00 and 0.517 hours, respectively. Conclusions: In this study,DICN demonstrated acceptable tolerability and a favorable PK profile. A 150 mg/m2 is the recommended phase II dose for DICN.
Modeling the combined efficacy of rilotumumab (R; AMG 102) plus epirubicin/cisplatin/capecitabine (ECX) for the treatment of locally advanced or metastatic gastric or esophagogastric junction (G/EGJ) cancer.
Authors: Doshi Sameer , Kathman Steven , Tang Rui , Gisleskog Per Olsson , Loh Elwyn , Dubey Sarita , Jiang Yizhou , Oliner Kelly S. , Donehower Ross C. , Iveson Timothy , Zhu Min
Published: March 2020

2594

Background: R is an investigational, fully human monoclonal antibody to hepatocyte growth factor/scatter factor (HGF/SF) that inhibits signaling though the MET receptor. In a double-blind, placebo-controlled, phase 2 trial of 121 patients with G/EGJ cancer, R (7.5 or 15 mg/kg) + ECX showed trends for improved progression-free survival (PFS) and overall survival compared to ECX alone. The combined effects of R and ECX on tumor reduction and PFS were modeled using the phase 2 data. Methods: A population pharmacokinetic (PK) model was used to estimate R PK parameters and individual R concentrations (C) over time. A tumor dynamic model was developed to characterize the combined effects of R with ECX on tumor growth and cell death and to evaluate the impact of baseline patient characteristics and lab values on model parameters. A discrete time-survival model was developed with PFS and C data to evaluate the effect of R, ECX, and the interaction between R and ECX on PFS within a given time interval. Results: R exhibited linear PKs with an estimated mean clearance of 0.216 L/d/70 kg. The tumor dynamic model suggested that R and ECX worked jointly to reduce tumor size from baseline via inhibition of the tumor growth rate constant (Kgrowth) and stimulation of the death rate of tumor cells (Kdeath). Assuming the maximal inhibition of Kgrowth is 100%, the estimated mean C that provided 50% maximal Kgrowth inhibition (EC50) was 6.71 µg/mL. The mean (SD) estimated effect of 7.5 and 15 mg/kg R on Kgrowth was 90.1% (3.8%) and 95.5% (1.9%) inhibition, respectively. None of the tested baseline factors appeared to significantly affect tumor reduction by R + ECX. In the discrete time-survival model, the R and ECX combination significantly improved PFS, and the model suggests that the magnitude of the effect of one treatment was dependent on the other. Conclusions: R and ECX appeared to work in combination to decrease tumor size and to improve PFS.
The role of phase I clinical trials in advanced malignant melanoma: Retrospective analysis of CTEP-sponsored trials 1995-2011.
Authors: Luke Jason John , Rubinstein Larry , Smith Gary L , Ivy S. Percy , Harris Pamela Jo
Published: March 2020

2606

Background: Standard chemotherapy for melanoma is DTIC (RR ~10%). Many physicians do not refer to phase I due to perceived limited clinical benefit (CB=CR+PR+SD) and increased toxicity. To understand the actual experience of melanoma patients (pts) in phase I trials, we analyzed the outcomes of melanoma pts treated on CTEP phase 1 trials (1995-2011) and compared them to DTIC. Methods: We queried the CTMS of CTEP for phase I trials in which advanced melanoma pts were treated. Trials were separated into targeted (T), chemo (C) and immunotherapy (I). Pt characteristics, response and toxicity data were collected. Chemotherapy included chemo with targeted or immunotherapy. Toxicity was drug related if attributed possibly, probably or definitely to drug. Fisher’s Exact Test (2-sided p) was used to compare groups. DTIC data was pooled from 6 modern phase III clinical trials (1999-2011). Results: 937 pts (M595:F342) participated in 148 trials (T: 68, C: 53, I: 27). Characteristics included (median) Age: 51.5 yrs; ECOG status: 0; Prior therapies: 2 (majority receiving prior DTIC); LDH: 206 and albumin: 4.1. Response and toxicity data are shown in the Table. Targeted therapy was associated with lower RR (p=.01), immuno with lower CB rate (p<.001) and chemo with higher incidence of G4 toxicity (p<.001) relative to the other groups. Comparing phase 1 to DTIC, RR and CB were not clinically different (phase I: 6.3% and 26.8% vs. DTIC: 8.8% and 27.9%) but G3-4 toxicity was significantly higher (54% vs. 28%) in phase I (p<.0001). Conclusions: Melanoma pts in prior CTEP phase I trials, a majority DTIC pre-treated, had similar therapeutic benefit but more toxicity compared to DTIC naïve pts in modern clinical trials. [Table: see text]
Phase I trial of an oral TORC1/TORC2 inhibitor (CC-223) in advanced solid and hematologic cancers.
Authors: Shih Kent C. , Bendell Johanna C. , Reinert Anne , Jones Suzanne , Kelley Robin Katie , Infante Jeffrey R. , Korn Michael , Hege Kristen , Chopra Rajesh , Xu Shuichan , Wong Lilly , Liu Yong , Mortensen Deborah , Munster Pamela N.
Published: March 2020

3006^

Background: The mammalian target of rapamycin (mTOR) signaling pathway is frequently activated in cancer. The mTOR kinase exists in two multi-protein complexes, TORC1 and TORC2, which drive key cellular metabolic and proliferative functions.  TORC1-selective inhibitors can induce feedback upregulation of TORC2 and treatment resistance.  CC-223 is an oral, potent, selective, ATP-competitive inhibitor of both TORC1 and TORC2, selected to address this escape mechanism. Methods: Subjects with advanced solid and hematologic cancers were enrolled using an accelerated (1+5) dose escalation design.  CC-223 was administered orally once daily (QD) in 28 day cycles until disease progression.  Safety, pharmacokinetic, pharmacodynamic and clinical endpoints were evaluated. Results:   28 subjects were treated across 5 dose levels:  7.5 (n=1), 15 (n=2), 30 (n=9), 45 (n=7) and 60 mg (n=8).  The most common (> 20%) related adverse events (all grades) were fatigue (64%), nausea (50%), hyperglycemia and diarrhea (43% each), mucositis (39%), anorexia and vomiting (32% each) and rash (29%).  Dose-limiting toxicity (all grade 3) occurred in 4 subjects:  hyperglycemia (30 mg), rash (45 mg), fatigue (60mg), and mucositis (60 mg).  The maximum tolerated dose (MTD) was 45 mg QD. Dose proportional exposure was observed with a terminal half life of 4 to 8 hrs (mean steady state Cmax 485 ng/mL, AUC0-24 2371 ngxhr/mL at 45 mg).  Inhibition of TORC1 (pS6, p4EBP1) and TORC2 (pAKT) biomarkers in blood cells was characterized to be exposure-dependent and described by an Emax model.   Near maximal inhibition of both TORC1 and TORC2 biomarkers was achieved at the peak concentrations of 30 or 45mg QD.  Target inhibition was predicted to last 8 to 20 hours at 45mg QD. Tumor responses included: 1 partial response lasting 9 months (ER+ breast) and 7 subjects with stable disease (SD) lasting 8+ weeks (range 8 to 23.3). Conclusions:   CC-223 was well tolerated with toxicities comparable to other drugs in this class.  Evidence of TORC1/TORC2 pathway inhibition was observed as well as preliminary signals of anti-tumor activity, including one durable PR.  Expansion cohorts in selected hematologic and solid tumors will evaluate CC-223 at the MTD of 45 mg QD.
First-in-human study of AMG 900, an oral pan-Aurora kinase inhibitor, in adult patients (pts) with advanced solid tumors.
Authors: Carducci Michael Anthony , Shaheen Montaser F. , Paller Channing Judith , Bauman Julie E. , Azad Nilofer Saba , Shubhakar Poornima , Tang Rui , Stroh Mark , Friberg Gregory R. , Verschraegen Claire F.
Published: March 2020

3009

Background: Aurora kinases A, B, and, C play essential roles in regulating cell division. Overexpression of aurora A and B in human tumors is associated with high proliferation rates and poor prognosis. AMG 900 is an investigational, orally administered, highly selective inhibitor of aurora A, B, and C that demonstrated activity in drug-resistant cell lines and human tumor xenografts. This study evaluated the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of AMG 900. Methods: Key eligibility criteria: ≥ 18 years old, advanced solid tumors, measurable disease, ECOG ≤ 2, and adequate organ function. AMG 900 was administered orally daily for 4 consecutive days (D) every 2 weeks (Q2W). In the dose-escalation phase, the starting dose was 1 mg and was escalated by 100% in subsequent cohorts (1 pt/cohort) until dose limiting toxicity (DLT) or grade 2 (G2) AMG 900-related toxicity occurred in the first 28 D. Dose escalation continued in a standard 3+3 design at ≤ 25% if DLT occurred or ≤ 50% if G2 related toxicity occurred. The maximum tolerated dose (MTD) was determined without prophylactic G-CSF support. Results: As of OCT 2011, 19 pts (1 pt at 1, 2, 4, and 8 mg; 3 pts at 16 mg; and 6 pts at 24 and 30 mg) had received ≥ 1 dose of AMG 900. Demographics were 58% women, median age 60 (32-77) years, and ECOG 0/1, 63%/37%. There were 4 DLTs: G4 neutropenia > 7 days at 24 mg (n=1) and 30 mg (n=1); G4 neutropenia > 7 days + G4 thrombocytopenia at 30 mg (n=1); and febrile neutropenia (FN) at 30 mg (n=1). MTD without G-CSF support was 24 mg. 89% of pts had treatment-related adverse events (AEs). G≥3 treatment-related AEs were neutropenia, 8 (42%); leukopenia, 4 (21%); anemia, 2 (11%); thrombocytopenia, 1 (5%); and FN, 1 (5%). Preliminary PK showed no obvious departures from dose-proportionality with a half-life of ~16 h. Tumor-response data were available for 17 pts: stable disease, 13 pts (range 0.4 to 43.7 wks); progressive disease, 4 pts. One pt (16 mg cohort) with recurrent ovarian cancer had 16% tumor shrinkage and 45% decrease in CA-125 (SD > 6 months). Conclusions: AMG 900 administered at 24 mg daily for 4D Q2W is the recommended dose for phase 2 trials. Dose escalation is now ongoing to determine the MTD with prophylactic G-CSF.
A first-in-human phase I study of MORAb-004 (M4), a humanized monoclonal antibody recognizing endosialin (TEM-1), in patients with solid tumors.
Authors: Diaz Luis A. , Azad Nilofer Saba , Gounder Mrinal M. , Coughlin Christina Marie , Fishel Jean , O'Shannessy Daniel , Grasso Luigi , Wustner Jason , Aluri Jagadeesh , Parno Jeff , Carvajal Richard D.
Published: March 2020

3016

Background: Endosialin (TEM-1) is a membrane glycoprotein on the cell surface of activated mesenchymal cells (e.g. pericytes, fibroblasts and mesenchymal tumor cells) and on a subset of human cancers. It is involved in the development of tumor vasculature, stromal/tumor organization and PDGFRb signaling. M4 is a humanized IgG monoclonal antibody which targets TEM-1. Preclinical studies suggest that M4 may have single agent activity via inhibition of the tumor microenvironment and by direct effects on tumors expressing this target. Methods: A phase I dose escalation study in patients (pts) with advanced solid tumors was conducted to evaluate the safety, pharmacokinetic profile and preliminary efficacy of M4 administered intravenously on a weekly schedule; final results are presented. Results: 36 pts refractory to therapy were treated at 10 dose levels (0.0625 to 16 mg/kg administered i.v. on a weekly schedule). Drug-related adverse events (AE) observed were primarily infusion toxicity (grade 1 and 2 fever, chills, headache, myalgia). The MTD was determined to be 12 mg/kg. DLT of grade 3 vomiting was observed at 16 mg/kg. Preliminary pharmacokinetic (PK) analyses demonstrate M4 accumulation beginning at 4 mg/kg, and that elimination mechanisms are saturable beginning at 0.25 mg/kg. Exposure (AUC) increases in a greater than dose-proportional manner, with the apparent t1/2 increasing proportionally with dose. Tumor shrinkage (Minor/mixed tumor responses, mR) were seen in four pts (soft tissue sarcoma (2), hepatocellular carcinoma, pancreatic neuroendocrine tumor). Each mR was associated with prolonged disease stabilization in these pts (6-14 months). A cohort (n=4) of pts with refractory colorectal carcinoma demonstrated disease stabilization (15-24 weeks). Analysis of archival tumor revealed TEM-1 stromal staining in all cases with tumor cell expression noted on a subset of tumors of mesenchymal origin. Conclusions: In this phase I study, M4 was tolerated up to 12 mg/kg (MTD) and early signs of potential activity were observed. Expanded cohorts of 1-12 mg/kg are ongoing to further define an optimal dose.
Clinical pharmacokinetics of the Smac-mimetic birinapant (TL32711) as a single agent and in combination with multiple chemotherapy regimens.
Authors: Fetterly Gerald J. , Liu Biao , Senzer Neil N. , Amaravadi Ravi K. , Schilder Russell J. , Martin Lainie P. , LoRusso Patricia , Papadopoulos Kyriakos P. , Adjei Alex A. , Zagst Patricia D. , McKinlay Mark A , Weng David Edward , Graham Martin
Published: March 2020

3029

Background: Birinapant is a novel small molecule Smac-mimetic that targets members of the inhibitor of apoptosis proteins (cIAP1, cIAP2 and XIAP) involved in the blockade of apoptosis. A population PK model was developed to characterize the interpatient variability in birinapant PK and to evaluate the effect of multiple combination regimens on birinapant disposition and safety. Methods: Birinapant was administered alone or in combination to 114 patients (55M/59F; 89% Caucasian) with advanced malignancies. Birinapant was administrated by a 30 min IV infusion QW alone (30 pats), or approx. 30 min. after chemotherapy with irinotecan (19 pats), docetaxel (20 pats), gemcitabine (17 pats), liposomal doxorubicin (13 pats), or paclitaxel/carboplatin (15 pats). Birinapant dose levels ranged from 0.18 to 35 mg/m2. Population PK modeling was performed to investigate the effect of the following patient covariates: [BW (38.5-127.5 kg), age (27.5-86.0 yrs), CrCL (36.4-219.2 ml/min), ALT (6-121 IU/L), and TBIL (0.1-1.7 mg/dL)]. Results: A 3-compartment PK model described the time course of birinapant disposition with predicted values for T1/2, CL, and Vd of 40 h, 21 L/h and 10.2 L, respectively. Birinapant displayed linear PK across the dose range with no significant accumulation in plasma following weekly dosing. Goodness of fit plots supported the model fit, with residual variability of 23%. The PK of birinapant remained unchanged when combined with irinotecan, docetaxel, gemcitabine and liposomal doxorubicin. Concomitant administration with paclitaxel/carboplatin resulted in a 2-fold increase in birinapant AUC possibly due to reduced OATP1B3 mediated tissue uptake. Conclusions: These data show that birinapant possesses an excellent PK profile with dose proportional kinetics, a long terminal half-life for target coverage, low/moderate interpatient variability in CL and no significant accumulation following weekly dosing. Importantly, the PK of birinapant remained unchanged when combined with multiple chemotherapy regimens and the increased exposure with paclitaxel/carboplatin was not associated with any change in birinapant tolerability.
Proof of mechanism (POM) in the first-in-human trial of two novel indenoisoquinoline, non-camptothecin topoisomerase I (TOP1) inhibitors.
Authors: Doroshow James H. , Ji Jiuping Jay , Chen Alice , Allen Deborah , Zhang Yiping , Lawrence Scott M , Pfister Thomas D. , Wang Lihua , Redon Christophe E. , Bonner William , Speranza Giovanna , Weil Marcie K. , Eiseman Julie , Holleran Julianne L. , Kinders Robert J. , Beumer Jan Hendrik , Parchment Ralph E. , Pommier Yves , Tomaszewski Joseph E. , Kummar Shivaani
Published: March 2020

3031

Background: Indenoisoquinolines LMP 400 and LMP 776 form stable DNA-top1 cleavage complexes, have a preference for unique DNA cleavage sites, and are not substrates for ABC transporters compared to camptothecins. We conducted a randomized phase I trial of LMP 400 and LMP 776 in patients (pts) with refractory tumors to establish safety and MTD of LMP 400 and LMP 776 administered IV daily x 5 d, q 28d; determine PK; evaluate TOP1 and γH2AX levels in tumor biopsies (bx); and compare pharmacodynamic responses of LMP400 and LMP776. Methods: Pts had refractory malignancies; ≥ 18 yrs old; KPS > 70%; adequate organ function. DLT: drug-related gr ≥ 3 non-hem or gr 4 hem toxicities during C1. Pts assigned to receive either LMP 400 or LMP 776. Dose level (DL) in mg/m2/day for LMP 776: 1, 2, 3, 4.5 mg; LMP 400: 2.5, 5, 10, 20, 40, 80. Accelerated titration design with one pt per dose level (DL), 100% dose escalation until one DLT or 2 gr 2 toxicities, then 3+3 design. Tumor bx and circulating tumor cells (CTCs) were obtained at baseline and C1D3. Results: Twenty pts accrued to date [LMP 400 (11 pts); LMP 776 (9 pts)]; M/F 7/13; median age 59 (range 32-71 yrs); diagnosis (# of pts): colorectal (10), vaginal adenocarcinoma (1), head and neck (2), bladder (1), melanoma (1), pancreas (1), thyroid (1), small cell lung (1), sarcoma (1), lymphoma (1). DLTs: LMP 400- gr 4 myelosuppression, gr 3 fatigue at DL 6; DL 5 expanded to establish MTD; LMP 776 (DL2)- gr 4 hypercalcemia, no other DLTs, dose escalation continuing. One pt with irinotecan-refractory colon cancer had shrinkage of lung nodules post one cycle of LMP 400. Relative to baseline, 5 of 6 tumor bx demonstrated 20-50% reduction in TOP1 levels (LMP 776); an increase in γH2AX foci in tumor was observed in 2/6 LMP 776 and 1/1 LMP 400 pts. An increase in γH2AX was also observed in hair bulbs (3/3 pts) and CTCs (9/20 pts). PK for LMP 400 and LMP 776: mean T1/2 48 and 36 h; Cl 1.5 and 2.0 L/h/m2; Vc 30 and 31 L/m2, respectively. Conclusions: POM, as assessed by reduction in TOP 1 levels and increase in γH2AX in tumor and CTCs, and preliminary evidence of activity, has been demonstrated in this first-in-human trial of indenoisoquinoline-class of TOP1 inhibitors. Accrual is ongoing.
Phase I study to determine the bioavailability and tolerability of a tablet formulation of the PARP inhibitor olaparib in patients with advanced solid tumors: Dose-escalation phase.
Authors: Gupta Avinash , Moreno Victor , Dean Emma Jane , Drew Yvette , Nicum Shibani , Ranson Malcolm , Plummer Ruth , Swaisland Helen , Burke Wendy , McCormack Peter , Tchakov Ilian , Middleton Mark R. , Kaye Stanley B. , Molife L Rhoda
Published: March 2020

3051

Background: We previously reported the comparative bioavailability of the olaparib tablet (TAB) up to 200 mg BID, with the initial capsule formulation; gmean AUC0–T following 200 mg BID TAB was ~20% lower than 400 mg BID capsule (CAP; Molife et al ASCO 2010). Olaparib 200 mg BID TAB had an acceptable tolerability profile suggesting further dose escalation might be justified. Methods: Study NCT00777582 was amended to include a dose-escalation phase, to define the maximum tolerated dose (MTD) and safety profile of the TAB, and 2 expansion phases to compare safety and efficacy of TAB doses vs 400 mg BID CAP. Expansion phase data are reported separately. Here, we report preliminary data from the dose-escalation phase where patients (pts) with advanced solid tumors, ECOG PS 0–2 and adequate organ function were assigned to treatment with increasing olaparib BID TAB doses in 28-day continuous dosing cycles. Pharmacokinetic (PK) sampling was performed on days 1, 8, 15, 29, 57. Results: 30 pts (M:F, 3:27; median age 54 yrs [range 19–70]) were enrolled in the dose-escalation phase and received treatment at 5 dose levels: 250, 300, 350, 400 and 450 mg (each dose level, n=6). Overall, the most common AEs were nausea (80%), fatigue (73%) and diarrhea (36%). The majority of AEs were mild to moderate (CTC grade [G] 1/2). Hematologic toxicity in terms of, mostly mild, anemia, neutropenia and thrombocytopenia, appeared to increase at doses of 300 mg BID or higher. Two pts had dose-limiting toxicities at 450 mg (G3 thrombocytopenia and G3 anemia); the TAB MTD was 400 mg BID. Exposure increased proportionally with increasing dose: mean exposure after 400 mg BID was double that following the previously reported 200 mg BID dose. Following 300 and 400 mg doses, gmean Cmax ss, AUC0–T and Cmin ss matched or exceeded the 400 mg BID CAP dose. Conclusions: The MTD of olaparib TAB was 400 mg BID. Based on PK analysis, the 300 and 400 mg BID doses were selected for evaluation in the MTD expansion phase to further define safety and preliminary efficacy.
Phase I study of sequential sapacitabine and seliciclib in patients with advanced solid tumors.
Authors: Shapiro Geoffrey , Kwak Eunice Lee , Cleary James M. , Tolaney Sara , Gandhi Leena , Clark Jeffrey W. , Wolanski Andrew , Frame Sheelagh , Rodig Scott J. , Chiao Judy H.
Published: March 2020

3053

Background: Sapacitabine is an orally administered nucleoside analogue; the active metabolite CNDAC generates ss DNA breaks that are converted to ds DNA breaks (DSB) during subsequent replication, resulting in cell death if unrepaired. CNDAC-induced DSB repair is dependent on homologous recombination (HR). Seliciclib is a potent orally bioavailable inhibitor of CDK2, 7 and 9, and sensitizes cells to CNDAC by decreasing DSB repair via compromise of HR protein activation and transcriptional inhibition of HR components. This phase I study evaluates sequential sapacitabine and seliciclib. Methods: Dose escalation was conducted in patients with incurable solid tumors and adequate organ function with sapacitabine b.i.d. x 7 consecutive days (d1-7), seliciclib b.i.d. x 3 consecutive days (d8-10) followed by 11 days of rest. At least 3 patients were evaluated per dose level. MTD was the highest dose level at which less than one-third of at least 6 patients experienced cycle 1 DLT. Skin biopsies were obtained to assess DNA damage following sapacitabine (d8 vs pre-treatment) and further augmentation of DNA damage after seliciclib (d11 vs d8). Results: 27 patients were treated. The MTD and RP2D is sapacitabine 50 mg b.i.d./seliciclib 1200 mg b.i.d. DLTs were reversible transaminase elevations and neutropenia. The most frequent adverse events (all cycles, regardless of causality) included anorexia, fatigue, abdominal pain, dizziness, nausea, anemia, neutropenia, creatinine elevation, hyperglycemia, hyperbilirubinemia, hypophosphatemia, hypokalemia and hypomagnesemia, the majority mild to moderate in intensity. Skin biopsies showed a 2.3-fold increase in H2AX staining post-sapacitabine (n=16; p=0.007) and a further 0.58-fold increase post-seliciclib (n=12; p=0.069). Two confirmed PRs occurred in patients with pancreatic and breast cancer, both BRCA mutation carriers. SD as best response >/= 12 weeks was observed in 6 additional patients, including one BRCA mutation carrier with ovarian cancer (ongoing at 24 weeks). Conclusions: Sequential sapacitabine and seliciclib is safe with preliminary antitumor activity. BRCA mutation carrier status may be a potential biomarker for response across multiple tumor types.
A phase I study of chronically dosed, single-agent veliparib (ABT-888) in patients (pts) with either BRCA 1/2-mutated cancer (BRCA+), platinum-refractory ovarian cancer, or basal-like breast cancer (BRCA-wt).
Authors: Huggins-Puhalla Shannon Leigh , Beumer Jan Hendrik , Appleman Leonard Joseph , Tawbi Hussein Abdul-Hassan , Stoller Ronald G. , Lin Yan , Kiesel Brian , Tan Antoinette R. , Gibbon Darlene , Jiang Yixing , Garcia Agustin , Chew Helen K. , Morgan Robert , Shepherd Stacie Peacock , Giranda Vincent L. , Chen Alice P. , Belani Chandra Prakash , Chu Edward
Published: March 2020

3054

Background: Veliparib (ABT-888) is an oral, potent inhibitor of PARP 1/2. Preclinically, PARP inhibitors have activity in tumors with defective homologous recombination (HR), particularly those that are BRCA+. Reduced levels of BRCA expression have been observed in ovarian cancer and basal-like breast cancer, which share genotypic and phenotypic similarities with BRCA+ cancers. We postulated that these tumors types may be similarly sensitive to single-agent PARP inhibition. This study sought to establish the maximum tolerated dose (MTD), dose limiting toxicities (DLT), pharmacokinetic and pharmocodynamic properties, and preliminary efficacy of chronically-dosed veliparib. Methods: A 3+3 dose escalation phase I trial was performed. Nine dose levels (DL) were planned, and dose escalation started at 50 mg BID to a maximum of 500 mg BID. Veliparib was administered orally continuously on a 28 day cycle. Results: 63 pts have been enrolled to date. Thirty-eight were BRCA+ (20 ovary, 12 breast, 2 pancreas, and one each - prostate, peritoneal, fallopian tube, endometrial); 25 BRCA-wt. (21 breast, 4 ovarian). DLTs occurred at the following dose levels: BRCA+: gr. 2 thrombocytopenia at 50 mg BID; BRCA+: gr.3 Nausea/vomiting at 400 mg BID; BRCA-wt: gr 2 seizure at 400 mg BID. The MTD has not been determined and 500 mg BID is presently enrolling. Notable toxicities have included low-grade fatigue and nausea. PK was linear and non-saturable with t ½ of 5 h. The number of cycles administered ranged from 1- 15, median 2. In BRCA+ pts, there were 2 partial responses (breast, ovarian) and 10 pts had evidence of prolonged SD ≥ 4 months. In BRCA-wt pts, there was 1 PR (breast) and 7 pts with SD≥ 4 months. Correlative studies, including assessment of PAR inhibition and BRCA methylation status, are ongoing. Conclusions: Veliparib is tolerable on a continuous oral dosing schedule with evidence of anti-tumor activity seen in BRCA+ and BRCA-wt tumors. A mandatory biopsy expansion cohort is planned at the recommended phase II dose, which will allow further insights regarding efficacy and mechanisms of resistance to PARP inhibition.
Testing targeted demethylation to overcome resistance to epidermal growth factor receptor (EGFR) blocking agents in wild-type (wt) KRAS metastatic colorectal cancer patients (mCRC).
Authors: Garrido-Laguna Ignacio , McGregor Kimberly , Wade Mark , Weis John R. , Burr Laura , Soldi Raffaella , Davidson Cynthia , Jakubowski Loni , Morrell Glen , Olpin Jeffrey , Jones David , Sharma Sunil
Published: March 2020

3057

Background: Panitumumab, a monoclonal antibody against EGFR, led to improved progression-free survival (PFS) in patients with (wt)KRAS mCRC. However, the benefit of panitumumab is limited to a not yet identified small subset of (wt)KRAS patients. The CpG island methylator phenotype (CIMP-high) is present in 15-20% of CRC patients. Epigenetic silencing through methylation of PTEN and/or genes in the EGFR pathway might play a role in resistance to therapy. We assessed whether decitabine (a hypomethylating agent) reverted resistance to anti-EGFR therapies. Methods: Patients (n=19) with (wt)KRAS mCRC previously treated with anti-EGFR therapies were enrolled. Patients were treated with decitabine 45mg/kg IV on day (d)1 and d15 and panitumumab 6mg/kg IV on d8 and d22 q28days. Peripheral blood, skin biopsies and buccal smear samples were collected on d1, d8, d15 and d22 to assess methylation changes in PTEN, RASSF1A and SOCS-1 in response to therapy. Tumors were analyzed for PIK3CA mutations using PCR-based DNA sequencing of exon 9 and 20 by PCR as well as for PTEN by immunohistochemistry. Results: Median age was 53 (range 31-72). Eleven (58%) patients were female; 15 (79%) had ECOG PS 1; 3 (16%) had ECOG PS 2; and 1 had ECOG PS 0. Median number of previous therapies was 4. The most common toxicities were rash (68%), hypomagnesemia (26%) and neutropenia (10%) (all grade 1-2). The most common grade 3-4 toxicities were neutropenic fever (5%) and hypomagnesemia (5%). Of 19 (wt)KRAS mCRC patients previously treated with anti-EGFR therapies, 2 (11%) had a partial response (PR) (-50% and -30%, respectively) and 3 (16%) had stable disease (SD) >4 months (7.8, 5.9 and 4.2 months). Both responders were (wt)PIK3CA and (wt)PTEN. Clinical benefit rate (PR+SD) was 27%. Median PFS was 60 days (95% CI 45.4-74.5), similar to median PFS after last anti-EGFR therapy, 61d (95% CI 50.6-71.3). Conclusions: Panitumumab + decitabine is an active combination in a subset of patients with mCRC previously treated with anti-EGFR therapies (2 PRs in this population). Efficacy assessment in an anti-EGFR therapy naïve population is warranted. Methylation studies are ongoing.
Feasibility to obtain a chemogram in circulating tumorigenic cells to guide further treatments in refractory solid tumors.
Authors: Cubillo Antonio , Calles Antonio , López-Casas Pedro P. , Ricigliano Mark , Calvo Emiliano , Duran Ignacio , López-Ríos Fernando , Rodriguez Margarita , Hidalgo Manuel
Published: March 2020

3066

Background: Circulating tumorigenic cells (CTCs) may be responsible for tumor progression, represent a new source of information of tumor biology, avoiding unnecessary biopsies. Gene-expression analysis (GEA) of CTCs could guide anti-cancer therapies in patients with refractory solid tumors. Methods: Pts >18y ECOG PS 0-2 with advanced refractory solid tumors were recruited. Twelve ml blood samples were collected from each pt and processed for isolation of CTCs using a novel cell adhesion assay (Vita-Cap, Vitatex Inc., Stony Brook, NY) following the manufacturer protocol. Total RNA was extracted with RNeasy Mini Kit (Qiagen Inc.) and GEA was performed with Affymetrix GeneChip Human Genome U133 Plus 2.0 array. The CEL file obtained for each pt sample was used in a gene-set expression analysis (GSEA) to determine the enrichment profile of the pt sample to a pre-determined set of 12 PGx-modeled drugs created from the GI50 data of the NCI-60 cell lines. The drug with the highest Normalized Enrichment Score (NES) obtained from the GSEA was selected as the most sensitive. The NES for each drug was standardized and rank-ordered according to Sensitive/Intermediate/Resistant categories to generate a nominal chemo-sensitivity profile for the pt. This generates a comprehensible report called chemogram (ChG). We assessed preliminary efficacy in pts treated based on ChG. Results: ChG was obtained in 74/75 pts (57% male/43% female, median age 57y [20-81]) Tumor’s type was GI 67% (CRC n=18; pancreatic n=18; gastric n=6; cholangiocarcinoma n=7), NSCLC 14%, breast 8%, sarcoma 8%, others 3%. Median of 2 previous lines of therapy [range 1-12]. ECOG PS was 1 in 56%. Average RNA/pt 2.4 ng/µl (95% CI 1.5-3.4) Median time to obtain the report from blood extraction was 4 wks [range 2-7] Pts treated after the ChG were 37 (49%), of them 25 (69%) based on ChG recommended drug. In patients treated with ChG sensitive drugs, PFSratio ≥ 1.3 (PFS on therapy after ChG/PFS on prior therapy) was 24%, and 3 partial responses (12%) were observed. Conclusions: It is feasible to generate a sensitivity drug profiling on CTCs which shows preliminary activity and merits further studies.
Phase I dose-finding study of golvatinib (E7050), a c-Met and Eph receptor targeted multi-kinase inhibitor, administered orally BID to patients with advanced solid tumors.
Authors: Doi Toshihiko , Yoshino Takayuki , Fuse Nozomu , Bando Hideaki , Tahara Makoto , Ohki Masahiro , Fujino Katsuki , Nishioka Yuki , Matsuura Kentaro , Sawada Takashi , Ohtsu Atsushi
Published: March 2020

3079

Background: Golvatinib is a highly potent, small molecule ATP-competitive inhibitor of the c-Met receptor tyrosine kinase and multiple members of the Eph receptor family as well as c-Kit and Ron, based on isolated kinase assays. Golvatinib showed antiproliferative activity in human cancer xenograft models, warranting further investigation in the clinical setting. Methods: Japanese patients (pts) with advanced solid tumors that had progressed after approved therapy received oral golvatinib at escalating doses of 50 to 100, 200 and 300 mg administered twice daily (BID) in conventional 3 pt cohorts. The primary objective was to determine the MTD of golvatinib when administered continually BID. The secondary objectives were to evaluate the safety, PK, PD biomarkers, and efficacy. Results: 16pts were enrolled (8 M, 8 F; med age 59 years; ECOG 0-1). Tumor types were colorectal (5), gastric (4) and others (7). One DLT (Gr 3 ALT increase) and 1 equivalent DLT (Gr 2 vomiting, nausea and anorexia) appeared in 2 pts in the 300 mg BID cohort and the dose escalation was terminated. The MTD was determined to be 200 mg BID. Frequently observed adverse drug reactions were proteinuria [50.0% (8/16)], ALT increased [43.8% (7/16)], AST increased, nausea, vomiting [37.5% (6/16)], and blood alkaline phosphatase increased, decreased appetite, diarrhea, leukopenia [31.3% (5/16)], which were all mild to moderate in severity with ≤ Gr 2. No related severe adverse event was observed. Responses included 4 stable diseases (84-113 days) in 3 pts with gastric cancer and 1 patient with NSCLC, 11 progressive diseases, and 1 non evaluable. The golvatinib plasma concentration after first-dose reached Cmax at a median time of 2 to 4 hours, and declined bi-exponentially with a t½ of approximately 40 hours. Cmax and AUC0-inf increased with dose. Analysis of blood PD biomarker showed a significant increase in soluble c-Met levels after golvatinib treatment. Conclusions: The MTD of golvatinib was achieved at 200 mg BID. Golvatinib was well tolerated with manageable toxicities at dose levels up to and including the MTD. 4 of 16 pts showed stable disease after golvatinib treatment.
A phase I study to assess oral bioavailability of a novel oral soft gelatin capsule formulation of rigosertib (ON 01910.Na) under fasted and fed conditions in patients with myelodysplastic syndromes.
Authors: Raza Azra , Komrokji Rami S. , Brooks Roserika , Lancet Jeffrey E. , List Alan F. , Ren Chen , Taft David R. , Wilhelm Francois , Maniar Manoj
Published: March 2020

3081

Background: Rigosertib (ON 01910.Na) is a novel multikinase inhibitor, with selective cytotoxic effects on tumor cells without impact on normal cells. Rigosertib, administered as a 3-day continuous infusion, is now undergoing phase 3 evaluation in higher risk MDS patients refractory to hypomethylating agents. Here, we report the results of the effect of food on the absolute bioavailability of a novel rigosertib oral formulation (soft gelatin capsule) in MDS patients. Methods: This was a single-dose, three-treatment, three-period sequential design for studying the effects of food on the bioavailability of an immediate-release soft gelatin capsule formulation. The following dosing groups were tested in 12 patients: IV Dose 800 mg/m2 over 24 hours and oral dose 560 mg (2 x 280 mg capsules) under fasting and fed conditions. The oral dose was the recommended phase 2 dose, as reported previously (R.S. Komrokji et al., Oral Formulation of Rigosertib (ON 01910.Na) in Patients with Myelodysplastic Syndrome (MDS) – Phase I Study Results. Blood 2011, 118:Abstract #3797). Plasma samples were collected pre-dose, and over 32 hours (IV dose) or 8 hours (oral dose) after dose initiation. Rigosertib plasma levels were analyzed by a validated LC/MS/MS method. Pharmacokinetic parameters were estimated by noncompartmental analysis (WinNonlinÒ). Results: Rigosertib pharmacokinetic parameters are presented in the table below. The results of the present study demonstrate good oral bioavailability under fasting condition.Oral administration of rigosertib after a meal decreased Cmax and AUC by 77% and 61%, respectively, compared to fasting conditions. Conclusions: The results of this study support the potential for oral delivery of rigosertib, which could become a preferred therapy over a 3-day continuous intravenous infusion. [Table: see text]
Preclinical activity of the Hsp90 inhibitor, ganetespib, in ALK- and ROS1-driven cancers.
Authors: Proia David A , Acquaviva Jaime , Jiang Qin , Xue Liquan , Smith Donald , Friedland Julie C , He Suqin , Sang Jim , Morris Stephan , Wada Yumiko
Published: March 2020

3090

Background: Ganetespib is a potent inhibitor of heat shock protein 90 (Hsp90) currently being studied in a broad range of clinical trials. Phase II results with ganetespib demonstrated an encouraging objective response rate of 50% in non-small cell lung carcinoma (NSCLC) patients whose tumors contained ALK translocations and had progressed on previous treatments. To further understand the clinical potential of ganetespib in ALK-driven cancers, we evaluated its activity in (1) crizotinib-sensitive and -resistant cancer cells harboring ALK fusions; (2) cells expressing amplified ALK or ROS1 translocations (a kinase structurally similar to ALK); and (3) in combination with crizotinib. Methods: H3122 NSCLC cells, which express EML4-ALK, were treated with ganetespib, crizotinib or the combination, and cell viability and signaling cascades were assessed. Similar experiments were done in cells with amplified, constitutively active ALK (NB-39-nu) or ROS1 kinase fusions (HCC-78, U118MG). To generate a model of crizotinib resistance, NPM-ALK-expressing BaF3 cells were exposed to various crizotinib concentrations. Fifteen different ALK kinase domain substitutions were identified; clonal NPM-ALK/BaF3 cells were made for each resistance mutation and assayed for sensitivity to ganetespib. Results: Ganetespib was 50-fold more potent than crizotinib in killing H3122 cells, and when combined together at sub-lethal doses, displayed strong synergistic anticancer activity. Ganetespib showed similar potency in other cells driven by constitutively active ALK or ROS1 kinase fusions, due to abrogation of their oncogenic kinase activity. All 15 of the crizotinib-resistant NPM-ALK/BaF3 mutant clones were highly sensitive to ganetespib (IC50 values ranging from 14-23 nM), including the 7 mutations reported to date in patients with ALK-driven tumors. Conclusions: Ganetespib effectively inhibits the activity of ALK and ROS1, kinases associated with several tumor types, resulting in marked single agent anticancer activity in cells driven by them. Importantly, ganetespib retains its potency irrespective of the mutational status of ALK. The strong synergy observed between ganetespib and crizotinib warrants further study.
Meta-analysis on the relationship between everolimus exposure and safety and efficacy.
Authors: Sellami Dalila B. , Urva Shweta Ramesh , Grosch Kai , Cheung Wing Kui , Anak Ozlem
Published: March 2020

3099

Background: Data on everolimus exposure–safety and response relationships are available from individual studies. We performed a meta-analysis to assess these relationships using everolimus predose minimum blood concentration (Cmin). Methods: Individual patient data from 5 phase 2 or 3 oncology studies in which steady-state predose pharmacokinetic samples were taken from patients administered everolimus monotherapy 10 mg/day were pooled. In a Cox regression, the times to first grade ≥3 select adverse events (AEs) associated with everolimus and first progression-free survival (PFS) event were related to log-transformed instant or time-averaged Cmin as time-varying covariates stratified by study. Probability of tumor size reduction according to RECIST (yes vs no) was assessed using a generalized linear mixed model fitted with GEE method with log-transformed instant or time-averaged Cmin as covariates and treatment arm as fixed effect. Results: 945 patients were evaluable for efficacy, 938 for safety. Patient characteristics were relatively well balanced across studies. Regardless of whether instant or time-averaged Cmin was used, a 2-fold increase in everolimus exposure increased the risk of grade ≥3 pulmonary, metabolic, and stomatitis events (Table); no increased risk of other grade ≥3 AEs was observed. A 2-fold increase in everolimus exposure increased the likelihood of tumor size reduction; there was a trend of reduced risk of a PFS event (Table). Conclusions: A 2-fold increase in everolimus exposure is associated with a higher probability of tumor size reduction and increased risk of high-grade pulmonary, metabolic, and stomatitis AEs associated with everolimus. [Table: see text]
Phase III CORRECT trial of regorafenib in metastatic colorectal cancer (mCRC).
Authors: Van Cutsem Eric , Sobrero Alberto F. , Siena Salvatore , Falcone Alfredo , Ychou Marc , Humblet Yves , Bouche Olivier , Mineur Laurent , Barone Carlo , Adenis Antoine , Tabernero Josep , Yoshino Takayuki , Lenz Heinz-Josef , Goldberg Richard M. , Sargent Daniel J. , Cihon Frank , Wagner Andrea , Laurent Dirk , Grothey Axel ,   on behalf of CORRECT Investigators
Published: March 2020

3502

Background: Regorafenib (REG) is an oral multi-kinase inhibitor. The CORRECT trial was conducted to evaluate REG in patients (pts) with mCRC who had progressed after all approved standard therapies. Methods: Enrollment criteria included documented mCRC and progression during or ≤3 months after last standard therapy. Pts were randomized 2:1 to receive best supportive care plus either REG (160 mg od po, 3 wks on/1 wk off) or placebo (PL). The primary endpoint was overall survival (OS). Secondary endpoints included progression-free survival (PFS), overall response rate, disease control rate, safety and quality of life (QoL). Efficacy analyses across prespecified subgroups were evaluated using univariate Cox regression. Results: 760 pts were randomized (REG: 505; PL: 255). The OS primary endpoint was met at a preplanned interim analysis. OS and PFS were significantly improved in REG arm compared to PL arm: hazard ratio (HR) for OS 0.77 (95% CI 0.64-0.94, 1-sided p=0.0052), median OS 6.4 vs 5.0 mos; HR for PFS 0.49 (95% CI 0.42-0.58, 1-sided p<0.000001), median PFS 1.9 vs 1.7 mos. Comparable OS and PFS benefits were observed in exploratory subgroup analyses by region, age, time from diagnosis of mCRC to randomization, prior lines of treatment, and KRAS status (shown in table). The most common grade 3+ AEs related to REG were hand-foot skin reaction (16.6%), fatigue (9.6%), hypertension (7.2%), diarrhea (7.2%) and rash/desquamation (5.8%). QoL data will be presented. Conclusions: REG demonstrated statistically significant improvement in OS and PFS over PL, as well as comparable efficacy benefits across pt subgroups analyzed. [Table: see text]
FOLFOX4 (12 cycles) versus sequential dose-dense FOLFOX7 (6 cycles) followed by FOLFIRI (6 cycles) in patients with initially resectable metastatic colorectal cancer: A GERCOR randomized phase III study (MIROX).
Authors: Hebbar Mohamed , Chibaudel Benoist , Andre Thierry , Mineur Laurent , Smith Denis , Louvet Christophe , Dutel Jean Luc , Ychou Marc , Legoux Jean-Louis , Mabro May , Auby Dominique , Brusquant David , Khalil Ahmed , Truant Stephanie , Hadengue Alexandra , Bonnetain Franck , Pruvot Francois-Rene , Dalban Cecile , De Gramont Aimery ,   GERCOR
Published: March 2020

3506

Background: Perioperative FOLFOX4 is the standard chemotherapy (CT) in patients with resectable metastases from colorectal cancer (CRC) (Nordlinger et al, Lancet 2008). To increase curability and reduce the risk of severe neuropathy, we evaluated the sequential administration of a dose-dense oxaliplatin-based regimen followed by an irinotecan-based regimen. Methods: Patients with CRC and initially resectable or resected metastases were randomized between arm A (control): FOLFOX4 (12 cycles; oxaliplatin 85 mg/m²) or arm B (investigational): FOLFOX7 (6 cycles; oxaliplatin 130 mg/m²) followed by FOLFIRI (6 cycles; irinotecan 180 mg/m²). CT was either perioperative or postoperative. Stratification criteria were: perioperative vs. postoperative CT, surgery alone vs. radiofrequency ablation +/- surgery, Blumgart’s prognostic score (0-1 vs. 2-3 vs. 4-5). Only one metastatic site was allowed, but the number of metastases per organ was not limited. The primary endpoint was disease-free survival (DFS). Results: From May 2004 to June 2010, 284 patients were randomized (142 in each arm). Baseline patient characteristics were similar in both arms. Liver was the main metastatic site. There was only one metastasis in 70 (49.3%) patients in arm A and 69 (48.6%) patients in arm B. CT was administered perioperatively in 168 (59.1%) patients, and postoperatively in 116 (40.9%) patients. In case of perioperative CT, R0-R1 resection was achieved in 58/85 (68.2%) patients in arm A and 67/83 (80.7%) patients in arm B. Grade 3 neuropathy occurred in 34 (23.9%) and 28 (20.0%) patients in arm A and B, respectively. Grade 3/4 thrombocytopenia and gastrointestinal toxicities (nausea, vomiting, diarrhea) were more frequent in arm B. Median follow-up was 50.4 months [95% CI: 45.6-54.4]. Median DFS were 22.4 months [95% CI: 17.9-36.2] in arm A and 23.0 months [95% CI: 19.7-35.6] in arm B (HR=0.97 [95% CI: 0.72-1.31]; p=.856). Conclusions: FOLFOX7 followed by FOLFIRI is not superior to the standard FOLFOX4 chemotherapy in patients with resectable metastatic colorectal cancer.