bluuebunny/crossref_metadata_2025 huggingface dataset:
A phase I trial of TAS-102 administered on a three times a day schedule in patients with solid tumors
Authors: Wolff R. A. , Hoff P. M. , Mita A. , Fukushima M. , Blais J. C. , Abbruzzese J. L. , Xiong H. Q.
Published: March 2020

2053

Background: TAS-102 consists of trifluorothymidine (FTD) and an inhibitor of thymidine phosphorylase (TP). FTD, like 5-fluorouracil, is an inhibitor of thymidylate synthase. However, when orally administered, FTD is rapidly degraded to an inactive form, primarily by TP. Co-administration of FTD with an inhibitor of TP elevates FTD concentrations. Since tumor xenograft models demonstrated greater anti-tumor activity with divided daily dosing of TAS-102, and a phase I trial of once-daily TAS-102 showed a short FTD half-life, this trial was designed to explore a three times a day dosing schedule. Methods: Patients with advanced solid tumors having received prior therapy, with adequate organ function, and performance status Zubrod 0–2, were eligible. TAS-102 was administered orally three times a day for 5 days a week for two weeks, followed by two weeks off. Courses were repeated every 4 weeks. Results: A total of 15 patients (8 female, age 37–72 years) were enrolled into the study; three at 60 mg/m2/day, 6 each at 70 mg/m2/day and 80 mg/m2/day. Nine patients had colorectal cancer, 2 carcinoma of unknown primary, 2 pancreatic cancer, one each medullary thyroid cancer and cholangiocarcinoma. Toxicity was assessed throughout all courses of therapy. Grade 3 and 4 hematological toxicities were the most common, including 3 episodes of grade 3 neutropenia at 60 mg/m2/day, 5 at 70 mg/m2/day, 5 at 80 mg/m2/day with only 1 instance of grade 3 thrombocytopenia at 80 mg/m2/day. Non-hematological grade 3 toxicities included nausea/vomiting (1 at 70 mg/m2/day), colitis, gout, and hematuria (1 each at 70 mg/m2/day), and fatigue (1 at 70 mg/m2/day and 2 at 80 mg/m2/day) Two episodes of dose-limiting toxicity were observed at 80 mg/m2/day: grade 3 fatigue and grade 4 neutropenia. Although there were no objective responses, nine patients (60%) maintained stable disease with a median duration of disease stabilization of 4.3 months (range, 1.9 to 8.6 months). Conclusions: TAS-102 is well tolerated with manageable hematologic toxicity and few non-hematological toxicities. The most common grade 3 or 4 toxicity was neutropenia. The suggested phase II dose of TAS-102 is 70 mg/m2/day when administered orally three times a day for 5 days a week for two weeks followed by two weeks off every 4 weeks.

[Table: see text]
Dihydropyrimidine dehydrogenase deficiency (DPD) in GI malignancies: Experience of 4 years
Authors: Mehra R. , Mattison L. K. , Ledbetter L. , Ezzeldin H. , Diasio R. B. , Saif M. W.
Published: March 2020

2056

Background: 5-Fluorouracil (5-FU) is an integral part of treatment of GI malignancies. While normal DPD enzyme activity is rate limiting in 5-FU catabolism, its deficiency could increase concentrations of bioavailable 5-FU anabolic products leading to 5-FU related toxicity syndrome. With DPD deficiency, 5-FU is discontinued. Data regarding safety of capecitabine (CAP) in this population is scarce. Methods: Patients were tested for DPD deficiency after excessive toxicities from 5-FU and CAP at UAB between 2001 and 2005. DPD activity was evaluated by PBMC radio assay, genotyping of DPYD gene by DHPLC, or 2-13C uracil breath test (UraBT). Results: Of 23 patients with GI malignancies (small intestine, gastric, pancreatic, HCC, and colorectal) evaluated, 7 (30%) were DPD deficient. Among these 7 patients, DPD activity ranged from 0.064 - 0.18 nmol/min/mg. Age ranged from 51–75 years, M:F ratio = 1.3:1, and ethnicities included Caucasian (71%), African-American (14%) and South-Asian (14%). Four were treated with 5-FU/LV (2 Roswell; 2 Mayo); 2 CAP (1800mg/m2); and 2 high dose bolus 5-FU (1400mg/m2) + PN401 (tri-acetyluridine). Toxicities included mucositis (71%), diarrhea (43%), nausea (29%), memory loss/altered mental status (43%), cytopenias (43%), hypotension (14%), respiratory distress (14%), acute renal failure (14%), and severe skin rashes (43%). Re-challenge with CAP in 1 patient after the Mayo regimen caused grade 3 HFS only on dorsal surfaces of hands. One patient on PN401 had a grade 3 facial rash as the worst toxicity. Genotypic analysis of the DPYD gene in the second on PN401, who had severe leucopenia, demonstrated a heterozygous mutation (IVS14+1 G>A, DPYP*2A). UraBT in 2 patients revealed 1 to be DPD-deficient (DOB50 of 112.8; PDR of 49.4%) and borderline normal values (DOB50 of 130.9; PDR of 52.5%) in a second patient. There were 2 toxicity-related deaths (28%): 1 on CAP and 1 on 5-FU + PN401. Conclusions: DPD deficiency was observed in several ethnicities. Patients with CAP toxicities should also be tested for DPD deficiency. Role of PN401 in rescuing 5-FU toxicity in DPD deficiency is not clear. Screening patients for DPD deficiency prior to administration of 5-FU or CAP, using UraBT, could potentially lower risk of toxicity. Future studies should validate this technique.

[Table: see text]
Distribution of UGT1A1 (TA) polymorphisms in Caucasian and Asian subjects
Authors: Liu J. , Qu K. , Ren Y. , Sferruzza A. , Bender R. A.
Published: March 2020

2063

Background: The hepatic isoform 1A1 of uridine diphosphate glucuronosyltransferase (UGT) is responsible for glucuronidation and detoxification of SN-38, the active metabolite of irinotecan. The presence of an additional TA repeat in the TATA sequence of the UGT1A1 gene is a common polymorphism, leading to a significant decrease in SN-38 glucuronidation. Patients with the UGT1A1 (TA)7 allele (either [TA]6/7 or [TA]7/7 ) are more likely to experience severe neutropenia and diarrhea following irinotecan chemotherapy. We assessed the distribution of the UGT1A1 (TA) polymorphism in Caucasian and Asian subjects. Methods: We used a fluorescent PCR-based assay to detect UGT1A1 (TA) polymorphisms in 129 healthy subjects (52 Caucasian, 34 Chinese, 36 Filipino, and 7 Japanese). The chi-square test was used to assess between-group differences in the distribution of UGT1A1 (TA) genotypes. Results: UGT1A1 (TA) genotype distribution differed significantly between Caucasian and Asian subjects (P = 0.003). The UGT1A1 (TA)6/7 and (TA)7/7 genotypes were more common in Caucasians than Asians. Genotype distributions did not differ significantly between men and women in either group ( Table ). Conclusions: The frequency of the deleterious UGT1A1 (TA)7 polymorphism was greater in Caucasians than in Asians; genotype frequencies were consistent with previous reports. In both groups, UGT1A1 (TA) genotype distributions were similar in men and women.

[Table: see text]

No significant financial relationships to disclose.
Phase I study of trabectedin (T) in combination with docetaxel (D) in patients with advanced malignancies
Authors: Von Mehren M. , Buck D. , Temmer E. , Elsayed Y. A. , Cohen R. B.
Published: March 2020

2068

Background: T is a novel cytotoxic agent that binds to the DNA minor groove and is active in several tumor types. The objective of this study is to determine the maximum tolerated dose (MTD) of the combination. Other objectives include safety and efficacy. Methods: Eligible patients (pts) had advanced cancer, PS 0–1 and adequate organ function. Restricted pts were limited to 1 prior cytotoxic regimen, while unrestricted pts had no limit. On day 1 of each cycle, Pts received D starting at 60 mg/m2 over 1 hour followed by T starting at 0.4 mg/m2 over 3 hours. Dosing was repeated q 3 weeks. Incremental doses of both drugs were explored. PK samples were collected. A standard “3+3” dose escalation, definitions of dose limiting toxicity (DLT), and dose modifications were implemented. Results: To date, 31 pts have been treated, receiving 147 cycles (Range 1–28, median 6). At dose level 2 (D 60 mg/m2 + T 0.6 mg/m2), 2/4 unrestricted pts and 3/5 restricted pts developed DLT (grade IV neutropenia and/or febrile neutropenia) requiring institution of prophylactic filgrastim. Therapy was well tolerated after institution of filgrastim and no DLTs have been observed through the current dose level 6 (D 60 mg/m2 + T 1.3 mg/m2). Most frequently related grade 3 and 4 adverse events (AE) were: neutropenia (51%), elevated liver enzymes (3.7%), DVT (3.7%), and hyponatremia (3.7%). The most frequently related grade 1and 2 AEs were: fatigue (56%), neutropenia (56%), nausea (55%), and anemia (40%). Anti-tumor activity included a complete response in a pt with peritoneal Ca and durable prolong stable disease (SD) in 2 pts with sarcoma (20 + and 10 + months) and a pt with prostate Ca (8+ months). Another pt with gastric Ca achieved SD lasting 8 months. PK evaluations of D and T are ongoing. Conclusions: The combination of T and D with filgrastim support is safe and well-tolerated. Preliminary data suggest that this regimen is active in pts with advanced cancers. Additional cohorts are planned giving D 75 mg/m2 and T 1.3 mg/m2.

[Table: see text]
Phase I clinical and pharmacological trial of trabectedin (T) in 3 hour infusion every 3 weeks (3h/q3w) in patients with advanced cancer and hepatic function disorder
Authors: Salazar R. , Pardo B. , Majem M. , García M. , Montes A. , Cuadra C. , Ciruelos E. , Cortés-Funes H. , Lebedinsky C. , Paz-Ares L.
Published: March 2020

2080

Background: Trabectedin (ET-743) is a marine-derived DNA and transcription interacting agent with activity in pretreated soft tissue sarcoma, breast, prostate and ovarian cancer. T is associated with 2 types of liver function alterations: a frequent acute and reversible elevation of ALT and AST and a less frequent cholestasis, usually reflected by low grade increases in alkaline phosphatase (AP) and bilirubin (B). The main predictors of dose limiting toxicity (DLT) or T-related serious adverse events appear to include elevated baseline or intercycle peaks of AP, B and ALT > 5 × ULN (Gomez J, ASCO 2000). The objectives of this trial are to determine the maximum tolerated dose (MTD) and pharmacokinetics (PK) of T 3h/q3w in patients (pts) with advanced cancer and baseline liver dysfunction. Methods: All pts are stratified according to basal liver function as follows: STRATUM (S) I: ULN < AP ≤ 1.5 × ULN S II: 1.5 × ULN < AP ≤ 2.5 × ULN S III: AP > 2.5 × ULN All pts had to have AST and ALT ≤ 2.5 × ULN, albumin > 2.5 g/dl and B < 2.5 mg/dl. T concentrations in plasma are determined using a validated LC-MS/MS method. PK parameters were calculated by non-compartmental methods. Results: 32 pts were recruited.Median age: 54 years (26–76); PS≤1:28 pts; prior chemotherapy (CT): 31 pts (97%); median number of prior CT: 2 (1–6); B > ULN: 0 pts. In S I, T was administered at 1.1 mg/m2 (3 pts) and 1.3 mg/m2 (13 pts). Two DLTs were reported at 1.3 mg/m2: neutropenia G4 > 5 days with febrile neutropenia and G3 ALT not recovered by day +28. In S II no DLT occurred in 4 pts at T 0.9 mg/m2 nor 3 pts at T 1.1 mg/m2, 1 out of 4 pts at 1.3 mg/m2 suffered DLT: G3 AST not recovered by day +24. In S III one out of 2 pts at 0.9 mg/m2 had DLT: AP increase. Initial PK evaluation from S I and II (8 from each) showed a long half life (geometric mean (GM) S I: 124.6 h, S II: 118.8 h) and wide distribution (GM Vss S I: 2366 l/m2, S II: 3830 l/m2). GM clearance: 18.3 l/(hr*m2) in S I; 26.3 l/(hr*m2) in S II. Clearance is somewhat lower than in normal liver function population (GM under equal dexamethasone treatment 33.8 l/hr*m2) in study ET-B-010. Conclusions: The recommended dose (RD) of T for pts with mild AP elevations (< 1.5 ULN) and B levels < ULN is 1.3 mg/m2 3h/q3w. The study is ongoing to define the RD for S II and III

[Table: see text]
Phase II trial of extended dose anti-CTLA-4 antibody ipilimumab (formerly MDX-010) with a multi-peptide vaccine for resected stages IIIC and IV melanoma
Authors: Weber J. S. , Targan S. , Scotland R. , Snively J. , Garcia M. , Yellin M. , Fischkoff S. , Nichol G.
Published: March 2020

2510

Background: Ipilimumab is a human anti-CTLA-4 antibody shown to have clinical activity in melanoma and renal cancer that is associated with inflammatory-type adverse events termed immune breakthrough events (IBEs). Methods: 25 patients with resected stages IIIC/IV melanoma received MART-1/gp100/tyrosinase peptides with adjuvant Montanide ISA 51 12 times injected subcutaneously with Ipilimumab at 3 mg/kg intravenously every eight weeks for 12 months. The primary endpoints were toxicity and the achievement of a 40% rate of tolerable IBEs, and 20% or less rate of intolerable adverse events. Immune responses measured by ELISPOT and peptide-tetramer assays, and time to relapse were also assessed. The three melanoma peptides differed from wild type by one amino acid modification to increase HLA binding, and were administered at 1000 mcg/dose each. Results: Median age was 55, with 13 men and 12 women. 15 patients had stage IV, and 10 had stage IIIC resected disease. Thus far, 12/25 (48%) patients had grades 2–3 IBEs; 5 (20%) were dose limiting; 7 had GI toxicity, of which 2 were dose limiting; four had skin toxicity, of which 2 were dose limiting; one patient had hypopituitarism, which was also dose limiting. No patient with dose limiting toxicity required hospitalization and all returned to baseline status with the use of systemic steroids. Serologic assays of IBD-related microbial and auto-antibodies showed that seven of eight patients tested had increases in ANCA IgG or I2 IgA, and 5/8 had increases in ASCA IgA. Four of 25 patients have relapsed with a median of 10 months of follow-up. Two were again rendered NED surgically. The two remaining patients were treated with biochemotherapy, with one CR and one PR. All 25 patients are alive, one with disease. No patient with grade 2–3 IBEs has relapsed. ELISPOT assays showed that 10/11 patients tested responded in fresh PBMC to MART-1 and gp100. Conclusions: These data suggest that IBEs are associated with clinical benefit in patients with resected high-risk melanoma receiving Ipilimumab at 3 mg/kg with a peptide vaccine, and support testing the current regimen in a larger randomized trial.

[Table: see text]
Clinical and immune responses of WT1-peptide vaccination in patients with acute myeloid leukemia
Authors: Keilholz U. , Letsch A. , Asemissen A. , Hofmann W. , Uharek L. , Blau W. , Thiel E. , Scheibenbogen C.
Published: March 2020

2511

Background: The transcription factor Wilms tumor protein (WT) 1 belongs to a new generation of tumor antigens, as it is essential for tumor cell proliferation. WT1 is highly expressed both in myeloid leukemias and many carcinomas. This phase 2 proof-of-concept trial was initiated to determine immunogenicity and toxicity of vaccination with a novel HLA-A2-restricted WT1 peptide vaccine. Methods: Sixteen HLA-A2-positive patients with acute myeloid leukemia and one patient with myelodysplasia received 3–18 vaccinations (median 8) of WT1. 126–134 peptide (0.2 mg) together with the T helper protein keyhole limpet hemocyanin (1 mg) and in addition GM-CSF (75 mcg for four days) and. Twelve patients had elevated blast counts at study entry and 5 patients complete remission with high risk for relapse. Results: Six of 12 patients with presence of leukemic blasts had evidence of antileukemic activity. One patient achieved complete remission for 12 months. The patient with myelodysplasia RAEB II had a major response of neutrophils and platelets. Two patients had minor responses with transient clearance of peripheral blasts or improvement of hematopoiesis, and two patients achieved disease stabilization for 3 and 14 months. WT1 transcripts as molecular disease marker decreased in 5 of these 6 patients and also in 4 of 5 high-risk patients. No significant toxicity occurred. The generation of a WT1-specific T cell response in peripheral blood and bone marrow was detected in 9 of 13 patients by tetramer analysis and 8 of 13 patients by intracellular cytokine staining. Conclusion: These results show that WT1 vaccination can induce functional T cell responses associated with antileukemic activity and warrant trials of WT1 vaccination in patients at high risk of relapse and with WT1-expressing carcinomas.

No significant financial relationships to disclose.
Inducing mammaglobin-A (mamA) specific HLA class I tetramer positive CD8+cytotoxic T-lymphocytes (CTL) against breast cancer by DNA vaccination
Authors: Bharat A. , Narayanan K. , Benshoff N. , Dietz J. , Gillanders W. , Fleming T. , Mohanakumar T.
Published: March 2020

2522

Background: We recently reported that DNA vaccination using MamA, a highly expressed human (hu) breast cancer specific protein, leads to immunity against breast cancer. Here we demonstrate that the induction of breast cancer immunity following MamA DNA vaccination occurs through the expansion of CD8+ CTL by using HLA class I MamA peptide tetramers. Methods: HLA-A2+huCD8+ double transgenic mice received four (100μg) two-weekly IM injections of PCI-neo vector cloned with hu MamA gene. HLA-A2 tetramers (tet) carrying an immunodominant Mam2.1 peptide (LIYDSSLCDL) were used to monitor development of mam-A specific CD8+ T cells. Specificity of tetramers was tested against CD8+ CTL lines developed in vitro by stimulation of normal hu HLA-A2+ peripheral blood lymphocytes with TAP-2 deficient T2 cells pulsed with pooled MamA HLA-A2 binding peptides. Results: There was a sequential expansion of Mam2.1 tet+CD8+ T cells during stimulation of hu PBLs with MamA peptides in vitro (<1% pre-stimulation to >15% after six stimulations). These Mam2.1 tet+CD8+ T cells were HLA-A2 restricted and MamA specific since they revealed cytotoxicity only towards UACC-822 (HLA-A2+MamA+, 75% lysis) but not MCF-7 (A2+MamA−) or DU-4475 (A2−MamA+) breast cancer cell lines. In contrast, there was no binding of MamA peptide tetramers to control Flu-specific CD8+ CTL lines (<1%). MamA DNA vaccination, but not PCI-neo vector alone, of HLA-A2+huCD8+ mice lead to the expansion of Mam2.1 tet+CD8+ T cells (<0.7% pre-vaccination to >2.5% post-vaccination) in the peripheral blood that revealed in vitro cytotoxicity against UACC-822 (70% lysis) but not against DU-4475 or MCF-7 breast cancer cell lines. Adoptive transfer of both whole splenocytes or fractionated CD8+ T cells from vaccinated mice into immunodeficient SCID-beige mice with previously established subcutaneous hu breast cancer colonies lead to tumor infiltration of tet+CD8+ CTLs and, at 4-weeks, at least 80% tumor regression of UACC-822 but not DU4475 or MCF-7 colonies. Conclusions: MamA DNA vaccination resulted in the expansion of CD8+ CTL. The CD8+ CTL were HLA class I MamA peptide tetramer positive, HLA class I restricted and specifically lysed mamA+ human breast cancer cells both in vitro and in vivo.

No significant financial relationships to disclose.
T regulatory cells (Treg) in patients with metastatic renal cell carcinoma (mRCC) decrease during sunitinib treatment: Correlations with clinical responses and T helper 1/T helper 2 (Th1/Th2) bias
Authors: Suppiah R. , Finke J. , Rini B. I. , Richmond A. , Wood L. , Elson P. , Shaheen P. , Garcia J. , Dreicer R. , Bukowski R.
Published: March 2020

2526

Background: High numbers of regulatory T cells (Treg) and high expression of forkhead box transcription factor (FoxP3) in Treg are associated with decreased survival in various malignancies, likely via immunosuppression. Studies demonstrate Th1 suppression (IFN-γ) and Th2 (Il-4) promotion in metastatic renal cell carcinoma (mRCC) patients (pts). The aim of the present study was to determine the profile of Th1, Th2, and Treg at baseline and after 28 days of therapy with the multi-targeted tyrosine kinase inhibitor, sunitinib malate (SU11248). Further, correlation of changes in these parameters and tumor shrinkage (TS) was examined. Methods: Blood was obtained from cytokine-refractory, clear cell mRCC pts on day 1 (pre-treatment) and after 28 days of sunitinib 50mg daily. T cell cytokine expression (IL-4, IFN-γ), percentage in peripheral blood mononuclear cells of CD3+/CD4+/CD25hi+/FoxP3+ cells, and percentage of Treg that were FoxP3+ were evaluated using flow cytometry. Tumor measurements were performed after 2 cycles of therapy. Correlations between immune parameters and TS were assessed with Spearman rank correlations. Results: Ten pts were evaluable for Th1/Th2 responses; 9 for Treg. At baseline 7/10 had Th2 bias and 3/10 had Th1 bias. On day 28, pts maintained Th1 bias (n=3), switched to Th1 bias (n=3), or had decrease in magnitude of Th2 response (n=4). Additionally, a median 74.5% decrease occurred after 28 days of sunitinib in the percentage of CD3/CD4/CD25hi+/FoxP3+ in peripheral blood mononuclear cells, with a median 68.0% decrease of FoxP3+ Treg (CD3/CD4/CD25hi+) cells. Decrease in number of Treg correlated with relative change in Th1 response and Th2 bias (p<.05 for all correlations). All pts had TS including 2 pts with partial response. Degree of TS correlated with relative change in Th1 response (p=.03), and Th2 bias (p=.06), as well as the relative change in FoxP3+ Treg (p=.06). Conclusions: Our results suggest that sunitinib promotes an immunostimulatory Th1 bias and reduces Treg. This immunostimulatory mechanism may contribute to the anti-tumor effect in mRCC. Further studies are on-going.

[Table: see text]
A phase I/II study of a HER2/neu (HER2) peptide vaccine plus concurrent trastuzumab
Authors: Webster D. J. , Waisman J. , Macleod B. , Dela Rosa C. , Higgins D. , Fintak P. , Childs J. , Slota M. , Salazar L. G. , Disis M. L.
Published: March 2020

2528

Background: HER2 is a tumor antigen in breast and ovarian cancer. Vaccines targeting both Class I and II epitopes of HER2 can elicit long-lived cellular immunity. Trastuzumab increases the activity of HER2-specific T cells in vitro. This study examines the safety and immunogenicity of a HER2 peptide vaccine given with trastuzumab to augment HER2-specific immune responses in vivo. Methods: 20 HLA-A2+ subjects will be enrolled on this Phase I/II single institution trial. Eligible subjects must have stage IV HER2 overexpressing breast or ovarian cancer, stable or no evident disease on maintenance trastuzumab and a normal baseline MUGA. Subjects must have ECOG performance status 0–1, creat ≤ 2.0, bili < 1.5 × ULN, SGOT < 2 × ULN. The HER2 vaccine used in this study has been previously reported and is composed of 3 HER2 Class II epitopes encompassing Class I epitopes in their natural sequence. (Knutson et al, J Clin Investigation 107:477–484, 2001). Subjects receive 6 vaccinations + GM-CSF at monthly intervals. Primary endpoints are safety and immunogenicity. Results: To date, 14 of 20 subjects have been enrolled. A total of 77 vaccinations have been given. Of 276 reported toxicities, 88% were Grade 1; most common were constitutional symptoms (25%), injection site reactions (14%), and cytopenias (14%). 11% of toxicities were Grade 2; most common were lymphopenia (34%) and headache (19%). There was one Grade 3 toxicity (syncope 5 hours after vaccination) and one Grade 4 toxicity (stroke secondary to brain metastases in long-term follow up). Cardiac toxicity included two Grade 2 asymptomatic decreases in LVEF (54 to 49% and 64 to 45%.) The average decrease in LVEF between baseline and 9 month post-vaccine follow up was 5% ± 5.85 (n = 10). Of the 10 patients who have had immunologic analysis performed at multiple time points, 5 have developed significant T cell immunity to either HER2 overlapping peptide pools and/or HER2 peptides. Complete immunologic analysis will be presented. Conclusions: Subjects with HER2 overexpressing Stage IV cancer can be safely immunized with a HER2 peptide vaccine while receiving concurrent trastuzumab without additional cardiac toxicity. In addition, the approach is immunogenic, generating significant levels of HER2-specific T cells in the peripheral blood.

No significant financial relationships to disclose.
An autologous Vγ9Vδ2 T lymphocytes cell therapy product generated by BrHPP (INNACELL Gamma Delta [IGD]) in metastatic renal cell carcinoma patients: Phase I clinical trial results
Authors: Bompas E. , Neidhardt E. M. , Rolland F. , Philip I. , Galéa C. , Salot S. , Tiollier J. , Saiagh S. , Negrier S. , Bennouna J.
Published: March 2020

2550

Background: Vγ9Vδ2 (γδ) T lymphocytes, a peripheral blood lymphocyte subset, have shown to be directly cytotoxic against renal carcinoma cells. Lymphocytes γδ can be selectively expanded ex vivo with BrHPP (Phosphostim) and IL-2. We conducted a phase I trial, to define the dose limiting toxicities (DLT), characterize the safety profile, the pharmacodynamics and potential efficacy. Methods: Patients (pts), with progressive mRCC, PS of 0–1 and no organ dysfunction, were included. A one hour iv infusion of IGD was administered alone at cycle 1, and combined with low dose of sc IL-2 (2 MIU/m2 d1 to d7) in the 2 subsequent cycles (every 3 weeks). IGD dose was escalated from 1, up to 8 billions cells (bil). Results: 10 mRCC pts were treated in the study at 3 IGD dose levels: 1 patient at 1 bil, 6 pts at 4 bil, 3 pts at 8 bil. One patient experienced a grade (G)3 hypotension (4 bil, cycle 3), and one patient presented reversible signs of biological disseminated intravascular coagulation (8 bil, cycle 2) graded as a serious adverse event and fulfilling a DLT criteria. At all doses the treatment was well tolerated during the product alone infusion (cycle 1). The most frequent type of adverse events presented was mild to moderate flue like symptomes as fever, chills and asthenia reported during the second and third cycles in the IL-2 combined cycles. Patients presented also gastrointestinal symptoms as nausea and vomiting of grade 1 or 2. Preliminary efficacy assessment evaluation shows: 2 pts were not evaluable, 3 pts were withdrawn for disease progression at 3, 8 and 11 weeks, 2 pts maintained a stable disease for 36 and 63 weeks, and 2 pts are still under follow up with a stable disease at >91 and >124 weeks post treatment. Of note, one patient showed a 19% decrease in tumour size and another one presented a significant pain decrease leading to quality of life improvement. One other patient recently treated, is still under follow-up without progression after >16 weeks post treatment. Conclusion: IGD in combination with sc low dose IL-2 is safe, well tolerated, and shows promising antitumor signs of efficacy. These results warrant further product evaluation in phase 2 clinical trials.

[Table: see text]
Evaluation of interferon-alfa 2b in a model of acute respiratory distress syndrome and pulmonary fibrosis induced by intratraqueal bleomycin in Wistar rats
Authors: Ferreira Filho A. F. , Rossari J. R. , Silva V. D. , Da Silva D. L. , Prolla J. C.
Published: March 2020

2566

Background: The acute respiratory distress syndrome (ARDS) is a common clinical entity, characterized by severe and acute pulmonary dysfunction, caused by a non-cardiogenic pulmonary edema, secondary to an increased permeability in the alveolar-capillary barrier due to a local or systemic inflammatory reaction initiated and amplified by pro-inflammatory cytokines, mostly interleukin (IL) 1, 6 and 8, and TNF-α. Despite recent advances in intensive care, the mortality associated to this syndrome remains around 40–50%. Interferons are natural proteins with antiviral, antiproliferative, antiangiogenic and immunomodulatory properties. Interferon-α reduces the synthesis and deposition of collagen I and III in hepatic tissue in experimental models of hepatic fibrosis. Interferon-α also modulates inflammation by inhibiting the action of TNF-α. The objective of this study was to evaluate the effect of interferon-α 2b in an experimental model of bleomycin-induced pulmonary fibrosis in Wistar rats. Methods: We evaluated 34 Wistar rats that were anesthetized with ketamine 100 mg/kg by the intraperitoneal route and divided in two groups of 17 animals each. Both groups received an intratracheal instillation of 1,5U of bleomycin and 0,2ml of saline solution in the first day (D1). Starting on D1, Group B received subcutaneous interferon-α 2b in a dose of 100,000 U/Kg/day for 14 days. In the fifteenth day (D15), all rats in both groups were anesthetized with thiopental and sacrificed. Their right lungs medium lobes were prepared for histological evaluation. Hematoxylin eosin and picrosirius stains were performed on 4 μm cuts of each specimen under carefully controlled conditions. The areas of collagen in their lungs were quantified in (μm2) by digital image analysis with the Image Pro for Windows software. All statistical tests were two-sided, and P < .05 was used to indicate statistical significance. Results: The mean pulmonary fibrosis area in the group A was 28,432 μm2 versus 8,866 μm2 in group B who used interferon-α 2b (P = 0,037). Conclusions: These results shows that the use of interferon-α 2b, in this animal model of ARDS, reduced the development of pulmonary fibrosis.

No significant financial relationships to disclose.
A phase II study of the cancer vaccine TG4010 alone and in combination with cytokines in patients with metastatic renal cell carcinoma (RCC)
Authors: Banu E. , Rixe O. , Linassier C. , Machiels J. P. , Baudard M. , Ringeisen F. , Velu T. , Lefrere-Belda M. A. , Limacher J. M. , Oudard S.
Published: March 2020

2581

Background: MUC1 is a glycoprotein often over-expressed and underglycosylated in renal cell carcinoma (RCC) making it an attractive antigenic target for tumor-specific immunotherapy. TG4010 is a cancer vaccine based on a modified vaccinia virus, strain MVA, expressing both MUC1 and Interleukin 2 (MVA-MUC1-IL2). The objective of this phase II, non-randomized study was to determine the efficacy of TG4010 alone and in combination with cytokines. Methods: Thirty seven patients (pts) with progressive metastatic RCC expressing MUC1 in at least 50% of the tumour cells were treated by subcutaneous injections of TG4010, 108 pfu/inj weekly, for 6 weeks then every three weeks until progression. At progression, TG4010 was continued in combination with Interferon α2a (INF) and Interleukin 2 (IL2). Results: Treatment efficacy and toxicities were previously presented at ASCO 2005 (abstr 4653). No objective responses have been observed, however, 7 pts (19%) remained stable for more than 6 months with TG4010 alone, 3 of them more than 22 months. After progression on TG4010 alone 22 pts received TG4010 in combination with cytokines. Six pts (27%) have been stabilized more than 6 months. The median TTP were 2.6 months (95% CI, 2.4–2.9 months) for TG4010 alone and 3.5 months (95% CI, 0.2–6.7 months) for the combined treatment. There were 24 deaths, with a median OS of 19 months (95% CI, 10–27.9) for the whole population. Seven pts were treated by sorafenib after immunotherapy failure. After censoring pts at the introduction of sorafenib, the median OS was 16 months (95% CI, 6–26), with 41% of pts alive at 2-years. The most frequent adverse effects related to TG4010 were minor to moderate injection site reactions, fatigue and flu-like symptoms. Twelve out of 24 pts evaluable for MUC1 ELISpot show evidence for MUC1-specific CD8+ T cell response while 14 out of 21 evaluable for MUC1 specific T cell proliferation were responsive. Conclusions: The cancer vaccine TG4010 alone and in combination with IL2 and INF induces some disease stabilizations in pts with progressive metastatic RCC and can improve survival in a population selected for MUC1 positivity, which is a factor of poor prognosis.

[Table: see text]
Phase I and pharmacological study of the novel aurora kinase inhibitor AZD1152
Authors: Schellens J. H. , Boss D. , Witteveen P. O. , Zandvliet A. , Beijnen J. H. , Voogel-Fuchs M. , Morris C. , Wilson D. , Voest E. E.
Published: March 2020

3008

Background: AZD1152 is a specific aurora kinase inhibitor, selective for Aurora B, currently undergoing Phase I evaluation in patients with advanced solid malignancies. AZD1152 induces p53 independent cellular multinucleation and polyploidy, resulting in apoptosis. It is rapidly converted to the active moiety (AZD1152-HQPA) in plasma. This is the first human study, aimed at determining the maximum tolerated dose, dose limiting toxicities (DLT), pharmacokinetic profile (PK), and to recommend a dose and schedule for further clinical evaluation. Methods: AZD1152 is being administered as a 2-hour IV infusion given weekly in a dose-escalating manner, utilizing an accelerated titration design in patients for whom no other therapy of proven benefit exists. Patients with WHO-PS of 0-2 and adequate bone marrow, liver and renal function were eligible. Results: To date, a total of 13 patients have been recruited: 10M/3F, median age 58 yrs (range 52–71). Patients had colon cancer (n = 3), melanoma (n = 2), or various other solid tumors. Doses were escalated from 100 mg to 200, 300 and 450 mg. DLT was CTC grade 4 neutropenia in 3 patients at 450 mg, signifying a non-tolerated dose on this schedule. Bone marrow recovery was generally noted by 2 wks post-dose. Problematic non-hematological toxicities have not been reported to date. Five patients have remained on therapy for >12 wks (2 × 12+ wks, 16+ wks, 20+ wks and 28+ wks, respectively). AZD1152 is rapidly converted to AZD1152-HQPA with an apparent dose proportional increase in the systemic exposures of both. Population PK analysis of AZD1152-HQPA in the first eight patients revealed a linear three compartment model with clearance 22.4 ± 1.03 L/h. Interoccasion variability was low (CV 5.7%). Conclusions: To date, AZD1152 has been well tolerated when administered IV over 2 hours on a weekly schedule at doses up to 300 mg, however further patients are being enrolled to confirm. Neutropenia is the DLT at 450 mg and no other clinically significant toxicities have been reported. Both AZD1152 and AZD1152-HQPA appeared to have linear kinetics. Significant disease stabilization observed in this rapidly progressive disease setting supports continued clinical development.

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Phase I, pharmacokinetic (PK), & pharmacodynamic (PD) study of 17-dimethylaminoethylamino-17-demethoxygeldanamycin, (17DMAG, NSC 707545) in patients with advanced solid tumors
Authors: Egorin M. J. , Belani C. P. , Remick S. C. , Erlichman C. , Teneyck C. J. , Holleran J. L. , Ivy S. P. , Ramalingam S. , Naret C. L. , Ramanathan R. K.
Published: March 2020

3021

Background: 17DMAG is a water-soluble analog of 17-allylamino-17-demethoxygeldanamycin (17AAG), the first geldanamycin compound to enter clinical trials. 17DMAG causes oncoprotein degradation by binding to heat shock protein 90 (HSP90) & has greater in-vitro activity than 17AAG. In animals treated with 17DMAG, liver toxicity is dose-limiting. The objectives of this first-in-human study are to: establish the dose-limiting toxicity (DLT); recommend a phase 2 dose; & characterize the PK & PD of 17DMAG. Methods: Using a modified accelerated schema, escalating doses of 17DMAG are given IV over 1 h daily x 5 (schedule A) or daily x 3 (schedule B) every 3 weeks. Plasma 17DMAG concentrations during cycle 1 are quantitated by LC/MS. HSP70 & ILK levels in peripheral mononuclear cells are measured by western blot at baseline & 24 h on d 1. Results: 37 pts have been enrolled. On schedule A, dose levels are 1.5, 3, 6, 9, 12 & 16 mg/m2/d (n = 20). On schedule B, the starting dose was 2.5 mg/m2/d. Based on safety information from schedule A, subsequent schedule B dose levels were 14, 19, 25 & 34 mg/m2/d (n = 17). One DLT was noted in schedule A (16 mg/m2) & consisted of reversible liver enzyme elevation. End-of-infusion (EOI) 17DMAG concentrations (33–2074 ng/ml) & AUC0–24 (200–5200 ng/ml x h) increase linearly with dose. Interpatient PK variability was substantial, with CV% of 16–59%. The daily administration schedule precluded precise definition of 17DMAG t1/2 & clearance, but estimates of t1/2 & clearance ranged from 10.8 to 77 h & 19–160 ml/min/m2, respectively. Between 0 & 24 h, 20.5 ± 8.6% (range 4–43.8%) of the administered dose was excreted in urine. HSP70 increased between 0.2 & 3.7 fold above baseline in PBMCs at 24 h at 12, 16, & 25 mg/m2. There is an indication of ILK degradation in 3 of 4 patients evaluated at 25 mg/m2. Conclusions: 17DMAG is well tolerated at current dose levels & maximal tolerated dose has not been reached. 17DMAG plasma PK are linear over the doses delivered to date, & there is evidence of a target effect as manifested by↑HSP70 & ↓ILK. Support: U01CA099168–01, U01CA62502, U01CA69912, R01CA90390 & NIH/NCCR/GCRC grants #5M01 RR 00056 & M01 RR00080

No significant financial relationships to disclose.
Differential circulation kinetics during antiangiogenic therapy of four distinct blood cell populations expressing endothelial markers
Authors: Duda D. G. , Cohen K. S. , Di Tomaso E. , Scadden D. T. , Willett C. G. , Jain R. K.
Published: March 2020

3038

Background: Circulating endothelial cells (CECs) are evaluated as potential biomarker of antiangiogenic therapy. CD146 is an endothelial marker, but its use as a single marker to detect CECs is questionable. In addition, several sub-populations of CECs are thought to exist. Methods: We analyzed the expression of CD31, CD34, CD45, CD133 and CD146 on mononuclear blood cells and primary tissue endothelial cells by flow cytometric and immunohistochemical analyses. Furthermore, we investigated by flow cytometry the phenotype of blood cells expressing endothelial markers and evaluated their changes VEGF blockade by bevacizumab in ten rectal cancer patients enrolled in a Phase I trial. Percent values obtained at days 3 and 12 after bevacizumab infusion were compared with pre-treatment values in individual patients using the Wilcoxon signed-rank test. Results: In the blood, CD146 primarily marked cells with lymphoid markers (CD3 and CD4). CD146 was largely undetectable on blood CD31+CD45- CECs or CD34+CD133+ progenitor cells. In contradistinction, CD146 was detectable in tissues on both cellular components of the vessel wall: CD31brightCD45- endothelial cells and CD31-CD45- pericytes. The CD31+CD45- CEC population contained two distinct populations: CD31brightCD34+CD45- (viable CECs) and CD31dimCD45- (mostly non-viable CECs). Unlike CD31brightCD45- CECs and CD34+CD133+ progenitor cells, CD146+ and CD31dimCD45- cell concentration in the peripheral blood of cancer patients did not decrease during VEGF blockade. Conclusions: In the blood of cancer patients, we identified 4 distinct populations using endothelial markers. CD146 identified T lymphocytes. Within the CD31+CD45- CEC population, there were 2 distinct subpopulations, while the rare progenitor populations localized primarily within the CD45+ hematopoietic cell pool. The changes in blood concentration of these 4 cell types during anti-VEGF therapy were distinct in individual patients. These results underscore the need for further characterization and identification of new markers for CEC subpopulations for their development as biomarkers of antiangiogenic therapy.

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Change in circulating endothelial cells (CEC) predicts progression free survival (PFS) in patients (pts) with hormone receptor positive metastatic breast cancer (MBC) receiving letrozole (L) and bevacizumab (B)
Authors: Rugo H. S. , Dickler M. N. , Traina T. A. , Scott J. H. , Moore D. H. , Bruckner J. , Hudis C. , Park J. W.
Published: March 2020

3039

Background: Antiangiogenic therapy has demonstrated efficacy in the treatment (tx) of metastatic breast cancer. Mechanism-based biomarkers of antiangiogenic therapy, if clinically validated, offer the potential to optimize this novel therapy. CECs have been proposed as a marker of tumor progression and/or response to antiangiogenic therapy with B. We performed a feasibility study testing B combined with L for the tx of hormone receptor-positive MBC. To explore markers of activity and response, we assayed CECs and circulating tumor cells (CTCs) at weeks (wks) 0 (baseline), 3, 12, and then Q 12 wks. Methods: CECs were defined as CD34/31+, CD45-. Progenitor (CD133+) (CECp) and activation markers (CD106+) were also measured. For CECs, 50 ul of blood was stained with the indicated MAbs; after RBC lysis, flow cytometry (FC) was performed for total CEC and CECp. For CTCs, 20 ml of blood was subjected to immunomagnetic capture using anti-EpCAM ferrofluid, followed by FC for EpCAM, CD45, and nucleic acid content. The log rank test was used to test for significant differences related to response. Results: 32 of 42 pts have been enrolled. As separately reported, prior non-steroidal AI (NSAI) use without progression is permitted; median (med) time on L before start of B was 6 mo (1–52). 28 pts have at least baseline and week 3 CEC and CTC along with clinical response data. Med CEC level at baseline was 10.4 CEC/ul (4–38); the peak value at any time point was 107. CTC levels were much less frequent with a med of 0.3 CTC/ml (0–95, and highest value 1153). An increase in CECs at wk 3 compared to wk 0 predicted worse PFS (p = 0.015). CTCs were ≤ 0.1 at study start in 40% of pts and ≥ 1.0 in only 17%, likely due to length of prior L; change in values at wk 3 did not correlate with PFS in this pretreated group. Conclusions: Consistent with our previous results in a separate trial of B containing treatment in MBC, changes in CEC levels appear to be a biomarker of response/progression on antiangiogenic therapy. CTCs did not reflect response or progression in this population of patients, likely due to lengthy prior exposure to letrozole. Supported in part by Genentech and Novartis.

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Phase I dose escalation study to determine the safety, pharmacokinetics and pharmacodynamics of BMS-582664, a VEGFR/FGFR inhibitor in patients with advanced/metastatic solid tumors
Authors: Rosen L. S. , Wilding G. , Sweeney C. , Casale D. , Kollia G. , Wu C. , Ayers M. , Hill C. , Galbraith S. M.
Published: March 2020

3051

Background: This is the first multiple-dose study with BMS-582664, an oral VEGFR/FGFR tyrosine kinase inhibitor (IC50 34, 10, 145, 125 nM for VEGFR2, VEGFR3, FGFR1 and FGFR2 respectively). Patients (pts) with metastatic solid tumors refractory to standard therapy were enrolled. Part A of this study has completed. Part B is ongoing to evaluate the effect of BMS-582664 on dynamic contrast enhanced MRI (DCE-MRI) parameters. Methods: Part A: Open label dose escalation, continuous qd schedule, 3 patients per cohort. The starting dose was 180 mg. Dose escalation continued until dose limiting toxicities (DLTs) at 1000 mg in 2/3 pts were observed. The next lower dose level (800 mg) was expanded to 6 pts. Blood sampling for pharmacodynamic [circulating endothelial cells (CECs) and Collagen IV ELISA] and PK analysis was performed on Days 1, 8 and 26. BMS-582664 (prodrug) and its active metabolite, BMS-540215 were analyzed using an LC/MS/MS assay. DCE-MRI was performed at 320 mg, 600 mg and 800 mg at baseline ×2, Days 2, 8 and 26. Results: Negligible BMS-582664 was detected. BMS-540215 AUC increased proportionally to dose increase across 180 mg to 1000 mg. The accumulation ratio (Day 26:Day 1) of C24hr, Cmax and AUC was 4.8, 2.0 and 2.1 respectively at 1000 mg, but close to 1 at lower doses. The median time on study for all patients in Part A was 84 days. Conclusions: DLT was dizziness/fatigue. BMS-582664 has pharmacodynamic and anti-tumor activity and was well tolerated at ≤ 800 mg qd.

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Phase I study of low-dose hypomethylating agent azacitidine (5-AC) combined with the histone deacetylase inhibitor valproic acid (VPA) in patients with advanced cancers
Authors: Braiteh F. , Soriano A. , Luis C. H. , David H. S. , Ng C. , Garcia-Manero G. , Kurzrock R.
Published: March 2020

3060

Background: By inhibiting DNA methyltransferase, 5-azacytidine (5-AC) reverses epigenetic silencing of aberrantly hyper-methylated genes restoring activity of tumor suppressor and pro-apoptotic genes. In leukemia, the responses achieved with the hypomethylating agent decitabine are considerably greater at low doses than at high dose levels. We explored the tolerance to a combination of valproic acid (VPA), a histone deacetylase inhibitor, given together with low-dose 5-AC and the ability of this combination to induce DNA hypomethylation. Methods: Every 28-day cycle, 5-AC was givenSC daily for 10 days, and VPA was administered orally daily in doses titrated up to therapeutic levels (75–100 mcg/mL). Planned dose-levels of 5-AC (6-patients/cohort) were determined per an adaptive algorithm based on toxicity in the previous cohort (toxicity-based adaptive dosing model (TAD model) with a starting dose of 20 mg/m2. The methylation status of long interspersed nuclear elements (LINE) was used as a surrogate marker of global methylation, and was performed on peripheral blood mononuclear cells on day 1 and 10 of the first 4 cycles for each patient. Results: To date, twenty-two patients have enrolled at 20, 25, 37.5 and 47 mg/m2 dose-levels. The VPA dose was titrated up to 18.8 ± 6.9 mg/kg. Side effects include mainly drowsiness (N = 5), tremor (N = 4), hypomagnesemia (N = 2), grade 1–2 anemia (N = 2), and neutropenia (N = 2). One DLT (neutropenic fever) occurred at a dose of 37.5 mg/m2. One patient with rapidly progressive disease (renal cell carcinoma) experienced stable disease (6 months), and three patients (adenocystic carcinoma = 1, leiomyosarcoma of the uterus = 2) experienced stable disease for 4 months. Eighty-two blood samples were obtained. Median LINE methylation pretreatment was 65% (range 59–70%, it declined to 61% (range 53–63%) by day 10 (p = 0.001)and returned to baseline by day 0 of the following cycle. Conclusions: Our preliminary data suggest that low-dose 5-AC combined with VPA (median = 17 mg/kg) is well tolerated and exhibits biological activity in patients with advanced cancer. Western blot assays for histone acetylation are in process. The trial is currently accruing at dose-level 47 mg/m2.

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A phase I study of two administration schedules of the Polo-like kinase 1 inhibitor BI 2536 in patients with advanced solid tumors
Authors: Munzert G. , Steinbild S. , Frost A. , Hedborn S. , Rentschler J. , Kaiser R. , Trommeshauser D. , Hoffmann M. , Steegmaier M. , Mross K.
Published: March 2020

3069

Background: BI 2536 is a novel highly potent and selective inhibitor of the serine-threonine Polo-like kinase 1 (Plk1), a key regulator of cell cycle progression. Objectives of this trial were the assessment of the maximum tolerated dose (MTD), overall safety, pharmacokinetics and preliminary efficacy of BI 2536 given intravenously. Methods: Sequential cohorts of 3–6 patients (pat) with advanced or metastatic solid tumors received infusions of BI 2536 following a toxicity guided dose escalation design. In the first part of the trial, a single administration was given every 21 days (d1). After completion of accrual BI 2536 was administered on three consecutive days (d1–3) in a dose intensified schedule in additional patient cohorts. Further treatment courses were given in the absence of disease progression and after recovery of toxicity after a 3-week observation period. Results: Of the 52 entered patients a total of 40 pts were treated at doses of 25 (n=3), 50 (n=3), 100 (n=3), 200 (n=25) and 250 mg (n=6) in the d1 schedule. The MTD for the d1 schedule was defined at 200 mg. Dose limiting toxicity (DLT) consisted of neutropenic infection and occurred in 2/6 patients at 250 mg. Reversible CTCAE grade ≥ 3 neutropenia represented the main drug related toxicity with an incidence of 13/25 in the 200 mg and 5/6 in the 250 mg dose cohorts. Alopecia was reported in 20% of pat. Further common drug related adverse events (AE’s) consisted of nausea (38%), anorexia (25%) fatigue (18%), vomiting (18%) and mucositis (12%) and were mostly of mild to moderate intensity (CTCAE grade ≤ 2). PK analysis showed dose proportionality of Cmax and AUC0-∞ with a high clearance (∼ 1400 mL/min) and a high volume of distribution (∼ 1200 L). A correlation between exposure and neutropenia was observed. Patients were treated for up to 10 courses without evidence of accumulating toxicity. One partial response was observed in a patient with metastatic squamous cell head and neck cancer treated at 250 mg. The DLT was determined at 3x70 mg in the dose intensified schedule with the MTD still pending. Conclusion: In summary BI 2536 is a Plk1 inhibitor with a favorable safety and PK profile. Neutropenia as a mechanism-related toxicity indicates target inhibition in vivo. First signs of antitumor activity were observed.

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