bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase 1b study defining the optimal dosing combinations of the mTOR inhibitor AP23573 and Paclitaxel (PTX)
Authors: Cresta S. , Tosi D. , Sessa C. , Viganò L. , Maur M. , Hess D. , Locatelli A. , Wages D. S. , Albanell J. , Gianni L. 
Published: March 2020

3509 Background: AP23573 is a novel mTOR inhibitor with demonstrated anti-tumor activity in clinical trials. In vitro, AP23573 exhibits at least additive anti-proliferative activity in combination with a variety of agents including taxanes. This trial studied the combination of AP23573 and paclitaxel (PTX) in patients with advanced solid tumors. Methods: This was a modified, sequential (3+3) dose finding study with starting doses of 25 mg AP23573 i.v. and 80 mg/m2 PTX i.v. as Dose Level 1 (DL1) on days 1, 8 and 15 of a 28 day cycle. Doses of either drug were adjusted in successive cohorts. Blood samples and skin biopsies were collected for pharmacokinetic (PK) and pharmacodynamic (PD) studies. Dose limiting toxicity definitions included neutrophils <500/μL; thrombocytopenia = Grade 3 (CTC), any non- hematologic toxicities = Grade 2; missing 2 consecutive doses due to any toxicity. For PK and PD analysis, AP23573 and PTX were administered one day apart at the start of Cycle 1, reversing the sequence at Day 8. Results: Enrollment is complete and 29 patients with a variety of tumors (sarcoma, pancreatic, H&N, melanoma, thymoma) have been treated. Grade 3 thrombocytopenia and Grade 2 mouth sores were seen at DL1 as well as missed doses due to moderate (Grade 2) neutropenia. Adverse events include mouth sores and fatigue which were mild and reversible. Available PK data for AP23573 and PTX suggest no interaction. PD analysis in peripheral blood mononuclear cells demonstrates no interference by PTX on mTOR inhibition by AP23573. PD data in skin biopsies are forthcoming. Both 12.5 mg AP23573/80mg/m2 PTX and 37.5mg AP23573/60mg/m2 PTX are maximal dose combinations that appear to be well tolerated. Activity has been observed at multiple AP23573 mg/PTX mg/m2 dose levels (25/60, 12.5/80, 25/80). Five patients have been on study for >4 cycles, including 2 patients with partial responses (H&N and pancreatic). Conclusions: Combined therapy with AP23573 and PTX is safe. It is notable that evidence of anti-tumor activity was observed at modest doses of each drug when in combination. Combinations of these agents at both doses cited would be recommended for evaluation in trials examining efficacy in specific tumors. No significant financial relationships to disclose.
A phase I study of R547, a novel, selective inhibitor of cell cycle and transcriptional cyclin dependent kinases (CDKs)
Authors: Diab S. , Eckhardt S. , Tan A. , Frenette G. , Gore L. , Depinto W. , Grippo J. , DeMario M. , Mikulski S. , Papadimitrakopoulou S. 
Published: March 2020

3528 Background: R547, a potent inhibitor of CDKs 1, 2, 4, 7, and 9, has shown broad antitumor activity in preclinical models. This phase Ia study assessed safety, pharmacokinetic (PK), and pharmacodynamic (PD) endpoints. Methods: R547 given as a 90 or 180 min infusion D1, D8 (21 day cycle). Key inclusion criteria: ECOG 0–2, adequate hematologic, hepatic, and renal function. Exclusion: brain metastases, NYHA III/IV CHF, CVA, current antihypertensive therapy. Blood samples on cycle 1, D1, D8 for PK and PD. PD endpoint is inhibition of retinoblastoma phosphorylation (pRB) in PBMCs. Results: 41 pts received R547 over dose range 8.6 - 195 mg/m2; 31 pts on 90 min and 10 pts on 180 min schedule. Mean age 53.4 yrs (20–81), 25F:16M. Mean R547 cycles 3.1(<1- 8) for 18 evaluable pts receiving doses ≥ 155 mg/m2. Toxicities: principal related events were nausea (54%), fatigue (34%), emesis (34%), headache (34%), and hypotension (32%). All of these limited to gr 1/ 2, except 4 gr 3 fatigue (1 in cycle 1) and 1 gr 3 nausea. DLTs: 90 min- gr 3 somnolence, gr 3 confusion, gr 3 fatigue, 1 pt each, all at 195 mg/m2; 180 min- 1 DLT of prolonged gr 3 pruritis at 195 mg/m2. PK: Mean AUC for 20 pts with PK receiving ≥ 155 mg/m2 R547 exceeds exposures efficacious in xenograft studies. At equivalent doses, the 180 min schedule produces equivalent AUC but 30% reduction of Cmax. PD: for pts with available data (n=21), an exposure-dependent decrease in pRB/total RB ratio was observed 1.5 to 24 hrs post R547. Activity: tumor regression in 1 pt with metastatic squamous ca skin; 8 additional pts received ≥ 4 cycles. Conclusions: Treatment with R547 is tolerable at a dose of 155 mg/m2 on D1, D8 (21 day cycle) for both 90 and 180 min schedules. Nausea, emesis, headache, and transient hypotension are manageable with anti-emetic, analgesic, and iv fluid support. The DLTs observed in the 90 min schedule have not occurred in pts receiving 180 min infusions, a schedule which maintains R547 exposure but reduces Cmax. Exposures predictive of preclinical efficacy have been achieved. Inhibition of a relevant PD marker (pRB) and antitumor activity have each been confirmed in the clinic. Phase II trials in advanced solid tumors and hematologic malignancies are planned. No significant financial relationships to disclose.
Tanespimycin (T) + bortezomib (BZ) in multiple myeloma (MM): Pharmacology, safety and activity in relapsed/refractory (rel/ref) patients (Pts)
Authors: Richardson P. G. , Chanan-Khan A. , Lonial S. , Krishnan A. , Carroll M. , Cropp G. F. , Albitar M. , Johnson R. G. , Hannah A. , Anderson K. 
Published: March 2020

3532 Background: Tanespimycin (17-AAG/KOS 953) disrupts Hsp90, a molecular chaperone of MM client proteins including IL-6 and IGF-1R that are key to MM growth, survival and drug resistance. Single agent T was well tolerated with modest anti- MM activity. Preclinical studies suggest potential synergy with BZ. Methods: Pts received BZ as IVB followed by 1-hr infusion of T on D1,4,8,11 q 21d. Results: 49 pts were enrolled in 7 cohorts (T 100- 340 mg/m2; BZ 0.7 - 1.3 mg/m2). PK of T was similar with or without BZ. Inhibition of 20S proteasome with T+BZ was not different vs. historical BZ single agent data. PBLs showed induction of Hsp70 4h post-infusion with maintenance of induction prior to T infusion across the dosing interval; pAKT plus total AKT were also reduced 4 and 72h following infusion. CD138 but not CD4 or CD8 cells from serial BM aspirates showed induction of apoptosis by flow cytometry. In addition, ↓expression of IGR-1R and IL-6R client proteins was seen after treatment. Safety: In Cohort 7, 19 pts received T 340 / BZ 1.3 mg/m2. Common all-grade (G) drug-related toxicity (n=19) included diarrhea (42%), nausea (32%), vomiting (26%), ↑ AST/ALT/Alk Phos (26%/21%/21%), myalgias (16%), and dizziness (16%). G3 thrombocytopenia was noted in 16% with no other G3 toxicity observed in more than 1 pt. DLT was seen in 2 pts: G3 myalgias/cramps and dehydration (reversible in both). G1–2 only treatment-emergent peripheral neuropathy was recorded in 15%. Activity: Responses have been seen across dose levels in BZ-naïve, pre-treated and ref pts (“ref” defined as no response to or disease progression within 60d of last dose of BZ-containing regimen). Specifically, 1 BZ-ref pt with 3 prior regimens had confirmed PR after 2 cycles and continues in Cycle 9 (M-spike ↓92%); a 2nd pt with 2 prior regimens achieved PR after 2 cycles and continues in Cycle 7; a 3rd pt with 7 prior regimens with confirmed PR after 3 cycles continues in Cycle 6. Conclusions: Treatment with T 340/ BZ 1.3 combination had generally manageable toxicity. Durable Hsp90 inhibition and similar proteasome inhibition (vs single-agent BZ) was seen. Importantly, anti-MM activity in BZ-ref pts was observed and further investigation of this combination in rel/ref MM is therefore warranted. No significant financial relationships to disclose.
Final results of a phase I study of wild-type oncolytic reovirus administered intravenously to patients with advanced cancer
Authors: Spicer J. F. , Vidal L. , Pandha H. , Yap T. , White C. , Coffey M. , Thompson B. , Kaye S. , Harrington K. , De Bono J. 
Published: March 2020

3572 Background: Reovirus has minimal pathogenicity in humans but selectively replicates in cells with activated Ras, which inactivates the anti-viral effects of double stranded RNA-activated protein kinase. Wild-type reovirus serotype 3 Dearing has selective antitumor activity in pre-clinical models. Methods: Wild-type reovirus serotype 3 Dearing was administered as a 1-hr IV infusion every 4 weeks, initially for 1 day, then for 3 and then 5 days every 4 weeks. The starting dose was 1 x 10^8 tissue culture infectious dose (TCID50), increasing in successive cohorts until the observation of grade 2 toxicity. Endpoints were safety, detection of viral replication, viral shedding, immune response and antitumor activity. Results: A total of 33 patients (25 males, median age 61; ECOG performance status 0/1/2 = 15/17/1) were treated. 8 cohorts were treated at dose levels of 1x10^8 TCID50 for 1 day, 1x10^8 for 3 days, and 1x10^8, 3x10^8, 1x10^9, 3x10^9, 1x10^10 and 3x10^10 for 5 days. Maximum tolerated dose (MTD) was not reached and toxicities were mild (grade 1 or 2), including chills, fever, headache, rhinorrhea, fatigue and myelosuppression. Reverse transcription polymerase chain reaction (RT-PCR) studies of blood, urine, stool and sputum post reovirus administration and every week thereafter were negative for viral shedding for all treated patients. Anti-reovirus antibodies were present at baseline in most patients, and titres increased after cycle 1 by between 1- and 4-log. Intratumoral reovirus replication was detected by electron microscopy in tumor biopsies. PSA decreased by 50% in a patient with metastatic prostate cancer treated at 3x10^9 TCID50, with evidence of tumor necrosis on CT scanning. 2 patients with metastatic colorectal cancer treated at 3x10^8 and 3x10^9 TCID50 had CEA reductions of 60% and 27%, and received 6 and 3 cycles respectively. 1 patient with metastatic bladder cancer treated at 1x10^9 TCID50 had a minor response and received 4 cycles. Conclusions: Wild-type reovirus serotype 3 Dearing is well tolerated, with minimal toxicity, and MTD has not been reached. Despite a vigorous host response to virus, tumor necrosis associated with intratumoral viral replication was observed. Clinical indications of anticancer activity were seen and phase II studies are planned. [Table: see text]
A phase I/II study of the safety and anti-cancer activity of IV-administered belinostat (PXD101) plus carboplatin (C) or paclitaxel (P), or both in patients with advanced solid tumors
Authors: Sinha R. , Moliffe R. , Scurr M. , Vidal L. , Engelholm S. A. , Buhl Jensen P. , Normann A. , Li S. , De Bono J. , Lassen U. 
Published: March 2020

3574 Background: Belinostat (PXD101), a HDAC inhibitor of the hydroxamate class has shown anti-tumor preclinical activity in combination with other standard chemotherapeutic agents. In Ph. I and II clinical trials the MTD for belinostat has been established at 1,000 mg/m2/d. This Ph I/II study assesses safety, and anti-cancer activity of belinostat administered in combination with C and/or P. Methods: Sequential cohorts of 3–6 patients (pts) with advanced solid tumors and PS 0–2 were recruited to determine the MTD of standard dose C and/or P with escalating doses of belinostat administered as a 30-min IV infusion daily for 5 days (d) every 21 d. C and/or P were administered 2–3 hours following infusion of belinostat on d 3. Results: 23 pts have been treated with a mean of 5 cycles (range 1 - 15) at 5 dose levels: C and belinostat (600 mg/m2) (5 pts); P and belinostat (600 mg/m2) (5 pts); C and P and belinostat (600 mg/m2) (3 pts); C and P and belinostat (800 mg/m2) (4 pts); C and P and belinostat (1,000 mg/m2) (6 pts). Possibly drug-related grade 3 or 4 toxicities were thrombocytopenia (2), vomiting (1), sensory neuropathy (1), myalgia (1), and fatigue (1).No DLT was observed. One SAE (grade 1 T-wave morphology change) was graded as possibly drug-related. No QTcf greater than 500ms were reported. There are 2 confirmed PRs: 1 with heavily treated metastatic rectal cancer and 1 with gemcitabine pre-treated metastatic pancreatic cancer. An additional 11[E1] patients had SD for 2–15 cycles, with 4 being SD for >10 cycles. One pt with mixed mullerian cancer of ovarian origin with SD had an 81% reduction in CA-125 to normal levels after 6 cycles. [E1]If you include MMMT pt as SD on radio. Conclusions: Belinostat with standard dose C and/or P is well-tolerated and shows clinical activity in heavily pre-treated patients with advanced metastatic disease. Recruitment to a phase II expansion in pts with recurrent ovarian cancer is ongoing. No significant financial relationships to disclose.
Pediatric preclinical testing program (PPTP) efficacy and pharmacodynamic evaluation of the Hsp90 inhibitor 17-DMAG
Authors: Smith M. A. , Maris J. M. , Keir S. T. , Lock R. B. , Carol H. , Gorlick R. , Kolb E. A. , Keshelava N. , Reynolds C. P. , Morton C. , Houghton P. J. 
Published: March 2020

3575 Background: 17-DMAG is a small-molecule inhibitor of the protein chaperone HSP90 that is being developed as an anticancer agent because of the multiple HSP90 client proteins involved in cancer cell growth and survival. Methods: The PPTP includes an in vitro panel (n=27) as well as panels of xenografts (n=61) representing most of the common types of childhood solid tumors and childhood ALL. 17-DMAG was tested against the in vitro panel at concentrations from 1 nM to 10 microM and was tested against the in vivo tumor panels by IP administration using a 50 mg/kg BID twice weekly x 6 weeks dose and schedule. The PPTP’s 3 measures of antitumor activity were used (Houghton et al. Ped Blood Cancer 2006): 1) an objective response measure; 2) treated to control (T/C) tumor volume at day 21; and 3) a time to event (EFS T/C) measure. HSP70 induction was was used as a pharmacodynamic measure of HSP90 inhibition and was determined in tumor and liver tissue at 8 and 24 hours following the second of two doses of 17-DMAG (50 mg/kg IP) administered at 12 hour intervals. Results: 17-DMAG had an EC50 of 62 nM against the PPTP’s in vitro panel, with a trend for lower EC50 values for the rhabdomyosarcoma panel (median EC50 31 nM) compared to the remaining PPTP in vitro cell lines (p=0.06) and for higher EC50 values for the neuroblastoma lines (median EC50 396 nM, p=0.01). 17-DMAG induced significant differences in EFS distribution in 15 of 30 of the solid tumor xenografts, and in 4 of 6 of the evaluable ALL xenografts. Using the time to event activity measure, 17-DMAG had intermediate or high activity against 4 of 28 evaluable solid tumor xenografts (1 of 2 rhabdoid tumor and 3 of 4 alveolar rhabdomyosarcoma). The only objective response (a PR) observed was for an alveolar rhabdomyosarcoma xenograft. HSP70 induction was observed in both liver and tumor tissue, with robust induction (up to 450% increase versus control) occurring in both responding and non-responding tumors. Conclusions: 17-DMAG produced its greatest antitumor activity against alveolar rhabdomyosarcoma xenografts. Robust HSP70 induction was observed in both responding and non-responding xenografts, suggesting that tumor-specific downstream effects of HSP90 inhibition are primary determinants of response. (Supported by NCI NO1CM42216) No significant financial relationships to disclose.
Phase I study of BAY 73–4506, a multikinase inhibitor, administered for 21 days on/7 days off in patients with advanced solid tumors
Authors: Hedbom S. , Steinbild S. , Frost A. , Büchert M. , Unger C. , Christensen O. , Kornacker M. , Voliotis D. , Heinig R. , Mross K. 
Published: March 2020

3593 Background: BAY 73–4506 is a multikinase inhibitor targeting both the tumor and its vasculature. BAY 73–4506 inhibits VEGFR-2 and -3, and tumor cell signaling kinases (RET, KIT, PDGFR, and Raf). This drug shows potent, oral activity in a wide variety of preclinical xenograft models. Methods: This phase I dose-escalation trial investigated the safety, pharmacokinetic (PK), and pharmacodynamic (PD) profile of BAY 73–4506 given orally in 21 days on/7 days off cycles, until discontinuation due to toxicity or tumor progression. PK was assessed on days 1 and 21 of cycle 1. PD markers included dynamic contrast-enhanced MRI (DCE-MRI) and circulating sVEGFR-2 and VEGF levels assessed at each cycle. Tumor response was evaluated per RECIST criteria. Results: 22 patients (pts) with documented progressive disease were enrolled at doses of 10 mg to 120 mg once daily. Tumor types included CRC (27%), RCC (18%) and pancreatic cancer (14%). Pts had received a median of 3 prior therapies, including anti-VEGF agents in 5 pts. BAY 73–4506 PK appeared linear with dose; the AUC target exposure level of 13 mg*h/L (from preclinical models) was reached at 30 mg. The major metabolite of BAY 73–4506 (active in vitro) reached a similar AUC(0–24)ss as the parent drug at 120 mg. Commonly reported drug-related adverse events (=10% of pts) were hoarseness (7 [32%], all CTC grade 1), hypertension (5 [23%], all CTC grade 1–2), fatigue (3 [14%], CTC grade 3 in 1 pt [5%]), hand-foot-skin reaction (HFSR) (3 [14%], CTC grade 3 in 1 pt [5%], mucositis (3 [14%], all CTC grade 1). Maximum tolerated dose was exceeded at 120 mg with dose-limiting toxicities including fever without documented infection, HFSR, fatigue, and leukopenia. 2 pts (RCC & osteosarcoma) achieved RECIST partial response. 4 pts had stable disease, one of them a cervical cancer pt with extensive tumor cavitation. PD parameters (decrease in sVEGFR-2 levels, decrease in iAUC60s of Gd-DTPA by DCE-MRI) correlated with drug exposure. Conclusions: BAY 73–4506 was well tolerated at 60 mg with report of dose-limiting toxicities at 120 mg. 6 (28%) of 22 pts demonstrated antitumor activity. Optimal dose and regimen are under evaluation in preparation for phase II trials. No significant financial relationships to disclose.
Pharmacodynamic analysis of receptor tyrosine kinase (RTK) activity reveals differential target inhibition in skin and tumor in a phase I study of advanced colorectal cancer patients treated with AEE788
Authors: Davis D. W. , Huang J. , Liu W. , Xiao L. , Thomas A. , Mita A. , Steward W. , Takimoto C. , Mietlowski W. , Xiong H. 
Published: March 2020

3601 Background: AEE788 (AEE) is an oral inhibitor against tyrosine kinases and has an IC50 of < 100 nM against EGFR and VEGFR-2. This PD study investigated the effects of AEE on its targets in vitro and in biopsies from advanced colorectal cancer patients. Methods: HUVECs and HT-29 cells were incubated with AEE for 4h at 0–1 mM. 22 pts were treated at doses of 25 (n=4), 50 (n=3), 100 (n=4), 250 (n=1), 300 (n=4), and 400 mg (n=6) mg/day in 28-day cycles. No major clinical respones were observed. Wound-induced paired skin biopsies were performed on days -8, -1, 22, 29. Tumor biopsies were obtained before and 28 days post-treatment. Evaluable paired skin and tumor samples were available in 18 and 14 patients respectively. The effects of AEE on pKDR, pEGFR, AKT, Ki67, and apoptosis were analyzed by laser scanning cytometry (LSC). Wilcoxon signed rank test and Spearman correlation were used to compare biomarker changes post-treatment and correlation with dose, respectively. Results: In vitro, AEE treatment resulted in a dose-dependent inhibition of pKDR and pEGFR with inhibition of 65% and 63% at 1 mM in HUVECs and HT-29 cells, respectively. pKDR levels increased in response to AEE treatment in HT-29 cells. In skin, AEE increased basal levels of pKDR (p=0.03) post-treatment. AEE increased AKT (p=0.02) and EGFR (p=0.01) in a dose-dependent manner. In wound-induced skin pairs, AEE significantly inhibited endothelial cell pKDR/KDR (ratio) in a dose-dependent manner (p=0.02). In tumors, AEE increased pKDR expression (p=0.05) and was dose-dependent (p=0.06). Tumor endothelial cell pKDR levels decreased (avg. 47%) after AEE treatment (p=0.08). Furthermore, levels of Ki67 increased (p=0.08) and no significant effects were observed on pEGFR or apoptosis at any dose level in post-treatment samples. Conclusions: LSC quantitative analysis confirmed the target inhibition of AEE in vitro and in wound-induced skin pairs. The lack of significant target inhibition in tumors is consistent with the lack of clinical activity of AEE in this cohort of patients. Quantifying pKDR/KDR in wound-induced skin pairs may serve as a surrogate for assessing the activity of an angiogenesis inhibitor such as AEE. [Table: see text]
How well do we communicate with patients concerning adjuvant systemic therapy? A survey of 150 colorectal cancer survivors
Authors: Love N. , Bylund C. , Meropol N. J. , Marshall J. L. , Curley S. A. , Ellis L. M. , Grothey A. , Lenz H. J. , Saltz L. B. , Elder M. A. 
Published: March 2020

4020 Background: Adjuvant chemotherapy (AC) presents a substantial patient education challenge to medical oncologists (MOs). Findings from our 2005 pilot survey suggest that a significant fraction of colorectal cancer (CRC) survivors are willing to undergo AC for modest treatment benefits, but their understanding of risks and benefits may be suboptimal. This project attempted to validate these findings by surveying patients with CRC (Pts) who previously received AC. Methods: 150 Pts who received AC for CRC in the last 5 years were recruited to listen to an audio program on AC featuring interviews with clinical investigators (CIs) and Pts who received AC. Based on this input, Pts were asked whether they would undergo the same AC again for varying absolute treatment benefits. A corresponding survey asked 24 CRC CIs and 150 MOs to predict how patients would respond. The survey also queried Pts about their expectations of and experiences with AC side effects. Results: About 1/3 of Pts would be treated again with AC for a 1% absolute reduction in recurrence risk (ARRR), and about 2/3 believed a 5% ARRR would justify treatment. There were no statistically significant differences between responses of males and females or between Pts receiving oxaliplatin (OX) and those receiving other regimens. ( Table 1 ) The corresponding estimates of CIs and MOs were lower. Additionally, AC side effects were different than expected: 57% and 66% of Pts experienced less GI toxicity and alopecia, respectively, while 38% and 46% of Pts receiving OX experienced greater cold intolerance and numbness. Conclusions: Many potential obstacles exist in communicating with Pts about AC including heterogeneity in Pts’ attitudes towards risk/benefit trade-offs and preconceptions about treatment side effects. The next step in this initiative will be to examine these issues prospectively by evaluating the impact of an audio/web education supplement on the decision-making process. [Table: see text] No significant financial relationships to disclose.