bluuebunny/crossref_metadata_2025 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.
EGFR, HER2 and Kras as predictive factors for cetuximab sensitivity in colorectal cancer
Authors: Finocchiaro G. , Cappuzzo F. , Jänne P. A. , Bencardino K. , Carnaghi C. , Franklin W. A. , Roncalli M. , Crinò L. , Santoro A. , Varella-Garcia M.
Published: March 2020

4021

Background: In colorectal cancer, biological mechanisms underlying response or resistance to cetuximab, a monoclonal antibody against the extracellular domain of the EGFR are not defined. Small retrospective studies suggested that EGFR increased gene copy number measured by fluorescence in situ hybridization (FISH) or presence of KRAS mutations were associated with cetuximab response or resistance, respectively. This study aimed to identify biological predictors for sensitivity/resistance to cetuximab treatment in colorectal cancer. We also compared biomarker results in primary tumors and corresponding metastases. Methods: We analyzed EGFR (IHC, FISH), HER2 (FISH), and KRAS (mutation) in paraffin embedded tumor blocks from 85 colorectal cancer patients treated with cetuximab. For FISH analyses, a positive result was defined according to criteria described in breast (Wolff et al. J Clin Oncol 2007), lung (Cappuzzo et al. JNCI 2005) and colorectal cancer (Moroni et al. Lancet Oncology 2005). EGFR, HER2 and PIK3CA mutation analyses are ongoing. Results: EGFR FISH positive patients (N=41), defined as ratio EGFR/nucleus =3, had a significantly higher RR (29.3% versus 6.8%, p=0.007) and TTP (6.6 versus 3.7 months, p=0.053) than EGFR FISH negative (N=44). No difference for clinical endpoints was observed using other scoring systems. EGFR expression assessed by IHC was not associated with any clinical end-point. Increased HER2 gene copy number was associated with shorter TTP (p=0.09) and survival (p=0.03). Compared to patients with wild type KRAS (N=49), KRAS mutation carriers (N=32) had a significantly lower RR (6.3% versus 26.5%, p= 0.02), shorter TTP (3.7 versus 6.3 months, p=0.07) and shorter survival (8.3 versus 10.8 months, p=0.2). In 22 patients with available primary and metastatic tumor tissue, there was no difference between these sites for EGFR FISH, HER2 FISH and KRAS results. Conclusions: This study, the largest biomarker analysis in colorectal cancer patients treated with cetuximab, shows a significant benefit in response and TTP for EGFR FISH positive patients. KRAS mutation analysis identifies a group of patients with the lowest chance to benefit from the therapy. Increased HER2 gene copy number predicts early escape from cetuximab therapy.

No significant financial relationships to disclose.
Is more aggressive lymph node assessment associated with improved survival in stage II-III colorectal cancer? Evidence from the Surveillance, Epidemiology and End Results (SEER) cancer registry
Authors: Yeh Y. , Cai Q. , Chao J. , Russell M.
Published: March 2020

4048

Background: NCCN guidelines recommend assessment of =12 lymph nodes (LN) to improve accuracy in colorectal cancer (CRC) staging. Previous studies have used various cut-points to assess the relationship between the number of LN sampled and survival. The association between NCCN guideline-compliant nodal sampling and survival is assessed, while controlling for other risk factors. Methods: We selected 145,485 adult patients newly diagnosed with stage II or III from SEER during 1990–2003. Kaplan-Meier curves were compared using the log-rank test. Cox proportional hazards models were constructed to determine the effect of sampling ≥ 12 LN on survival. Results: Median patient follow-up was 5.7 years. The table shows overall survival rates in CRC patients with < 12 versus =12 LN assessed: After adjusting for age, sex, tumor size and grade, sampling ≥ 12 LN was independently associated with improved survival. For patients with =12 versus <12 LN assessed, survival increased by 13% for stage IIa [HR=0.75; 95%CI 0.72–0.78; p< .001], 16% for stage IIb [HR=0.69; 95%CI 0.67- 0.71; p< .001], 12% for stage IIIb [HR=0.75; 95%CI 0.72–0.77], and 10% for stage IIIc [HR=0.85, 95%CI 0.81–0.89]. The association was not statistically significant for stage IIIa patients. Conclusion: Consistent with previous reports, this analysis found that optimal nodal sampling increased survival across stage II and III, specifically when ≥ 12 LN are sampled and when controlling for other risk factors. Furthermore, the results underscore the need for adhering to the NCCN guidelines. The lack of a statistically significant association in stage IIIa patients may be due to small cohort size.

[Table: see text]

[Table: see text]
Phase II trial of FOLFOX6, bevacizumab and cetuximab in patients with Colorectal Cancer
Authors: Ocean A. J. , O’Brien K. , Lee J. , Matthews N. , Holloway S. , Christos P. , Kung T. S. , Kaubisch A. , Chen H. , Wadler S.
Published: March 2020

4075

Background: Bevacizumab (B) + FOLFOX is widely accepted as a standard first-line therapy for metastatic colorectal cancer (mCRC). Recent treatment strategies have included the use of targeted therapies combined with chemotherapy to improve efficacy and to reduce chemotherapy-related toxicities. This Phase II study assesses first-line mFOLFOX6 + B + cetuximab (C), a monoclonal antibody approved for use in irinotecan-refractory mCRC. Methods: All pts had ECOG PS = 1, normal bone marrow, hepatic and renal function. Pts received mFOLFOX6 + B (5mg/kg) biweekly and C weekly (initially at 400 mg/m2, then subsequent doses at 250 mg/m2). Tumor assessment by imaging was done every 8 weeks. Primary endpoints are response rate, progression free-survival (PFS), overall survival (OS), and safety. The regimen would be considered promising if there were = 32 responses, or if = 60% of pts were progression-free for at least 8 months. Results: 67 pts (37 males, 30 females) were enrolled from 12/04–11/06. Median age was 57. Toxicities included Grade 4: neutropenia (6%), thrombosis/embolism (5%). Grade 3: neutropenia (13%), rash (13%), fatigue (11%), diarrhea (11%), abdominal pain (6%), neuropathy (5%), infection with ≤ Grade 2 ANC (4.5%). There were 2 deaths, 1 due to neutropenia and diarrhea and 1 to pulmonary fibrosis. As of 12/06, 9 pts were too early to evaluate. Of the remaining 58 pts, there were 32 responses (55%; 95% CI: 42%, 68%), including 3 CRs and 29 PRs; Median PFS was 9.6 months (95% CI: 8.8, 13.9 months), 71% were progression-free for at least 8 months, and median OS was not reached after a median follow-up of 11.4 months (range 1.5–25.2 months). Conclusions: Treatment with mFOLFOX6+ B + C met the pre-specified criteria for objective response and PFS to be considered promising. This regimen is associated with an acceptable toxicity profile and merits further evaluation. Supported by N01-CA-62204.

No significant financial relationships to disclose.
Panitumumab activity in metastatic colorectal cancer (mCRC) patients (pts) with low or negative tumor epidermal growth factor receptor (EGFr) levels: An updated analysis
Authors: Mitchell E. P. , Hecht J. R. , Baranda J. , Malik I. , Richards D. , Reiner M. , Stout S. , Amado R. G.
Published: March 2020

4082

Background: Panitumumab, a fully human monoclonal antibody against EGFr, is approved for EGFr-expressing mCRC pts with disease progression (PD) on or after fluoropyrimidine-, oxaliplatin-, and irinotecan-containing chemotherapy. However, the predictive value of EGFr tumor-membrane staining as measured by immunohistochemistry (IHC) is undetermined. Methods: This multicenter, single arm, phase 2 study enrolled pts with documented PD during or after fluoropyrimidine and adequate doses of irinotecan and oxaliplatin, and within 6 months after the most recent chemotherapy regimen (determined by an independent eligibility review committee [IERC]), 2–3 prior regimens, and low (1%-9%) or negative (<1%) EGFr tumor membrane staining (by IHC). Pts received panitumumab 6mg/kg Q2W until PD or intolerability. Tumor assessments (modified WHO, blinded central review) were performed every 8 weeks until PD or discontinuation. Endpoints were objective response rate (ORR) through wk 16 (+ =4 wk confirmation; primary), overall ORR, response duration, progression-free survival (PFS), and safety (secondary). Results: In this interim analysis, 91 pts had =20 wks of potential follow-up and comprised the IERC efficacy set; 118 pts comprised the evaluable safety set (=20 wks potential follow-up). In the IERC efficacy set, 57% were male, 86% were white, and median age (range) was 61 (26–85) years. ORR through week 16 is shown; overall ORR was the same ( Table ). The most common adverse events (all, grade 3/4) were dermatitis acneiform (72%, 6%), erythema (69%, 6%), pruritus (65%, 4%), and hypomagnesaemia by lab values (53%, 10%). Four pts (3%) had an infusion reaction per investigator (1 was grade 3). Conclusions: This analysis confirms earlier findings that panitumumab has anti-tumor activity in pts with low or undetectable EGFr tumor membrane levels as measured by IHC. This study has completed enrollment, and updated data will be presented.

[Table: see text]

No significant financial relationships to disclose.
Phase I/II study of oral fluoropyrimidine S-1 plus oral Leucovorin as first-line treatment for metastatic colorectal cancer
Authors: Yoshino T. , Koizumi W. , Yamaguchi K. , Miyata Y. , Kato T. , Toh Y. , Sawaki A. , Hyodo I. , Nishina T. , Boku N.
Published: March 2020

4093

Background: The results of phase I portion of the treatment with the oral S-1 (a new oral fluoropyrimidine) plus oral leucovorin (LV) in patients (pts) with untreated metastatic colorectal cancer (mCRC) was reported at ESMO 2006. Dose limiting toxicities (DLTs) were grade 3 stomatitis/pharyngitis, nausea, diarrhea, ileus and exanthema. The recommended doses (RDs) for this phase II portion were determined to be S-1 40 mg/m2 and LV 25 mg/body orally given twice daily on days 1 to 14 of a 28-day cycle. The PK profiles of S-1 plus LV were similar to those of S-1 monotherapy and UFT plus LV, respectively. The main purpose of this phase II portion is to evaluate the efficacy and safety of S-1 plus LV at RD level in pts with untreated mCRC. Methods: Pts were eligible as follows; unresectable mCRC with no prior chemotherapy or receiving adjuvant chemotherapy completed at least 6 months before, histologically proven adenocarcinoma, PS(ECOG) 0–2, age 20 to 75, measurable lesions, adequate organ function and written informed consent. The pts received 40 mg/m2 of S-1 plus 25 mg/body of LV twice daily as RD in this phase II portion. The primary endpoint was the objective response rates (RRs), and secondary endpoints were time to progression (TTP) and toxicities. Results: Between Sep 2004 and Jun 2006, 56 pts of 65 enrolled pts received the treatment at RD level. The objective RRs were 55% (36 of 65) for all pts and 55% (31 of 56) for pts at RD. Disease control rates (DCRs) were 86% (56 of 65) for all pts and 86% (48 of 56) for pts at RD. Median TTP was 5.5 months for pts at RD, with a median follow-up of 5.5 months. The median survival time is under observation. During the 6 months from starting the treatment, the most common grade 3/4 toxicities at RD were as follows: diarrhea, 23%; stomatitis, 20%; anorexia, 18%; and neutropenia 13%. Conclusions: A combination of S-1 plus oral LV is an effective, well tolerated, and convenient regimen in pts with untreated mCRC, without the addition of either oxaliplatin or irinotecan. The updated results of the objective RRs, DCRs, TTP reviewed extramurally, and detailed safety profile will be presented at the meeting. This trial was supported by Taiho pharmaceutical co., Ltd., Tokyo, Japan.

No significant financial relationships to disclose.
Modified (m)Folfox7/bevacizumab (B) or modified (m)Xelox/bevacizumab with or without erlotinib (E) in first-line metastatic colorectal cancer (MCRC): Results of the feasibility phase of the DREAM-OPTIMOX3 study (GERCOR)
Authors: Tournigand C. , Lledo G. , Delord J. , André T. , Maindrault-Goebel F. , Louvet C. , Scheithauer W. , de Gramont A.
Published: March 2020

4097

Background: Targeted therapy against VEGF and EGFR both demonstrated clinical activity in combination with chemo in MCRC. In 1st line, B with Folfox or Xelox increase progression-free survival (Cassidy ESMO 2006). In 2nd L, B with Folfox increases overall survival (Giantonio 2005). In this preliminary study, a double inhibition is tested combining mFolfox+B or mXelox+B with or without E, an oral EGFR tyrosine kinase inhibitor. Methods: 38 pts with untreated MCRC were randomly assigned to: mFolfox+B (1A), mFolfox+B+E (1B), mXelox+B (2A) or mXelox+B+E (2B). mFolfox-B=LV 400 mg/m2, Oxaliplatin (ox) 100 mg/m2, B 5 mg/kg day 1, 5FUc 2.4- 3g/m2 46h q2w, mXelox-B=Ox 100 mg/m2 d1 q2w, capecitabine 3–3.5 g/m2 d1 to 7 q2w, B 5mg/kg q2w. Erlotinib=100 mg/day. 6 cy planned. The primary end-points were toxicity and RR. Results : 9pts/41cy in 1A, 10/60 (1B), 9/39 (2A), 10/44 (2B). Median age 62yrs (43–78). 24/38 pts had poor prognosis factors (>1 met. site and/or PS2, LDH>3N, elevated alk Ph): 5, 6, 7, 6 in each arm respectively. 17 pts had a gr3- 4 toxicity: 4/9 arm 1A, 4/10 arm 1B, 2/9 arm 2A, 7/10 arm 2B. Diarrhea (dia) was the main gr3–4 tox: 2/10pts in 1B, 1/9 in 2A & 6/10 in 2B. 3 pts had gr4 dia in arm 2B. Other gr3 tox were nausea-vomiting 4pts (2/0/0/2), cutaneous rash 2 pts (0/1/0/1), hypertension 1 pt (1B), mucositis 1pt (1A), neutropenia 1 pt (1A), thrombocytopenia 1 pt (1A). 1pt had a gr4 venous thrombosis (2A) and 1pt had pulmonary embolism. 1pt died with perforation in arm 1A, and 1pt died with gr4 dia in arm 2B. Amongst the 17pts with gr3–4 toxicity, 11 pts had poor prognosis criteria and 6 had good prognosis. PR, SD, PD and NE are respectively: arm 1A: 5/2/0/2, 1B: 4/6/0/0, 2A:5/3/1/0, 2B:4/3/0/3. Conclusion: The results of this feasibility phase indicate that adding E with mXelox and bevacizumab increases toxicity (70% gr3–4) and is not feasible. Based on these results, the DREAM study was redesigned to evaluate erlotinib in maintenance with B after 6 cycles of mXelox-B or mFolfox-B.

No significant financial relationships to disclose.
A comparison of medical resource use for 4 chemotherapy regimens as first-line treatment for metastatic colorectal cancer (MCRC): XELOX vs. FOLFOX4 ± bevacizumab (A)
Authors: Scheithauer W. , Cassidy J. , Figer A. , Wong R. , Koski S. , Lichinitser M. , Yang T. , Clarke S. , Diaz-Rubio E. , Garrison L.
Published: March 2020

4098

Background: A recent randomized phase III trial with a 2x2 factorial design compared 4 chemotherapy regimens as first-line treatment for MCRC: oral capecitabine + i.v. oxaliplatin q3w (XELOX); 5-FU/LV + i.v. oxaliplatin (FOLFOX4); XELOX+A; and FOLFOX4+A. The XELOX regimens were found to be non-inferior to FOLFOX4 in terms of progression-free survival (the primary endpoint), and the A regimens were superior to the placebo arms. The attractiveness of these regimens to providers, patients, and payers will also depend on the medical resources involved. The purpose of this analysis was to compare the expected resource use across the 4 groups. Methods: A resource use model was constructed based on trial data and projections from trial protocols. Both medical resources and patient time were considered. The medical resources included visits for chemotherapy administration, central venous access (CVA), treatment of adverse events (AEs), and hospital use for common treatment-related AEs. Patient time for chemotherapy administration, ambulatory visits, and hospital stays was estimated. Results: FOLFOX and FOLFOX4+A required more administration visits due to the q2w cycle (22–27 visits in total for the FOLFOX arms vs. 7–9 visits for the XELOX arms). With FOLFOX regimens, patients spend 60–200 additional hours receiving i.v. drug administration, and 22–27 additional hours traveling and waiting to receive chemotherapy. The rate of hospital admissions for common AEs did not differ among the arms, but mean hospital days for common AEs were slightly higher in the XELOX arms. Ambulatory encounters to treat AEs added only about 1 hour of encounter time per patient on average in all 4 arms. The 2 FOLFOX4 arms had twice as many placements for CVA. Conclusion: In the first-line setting, the 2 FOLFOX4 chemotherapy regimens involve substantially more i.v. drug administration visits and time - the equivalent of more than two 40-hour workweeks. The 4 regimens were similar in terms of the amount of resource use needed to treat AEs.

No significant financial relationships to disclose.
Serious arterial thromboembolic events (sATE) in patients (pts) with metastatic colorectal cancer (mCRC) treated with bevacizumab (BV): Results from the BRiTE registry
Authors: Sugrue M. M. , Yi J. , Purdie D. , Dong W. , Grothey A. , Kozloff M.
Published: March 2020

4136

Introduction: BV prolongs overall survival (OS) and progression-free survival (PFS) when added to 1st- or 2nd -line chemotherapy (CT) in mCRC. Though serious toxicities specific to BV are uncommon, a retrospective pooled analysis of 5 randomized trials showed an association of arterial thromboembolic events (ATEs) with BV use (3.8% vs 1.7% with CT alone), with age ≥65 and prior history (Hx) of ATE identified as associated risk factors (Skillings, JCO 2005). The BRiTE mCRC registry evaluated BV-associated serious adverse events (SAEs), including ATEs presenting as SAEs (sATE), in a general practice setting. Methods: Pts and methods have been described (Hedrick ASCO 2006). Hx of sATE, timing of prior sATE relative to starting BV, and anti-platelet agent (anti-plt) use were summarized. Definition of sATE included myocardial infarction (MI), cerebral vascular accident (CVA), transient ischemic attack (TIA), and peripheral arterial disease. Incidence rate of sATE was expressed as events per pt-yr of follow-up. Fisher’s exact test and multiple logistic regression was used to assess the univariate and multivariate associations. Results: Median follow- up was 17.5 mo. Of 1953 evaluable pts, 45.9% (n=896) were ≥65, 18.0% (n=352) had Hx of sATE, and 11.2% (n=219) received anti-plt. A total of 38 sATE [CVA (n=14), MI (n=11), sudden cardiac death (n=1), TIA (n=7), and other (n=5)] were reported in 34 (1.7%) pts. Median time to sATE was 3.6 mo. The calculated sATE rate was 2.2/100 pt-yr overall and 4.7/100 pt-yr in pts with prior sATE. Table 1 summarizes the results of univariate and multivariate analyses. Conclusions: In this series of BV-treated pts, the incidence of sATE associated with BV use was comparable with the rate of analogous events reported in previous controlled trials of BV in mCRC. In this series, prior history of sATE and ECOG PS were found to be associated with sATE risk in multivariate analyses.

[Table: see text]

[Table: see text]
Final results of a randomized trial comparing preoperative 5-fluorouracil (F)/cisplatin (P) to surgery alone in adenocarcinoma of stomach and lower esophagus (ASLE): FNLCC ACCORD07-FFCD 9703 trial
Authors: Boige V. , Pignon J. , Saint-Aubert B. , Lasser P. , Conroy T. , Bouché O. , Segol P. , Bedenne L. , Rougier P. , Ychou M.
Published: March 2020

4510

Background: The combination of 5FU in continuous infusion and cisplatin (FP) is one of the most active regimen in advanced ASLE. The trial was designed to evaluate the impact on survival of 2–3 cycles of preoperative FP in resectable ASLE. Methods: Patients (pts) with resectable adenocarcinoma of the stomach (S) without cardia involvement, cardia (C) or lower esophagus (LE), age ≤ 75 yrs, WHO performance status (PS) < 2 were eligible. Pts were centrally randomized between surgery alone (arm 1) and preoperative FP (arm 2). Chemotherapy (CT) included 2–3 cycles of P (100 mg/m2) and F (800 mg/m2 d1-d5 continuous infusion) every 28 days. Post- operative FP was recommended in arm 2 in case of response to FP preoperative or stable disease with pN+. The main endpoint was overall survival. Comparison of disease-free survival (DFS) used 6-month landmark method and two-sided logrank test. Results: Between 1995 and 2003, 224 pts (arm 1 = 111 pts, arm 2 = 113 pts) were randomized from 28 centers. Initial pts characteristics were equally balanced for age (mean, 61 yrs), gender (83 % male), PS (75 % WHO 0), tumor site (S = 25 %,C = 64 %, LE = 11 %). Median follow-up was 5.7 years. In arm 2, FP was given before surgery in 109 pts (98 pts > 2 cycles) and after surgery in 54 pts. R0 resection rate was 73 % in arm 1 versus 84 % in arm 2 (p=0.04). Preoperative CT improved DFS (p=0.003): hazard ratio (HR) 0.65 (95%CI 0.48–0.89), with 3 and 5-year DFS of 25% (18–34%) and 21% (14–30%) in arm 1 vs. 40% (31–49%) and 34% (26–44%) in arm 2, respectively. HR of death was 0.69 (0.50–0.95, p=0.02) with 3 and 5- year overall survival (OS) of 35% (27–44%) and 24% (17–33%) vs. 48% (39–57%) and 38% (29–47%), respectively. Similar results on OS were observed using Cox model stratified on center and adjusted on gender, age, performance status, and tumor localization. No significant variation of chemotherapy effect with tumor localization was observed. Conclusions: Preoperative chemotherapy using 5- fluorouracil/cisplatin improves disease-free and overall survival in patients with resectable adenocarcinoma of stomach and lower esophagus.

No significant financial relationships to disclose.
Gemcitabine-based combinations (gem+x) vs gemcitabine (gem) alone in the treatment of advanced pancreatic cancer: a meta- analysis of sixteen randomized trials
Authors: Heinemann V. , Hinke A. , Böck S. , Labianca R. , Louvet C.
Published: March 2020

4515

Background: Sixteen randomised trials have compared Gem-based combination chemotherapy to Gem alone in advanced and metastatic pancreatic cancer. This analysis was performed to better define the role of combination chemotherapy in pancreatic cancer. Methods: The meta-analysis included 16 studies comparing Gem vs. Gem+X. Fifteen trials were evaluable for survival, the primary end-point of the investigation. Overall, 4465 patients (pts) were included, 2222 pts in the Gem+X arm, and 2243 pts in the Gem arm). The analysis was predominantly based on published summary data. Results: Three groups were formed: combinations with platinum analogs, fluoropyrimidines, or other cytotoxic agents. Five trials evaluated platinum-based combinations (3 cisplatin, 2 oxaliplatin). The combined analysis indicated a hazard ratio (HR) of 0.85 (95% CI: 0.76–0.96) demonstrating a significant (p=0.010) superiority of the combination. Further 6 trials investigated the combination of Gem with fluoropyrimidines (3 5-FU, 3 capecitabine). Again, a significant superiority of the combination therapy was observed with a HR of 0.90 (95% CI: 0.81–0.99; p=0.030). Among the fluoropyrimidine combinations greatest homogeneity of results was observed in trials combining gemcitabine with capecitabine. In four randomised trials no improvement of survival was observed when Gem was combined with other cytotoxic agents such as pemetrexed, exatecan or irinotecan (HR=0.99; 95% CI: 0.88–1.10; p=0.80). When all 15 evaluable trials are taken together, an overall hazard ratio of HR=0.91 (95% CI: 0.85–0.97; p=0.004) was achieved. Five trials including 1682 pts provided adequate information on baseline performance status (PS). Combination chemotherapy had a marked benefit on survival in pts with a good PS (HR=0.76; 95%CI: 0.67 - 0.87; p<0.0001), while it was not more effective than Gem alone in pts with an initially poor PS (HR=1.08; 95% CI: 0.90 - 1.29). Conclusions: A meta-analysis of fifteen randomised trials indicated a significant survival benefit for Gem+X as compared to Gem alone when Gem was combined with either a platinum analog or capecitabine. This benefit was greatest in pts with a good PS, while no benefit was evident in poor PS pts.

No significant financial relationships to disclose.