bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I study of GTI-2040 (G), an antisense to ribonucleotide reductase (RNR), in combination with high-dose AraC (HiDAC) in acute myeloid leukemia (AML)
Authors: Marcucci G. , Klisovic R. B. , Wei W. , Liu S. , Paschka P. , Huynh L. , Zwiebel J. A. , Byrd J. C. , Grever M. R. , Chan K. , Blum W.
Published: March 2020

6561

Background: RNR converts ribonucleotides to deoxyribonucleotides for DNA synthesis. AraC is converted into AraC triphosphate (AraCTP) and competes with deoxycytidine for DNA incorporation. We hypothesized that RNR downregulation by G leads to lower deoxycytidine levels, preferential AraCTP incorporation into DNA and increased cytotoxicity. A CTEP-sponsored Phase I dose escalation study of G +HiDAC in relapsed/refractory AML tested this hypothesis. Methods: Cohort I (18–59 yrs) received G (dose level (DL) 1: 3.5 mg/m2/d) by continuous IV infusion (CIVI) on d 1–6 + AraC IV q12 hrs on d 2, 4, 6 (DL1: 2500 mg/m2/dose). Cohort II (≥60 yrs) received G CIVI on d 1–6 +AraC IV on d 2 −6 (DL1: 1500 mg/m2/d). An ELISA-based assay measured plasma and intracellular concentration (IC) of G. Results: To date, cohort I included 9 pts with relapsed and 9 with refractory AML; 9 had intermediate and 9 adverse risk cytogenetics (CyG); 8 received prior HiDAC. Cohort II included 10 pts with relapsed and 6 with refractory AML; 8 pts had intermediate and 8 high risk CyG; 5 pts received prior HiDAC. Toxicities were comparable to HiDAC alone. The younger pts had higher AUC and longer t1/2. Of 16 pts evaluable in cohort I (median time to 1st relapse 6 mos), 6 had complete remission (CR) and 1 incomplete CR (no disease and incomplete blood count recovery). In cohort II, no responses were observed. At 120 hrs of antisense infusion, median G IC in marrow cells was higher (i.e., 175 vs75 nM) in younger than in older pts. A median 50% decrease in RNR protein was noted in 5/9 and 5/10 pts in cohort I and II, respectively. In cohort I, a median 50% decrease and 200% increase in RNR was noted in CR (n=4) and non-responder (NR; n=9) pts, respectively. In cohort II R2 downregulation did not predict response. In cohort I 62% of the ICs was in nucleus and 21.2% in cytoplasm in CR pts (n=3) vs. 20.3% and 53.5% in NR pts(n=5). Conclusions: G/HiDAC is feasible. Robust plasma and IC levels of G and target downregulation are achievable in vivo. Responses (41%) were observed only in the younger cohort, where CR pts had higher G nuclear IC and target downregulation than NR pts. Dose escalation continues in the younger cohort to establish a dose for Phase II trials.

No significant financial relationships to disclose.
Tranfusion independence assessed using three alternative dosing schedules of azacitidine in patients with myelodysplastic syndromes
Authors: Anthony S. , Lyons R. , Cosgriff T. , Modi S.
Published: March 2020

6574

Background: The dosing schedule of azacitidine (75 mg/m2/day subcutaneous [SC] × 7 days, every 28 days) decreased transfusion requirements in myelodysplastic syndrome (MDS) patients in a CALGB trial by Silverman et al (JCO 2002;20:2429). Our study assessed effects on transfusion requirements in MDS patients receiving 3 alternative azacitidine dosing regimens not requiring weekend injections. Methods: This phase II, multicenter study enrolled MDS patients with any FAB subtype, life expectancy ≥7 months, and ECOG performance grade of 0–3. RA/RARS patients had to have ≥1 of the following: hemoglobin <110 g/L with transfusion need, platelet counts <100 × 109/L, or ANC <1.5 × 109/L. Patients were randomized to 1 of 3 SC regimens: AZA 5–2-2 (75 mg/m2/day × 5 days, followed by 2 days no treatment, followed by 75 mg/m2/day × 2 days), AZA 5–2-5 (50 mg/m2/day × 5 days, followed by 2 days no treatment, followed by 50 mg/m2/day × 5 days), or a 3rd regimen added later by protocol amendment: AZA 5 (75 mg/m2/day × 5 days). After 6 cycles, patients meeting International Working Group MDS response/improvement criteria (Blood 2000;96: 3671) of ≥ stable disease could continue in study for 12 more cycles. Results: In all, 75 patients (median age, 74.5 years; 61% male) are currently enrolled with 49 evaluable (completed ≥ 2 treatment cycles). To date, 12, 9, and 1 patient(s) have received ≥6 cycles of AZA 5–2-2, AZA 5–2-5, or AZA 5, respectively. RA + RARS, defined by FAB (60%) or WHO (47%), are the most common MDS subtypes. Of 24 patients, RBC transfusion dependent at baseline, 13 (54%) became independent ( Table ). Only 2 patients were platelet transfusion dependent at baseline; both became independent. After a median followup of 24 weeks, median duration of transfusion independence has not been reached. Conclusions: Treatment with azacitidine yields transfusion independence rates of 40%-60%. These preliminary results are similar across the 3 alternative doses and consistent with previous azacitidine data.

[Table: see text]

No significant financial relationships to disclose.
Response to azacitidine (AZA) in patients with secondary myelodysplastic syndrome
Authors: Abdulhaq H. , Haq B. , Rossetti J. , Lister J. , Shadduck R.
Published: March 2020

6578

Background: Myelodysplastic syndrome (MDS) is characterized by maturation defects in hematopoietic progenitor cells that result in ineffective hematopoiesis, various cytopenias and risk of progression to acute myeloid leukemia. MDS can arise de novo or secondary to exposure to myelotoxic drugs or ionizing radiation. Secondary MDS (t-MDS) tends to have more aggressive behavior than de novo MDS. Azacitidine (AZA), a DNA methyl transferase inhibitor has activity in MDS. To date there is little data in patients with t-MDS Methods: The records of 21 patients with t-MDS treated with AZA between 05/96 and 01/06 were reviewed to determine response, duration of response and tolerability in these high-risk patients. 15 of the 21 patients received AZA as part of a National Cancer Institute special exception program (75mg/m2 subcutaneously for seven days every four weeks). Patients who received at least 2 cycles were considered evaluable for response (N=16). All patients were evaluated for toxicity. The International working group standardized response criteria for MDS were used for evaluation. Results: Patients had a median age of 68 years; male: female ratio was 3:1. 11 patients had refractory anemia, 6 had refractory anemia with excess blasts, 3 had chronic myelomonocytic leukemia, 1 had refractory anemia with ringed sideroblasts. Response was seen in 8 (50%) of 16 patients, with 2 (12.5%) partial remissions, 6 (37.5%) showed major hematological response. The median duration of response was 12.3 months (range 4–38). Stable disease was seen in 5 patients (31%), with an average duration of 6.5 months (range 2–15). 3 patients failed therapy due to disease progression or death. Treatment was well tolerated in general, with the most side effects being nausea, vomiting, diarrhea and cytopenias. Febrile neutropenia was seen in 5 patients. Conclusions: Azacitidine appears to be effective and well tolerated in patients with t-MDS.

[Table: see text]
A phase I study of busulfan consolidation/intensification therapy for patients with high risk acute myeloid leukemia (AML)
Authors: Gharibo M. M. , Schaar D. , Rubin A. , Grospe S. , Dudek L. , Strair R.
Published: March 2020

6580

Background: Elderly AML patients have a poor prognosis. More effective well-tolerated treatments are needed to improve outcomes. Busulfan is an effective anti-leukemia drug commonly used in transplant regimens. We designed a phase I dose escalation study of single dose busulfan as consolidation/intensification therapy for elderly patients with AML. Methods: Patients in CR1 not candidates for transplantation or anticipated to benefit from high-dose cytarabine were enrolled. Cohorts were studied at 100mg/m2-120mg/m2, as a single oral dose of busulfan. The starting dose was based on a previous report (Ranson et al. Br J Haematol 79:162.1991). GM-CSF was started after busulfan until ANC> 2000/mm3. Dilantin was used for seizure prophylaxis. Results: 15 patients median age 71 (range 64–82) received treatment and are evaluable for toxicity, 14 are evaluable for response. No DLT was observed. Ongoing remission was seen in 3 patients (range 3 +- 7 + years). One patient (AML/MDS) was in remission for 52 months and died from small cell lung cancer and 1 patient was in remission for 15 months and died from cervical cancer. Two additional patients had prolonged remissions (32 and 55 months) prior to relapse. Seven patients relapsed between 4 weeks and 6 months. Treatment was well tolerated with no prolonged neutropenia. In patients who recovered without evidence of leukemia transient grade 3/4 thrombocytopenia occurred with average duration of 16 days (10–23 days) requiring 0–5 transfusions (average 2). Only 2 patients required RBC transfusion. No infectious complications or hospitalizations occurred in the absence of recurrent AML. Three patients experienced side effects from GM-CSF and received G-CSF in it’s place. Two patients experienced grade 2 fatigue and dyspnea. Conclusions: Single dose oral busulfan is an effective and well-tolerated outpatient consolidation/intensification therapy for patients with high-risk, AML. Prolonged remissions have been seen in 6 of 14 evaluable patients treated to date. Only transient bone marrow suppression requiring minimal transfusion support was seen. There were no hospitalizations or infections noted in patients without recurrent AML. The dose escalation will continue until MTD reached.

No significant financial relationships to disclose.
A phase I clinical trial of the notch inhibitor MK-0752 in patients with T-cell acute lymphoblastic leukemia/lymphoma (T-ALL) and other leukemias
Authors: Deangelo D. J. , Stone R. M. , Silverman L. B. , Stock W. , Attar E. C. , Fearen I. , Dallob A. , Matthews C. , Stone J. , Freedman S. J. , Aster J.
Published: March 2020

6585

Background: Functional screening of T-ALL cell lines for sensitivity to NOTCH inhibitors has led to the discovery of frequent NOTCH1 gain-of-function mutations in the majority of human T-ALL. Gamma secretase catalyzes the cleavage of the Notch receptor within the transmembrane domain thereby releasing the Notch intracellular domain, which translocates to the nucleus to activate transcription of target genes. Gamma secretase inhibitors can induce G0/G1 arrest, decrease cell viability, and cause apoptosis of T-ALL cell lines carrying Notch activating mutations. MK-0752 is a potent gamma secretase inhibitor in clinical development (IC50 ∼50 nM). Methods: Patients with relapsed T-ALL and other leukemias were enrolled using an accelerated dose escalation scheme with 1 patient/dose level until ≥ grade 2 toxicity, followed by 3–6 patients/level. MK-0752 was administered by once-daily oral dosing in 28 day cycles. DLT was grade 3 or 4 non-hematologic toxicity during cycle 1. Plasma pharmacokinetic (PK) profiles and Abeta40 peptide levels were measured. Results: Six adult and two pediatric patients with leukemia (seven with T-ALL and one with AML) received MK-0752 dosed at 150, 225, and 300 mg/m2. Treatment duration ranged from 2 days to 56 days before patients discontinued for disease progression or drug-related toxicity. Dose-limiting toxicity (DLT) was Grade 3/4 diarrhea at 300 mg/m2. Four of the seven T-ALL patients had Notch activating mutations. One patient with T-ALL and a Notch activating mutation treated with 150 mg/m2 (300 mg) daily achieved a 45% reduction in a mediastinal mass at the end of 28 days as best response, but subsequently progressed by 56 days. Mean PK parameters at 150, 225, and 300 mg/m2 on Day 1 were AUC0–24hr = 723, 754, 1592 μM·hr, Cmax = 55, 40, 121 μM, C24hr = 18, 28, 59 μM, and tmax = 1, 8, 9 hr. Measurements of gamma secretase inhibition showed a 24–69% decrease in plasma Abeta40 peptide levels on Day 14 compared to predose. Conclusions: MK-0752 was well-tolerated in a limited number of patients below 300 mg/m2, and further enrollment is underway to establish the MTD. Plasma concentrations of MK-0752 at all doses were sufficient to inhibit gamma secretase. Leukemia samples will be assessed for Notch inhibition.

[Table: see text]
A phase II study of AMN107, a novel tyrosine kinase inhibitor, administered to patients (pts) with systemic mastocytosis (SM)
Authors: Schatz M. , Verhoef G. , Gattermann N. , Ottmann O. G. , Schimansky T. , Alland L. , Rafferty T. , Gratwohl A. , Follows G. , Hochhaus A.
Published: March 2020

6588

Background: SM is a clonal hematologic disorder associated with a constitutive activation of c-kit based on point mutations of this tyrosine kinase and is characterized by mast cell infiltration of extracutaneous organs. AMN107 is a novel aminopyrimidine which potently inhibits Bcr-Abl, as well as the PDGFR and c-kit kinases. Methods: This phase II, open-label study was designed to evaluate the safety and efficacy of AMN107 (400 mg bid). SM pts meeting specific disease criteria and with a clinical indication for treatment were enrolled. Preliminary data are presented for the first 23 pts accrued prior to September 1, 2005. Results: The median age was 49 (range 33–78) yrs and the median time from diagnosis of SM was 27 (range 1 to 292) months. For those with data available, 13/17 pts had a c-kit D816V mutation in bone marrow cells. The median exposure to AMN107 was 144 days. Treatment is ongoing for 18 (78%) pts; 5 (22%) discontinued, 3 (13%) for adverse events and 2 (9%) withdrew consent. Three (13%) responses were reported (2 incomplete remissions and 1 minor response), based on serum tryptase, bone marrow mast cell infiltration and improvement of clinical symptoms. Baseline mutation data are available for 2 of the 3 responding pts and revealed the c-kit D816V mutation. Anemia was reported in 2 (9%) pts. Non-hematologic toxicities in ≥10% of pts were headache in 12 (52%) pts (Gr 3/4 in 2; 9%), fatigue in 9 (39%) pts (Gr 3/4 in 1; 4%), nausea in 8 (35%) pts, vomiting in 7 (30%) pts, pruritus in 7 (30%) pts (Gr 3/4 in 2; 9%), muscle spasms in 6 (26%) pts (Gr 3/4 in 1; 4%), diarrhea in 5 (22%) pts (Gr 3/4 in 1; 4%), upper abdominal pain, rash in 5 (22%) pts each, dizziness, pain in extremities in 4 (17%) pts each (Gr 3/4 in 1; 4% each), dyspnea, myalgia, in 4 (17%) pts each, increased ALAT in 4 (17%) pts (Gr 3/4 in 2; 9%), bone pain, abdominal pain, cough, hard feces, pustular rash in 3 (13%) pts each, and hypotension in 3 (13%) pts (Gr 3/4 in 2; 9%). There were no deaths. Conclusions: These data suggest that AMN107 has clinical activity and an acceptable safety and tolerability profile in pts with SM.

[Table: see text]
Prospective study of incidence and severity of epiphora and canalicular stenosis in patients with metastatic breast cancer receiving docetaxel
Authors: Amin S. R. , Valero V. , Rivera E. , Adinin R. , Banay R. , Arbuckle R. , Do K. , Esmaeli B.
Published: March 2020

659

Background: To determine the incidence and severity of epiphora and canalicular stenosis in patients receiving weekly or every-3-weekly docetaxel. Methods: In this prospective trial, each patient underwent an ophthalmologic examination and probing and irrigation of the lacrimal drainage apparatus at baseline and at every 4–6 weeks after initiation of docetaxel. During each visit, epiphora and canalicular stenosis were graded. Patients with epiphora were treated with Tobradex drops. If epiphora worsened or findings on probing and irrigation suggested further canalicular narrowing, silicone intubation was offered. Results: 28 patients received weekly and 28 patients received every-3-weeks docetaxel. 18(64%) patients who received weekly docetaxel developed epiphora. Epiphora was mild in 7 patients, moderate in 5, and severe in 6. Nine patients had resolution of epiphora with Tobradex. Nine patients had worsened canalicular stenosis; 6 underwent surgery. The median cumulative docetaxel dose was 496.5 mg at onset of epiphora and 889.5 mg at surgery. 11 (39%) patients who received every-3-weeks docetaxel developed epiphora. The median cumulative docetaxel dose at the time of onset of epiphora in this group was 420 mg. Epiphora was mild in 9 patients, moderate in 1, and severe in 1. Nine patients had resolution of epiphora in response to Tobradex. Two patients underwent surgery. Conclusions: Epiphora occurred in 64% of patients in the weekly group and 39% of patients in the every-three-weeks group. Moderate or severe canalicular stenosis was seen in about one-third of patients in the weekly group and none of the patients in the every-3-weeks group.

[Table: see text]
The combination of rituximab and GM-CSF in elderly patients with chronic lymphocytic leukemia (CLL)
Authors: Ferrajoli A. , O’Brien S. , Faderl S. , Wierda W. G. , Schlette E. , Jorgensen J. L. , Reuben J. M. , Albitar M. , Keating M. J.
Published: March 2020

6602

Background: CLL is a disease found more frequently in the elderly (50% of the patients are age ≥70 at diagnosis). Nevertheless treatment startegies for elderly patients have not been optimized. Elderly patients are often excluded from chemotherapy programs because of fear of severe toxicities resulting from myelosuppression. Therefore, we explored the activity of rituximab in combination with GM-CSF in elderly patients with CLL. The rationale for this combination stems from in vitro data showing increased activity of rituximab when administered togheter with GM-CSF (Venugopal P. Leuk. Res.2000). Methods: Patients age ≥70 years, untreated or previously treated, were eligible if they had indications for treatment (NCI-WG criteria). Treatment consisted of rituximab 375 mg/m2 administered weekly for 4 weeks and GM-CSF 250 mcg s.q. three times weekly for 8 weeks. In the first week GM-CSF was given on day 1 and 3 and rituximab was given on day 4. Genomic aberrations, IgVH mutation status, ZAP-70 and CD38 expression were evaluated prospectively. Correlative studies measured changes in cell surface and soluble CD20, apoptosis and quality of life (FACT-An V4). Results: 39 patients have been enrolled, 28 are evaluable for response and 31 for toxicity. According to NCI criteria the OR rate was 61%. 7% of the patients achieved CR, 11% nodular PR and 43% PR. Thirty patients are alive and the median time to treatment failure has not been reached with a median follow up of 5 months. Toxicity attributable to GM-CSF was G1 injection site reaction observed in 16% of the patients. OR rates were higher in naive than in previously treated patients (74% vs 46%), in patients with favorable genomic features (73% vs 40%) and mutated IgVH (89%vs 44%). No difference in OR was found in patients expressing high or low CD38 (60% vs 55%). Upregulation of surface CD20, measured 24h after the 2nd dose of GM-CSF, was observed in 3 out of 4 patients studied. Fatigue level was reduced by a mean of 7 points according to the FACT-An scale (6 patients). Conclusions: Treatment with rituximab and GM-CSF induced a high response rate with minimal toxicity in elderly patients with CLL. Priming with GM-CSF resulted in increased expression of surface CD20. This combination of rituximab and GM-CSF improved systemic symptoms such as fatigue.

[Table: see text]
A single arm phase II trial of gemcitabine (G) and irinotecan (I) in metastatic breast cancer: Can localization of topoisomerase I (topo I) predict response to topo I inhibitors?
Authors: Moulder S. L. , Valkov N. , Minton S. , Munster P. , Gump J. , Lacevic M. , Rocha-Lima C. , Horton J. , Lush R. , Sullivan D.
Published: March 2020

661

Background: The incorporation of G into DNA enhances cleavage complexes in vitro when combined with a topo I inhibitor. Topo I poisons require enzyme interaction with DNA to exert activity. Methods: Two stage accrual design, primary endpoint: response (RR) using RECIST criteria. Inclusion criteria: male and female patients (pts) with MBC, prior anthracycline therapy, measurable disease, ECOG PS of ≤ 2, adequate organ function, and ≤ 3 prior chemotherapy regimens for MBC. 51 eligible pts received therapy with G at 1000mg/m2 and I at 100mg/m2 on days 1 and 8 of a 21-day cycle. Optional tumor biopsies were obtained in 9 pts (18%) prior to therapy to determine localization of topo I using immunofluorescence. PK: Irinotecan: A validated limited sampling strategy was used. Gemcitabine: Serial blood samples were collected over 24 hrs following the first dose. Intracellular nucleotides were quantitated in PBMCs. Results: 45 pts have been evaluated with a RR of 27% (CR=0, PR=12; 95% CI 13–37%). 4 pts had SD for ≥6 months for a clinical benefit rate (PR+SD) of 36%. 3 pts received < 1 cycle of therapy before protocol withdrawal and were not evaluable for RR. RR for the final 3 patients will be available at the time of presentation. 7/9 tissue biopsies were assessable for topo I with results listed below. PK and toxicity data will be available at presentation.Conclusion: GI is active in MBC. Topo I localization can be measured in MBC. In this limited data set, the two lowest nuclear to cytoplasmic (N/C) ratios were associated with lack of response to irinotecan. Further validation is needed.

[Table: see text]

[Table: see text]
A phase II trial of the novel oral camptothecin gimatecan (G) in women with anthracycline (A) and taxane (T) pre-treated advanced breast cancer
Authors: Mariani P. , Moliterni A. , Da Prada G. , Hess D. , Gamucci T. , Zaniboni A. , Malossi A. , Barbieri P. , Marsoni S. , Gianni L.
Published: March 2020

662

Background: Gimatecan (G) is a new oral camptothecin with a favourable therapeutic index in several tumor xenograft models and with documented antitumor activity in breast, endometrial and NSCLC cancer in Phase I. A Phase II trial was implemented to determine the antitumor activity of G in women with pre-treated metastatic breast cancer (MBC). Methods: A Simon 2-step design was used: patients with MBC who failed A & T were eligible. Treatment failure was defined as disease progressing after receiving both A and T (adjuvant or metastatic setting). All patients had ECOG 0–1. Baseline neuropathy > gr 1 or CNS metastases were criteria of exclusion. G was administered for 5 days every week on weeks 1 & 2 q4weeks at 4–5 mg/m2 total dose per cycle. Results: To date, 21 patients have received 67 cycles of G (median 3); 18 are evaluable for the 1st step analysis. Median age was 53 years (range, 32–70), all had received A & T prior treatment. The initial dose of 5 mg/m2 was reduced to 4 mg/m2 after treating the first 7 cases due to hematological toxicity (thrombocytopenia G3 30% and neutropenia G3–4 40%) that prevented the planned monthly retreatment. The toxicity at 4 mg/m2 included thrombocytopenia (% of cycles with any grade: 36%, G3 9%); neutropenia (G3 18%), diarrhea (1 case), nausea (81%, G3 18%), vomiting (G1 18%), and asthenia (G1 36%). To date, three confirmed partial responses (PR) lasting respectively 5.5, 5.7+, and 9.4+ months and two unconfirmed PR were observed in visceral and nodal sites. Accrual into step 2 is proceeding. Conclusions: Gimatecan at a dose of 4 mg/m2 is well tolerated and active. The antitumor activity of 27% observed in the first step of the study is unusual for camptothecins and prompted to continue to the second step and complete the ongoing enrolment of 43 patients overall.

[Table: see text]
Phase II study of capecitabine (X) + docetaxel (T) as neoadjuvant treatment in patients (pts) with locally advanced breast cancer (LABC) including biological correlates
Authors: Bellet M. , Muñoz M. , Bellosillo B. , Corominas J. , Pena T. , Suárez M. , Maristany M. , Perich J. , Tusquets I. , Fabregat X.
Published: March 2020

664

Background: X and T have demonstrated synergy in preclinical studies and survival benefits in metastatic BC. We aimed to determine whether the high efficacy of XT could translate into the neoadjuvant setting. Methods: Expression levels (mRNA) of 3 enzymes involved in X intratumoral activation and metabolism (thymidylate synthase [TS], thymidine phosphorylase [TP] and dihydropyrimidine dehydrogenase [DPD]), were determined in tumor biopsies before treatment and their relationship with clinical and pathological response analyzed using Fisher’s Exact Test. Pts with stage IIIA/IIIB LABC, adequate organ function and KPS ≥80 received 4 cycles of X 1250mg/m2 (1000mg/m2 for age >60) bid d1–14 and T 75mg/m2 d1 q3w followed by surgery, adjuvant AC q3w × 4 ± tamoxifen according to ER and PR status. The primary endpoint was pCR. Results: We enrolled 34 pts with LABC IIIA (44%)/IIIB (56%): median age 52y (30–72); KPS ≥90 (76%); median tumor size 6.8cm (2–20); N0 (20%), N1 (41%), N2/3 (35%); ER+PR-/p53+/HER2+ (23/24/28%). 128 cycles of X and T were administered (median 4, range 1–5). Main G3/G4 toxicities were: HFS 32%, diarrhea 15%, asthenia 9%, stomatitis 6% and neutropenia 71%. There were no treatment-related deaths. 2 pts were withdrawn prematurely due to adverse events. The overall response in 32 evaluable pts was 78%, including 5 CRs and 20 PRs. 6/29 pts evaluable for pathological response had pCR (20%), and 10 (33%) had ≤10mm residual tumor (3 microscopic RD) in breast. Nodal involvement after chemotherapy was N0 (33%), N1 (33%), N2 (27%), N3 (7%), and the rate of breast-conserving surgery was 17%. High TP/DPD ratio was associated with CR (p=0.037) and both high TP/DPD and low TS/DPD ratio appeared to correlate with residual tumor ≤10 mm (p=0.028). Conclusions: Neoadjuvant XT appears to be highly active. Safety was similar to that reported in anthracycline-pretreated pts but with less stomatitis. In this small sample, a high TP/DPD ratio appears to correlate with clinical response and a favorable enzymatic profile (high TP/DPD and low TS/DPD ratio) may predict for high pCR. A further prospective study is required to validate this hypothesis.

No significant financial relationships to disclose.
Clinical response assessment after 2 cycles of neoadjuvant chemotherapy for primary breast cancer fails to predict for final clinical response, but does predict for pathological complete response
Authors: Beresford M. J. , Chin Y. , Burcombe R. , Ah-See M. , Makris A.
Published: March 2020

667

Background: Neoadjuvant chemotherapy (NC) is increasingly being used for large primary breast carcinomas. Clinical trials have established its role in improving breast-conserving surgery (BCS) rates and have shown that complete pathological response (pCR) is associated with improved survival. Early evaluation of response is important for selecting patients with possible worse outcomes, who may benefit from alternative treatments. Methods: 107 women received NC for large operable breast cancers (T2–4, N1–2, M0). Patients received 6 cycles of FEC chemotherapy (5-FU 500mg/m2, epirubicin 75mg/m2, cyclophosphamide 500mg/m2 every 21 days) prior to a planned operation. Clinical response was recorded at baseline, after 2 cycles of NC and on completion of 6 cycles. Baseline and completion ultrasound and/or mammography were performed and a pathological assessment of response was made in those patients who underwent surgery. Results: Median age was 50 (range= 29–78). Overall clinical response rate after 2 cycles of chemotherapy was 59.8% (64/107) and after 6 cycles was 84.1% (90/107). 56 patients (52.3%) underwent BCS, 37 (34.6%) mastectomy and 14 (13.1%) no operation. Overall pCR rate was 15.0% (16/107). Of the 43 patients who failed to respond clinically after 2 cycles, 27 (62.8%) went on to exhibit a clinical response on completion of chemotherapy. 3 (7.0%) patients went on to have a complete clinical response and 21 (48.8%) underwent BCS. However, none of these 43 patients demonstrated a pCR. Conclusions: Lack of clinical response after 2 cycles of neoadjuvant chemotherapy does not preclude clinical response after further treatment with the same schedule, and many women will have sufficient down-staging to enable breast-conserving surgery. However, a pathological complete response is unlikely if no clinical response is observed after 2 cycles.

No significant financial relationships to disclose.
Impact of symptoms and toxicity on quality of life: Exploratory analysis of gemcitabine plus docetaxel vs capecitabine plus docetaxel in metastatic breast cancer
Authors: Fumoleau P. , Romieu G. , Chan S. , Huober J. , Tubiana-Hulin M. , Schneeweiss A. , Lluch A. , Bougnoux P.
Published: March 2020

682

Background: A recent phase III trial comparing gemcitabine-docetaxel (GD) with capecitabine-docetaxel (CD) for metastatic breast cancer (MBC) found comparable progression-free survival but patients (pts) on GD had less toxicity (Chan, ASCO 2005). To better understand how quality of life (QoL) is impacted by toxicity and symptoms, we conducted an exploratory analysis. Methods: The study had 305 pts who relapsed after anthracycline-based treatment either in (neo)adjuvant or first-line MBC. Pts were randomized to GD or CD for 21-day cycles until PD or unacceptable toxicity. QoL was assessed every cycle with Rotterdam Symptom Checklist (RSCL). Only pts with RSCL data were included in the QoL analysis. Comparison between arms of changes from baseline in RSCL dimensions at each cycle were analyzed using analysis of co-variance (ANCOVA). Because the physical symptom distress scale (PSDS) includes symptom- and toxicity-related items, distributions of responses to each item were explored. Results: 302 pts received treatment (GD 152; CD 150); median number of cycles was 6 for both arms. 267 pts (88%) had baseline RSCL data; compliance ranged from 79%-88% for the first 6 cycles. Baseline RSCL scores were comparable between arms. No statistical differences between arms were seen for any of the RSCL dimensions (p>.05 at all cycles). Both arms had worsening in the PSDS (median increases of 3–6.8 on 69-point scale). Numerical differences were seen in some PSDS items rated as “quite a bit” or “very much.” By cycle 3, more GD pts reported tiredness (58% v 47%), lack of energy (45% v 38%), back pain (19% v 9%), and by cycle 2, alopecia (76% v 66%). By cycle 1, more CD pts reported tingling hands/feet (15% v 7%) and burning/sore eyes (14% v 3%). Conclusions: Preliminary analysis indicated no QoL differences between GD and CD; however, further exploration shows that physical distress is explained by different symptoms and toxicities in each arm. Results, particularly at later cycles, should be cautiously interpreted because of pt attrition and different reasons for discontinuation (eg, more CD than GD pts discontinued due to serious adverse events [28% v 13%]). Further analysis incorporating clinical outcomes may better explain QoL outcomes

[Table: see text]
Prevalence and correlates of fatigue and depression in breast cancer survivors: Breast cancer quality care study
Authors: Kim S. H. , Park B. W. , Ahn S. H. , Noh D. Y. , Nam S. J. , Lee E. S. , Yun Y. H.
Published: March 2020

683

Background: Fatigue and depression may persist for months or even years after completion of breast cancer treatment. We investigated the prevalence and correlates of fatigue and depression in disease-free breast cancer survivors. Methods: 1,933 breast cancer survivors recruited from five large hospitals in Korea completed standardized questionnaires as part of a survey study, including the patient demographics, Brief Fatigue Inventory, Beck Depression Inventory, European Organization for Research and Treatment of Cancer (EORTC) QLQ-C30, and QLQ-BR23. Women were eligible to participate if they had a past diagnosis of breast cancer (stage 0, I, II, or III) and were currently free of the disease more than one year. Eligible patients were contacted by telephone, and those who agreed to participate were sent the questionnaire with consent forms and a postage-paid return envelope. Multivariate logistic regression models were used to identify factors associated with fatigue and depression. Results: Sixty six percent of the breast cancer survivors reported moderate to severe fatigue, which was defined as a “fatigue worst” rating of 4 or greater, 24.9% reported clinical moderate to severe depression, which was defined as a rating of 19 or greater. Fatigue and depression were highly correlated (Pearson r=.593). Fatigue was associated with significantly employment status (OR=1.58), low income (OR=1.29), having gastrointestinal disease (OR=1.94), dyspnea (OR=2.15), appetite loss (OR=3.02), insomnia (OR=2.72), breast symptoms (OR=1.82), and hair loss (OR=1.75). Depression was strongly related to low income (OR=2.50), fatigue (OR=4.52), insomnia (OR=1.98), appetite loss (OR=2.24), constipation (OR=2.12), and financial difficulties (OR=1.89), systemic therapy side effect (OR=3.12). Fatigue and depression were negatively associated to QOL. Conclusion: There were subgroups of survivors who report more severe and persistent fatigue and depression. This information may be helpful in elucidating the mechanisms underlying fatigue and depression in this population, as well as directing intervention efforts.

No significant financial relationships to disclose.
Phase II trial of single-agent sorafenib in patients with advanced non-small cell lung carcinoma
Authors: Gatzemeier U. , Blumenschein G. , Fosella F. , Simantov R. , Elting J. , Bigwood D. , Cihon F. , Reck M.
Published: March 2020

7002

Background: Sorafenib, an oral multi-kinase inhibitor, targets the Raf/MEK/ERK pathway at the level of Raf kinase and receptor tyrosine kinases, and has shown efficacy against several tumor types in phase I/II trials. Non-small-cell lung cancer (NSCLC) is associated with mutations in k-ras, upstream of Raf/MEK/ERK. Methods: This multi-center, uncontrolled, phase II trial evaluated efficacy (every 8 weeks using RECIST) and safety of sorafenib (400 mg bid, continuous) in patients with relapsed or refractory advanced NSCLC. Plasma for proteomic biomarker analysis (ELISA [n=44]; mass-spectrometry [n=43]) was taken at screening, Day 21 of Cycle 1, and Day 1 of Cycle 3. Results: Fifty-two of 54 patients enrolled received sorafenib. Most (49/52) patients who received sorafenib had stage IV NSCLC. Thirty patients (59%) out of 51 evaluable for efficacy had SD. Although there were no confirmed PRs, tumor shrinkage was observed in 15 (29%) patients (four had ≥30% shrinkage). Patients with SD had a median progression-free survival (PFS) of 23.7 weeks, while all evaluable patients (n=51) had a median PFS of 11.9 weeks and median overall survival of 29.3 weeks. The most frequent drug-related adverse events observed in 52 patients were diarrhea (21 [40%] patients), hand-foot skin reaction (HFS; 19 [37%]), fatigue (14 [27%]), and nausea (13 [25%]). Frequent drug-related adverse events ≥ grade 3 included HFS (n=5 [10%]) and hypertension (n=2 [4%]). Three patients discontinued due to adverse events (HFS, elevated lipase, and myocardial infarction). There were nine deaths within 30 days of discontinuation of sorafenib (n=5 PD; n=2 cardiopulmonary arrest; n=1 hemoptysis; and n=1 unknown cause). The levels of five proteins measured by ELISA, either at screening or change over treatment duration, correlated significantly with time to progression (TTP) or maximum tumor shrinkage. Levels of five additional proteins, identified by mass-spectrometry, also correlated with TTP. Conclusions: Identified biomarkers may help assess efficacy of sorafenib in NSCLC patients. Sorafenib 400 mg bid is generally well tolerated and shows promising efficacy in patients with advanced, progressive NSCLC, with approximately 60% of pts achieving disease stabilization.

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Prediction of clinical outcome in non-small cell lung cancer (NSCLC) patients treated with gefitinib using Matrix-Assisted Laser Desorption/Ionization-Time of Flight Mass Spectrometry (MALDI-TOF MS) of serum
Authors: Solomon B. , Gregorc V. , Taguchi F. , Kasahara K. , Nishio M. , Roder H. , Hirsch F. R. , Duncan M. W. , Bunn P. A. , Carbone D. P.
Published: March 2020

7004

Background: Assessment of epidermal growth factor receptor (EGFR) gene copy number, mutational status, and protein levels may predict response and possibly survival following treatment with EGFR tyrosine kinase inhibitors, but all these methods require tumor tissue, highlighting the need for a non-invasive predictive test. We evaluated the ability of MALDI-TOF MS profiling of serum to predict which patients (Pts) with NSCLC were likely to benefit from gefitinib treatment. Methods: Serum from Pts with NSCLC, collected prior to treatment with gefitinib, was subjected to MALDI-TOF MS using Voyager DE-STR or DE-PRO instruments. Replicate mass spectra obtained at two institutions were submitted to a third party for processing (background subtraction, noise estimation, normalization, spectral alignment and peak identification) and selection of discriminating mass/charge (m/z) values from a training cohort of 70 Caucasian Pts. The predictive capability of the profile was then assessed in independent cohorts of NSCLC Pts. Results: Intra- and inter- laboratory reproducibility of MALDI spectra were excellent. A set of 11 m/z values (mass range 5 - 12.5 kDa) predictive of clinical benefit were identified in the training cohort and confirmed by leave-one-out cross validation. Spectra from 19/70 Pts in the training cohort were unclassifiable. For the remaining 51 Pts the algorithm discriminated groups more or less likely to benefit with respect to time to progression (median 3.0 vs. 1.5 mo., p = 0.0325) and overall survival (median 14.6 vs. 2.3 mo., p = 0.0128). Validation was performed in an independent cohort consisting of serum from 69 Japanese Pts. Spectra from 13/69 Pts were unclassifiable. For the remaining 56 Pts it was possible to identify a group with superior time to progression (median 14.8 vs. 2.1 mo., p = 0.0012) and overall survival (median 19.1 vs. 7.9 mo., p = 0.0102). Conclusions: MALDI-TOF MS of pretreatment serum may aid with the identification of subsets of NSCLC Pts that will benefit from treatment with gefitinib. This algorithm is currently being evaluated in an expanded cohort of Pts receiving gefitinib treatment and in Pts treated with erlotinib.

[Table: see text]
A phase III randomised trial comparing sequential to standard chemotherapy in advanced non-small cell lung cancer (NSCLC)
Authors: Sculier J. , Lafitte J. , Lecomte J. , Alexopoulos C. , Van Cutsem O. , Giner V. , Efremidis A. , Scherpereel A. , Paesmans M. , Berghmans T.
Published: March 2020

7012

Background: Cisplatin-based chemotherapy and taxans are effective treatments for advanced NSCLC. We performed a phase III randomised trial to determine if the sequential administration of cisplatin-based chemotherapy followed by paclitaxel is superior to a cisplatin-based standard chemotherapy, with the use of paclitaxel as salvage treatment. Methods: Untreated advanced NSCLC with adequate PS, hematological, hepatic, cardiac and renal functions were treated by 3 courses of GIP (cisplatin 50 mg/m2, ifosfamide 3 g/m2, gemcitabine 1 g/m2). Patients with a non-progressing tumour were randomised between 3 further courses of GIP or 3 courses of paclitaxel (225 mg/m2). To detect an increase in the survival rates (primary endpoint) from 20% in the GIP arm to 35% in the sequential arm, with 80% probability using a two-sided logrank test with a significance level of 5%, we needed to observe 178 events, requiring to randomise 123 patients in each arm. Results: From January 2000 to February 2004, 485 patients received 3 courses of induction GIP of which 140 were randomised in the GIP arm and 141 in the paclitaxel arm. Median survival times were 14.1 (95% CI: 12.0–16.3) and 16.4 (95% CI: 14.0–18.8) months for the paclitaxel and the GIP arms, respectively (p = 0.17). When treatment comparison was adjusted for the two independent prognostic factors (sex and haemoglobin) revealed by a Cox multivariate analysis, the observed HR was 0.81 (95% CI: 0.63–1.09) in favour of the GIP arm (p = 0.10). There were more grades III/IV thrombopenia with GIP (p< 0.01) and more alopecia with paclitaxel (p = 0.04). Conclusion: Sequential cisplatin-based chemotherapy by paclitaxel does not result in better survival than standard chemotherapy, with the use of paclitaxel as salvage treatment.

No significant financial relationships to disclose.
Bortezomib + gemcitabine (Gem)/carboplatin (Carbo) results in encouraging survival in advanced non-small cell lung cancer (NSCLC): Results of a phase II Southwest Oncology Group (SWOG) trial (S0339)
Authors: Davies A. M. , McCoy J. , Lara P. N. , Gumerlock P. H. , Crowley J. , Gandara D. R.
Published: March 2020

7017

Background: Bortezomib (PS-341), a small molecule proteasome inhibitor, has single agent activity in NSCLC and potentiates Gem/Carbo in pre-clinical models in a sequence-specific manner (Mortensen, Cancer Chem Pharm, 2004). A phase I trial of Gem/Carbo + PS-341 in patients (pts) with advanced NSCLC yielded an encouraging response rate of 48%. Here we describe the results of a SWOG phase II study of this regimen in advanced NSCLC. Methods: 114 eligible chemonaive stage IV and selected stage IIIB (pleural effusion) NSCLC pts received Gem 1000 mg/m2 on days 1, 8 and Carbo AUC 5 on day 1, followed 1 hour later by PS-341 1.0 mg/m2 on days 1, 4, 8, 11, with cycles repeated every 3 weeks. Non-progressing pts could continue PS-341 alone after 4 cycles. Results: Pt characteristics: Median age: 64 years; Sex M/F = 68/46; Performance status 0/1 = 50/64; stage IIIB/IV = 13/101. Response rate: 20% (95% CI 13–29%); 66% (95% CI 56–75%) had stable disease. At a median follow-up of 13 months, progression free and median survival times were 5 months (95% CI 3.5–5.3) and 11 months (95% CI 8.2–12.5). One-year survival was 46% (95% C.I. 37–55%). Most common grade 3/4 toxicities: neutropenia (52%), thrombocytopenia (63%), and fatigue (13%). Ongoing correlative studies are examining markers of proteasome inhibition (Bcl2 family, NFKB, IKB) and hypoxia (PAI-1, VEGF, OPN, HIF-1) in tumor tissue and surrogate specimens. Conclusions: The 11 month median survival achieved with the addition of PS-341 to Gem/Carbo in this phase II study is unprecedented in prior SWOG trials in advanced NSCLC, and does not appear to be explained by altered patient characteristics. The toxicity profile of this regimen is favorable. A phase III trial of Gem/Carbo ± Bortezomib in advanced stage NSCLC is under development. Supported by CA38926, CA32102.

No significant financial relationships to disclose.
Clinical and biological effects of gefitinib in EGFR FISH positive/phospho-akt positive or never smoker non-small cell lung cancer (NSCLC): Preliminary results of the ONCOBELL trial
Authors: Cappuzzo F. , Toschi L. , Trisolini R. , Bemis L. , Sujita M. , Domenichini I. , Franklin W. , Crino L. , Ciardiello F. , Varella-Garcia M.
Published: March 2020

7023

Background: Effectiveness of gefitinib, a tyrosine kinase inhibitor of the epidermal growth factor receptor (EGFR), in never smokers and/or EGFR FISH positive NSCLC patients has been evaluated only in retrospective studies and few data exist on the biological effects of gefitinib therapy in tumor samples. Methods: The ONCOBELL trial is a multicenter prospective phase II study designed to include 39 patients EGFR FISH positive/phospho-Akt (p-AKT) positive and/or never smokers with advanced or metastatic NSCLC. Gefitinib is given at the daily dose of 250 mg. When feasible, primary tumor biopsy was repeated immediately before therapy, during therapy and at progression. Specimens were evaluated for EGFR and HER2 gene copy number by FISH, EGFR gene mutation by DNA sequencing, and EGFR and p-AKT protein expression by immunohistochemistry. Results: Data from the first 28 enrolled patients are available: median age was 60 years (range, 43–80); male/female: 7/21; stage IIIB/IV: 2/26; ECOG PS 0/1/2: 18/6/4; 25 patients had a diagnosis of adenocarcinoma and/or bronchioloalveolar carcinoma; 13 patients had brain metastases, and in 10 cases gefitinib was offered as first-line therapy. Twenty-four patients were never smokers and 19 were EGFR FISH positive. Overall response rate was 54%, including 1 complete and 14 partial responses. Median time to progression was 6.45 months, and median survival was not reached. Response to therapy was not influenced by previous therapies or presence of brain metastases. Toxicity was mild, and consisted in grade 1–2 skin rash (68%) and diarrhea (57%). One patient developed grade 3 diarrhea and another patient was hospitalized for acute interstitial lung disease. In patients exposed to previous chemotherapy, no difference in EGFR or HER2 FISH results were observed in specimens collected at the time of original diagnosis compared to specimens collected immediately before gefitinib therapy. In 14 cases primary tumor biopsy was repeated during gefitinib therapy. Conclusions: These preliminary data indicate that gefitinib is highly effective in patients with trial characteristics. Clinical and biological data for the entire cohort will be available in June 2006.

No significant financial relationships to disclose.
Gefitinib plus celecoxib in chemotherapy-naïve patients with stage IIIB/IV non-small cell lung cancer (NSCLC): A phase II study from the Hoosier Oncology Group
Authors: Agarwala A. K. , Einhorn L. , Fisher W. , Bruetman D. , McClean J. , Taber D. , Titzer M. , Juliar B. , Breen T. , Hanna N.
Published: March 2020

7066

Background: Gefitinib, an inhibitor of the epidermal growth factor receptor (EGFR) pathway, has single agent activity in NSCLC. Preclinical studies demonstrate significant interactions between the EGFR and cyclo-oxygenase 2 (COX-2) pathways and that simultaneous inhibition against NSCLC may have benefits over gefitinib alone. Methods: Eligibility required that pts were chemotherapy-naïve, had stage IIIb (with pleural effusion) or IV NSCLC and an ECOG PS 0–1. Pts received gefitinib 250mg orally daily plus celecoxib 400mg orally every 12 hours. Cycles consisted of 21 day treatment and continued until unacceptable toxicity or progression of disease. The primary objective of this single arm, two-stage, phase II study was to evaluate the overall response rate. If ≤ 10 out of 30 pts achieved a complete (CR) or partial response (PR), the study would be stopped early. If >10 out of 30 pts had a CR or PR, enrollment would continue to 50 pts. Results: From 1/04 to 11/04, 31 pts were enrolled: male/female 13/18; median age 70.8 years (range, 19–93); 67.7% had adenocarcinoma; ECOG PS 0/1 13/18; stage IIIb/IV 2/29; 5 were current smokers, 9 were remote (>30 years) or never smokers, 16 quit smoking > 3 months ago. Median number of cycles was 4 (range, 0–16). 6 pts (19.4%) discontinued therapy due to toxicity, including 3 who died due to treatment. Select grade 3/4 toxicities included: pulmonary (6.5%), hepatic (6.5%), diarrhea (6.5%), skin (3.2%). Responses included PR 5 (16.1%), stable disease 8 (25.8%), and progressive disease 18 (58.1%). Median duration of response, progression free survival, and overall survival was 5.7, 2.8, and 7.2 months, respectively. All responders were females with adenocarcinoma, 2 were remote or never smokers and 3 were former smokers. Conclusion: Gefitinib plus celecoxib in an unselected population of chemotherapy naïve patients with advanced NSCLC and a PS of 0–1 has a lower response rate and overall efficacy compared with historical controls of chemotherapy.

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