bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I and pharmacokinetic evaluation of enzastaurin combined with gemcitabine and cisplatin in advanced cancer
Authors: Beerepoot L. , Rademaker-Lakhai J. , Witteveen E. , Radema S. , Viseren-Grul C. , Musib L. , Van Hal J. , Beijnen J. , Schellens J. , Voest E. 
Published: March 2020

2046 Background: Enzastaurin (Enz), an oral PKC inhibitor that also suppresses PI3K/AKT pathways, blocks tumor angiogenesis and tumor cell proliferation and induces tumor cell death. Gemcitabine (Gem) and cisplatin (Cis) combination is often used for treatment of solid tumors. Addition of Enz to the regimen has the potential for enhanced clinical benefits without increasing toxicity. Methods: In this phase I, dose-escalation trial, patients (pts) with advanced, refractory, solid tumors received a lead-in treatment (cycle 1) with oral Enz for 14 days to achieve steady-state exposures. Starting with cycle 2, pts received Enz orally (350 mg qd to 500 mg bid) on days 1–21 combined with Gem (1000 or 1250 mg/m2) as a 30-min iv infusion on days 1,8 and Cis (60 or 75 mg/m2) as a 3-h iv infusion on day 1, every 21 days, for up to 7 cycles. Results: 33 pts (22 males, 11 females; ECOG: 0–2), with a median age of 58 yrs (range: 38–79 yrs), were enrolled in 7 dose levels. The MTD was not identified. Two DLTs were reported, 1 grade (Gr) 2 QTc interval prolongation and 1 Gr 3 fatigue, both during cycle 1 in bid cohorts. Laboratory toxicities included Gr 3/4 neutropenia (3/6 pts), thrombocytopenia (1/6 pts), and Gr 3 leukopenia (2 pts), hyperglycemia (1 pt), and creatinine (1 pt). Gr 3 toxicity reported in >1 pt was fatigue (5 pts). Enz bid (≥ 250 mg bid) was associated with more discontinuations in early cycles, more Enz dose adjustments, higher numbers of possibly-related SAEs, and increased numbers of low-grade CTC toxicities compared to the corresponding qd dosing. Exposures of Enz in the presence of Gem and Cis decreased slightly but the decrease was not clinically significant as the mean exposure remained above the targeted exposure of 1400 nM. Gem and Cis exposures were not altered when given in combination with enz, as compared to historical data. Of 24 evaluable pts, 3 pts (pancreatic, head/neck, and ovarian cancer) achieved a partial response, whereas 13 achieved stable disease for ≥ 2 cycles. Conclusions: Based on safety and PK data, the recommended phase II dose is Enz 500 mg qd, Gem 1250 mg/m2, and Cis 75 mg/m2. This regimen is generally well tolerated across all dose levels and there are no significant alterations in PK parameters of any drug, when given in combination. [Table: see text]
A phase I/II study to assess the safety, tolerability and pharmacokinetics (PK) of intravenous (IV) infusion of MB07133 in subjects with unresectable hepatocellular carcinoma (HCC)
Authors: Ma B. , Forbes W. , Venook A. P. , Bissell D. M. , Peterson C. , Niculae I. , Bullough D. 
Published: March 2020

2054 Background: MB07133 is a novel cytarabine (araC) prodrug that uses the HepDirect technology to target production of the active form of araC, araC triphosphate (araCTP), to the liver. The study objectives were to determine the maximum tolerated dose, toxicity profile (NCI-CTC 2.0), PK & antitumor activity of MB07133 in patients (pts) with unresectable HCC. MB07133 was given as a continuous IV infusion at escalating doses during the first 7 days of a 28-day cycle until disease progression or unacceptable toxicity occurred. To date, 22 pts with Child-Pugh Class A liver function have been enrolled in 4 cohorts (300, 600, 1200, 1800 mg/m2/d, D1–7), with 3–6 pts/cohort. Enrolled pts had a median age of 57 yrs (range 20–67) & consisted of 21 males, 1 female, 19 Asians & 3 Caucasians. A total of 66 cycles have been administered (maximum 10 cycles in 1 pt) with no dose-limiting toxicities associated with therapy. Most drug-related toxicities (67%) were mild to moderate (gr 1–2 neutropenia, thrombocytopenia & increased ALT). There was 1 gr 3 ascites unrelated to study drug and no gr 4 toxicity. Six pts experienced 10 serious adverse events, all unrelated or unlikely related to study drug. The very low araC concentrations in the plasma (see table ) were consistent with previous animal studies, which demonstrated MB07133 to target araCTP production in the liver. 36% of pts who had ≥ 2 cycles of MB07133 had disease stabilization. Conclusions: MB07133 is well tolerated at doses up to 1800 mg/m2/d in pts with unresectable HCC. Enrollment of a 2400 mg/m2 cohort is ongoing. The disease stabilization observed in this study, although preliminary, warrants further investigation in Phase 2. [Table: see text] [Table: see text]
Phase I study of ATN-224 in patients (pts) with advanced solid tumours
Authors: Lowndes S. A. , Adams A. , Timms A. , Middleton M. , Hayward C. , Reich S. D. , Mazar A. P. , Harris A. L. 
Published: March 2020

2065 Background: Copper chelation reduces the secretion of many angiogenic factors and reduces tumour growth and microvascular density in animal models. ATN-224 is a second generation analogue of ammonium tetrathiomolybdate, which reportedly can stabilise disease but was limited by the slow onset of copper depletion (50–60 days). Preclinical studies suggest ATN-224 may act primarily by superoxide dismutase 1 (SOD-1) inhibition. The aim of our phase I study was to reduce serum copper levels, as measured by ceruloplasmin (Cp), to 5–15 mg/dl (normal 16–60) in 14–21 days, to determine the pharmacokinetic profile, and to evaluate dose-limiting toxicities. Methods: Cohorts of pts were treated with escalating doses of ATN-224, twice daily, until copper depletion, followed by a titrated maintenance dose. Serum Cp was used as a surrogate marker of copper levels and was titrated to a target range of 5–15mg/dL (normal 16–60). Results: 18 pts have received 54 cycles of ATN-224. Tumours were breast (4), renal (2), melanoma (2), colon (2), and a variety of other types (1 each). Pts received ATN 224 loading doses in cohorts of 1 to 6 pts: 150 (1), 210 (2), 240 (1), 270 (6), 300 (5), and 330 mg/day (3). Mean age was 56 yrs (range 37–78) and PS 0–2. Mean baseline Cp was 39.6 (range 22–63 mg/dL). The maximum administered dose was 330 mg/day where grade 3 lethargy was observed in 3 pts. Of the 4 pts at the maximum tolerated dose of 300 mg/day who have currently completed the loading schedule, all 4 have achieved a reduction of Cp to within 10% of the target range within 21 days. Other toxicities at this dose level included sulphur burps (Gr 1), vomiting (Gr 2), neutropenia (Gr 2), and anaemia (Gr 3). Toxicities reduced in the second and subsequent cycles when doses were titrated downward to maintain Cp levels in target range. PK data indicate greater absorption of ATN 224 and more rapid reduction in Cp with concurrent administration of a proton pump inhibitor. Stable disease of >6 months was observed in 4 pts. Conclusions: Oral ATN-224 is a well-tolerated therapy and at a loading dose of 300 mg/day leads to a reduction of serum Cp levels to 20% normal within 21 days. This will be the recommended starting dose level for phase II study. (Sponsored by Cancer Research UK; funded by Attenuon, LLC). [Table: see text]
Evaluation of the safety of C-1311 administered in a phase I dose-escalation trial as a weekly infusion for 3 consecutive weeks in patients with advanced solid tumors
Authors: Isambert N. , Campone M. , Bourbouloux E. , Drouin M. , Major A. , Loadman P. , Capizzi R. , Grieshaber C. , Fumoleau P. 
Published: March 2020

2069 Background: C-1311 is the most active member of a new series of anti-cancer agents, the imidazoacridinones, specially designed compounds developed from research on the structure-activity relationships of other cancer therapies such as the anthracenediones (e.g. mitoxantrone) and the anthracyclines (e.g. doxorubicin). This first-in-man clinical trial was designed to assess the safety profile of C-1311 and determine the recommended dose upon weekly administration for 3 consecutive weeks, within a 28-day cycle. Methods: Patients with advanced solid tumors refractory to conventional therapy were enrolled. The dose escalation scheme was divided into 2 phases: an initial accelerated phase of cohorts of 1 patient at doubling doses and a modified Fibonacci phase of cohorts of 3 pts at 25–33% dose increments. The maximum tolerated dose (MTD) was defined as the dose at which 2/3 or 2/6 pts experienced a dose-limiting toxicity (DLT). The recommended dose (RD) was defined as the dose level below the MTD, confirmed by expansion of the cohort to 9 pts. Results: 16 pts received doses of 15, 30, 60, 120, 240, 480 and 640 mg/m2/wk. The 2 pts treated at 640 mg/m2 experienced a DLT (grade 3 neutropenia preventing the administration of the 2nd and 3rd dose of the first cycle respectively). The RD was defined as 480 mg/m2/wk (cohort of 9 pts). Six additional pts were treated at the RD in an extension study in which one of the first 2 doses was given orally. Overall, 2 serious adverse events have been reported as possibly drug-related, both consisting of post-infusion fever without evidence of infection, resolving within 24 hours. Transient neutropenia was the only recurring grade 3 or 4 drug-related adverse event (AE). Grade 1 or 2 AEs most commonly reported as drug-related were nausea, asthenia, vomiting and diarrhea. Stable disease was observed in 3 patients with advanced malignancy. One pt had a stable course over > 8 cycles, and two had stable courses over 4 cycles. Plasma drug concentrations were linear and proportional to dose. Conclusions: The recommended phase 2 dose of 480 mg/m2, weekly × 3 q 28 days, offers a predictable safety profile and excellent tolerability. [Table: see text]
Phase I combination study of trabectedin (T) and capecitabine (C) in patients with advanced malignancies
Authors: Gore L. , Rivera E. , Lavallee K. , Holden S. , Grolnic S. , Cleere D. , Moulder S. L. , Elsayed Y. A. , Eckhardt S. 
Published: March 2020

2079 Background: T binds to the minor groove of DNA, synergizes with functional nuclease excision repair and targets inducible transcription. T is active in several tumor types and exhibits preclinical synergy with C. The primary objective of this study is to determine the maximum tolerated dose (MTD) of T in combination with C. Secondary objectives include safety and pharmacokinetic (PK) analyses. Methods: Pts with advanced cancer, performance status 0–1 and adequate organ function are eligible. Pts received T starting at 0.4 mg/m2 over 3 hours on day 1 followed by C on days 2 through 15. The initial dose of C was 2000 mg/m2/day and was reduced to 1600 mg/m2/day due to GI dose-limiting toxicity. Dose escalation of T continued. Cycles are repeated every 3 weeks, with PK sampling included. Standard “3+3” dose escalation design, definitions of dose limiting toxicity (DLT), and dose modification for toxicity are implemented. Results: To date, 30 patients have received 112 cycles (range 1–12, median 4) of treatment at 7 dose levels. Two of 3 pts at dose level 4 (C 2000 mg/m2/d and T 0.9 mg/m2) and 2/6 pts at dose level 3 (C 2000 mg/m2/d and T 0.75 mg/ m2) developed gastrointestinal DLT (emesis, diarrhea, pancreatitis). C was subsequently reduced to 1600 mg/m2/d and a new T dose escalation was initiated at 0.6 mg/m2. Treatment has been well tolerated with C 1600 mg/m2/d and T up to the current dose of 0.9 mg/m2 (dose level 4a), with 1of 6 subjects experiencing grade 1 alkaline phosphatase. The most frequently reported related grade 3–4 adverse events (AEs) are diarrhea (23%), neutropenia (20%), nausea (16.6%), hand-foot syndrome (16.6%) and vomiting (13%). Anti-tumor activity to date includes a confirmed partial response lasting 8 months (m) in a patient with cholangiocarcinoma, and prolonged stable disease in 2 patients with breast cancer (6 and 7m), ovarian cancer (11m) and chondrosarcoma (9m). Conclusions: The combination of C 1600mg/m2/d and T up to 0.9mg/m2 is tolerable and has promising activity in several tumor types. Dose escalation of T continues at 1.1 mg/m2. Biologic and pharmacokinetic analyses will be presented. [Table: see text]
Phase 1, pharmacokinetic (PK) and pharmacodynamic (PD) study of of the Hsp-90 inhibitor, KOS-1022 (17-DMAG), in patients with refractory hematological malignancies
Authors: Lancet J. , Gojo I. , Baer M. , Burton M. , Klein M. , Nowadly C. , Gorre M. , Zhong Z. , Johnson R. G. , Hannah A. L. 
Published: March 2020

2081 Background: Disruption of Hsp90-client protein heterocomplexes leads to degradation of a variety of oncoproteins. KOS-1022, an Hsp90 inhibitor and water-soluble geldanamycin derivative, is in trials in patients with solid tumors. Compared to a prior geldanamycin derivative (17-AAG), KOS-1022 is ∼3–5 fold more potent (comparing in vitro cytotoxicity or the MTD in toxicology studies on the same schedule). Primary study objectives: establish safety and MTD of KOS-1022 in patients with advanced hematologic malignancies; characterize PK and PD. Methods: Escalating doses of KOS-1022 are given IV over 1 h twice weekly for 2 out of 3 weeks. Plasma KOS-1022 concentrations (1st and 4th infusion, Cycle 1) are quantitated by LC/MS/MS. Pre and on-study CD34+ bone marrow and peripheral blasts undergo flow cytometry to quantify Hsp70/90, pAKT/total AKT, markers of apoptosis and proliferation. Response in AML pts used IWG criteria. Results: 13 pts have been enrolled at doses of 8 (n=4), 16 (n=6), 24 (n=1) and 32 mg/m2 (n=2). All were AML (except 1 CML). Most (n=11) patients had 2–3 prior induction regimens. DLT was seen in 2 pts at 32 mg/m2 (acute myocardial infarction and elevation of troponin). Both patients had significant co-morbidity, including (1) prior myocardial infarction and (2) progressive AML with a similar troponin elevation during induction chemotherapy prior to study. Common drug-related toxicities (all Grade 1–2): fatigue, nausea, diarrhea and arthralgias. From 8 to 32 mg/m2, approximately linear PK was observed. Mean terminal half-lives varied from 13.0–31.2 hours. Day 1 clearance for 8, 16 and 32 mg/m2 was 5.6, 9.7 and 10.8 L/hr/m2; mean Vz (L/m2) for these groups were 238, 433 and 489. Although pre-infusion drug was quantifiable on Day 11 in most patients, Day 11/Day 1 AUC0–25h ratio was 0.96. Activity in AML: 2 CRi and 1 SD x 9 cycles were observed. Comparing BMAs taken at Day 8 and Day 15 to baseline: decreased Hsp90 (41% to 13%), increased Hsp70 (8% to 84%) with decreased pAKT (Ser), pAKT (Thr) and total AKT in CD34+ cells. Conclusions: KOS-1022 appears to be well tolerated, with preliminary signs of clinical and biologic activity in refractory leukemia. MTD has not been defined. Plasma PK is linear over this dose range. [Table: see text]
A dose-escalation trial of GM-CSF-gene transduced allogeneic prostate cancer cellular immunotherapy in combination with a fully human anti-CTLA antibody (MDX-010, ipilimumab) in patients with metastatic hormone-refractory prostate cancer (mHRPC)
Authors: Gerritsen W. , Van Den Eertwegh A. J. , De Gruijl T. , Giaccone G. , Scheper R. J. , Lowy I. , Levy E. , Hege K. , Sacks N. 
Published: March 2020

2500 Background: A Phase 1 trial is underway to study the combination of GM-CSF-gene-transduced allogeneic prostate cancer cellular immunotherapy (GVAX immunotherapy (IT) and ipilimumab in patients (pts) with mHRPC. Ipilimumab is a fully human IgG monoclonal antibody specific to the CTLA-4 receptor on T cells that augments immune responses by blocking the inhibitory CTLA-4/B7 interactions. Pre-clinical studies of antibodies to CTLA-4 in combination with GM-CSF secreting tumor cell vaccines demonstrate potent synergy. Methods: Eligible pts have documented mHRPC and are chemotherapy-naïve. All pts receive a 500 million cell priming dose of GVAX IT on day 1 followed by bi-weekly intradermal treatments (tx) of 300 million cells for a 24 week (wk) period. Ipilimumab is administered every 4 wks starting on day 1 for the same period. Pts are enrolled in cohorts of 3; each cohort is assigned an escalating dose of ipilimumab: 0.3, 1, 3 or 5 mg/kg. PSA is measured every 4 wks, and tumor assessments performed every 12 wks. 15 pts will be enrolled at the maximum tolerated dose. Pts are followed for disease progression and survival. Results: Ten pts have been enrolled. All 6 pts in Cohorts 1 and 2 have completed tx and are in follow-up; 5 of 6 completed all planned tx. Three pts in Cohort 3 have completed 75% of tx and are on-going. One pt in Cohort 4 has completed 25% of tx and is on-going. No dose-limiting or immune mediated toxicities have been observed. The most common adverse event is injection site reaction which occurs in 100% of pts. PSA responses by NCI working group criteria include 1 partial response (PR), 4 stable disease (SD), and 4 progressive disease (PD). Of note, 3 PD occurred in Cohort 1; 2 SD and 1 PD occurred in Cohort 2, and 1 PR and 2 SD occurred in Cohort 3. Any decline in PSA was evident within 2–4 wks of initiating tx. Conclusions: The combination of GVAX IT and ipilimumab appears well-tolerated in pts with mHPRC. These preliminary data suggest a relationship between PSA response and the dose level of ipilimumab in combination with GVAX IT. [Table: see text]
A phase I study of ultra low dose interleukin-2 (IL-2) and stem cell factor (SCF) in patients with cancer and or HIV infection
Authors: Benson D. M. , Shah M. , Freud A. , Ferketich A. , Dezube B. J. , Bernstein Z. P. , Caligiuri M. A. 
Published: March 2020

2503 Background: HIV infection depletes crucial lymphocyte subsets and often culminates in patients’ demise due to infectious or malignant complications. We have shown in previous work that ultra low dose interleukin-2 (IL-2) expands natural killer (NK) cells and other lymphocyte subsets in patients with AIDS-associated malignancies. Preclinical work by our group has demonstrated that CD56bright NK cells, an important source of interferon-γ, constitutively express the c-kit receptor and proliferate synergistically in vitro and in vivo in response to IL-2 and stem cell factor (SCF) presented together. To determine the safety, toxicity, and immune modulatation of IL-2 and SCF in patients, we report a first-in-man Phase I trial of this combination of cytokines in patients with HIV and HIV-associated malignancies. Methods: Eligible adults had a history of cancer and HIV or an AIDS defining illness, Karnofsky score > 70%, CD4 T-cell count > 20/mm3, and had to be on HAART therapy. Patients received IL-2 subcutaneously (SQ) daily at 900,000 IU/m2 (cohort 1) or 450,000 IU/m2 (cohorts 2 and 3) except Sunday and SCF (SQ) three times a week (at 5 mcg/kg/d or 10 mcg/kg/d) for 8 weeks. Toxicities and side effects of therapy were closely monitored. Changes in lymphocyte subsets were assessed by flow cytometry. Results: 13 patients (median age = 42, range 33–62) with cancer and HIV (5) or AIDS (8) were enrolled. 10 patients completed therapy, whereas three exhibited the grade 3 dose limiting toxicity (DLT) of fatigue and withdrew. Treatment led to statistically significant increases in NK cells (2.2-fold, p = 0.02) and regulatory T cells (Tregs) (6-fold, 0.005). These were similar to a previous study using a slightly higher dose of IL-2 alone (1 million IU/m2) in which NK were expanded 1.6 fold (p = 0.02) and Treg were expanded nearly 9-fold (p = 0.0003). Conclusions: Simultaneous administration of IL-2 and SCF is safe and well tolerated. The maximum tolerated doses of IL-2 and SCF were 450,000 IU/m2 and 5 mcg/kg/d respectively. Fatigue was the DLT. A trend towards preferential expansion of CD56bright NK cells as opposed to Tregs was seen; however, these changes were not significantly different from changes in response to a similar ultra low dose of IL-2 alone. No significant financial relationships to disclose.
In vivo efficacy of the CD40 agonist antibody CP-870,893 against a broad range of tumor types: Impact of tumor CD40 expression, dendritic cells, and chemotherapy
Authors: Gladue R. P. , Cole S. H. , Donovan C. , Paradis T. , Alpert R. , Natoli E. , Bedian V. 
Published: March 2020

2514 Background: CP-870,893 is a fully human IgG2 CD40 agonist antibody currently in early clinical trials. In vitro studies demonstrate its ability to bind human CD40 and enhance dendritic cell costimulatory molecule expression and cytokine production. Methods: In order to assess its potential for cancer therapy, we evaluated the anti-tumor efficacy of CP-870,893 against several CD40pos and CD40neg human tumors in SCIDbeige mice. We specifically addressed the role of tumor CD40 expression, the impact of re-population with human dendritic and T cells on efficacy, and it’s potential to act in synergy with chemotherapeutic agents. Results: We demonstrate that a single i.p. injection of CP-870,893 (T1/2 ∼ 7 days) prevented the growth of several subcutaneous CD40pos tumors including two B cell lymphomas, the breast carcinoma BT-474, and the prostate tumor PC-3 (ED50 = 0.02 mg/kg; Ceff ∼100 ng/mL). Efficacy was demonstrated when CP-870,893 was administered at the time of tumor challenge, but was also observed when treatment was delayed until tumors were well established. Although efficacious against CD40pos tumors, CP-870,893 had no effect on the growth of CD40neg/low tumors unless mice were repopulated at the tumor site with both naïve human dendritic cells and T cells. In these repopulated animals, i.p. administration of CP-870,893 inhibited the growth of a CD40low colon carcinoma and a CD40neg erythroleukemic tumor (ED50 = 0.005 mg/kg). The presence of human T cells and dendritic cells at the tumor site also improved the activity of CP-870,893 against CD40pos tumors, reducing the ED50 and Ceff >10-fold as compared to its effects in the absence of these cells, suggesting a synergy between direct CD40 mediated tumor killing and immune activation. Further, when administered as part of a combination treatment with a sub-optimal dose of cisplatin, improved activity was observed which resulted in tumor regression. Conclusions: These studies demonstrate the potent, broad-spectrum anti-tumor activity of CP-870,893 through both direct and immune mediated effects, its increased efficacy when co-administered with chemotherapeutic agents, and suggest its potential utility as a therapy for human cancer. [Table: see text]