bluuebunny/crossref_metadata_2025_split huggingface dataset:
PX-866 and docetaxel in patients with advanced solid tumors.
Authors: Jimeno Antonio , Senzer Neil N. , Rudin Charles M. , Ma Wen Wee , Halmos Balazs , Schnadig Ian D. , Levy Benjamin , Hausman Diana Felice , Peterson Scott , Walker Luke N. 
Published: March 2020

3024 Background: PX-866, an irreversible pan-isoform inhibitor of Class 1 PI-3K has additive to synergistic effects when combined with docetaxel in xenograft models of NSCLC and SCCHN. A phase I/II study of PX-866 and docetaxel was initiated to further evaluate this combination. Enrollment in phase I is complete, and the randomized, controlled phase II portion is now enrolling patients with either NSCLC or SCCHN. Phase I safety and pharmacokinetics were previously described; the recommended phase II dose of PX-866 was 8 mg daily, the same as the single agent MTD (Jimeno A, et al. AACR-NCI-EORTC, 2011). Updated phase I antitumor and biomarker results are presented here. Methods: Phase 1 consisted of dose escalation of PX-866 at 4, 6, or 8 mg po qd in combination with docetaxel 75 mg/m2 IV once every 21 days (d). Patients had advanced solid tumors for which docetaxel was compendia listed. Tumor restaging was performed every 2 cycles. Archived tumor biopsies were collected for assessment of potential biomarkers of response, including PIK3CA and KRAS mutations and PTEN expression. Results: 43 pts were enrolled: NSCLC (n=6), prostate (n=5), ovarian (n=5), SCCHN (n=3), and pancreatic (n=3) were the most common tumor types. Median time on study (TOS) was 81 d (5-361), with 9 pts still on study. 16 pts received ≥ 6 cycles (6-17), including 3 pts with NSCLC, and 4 pts with ovarian cancer. Biomarker data are available for 20 evaluable pts. Median days on study by mutational status was: PIK3CA/KRAS WT (n=13): 91 d (28-286); PIK3CA-MUT (n=5): 183 d (64-342); KRAS-MUT (n=3): 141 d (125-361); and PIK3CA/KRAS-MUT (n=2): 96 d (86-105). A trend toward longer TOS was observed in pts with PIK3CA-MUT vs PIK3CA/KRAS-WT (p=0.14). Assessment of PTEN is ongoing. Best response in 32 evaluable pts was 2 PR (6%), 22 SD (69%), and 8 PD (25%). The PRs were in NSCLC and ovarian cancer (both PIK3CA/KRAS WT). 8 other pts had ≥15% tumor shrinkage, including NSCLC (n=2). Conclusions: PX-866 with docetaxel was associated with a disease control rate of 75%, with 50% of evaluable pts demonstrating SD or better for ≥ 6 cycles. Based on available data, a trend for a longer TOS was seen with PIK3CA-MUT pts. This relationship will be further evaluated in phase II.
NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 targeted agent.
Authors: Thompson Dana Shelton , Weiss Glen J. , Jones Suzanne Fields , Burris Howard A. , Ramanathan Ramesh K. , Infante Jeffrey R. , Bendell Johanna C. , Ogden Angela , Von Hoff Daniel D. 
Published: March 2020

3033 Background: NKP-1339 is a first-in-class small molecule anti-cancer compound that down-regulates GRP78, a key regulator of misfolded protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation occurs in many tumors, and is associated with intrinsic and chemotherapy-induced resistance. Preclinically, single agent NKP-1339 demonstrates activity against multiple tumor types, including chemoresistant lines. This phase I trial evaluates the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339. Methods: Patients (pts) with advanced solid tumors, adequate organ function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15 of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then adjusted to standard 3+3 design. Doses from 20-780 mg/m2 are evaluated. PD samples for plasma GRP78 are collected. At MTD, an expanded cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation: 30 evaluable for dose determination; 4 replaced due to tumor progression in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79). Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8); neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8). Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt, occurred at 780 mg/m2; MTD is 625 mg/m2. Gr 1 fever/chills is observed above 420 mg/m2, but is prevented by steroid premedication. The most common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2 fatigue. No lab abnormalities were noted except reversible creatinine elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial response was in 1 pt (NET); stable disease in 7 pts, including NET (2), NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy duration 14+-88+ weeks. Soluble GRP78 is detected in the plasma of patients at baseline. Conclusions: NKP-1339is well tolerated with manageable side effects. Single agent activity is noted in multiple tumors including NET. Results from the expanded cohort and pre/post-therapy PD will be presented. Phase II single agent NKP-1339 and phase I NKP-1339 combination trials are planned.
MGCD265, a multitargeted oral tyrosine kinase receptor inhibitor of Met and VEGFR: Dose-escalation phase I study.
Authors: Kollmannsberger Christian K. , Hurwitz Herbert , Cleary James M. , Strickler John H. , Drouin Michel A. , Juretic Manuela , Hunt Wendy , Reid Gregory K. , Maroun Christiane R. , Bonfils Claire , Wang James , Karam Andre , Besterman Jeffrey M. , Mehran Mariam , Shapiro Geoffrey 
Published: March 2020

3039 Background: MGCD265 is a multikinase inhibitor, with nanomolar IC50 against Met, VEGFR 1, 2, and 3, Tie-2, and Ron. This spectrum may confer greater anti-tumor activity than inhibiting either target alone. MGCD265 has broad anti-tumor effects in preclinical models. Methods: Patients (pts) with advanced malignancies were enrolled in this Phase I, open-label, dose escalating study using the classic 3+3 study design. MGCD265 was administered every day over a 21-day cycle. The aim of this study is to determine the safety profile including the maximum tolerated dose and the dose limiting toxicities (DLTs) of MGCD265. The pharmacokinetic (PK), pharmacodynamic (PD) profiles and the anti-tumor activity of MGCD265 were also evaluated. Results: As of January 10, 2012, 56 patients were enrolled (M/F: 37/19; ECOG 0/1/2: 16/38/2; median age: 61 years old). MGCD265 was dose escalated from 24 mg/m2 QD to 235 mg/m2 BID with a favorable safety profile. The DLTs (n=1 for each event) captured were: grade 2 hypertension (per protocol’s definition), grade 3 lipase elevation, grade 3 fatigue and grade 3 pituitary hemorrhage, all occurring at daily doses ≥ 250 mg/m2. Additional ≥ grade 3 drug-related adverse events (observed beyond Cycle 1) were diarrhea, fatigue, elevated lipase and elevated alkaline phosphatase (n=1 for each event). Two schedules of MGCD265 were tested sequentially: once (QD) and twice daily (BID), respectively. Increasing the dose frequency to BID increased the exposure of MGCD265 by ~ 2 fold at steady state. To date, the exposure (Cmax) attained at steady state with the BID schedule was ~20 fold higher than the IC50 for Met and VEGFR inhibition and was also above the plasma exposures associated with efficacy in the Met-sensitive xenograft model (MKN45). Six patients achieved SD for 6 cycles or more (up to 12 cycles). Conclusions: The safety profile of MGCD265 continues to be favorable in this Phase I dose escalating study. While no evidence of objective responses have been noted to date, several pts have had prolonged SD. Dose escalation is ongoing.
Clinical and correlative science results in a phase II study of UCN-01in combination with irinotecan in recurrent triple-negative breast cancer (TNBC).
Authors: Ma Cynthia X. , Ellis Matthew J. , Petroni Gina R. , Lockhart A. Craig , Naughton Michael , Pluard Timothy J. , Brenin Christiana , Picus Joel , Creekmore Allison N , Mwandoro Tibu N. , Guo Zhanfang , Cai Shirong , Ryan Christine , Yarde Erin , Hoog Jeremy , Dancey Janet , Watson Mark , Piwnica-Worms Helen , Fracasso Paula M. 
Published: March 2020

3047 Background: Chk1 inhibitors enhance chemotherapy efficacy by inducing “mitotic catastrophe” in p53 deficient TNBC preclinical models. Irinotecan (I) combined with UCN-01, a nonselective Chk1 inhibitor, showed promising activity in TNBC in our phase I study. The primary objective of the phase II trial was to determine the efficacy and toxicity. Correlatives included assessing tumor molecular subtype, TP53, PTEN and pathways targeted by UCN-01. Methods: Pts with measurable, metastatic (met) TNBC, prior anthracycline (A) and taxane (T), received I (100-125 mg/m2 IV on days (d) 1, 8, 15, 22) and UCN-01 (70 mg/m2 IV on d2 and 35 mg/m2 on d23 and later doses) on a 42-d cycle (C). Archival tumors and serial peripheral blood mononuclear cells (PBMC) and optional tumor biopsies were collected. Results: Twenty five pts were enrolled. All had prior A and T. The median no. of prior regimens for met disease was 3 (range 1-4). Toxicities included neutropenia, diarrhea, nausea, vomiting, and hyperglycemia. Best responses included 1 PR, 8 SD (range 2.3-8.6 mos) for a clinical benefit rate (CR+PR+SD>6 mos) of 3/25 (12%), 95% CI (3, 31%). The median PFS and OS were 2.3 and 11.3 mos, respectively. pS6 was examined since UCN-01 inhibits PDK1. pS6 was reduced in PBMC 24h post UCN-01, but close to baseline by d8. Immunostain of cleaved caspase 3 (CC3), pHistone H3 (pHH3), γH2AX, and pS6 were done on serial biopsies from 4 pts with adequate biopsy materials. In all cases, pS6 was reduced 24h post UCN-01. Results for other markers were variable. One case with TP53 deletion showed an induction of CC3, with an increase in pHH3 and γH2AX, suggesting abrogation of cell cycle arrest and enhanced DNA damage. Among 15 with sufficient specimen for analysis, most were basal-like (basal 10, basal/HER2-E 1, HER2-E 2, Luminal B 2) by PAM50, low in PTEN level (11) and carried mutations in TP53 (8). Median OS was 5.5 (95% CI: 2, 11.3) mos in TP53 mutant and 20.3 (95% CI: 2.9, - ) mos in wild type populations (p=0.004). Conclusions: This regimen had limited activity in TNBC. Despite the long half-life, drug activity is not detectable by d8 based on PBMC analysis. Our data indicates that future trials in TNBC should consider p53 status.
Developing rational drug combination strategies for PARP inhibitors.
Authors: Rehman Farah , Elliott Richard , Brough Rachel , Frankum Jessica , Ragab Anan , Lord Christopher J. , Ashworth Alan 
Published: March 2020

3050 Background: The recent clinical development of Poly (ADP-ribose) polymerase (PARP) inhibitors has provided formal proof-of-concept that synthetic lethal approaches can be used to treat cancer. The promise of PARP inhibitors in BRCA mutant tumours is apparent but questions regarding their wider clinical use remain. To date, a number of clinical trials have been designed using PARP inhibitors as single agents as well as in combination with current standards of care. However, there is a paucity of pre-clinical information about PARP inhibitor/drug combinations and empirical clinical trials of standard of care plus PARP inhibitors may not represent the most effective approach to dissect this. We aim to identify effective drug combination strategies that could be used clinically in selected patient groups. Methods: Using a combination of high and medium throughput techniques and established methodologies for determining synergy, additivity and antagonism, we have characterised the effects of combining PARP inhibitors with a diverse panel of over 3,000 compounds in a range of tumour cell models including isogenic matched cell line pairs to determine the impact of genetic background on drug combination efficacy. We have integrated this data with functional profiling data to identify genetic backgrounds where these combinations may be most effective. Results: Results to date suggest promising combinations of PARP inhibitors with temozolomide, CHK1 inhibitors, ATM inhibitors and other agents. Some of these combinations show specificity for genetic backgrounds such as PTEN mutations. Conclusions: Screening of drug libraries has identified promising PARP inhibitor drug combinations and demonstrates how some drug combinations show specificity in particular genetic backgrounds. This raises the possibility of widening the therapeutic index in patients with these genetic backgrounds and treating a wider group of patients with PARP inhibitors.
Using proton MRSI to predict response to vorinostat treatment in recurrent GBM.
Authors: Shim Hyunsuk , Voloschin Alfredo Daniel , Wei Li , Hwang Scott N , Miller Andrew H. , Guo Ying , Brat Daniel , Holder Chad A , Read William L. , Kopcewicz Katarzyna , Harvey R. Donald , Barker Peter , Shu Hui-Kuo George , Hu Xioaping P , Olson Jeffrey J. 
Published: March 2020

3055 Background: A major impediment to the development of new therapies for glioblastoma (GBM) is a lack of biomarkers indicating response. Epigenetic modifications are now recognized as a frequent occurrence in the early phases of tumorigenesis, playing a central role in tumor development. Epigenetic alterations differ significantly from genetic modifications in that they may be reversed by ‘‘epigenetic drugs’’ such as histone deacetylase inhibitors (HDACis). As a promising new modality for cancer therapy, the first generation of HDACi is currently being tested in phase I/II clinical trials. Methods: GBM alterations from therapy with HDACis, such as vorinostat (SAHA), include tumor redifferentiation/cytostasis rather than tumor size reduction limits the utility of traditional imaging methods such as MRI. Magnetic resonance spectroscopic imaging (MRSI) quantitates various metabolite levels in tumor and normal brain, allowing characterization of metabolic processes in live tissue. Results: In our preclinical model, MRS detected metabolic response to SAHA after only 3 days of treatment: reduced alanine and lactate and elevated myo-inositol, N-acetyl aspartate and creatine; each returning toward normal brain levels. This led to our clinical study of MRSI to evaluate the metabolic response of recurrent GBMs to SAHA + temozolomide. After only 7 days of SAHA treatment, MRSI can distinguish metabolic responders (normalization/restoration of tumor metabolites towards normal brain-like metabolism) from non-responders (no significant change in tumor metabolites). Our initial cohort (n=6) consists of 3 responders and 3 non-responders with highly significant differences in their change in metabolite levels (p < 0.001). Conclusions: Our results provide exciting insights into the mechanisms by which HDACi exerts its effect on GBMs. Tumor cells have increased biosynthetic needs requiring reprogramming of cellular metabolism. This creates increased energy demands, making tumor cells even more vulnerable to interventions targeting their metabolism. HDACi may induce redifferentiation in tumors by targeting tumor metabolism. Thus, MRSI provides a novel modality to predict response to HDACi-containing combination therapy in GBM.
A phase I/II study to evaluate the ability of decitabine and panobinostat to improve temozolomide chemosensitivity in metastatic melanoma.
Authors: Xia Chang , Laux Douglas Earl , Deutsch Jeremy Michael , Frees Melanie , Smith Brian , Hohl Raymond J. , Milhem Mohammed M. 
Published: March 2020

3056 Background: Epigenetic gene regulation is likely a contributing mechanism of cancer initiation and progression. Emerging evidence indicates that epigenetics may also play a key role in the development of chemoresistance in melanoma. We proposed combining the histone deacetylase inhibitor panobinostat (PT) and the demethylator decitabine (D) to overcome the development of epigenetic mediated temozolomide (TMZ) resistance in metastatic melanoma. Methods: Eligible patients must be ≥18, stage IV melanoma, and naïve or previously treated, with good performance status (ECOG ≤ 2) and normal organ functions. Patients with previous exposure to TMZ were allowed on study. The study includes the dose escalation of D and PT followed by expansion cohorts. D (0.1mg/kg SQ, 0.2mg/kg SQ) on days 1, 3, 5, 8, 10,12, PT (10mg PO, 20mg PO, 30mg PO) Q96h starting day 8, and TMZ 150mg/m2 PO daily on days 9-13 of each 42 day cycle. TMZ was increased to 200mg/m2 in the absence of grade 2 thrombocytopenia. Primary endpoints of phase I study are to determine the toxicity, safety and maximum tolerated dose (MTD) of the D, PT and TMZ combination. Results: To date, the phase I portion of this trial is completed. We report on the safety data for this combination. 17 patients received treatment (1st cohort: 5; 2nd cohort: 4; 3rd cohort: 4; 4th cohort: 4 ). M:F 11:6. Median age: 56 (32-77); Median ECOG PS: 1; 82% of the patients received at least one cycle (n=14). Median number of cycles given: 2 (0-6). To date, no DLTs have occurred. The MTD was not reached. The only grade (G) 4 adverse event (AE) is neutropenia on a patient in cohort 3 and it resolved within 3 days. G3 AEs included lymphopenia (n=4, 23%), anemia (n=2, 12%), leukopenia (n=2, 12%) and fatigue (n=2, 12%). Common G2 toxicities were leukopenia (n=5, 30%), neutropenia (n=4, 23%), nausea (n=4, 23%) and lymphopenia (n=3, 18%). Conclusions: The combination of D, PT, and TMZ appears to be safe and well-tolerated. The recommended dose for the phase II study remains to be determined.
A phase I study of EP-100, a luteinizing hormone releasing hormone (LHRH) ligand conjugated to a synthetic cytolytic peptide in patients with advanced refractory LHRH- receptor (R)-expressing tumors.
Authors: Ramanathan Ramesh K. , Chadha Manpreet , Sarantopoulos John , Northfelt Donald W. , Weiss Glen J. , Mita Monica M. , Barnhart Kerry M. , Whisnant John , Leuschner Carola , Alila Hector , Curtis Kelly Kevelin 
Published: March 2020

3060 Background: EP-100 is a synthetic 28 amino acid LHRH peptide conjugated to an 18 aa cytolytic peptide. Selective targeting in LHRH-R expressing cells occurs via direct binding to the extracellular membrane receptor followed by disruption of the membrane by the cytolytic peptide portion. A first in human, phase I study was performed. Methods: Eligible pts had adequate organ function and LHRH-R tumor expression, as determined by IHC. EP-100 was given IV (30-60 min) weekly x 3 for cohorts 1- 6 (n=20 at 0.6 - 5.2 mg/m2) and then twice weekly x 3 for cohorts 7- 11 (n=18 at 7.8 - 40 mg/m2) with a week break. The pharmacokinetic profile of EP-100 and antibody production against EP-100 was determined by a validated HPLC/MS and ELISA respectively. Potential activity of EP-100 on the pituitary gonadotropes was determined by plasma LH and FSH. Results: We screened 97 pts, archival tumor tissue obtained from 81 pts; 53 (65%) were positive for LHRH-R, of which 37 were enrolled (female 76%) and treated. The LHRH-R expression rate in breast was 81% (N=21) and in ovarian cancer 56% (n=18). Most pts had breast (n= 16, 42%) ovary (n=7,18%), colon (n=4, 11%) or uterine (n=3, 8%) cancer. Pts were treated in a 3 + 3 standard dose escalation scheme. Doses were escalated 100% in the absence of a grade 2 drug related toxicity. MTD was not reached at the highest dose level of 40 mg/m2. Only one DLT occurred, a grade 2 increase in ALT/AST. The only other drug-related toxicity was a self limited infusion-related skin reaction (grade 1-2) in 10 pts. EP-100 was rapidly cleared from circulation, mean half life ranged from 7.1 ± 3.8 min to 15.9 ± 3.6 min. Best response was stable disease for >12 weeks in 5 pts. In 3 pts rapid, sustained decreases in LH/FSH levels were noted. Antibody production against EP-100 was absent in all pts. Conclusions: The study has completed accrual, the phase II dose is 30-40 mg/m2 twice a week x 3 weeks.EP-100is safe, well tolerated and not antigenic/immunogenic. Preclinical studies indicated synergy with paclitaxel and doxorubicin. A phase II study of EP-100 plus paclitaxel in ovarian cancer is planned.
Inhibition of autophagy: Phase I safety, tolerability, and pharmacokinetics (PK) of hydroxychloroquine (H) in combination with vorinostat (V) in patients with advanced solid tumors.
Authors: Mahalingam Devalingam , Mita Monica M. , Sarantopoulos John , Wood Leslie , Mita Alain C. , Curiel Tyler J. , Argiris Athanassios , Nawrocki Steffan T , Carew Jennifer S. , Giles Francis J. 
Published: March 2020

3073 Background: The histone deacetylase (HDAC) inhibitor V has pleiotropic effects, and induces both apoptosis and autophagy. As autophagy can promote cancer cell survival, we hypothesized that inhibiting autophagy would enhance the anti-cancer activity of V. Our pre-clinical studies showed that inhibition of autophagy using H significantly increased the pro-apoptotic effects of V. The primary objective of this NCI-funded study was to determine the maximum tolerated dose (MTD) of H in combination with V in patients (pts) with advanced solid tumors. Methods: Pts with ECOG PS 0-2 and adequate organ function received PO V 300-400 mg QD and H 400-1000 mg QD in 21d cycles. 3+3 dose escalation. Dose limiting toxicities (DLTs) = non-hem toxicity ≥ grade (Gr) 3 or hem toxicity ≥ Gr 4 in the first 2 cycles. PBMCs were analyzed for autophagic changes at baseline, week 1 + 6. PKs done on cycle 1.Tumor biopsies were performed at baseline and post-cycle 2 on 3 pts at MTD. Results: 31 pts enrolled, 27 evaluable for DLT. No DLT was observed in cohort 1 (300 mg V/400 mg H) or cohort 2 (400 mg V/400 mg H). In cohort 3 (400 mg V/600 mg H) 1/6 pts experienced a DLT of Gr 3 fatigue. Cohort 4 (400 mg V/800 mg H) 3/6 pts had DLT of Gr 3 fatigue, and 1 had a Gr 2 seizure. Expansion of cohort 3 resulted in no further DLTs. 10 pts got the MTD. Treatment-related toxicities were mostly Gr 1- 2: nausea/vomiting (10 pts), diarrhea (7), fatigue (5), anorexia (4), weight loss (3), anemia (4), elevated creatinine (4) and thrombocytopenia (2). Gr 3 toxicities were fatigue (4), anemia, thrombocytopenia and neutropenia (1 each). No drug-related deaths or Gr 4 toxicities were noted. One pt (RCC) had a confirmed PR (cohort 2 active on cycle 32) and 2 pts with CRC had prolonged SD (>4 cycles). PK analysis indicated dose-proportional exposure for H. Changes from baseline in biomarkers of autophagy and HDAC inhibition were observed in PBMC and primary tumors with therapy. Conclusions: Recommended dose is V 400 and H 600 mg QD. Dose-dependent fatigue was observed with the combination, but well tolerated at the MTD without any further increase in toxicities compared to V alone. Analyses of PK-PD interactions are underway.