bluuebunny/crossref_metadata_2025_split huggingface dataset:
Phase I study of obatoclax mesylate (GX15–070MS), a bcl-2 antagonist, plus topotecan in relapsed small cell lung carcinoma and other solid tumors
Authors: Brown A. B. , Rudin C. , Rizvi N. , Travis W. , Takebe N. , James L. P. , Subzwari S. , Tyson L. , Markus S. , Krug L. M. 
Published: August 2020

3504 Background: Bcl-2 is a rational target in SCLC since it is overexpressed in 60%-90% of tumors and may play a role in resistance of SCLC to chemotherapy. Obatoclax is a small molecule BH3 mimetic that blocks bcl-2 binding to proapoptotic family members. Obatoclax has growth inhibitory effects in several solid tumor cell lines and xenografts, with at least additive effects in combination with topotecan. The primary objective of this study was to evaluate the safety profile and maximum tolerated dose (MTD) of obatoclax plus topotecan in patients with relapsed SCLC and other solid tumors. Methods: We conducted a phase I dose escalation study using a standard “3+3” design. Obatoclax was administered at 14 or 20 mg/m2 over 3 hours on day 1 every 21 days. A subsequent cohort received obatoclax 14mg/m2 on days 1 and 3. Topotecan was given at 1.25 mg/m2 days 1–5. All patients received pegfilgrastim on day 8. Eligible patients were adults with solid tumors appropriate for treatment with topotecan. Patients with neurologically stable, treated brain mets were eligible. Results: 14 patients have been treated including 8 SCLC, 3 extrapulmonary small cell, 1 carcinoid, 1 Merkel cell and 1 melanoma previously treated with 1 or 2 lines of chemotherapy. Nearly all patients experienced neurologic toxicities during the obatoclax infusion which included ataxia, dysarthria, somnolence and/or mood alteration; these typically resolved 1–2 hours after completion of the infusion. The MTD of obatoclax was 20 mg/m2 on day 1 with Dose Limiting Toxicities (DLT) including grade 3 neurotoxicity (2 pts) and febrile neutropenia. Hematologic toxicity included grade 3/4 anemia (6 pts), thrombocytopenia (5 pts) and neutropenia (5 pts). Other toxicities included mild nausea/vomiting, fatigue, pruritus, and constipation. Clinical activity was seen in patients with SCLC including 1 PR and 4 SD out of 7 evaluable. The median TTP for these SCLC patients was 11 weeks. Conclusions: The recommended phase II dose is obatoclax 14 mg/m2 on days 1 and 3 with topotecan 1.25 mg/m2 on days 1–5 in 21 day cycles. A phase II study in second-line SCLC is open. Supported by NCI U01-CA69856. No significant financial relationships to disclose.
Phase I study of chidamide (CS055/HBI-8000), a novel histone deacetylase inhibitor, in patients with advanced solid tumors and lymphomas
Authors: Dong M. , Ning Z. , Newman M. J. , Xu J. , Dou G. , Cao H. , Shi Y. , Gingras M. A. , Lu X. , Feng F. 
Published: August 2020

3529 Background: Chidamide (CS055/HBI-8000) is a new benzamide type of histone deacetylase (HDAC) inhibitor with low nanomolar activity against HDAC1, 2, 3 and 10. This Phase I study evaluated the safety and tolerability of chidamide in patients (pts) with advanced solid tumors and lymphomas. Methods: 31 pts with refractory or relapsed advanced solid tumors (22) and lymphomas (9) were enrolled in this study. Escalating doses of 5, 10, 17.5, 25, 32.5 and 50 mg Chidamide (each with 3 to 7 pts) were administered orally either twice or three times per week for 4 consecutive weeks every 6 weeks. Results: No dose limiting toxicities (DLTs) were identified in the 2 x per week cohorts (22 pts) up to 50 mg; G2 and G3 hematological toxicities (leukopenia/neutropenia and thrombocytopenia) were observed at 50 mg. DLTs were reported as G3 diarrhea or vomiting in 2 pts in the 3 x per week cohort at 50 mg. Common adverse events were G1/G2, fatigue (n = 11), thrombocytopenia (n = 9), anorexia (n = 8), nausea/vomiting (n = 7), leukopenia/neutropenia (n = 6), hypochromia (n = 6), and diarrhea (n = 5). No cystitis, pericarditis, pericardial effusion or prolonged QTc intervals were observed. Single dose PK analysis in pts with 25, 32.5 and 50 mg revealed T1/2 of 16.8–18.3 h, Tmax of 1–2 h in most cases, and a dose-related increase in Cmax and AUC. Multiple dose PK analysis in pts with 32.5 mg 3 x per week suggested drug accumulation with this regimen. Significant induction of histone (H3) acetylation was observed in peripheral white blood cells, which lasted for 2–3 days in most pts after single dosing. 25 pts with total treatment cycles of 49 (range 1–6) were evaluable for efficacy. 4 pts with T-cell lymphomas (4/5 evaluable) and 1 pt with submandibular adenoid cystic carcinoma achieved PR, and 11 pts (2 B-cell lymphomas and 9 solid tumors) experienced SD. Conclusions: Chidamide was well-tolerated in pts with advanced solid tumors and lymphomas in the tested regimens. In addition, the compound exhibited a relatively long half-life, a long-lasting biomarker response and encouraging antitumor activity at well-tolerated doses. The overall phase I results recommend the 2 x per week regimen for phase II studies. [Table: see text]
A first-in-human phase I trial of PBI-05204 (oleandrin), an inhibitor of Akt, FGF-2, NF-Kb, and p70S6K in advanced solid tumor patients
Authors: Bidyasar S. , Kurzrock R. , Falchook G. S. , Naing A. , Wheler J. J. , Durand J. , Yang P. , Johansen M. J. , Newman R. A. , Khan R. , Hong D. 
Published: August 2020

3537 Background: PBI-05204 contains oleandrin, a cardiac glycoside, which inhibits the α-3 subunit Na-K ATPase pump. Over-expression of the α-3 subunit in malignant cells correlates with the tumor proliferation. Oleandrin inhibits FGF- 2 export and activation of NF-Kβ and inhibits phosphorylation of Akt. PBI-05204 also inhibits p70S6K, decreasing mTOR activity. In this ongoing study of PBI-05204, we sought to determine the DLTs, MTD and recommended phase II dose in advanced solid tumors patients (pts) and to characterize its’ pharmacokinetics (PK) and pharmacodynamics (PD). Methods: This was a standard 3+3 phase I design. PBI-05240 was given orally for 21 days of 28 days. Dose was increased by 100% if no related grade 2 adverse event (AE) was observed and increased by 50% if a grade 2 AE occurred. If no other grade 2 AE were observed then subsequent dose escalation was resumed at 100%. In order to determine drug-mediated changes in pAkt, p70S6K, and S6 (mTOR effectors) expression as a surrogate marker of target effect, peripheral blood mononuclear cells (PBMCs) were obtained in addition to PKs. Results: To date 15 pts have received PBI-05204 at 5 dose levels (0.6 mg to 10.2 mg/day), 2 pts are currently active at dose level 5. No DLT has been observed thus far. 10 out of 15 pts (67%) experienced only grade 1 AEs, most common: fatigue and constipation (20%). No significant cardiac toxicities have been observed, only first degree AV block and grade 2 PVC's. Of the 15 evaluable pts, 3 had stable disease for > 4 months, with bladder, colorectal, and fallopian tube cancer pts having an 11, 16, and 10% reduction by RECIST respectively. PKs initially show dose-dependent peak plasma oleandrin concentrations are reached at 2–4 hr following administration with > 50% cleared in 6 hrs. Western blots of PBMCs showed PBI-05204 markedly reduced phosphorylation of Akt, p70S6K, and S6 in a time dependent manner in 4 pts (1 at dose level 2, and 3 and 2 at dose level 5). Reduction of these effectors was observed concomitantly with relatively higher levels of Na, K-ATPase α-3 subunit expression. Conclusions: PBI-05204 is tolerated up to 10.2/mg/day with very little AE's or cardiotoxicity. Initial response evaluation shows activity in diverse tumors with PD analysis suggesting target effect. [Table: see text]
Preliminary activity in adrenocortical tumor (ACC) in phase I dose escalation study of intermittent oral dosing of OSI-906, a small-molecule insulin-like growth factor-1 receptor (IGF-1R) tyrosine kinase inhibitor in patients with advanced solid tumors
Authors: Carden C. P. , Frentzas S. , Langham M. , Casamayor I. , Stephens A. W. , Poondru S. , Wheaton J. , Lippman S. M. , Kaye S. B. , Kim E. S. 
Published: August 2020

3544 Background: IGF-1R is overexpressed in various malignancies, and implicated in proliferation, survival, and metastasis. IGF-1R blockade increases apoptosis and reduces tumor growth in preclinical models. OSI-906 is an oral small molecule tyrosine kinase IGR-1R inhibitor. Methods: Patients (pt) with advanced solid tumours were enrolled to determine safety, tolerability, maximum tolerated dose, pharmacokinetics (PK), pharmacodynamics (PD) and preliminary anti-tumor activity. Results: 26 pt have been treated (14M:12F, median age 61 yrs) at 10, 20, 40, 80, 150, 300, and 450 mg on days (d) 1–3 q14 d. No dose-limiting toxicities have been observed to date. Drug-related toxicities include grade 1 fatigue, nausea, rash, diarrhea, tachycardia, proteinuria, pruritis and peripheral oedema. Linear PK was observed, with median terminal t1/2 3.5 hr; AUC0-∞ 25.8 μg.hr/mL; Cmax 3.20 μg/ml at 450mg. Plasma OSI-906 concentrations above the estimated efficacious concentration (1 μM) were attained at doses > 40mg. Glucose did not increase with rising OSI-906 concentration, but plasma insulin levels showed an upward trend, indicating potential PD effects. PD data on IGFR phosphorylation were analyzed. In total, 11 pt were treated for > 12 weeks (w). Of 3 pt with ACC, 1 pt had a partial response (43% reduction in primary and multiple lung metastases) and remains on treatment after 16 w, 1 pt was treated for 32 w, and 1 pt progressed after 4 w at 40mg. In addition, 1 pt with heavily pretreated NSCLC was treated for 43 w and 1 pt with progressive myxoid chondrosarcoma remains on treatment after 38 w. Conclusions: OSI 906 had minimal toxicity, dose proportional PK at dose levels up to 450mg tested d 1–3 q14 d, with preliminary antitumor activity seen, particularly in ACC. Dose escalation with 5 and 7 d schedules q14 d continues. [Table: see text]
Final results: A dose escalation phase I study of ARQ 197, a selective c-Met inhibitor, in patients with metastatic solid tumors
Authors: Mekhail T. , Rich T. , Rosen L. , Chai F. , Semic-Suka Z. , Savage R. E. , Senzer N. 
Published: August 2020

3548 Background: ARQ 197 is a selective, non-ATP competitive inhibitor of c-Met, a receptor tyrosine kinase implicated in tumor cell migration, invasion, and proliferation. Methods: This phase I dose escalation study enrolled patients (pts) with metastatic solid tumors to determine the drug's safety profile, maximum tolerated dose (MTD), recommended phase 2 dose (RP2D), pharmacokinetics (PK), and preliminary antitumor activity. Dose escalation followed an accelerated titration design and was modified to the traditional escalation design (3+3 pts) once grade 2 toxicity was observed. ARQ 197 was initially administered orally twice daily (BID) for 2 weeks followed by 1 week off and then modified to evaluate continuous BID dosing based on favorable safety data. Intra-patient dose-escalation was allowed in this study. Additional pts were enrolled and treated at the 360 mg bid continuous dose, which was determined to be the RP2D in another phase I clinical trial. Results: To date, 65 pts (38 male/27 female; median age 61; 9 colon/colorectal, 8 renal cell carcinoma/kidney, 6 ovarian, 6 sarcoma, 5 lung cancer and 31 others) have been treated at 11 dose levels (10 mg bid to 360 mg bid). All treated pts achieved plasma drug concentrations significantly above in vitro IC50 values. The most common drug-related adverse events (AEs) were fatigue (18.5%) and nausea (12.3%). One case each of the following drug-related serious AEs were reported in 4 pts: anemia, leukopenia, neutropenia, thrombocytopenia, dehydration, liver failure, abdominal pain, nausea, and vomiting. Three pts with neuroendocrine, prostate, or testicular cancer achieved a partial response (PR), 32 demonstrated stable disease (SD) and 13 progressed. The 3 PR pts were initially treated at 10, 40 or 90 mg BID respectively. Their doses were escalated to 50, 70, or 120 mg BID respectively after 18 to 33 weeks on treatment. An overall response rate of 6.3% and a disease control rate (CR+PR+SD) of 72.9% were demonstrated among 48 pts who are evaluable for efficacy. Conclusions: ARQ 197 has demonstrated a favorable safety profile up to the dose of 360 mg bid. Preliminary evidence of anti-cancer activity was observed. Final study data on drug safety, PK and efficacy will be presented. [Table: see text]
Hypoxia-inducible factor-1α (HIF-1α) modulation in combination with anti-angiogenic therapy
Authors: Falchook G. S. , Wheler J. J. , Tannir N. M. , Naing A. , Jackson E. , Hong D. , Lawhorn K. N. , Ng C. , Amin H. , Kurzrock R. 
Published: August 2020

3555 Background: HIF-1α mediates adaptive responses to hypoxic conditions induced by anti-angiogenic therapy. Bortezomib has demonstrated the ability to inhibit transcriptional activity of HIF-1α. We hypothesized that the addition of bortezomib to bevacizumab would augment response, and we performed this phase I trial to assess safety, MTD, and correlative studies of anti-angiogenic activity. Methods: Patients with advanced malignancy refractory to standard therapy were eligible. Cohorts of 6 patients received bevacizumab and bortezomib on a 3-week cycle, with a stair-step dose escalation design. Pharmacodynamic assessment included plasma VEGF, VEGFR2, 20S proteasome inhibition, DCE-MRI, and tumor expression of HIF-1α, VEGF, VEGFR2, and polymorphisms of VEGF and VEGFR2. Results: 71 patients were treated, and the MTD was identified at the highest dose level (bevacizumab 15 mg/kg, bortezomib 1.3 mg/m2). Two partial responses were observed in patients with renal cell carcinoma (RCC) (Total patients with RCC = 6). Minor responses or stable disease lasting ≥4 months was achieved in 8 patients, including RCC (1), breast (1), leiomyosarcoma (1), nasopharyngeal (2), hepatocellular (1), neuroendocrine (1), lacrimal gland adenocystic carcinoma (1). The most common drug-related toxicities observed included hypertension (36%), fatigue (34%), thrombocytopenia (29%), and myalgia (19%). 22 patients (31%) experienced no drug-related toxicities greater than grade 1. 56 patients (79%) experienced no drug-related toxicities greater than grade 2. One DLT (G5 bleeding) was observed at the MTD. Plasma VEGF levels demonstrated decreases at 1 and 4 hours post-infusion, followed by increases to levels above baseline on days 2, 3, and at the end of cycle 1. DCE-MRI analysis demonstrated decreases in Ktrans on days 2 and 3. Analysis of HIF-1α expression in biopsies is underway. Conclusions: Combination bevacizumab and bortezomib is well-tolerated and has demonstrated clinical activity in patients with previously treated, advanced malignancy. Pharmacodynamic assessment with biomarkers and DCE-MRI suggests that inhibition of angiogenic activity was achieved. Updated clinical and biomarker data will be presented. No significant financial relationships to disclose.
Safety and efficacy of neratinib (HKI-272) in combination with paclitaxel in patients with solid tumors
Authors: Chow L. , Jiang Z. , Epstein R. , Bondarenko I. , Awada A. , Coughlin C. , Gauthier E. , Zhao Y. , Abbas R. , Hershman D. 
Published: August 2020

3557 Background: Neratinib (HKI-272) is a potent irreversible pan-ErbB inhibitor of the tyrosine kinase receptors, erbB-1,-2 and -4. In this phase 1 study, a combination dose of neratinib plus paclitaxel that is tolerable was determined in patients (pts) with solid tumors, and safety and preliminary efficacy were assessed in pts with erbB-2+ metastatic breast cancer. Methods: In this open label, 2-part study, ascending multiple daily oral doses of neratinib (160 mg, 240 mg) were administered in combination with IV paclitaxel 80 mg/m2, if tolerable, or 70 mg/m2 on days 1, 8 and 15. Pts with solid tumors and pts with only metastatic erbB-2+ breast cancer are enrolled in part 1 and 2, respectively. Tumor measurements were made at screening and at every 8 weeks (2 cycles) by modified RECIST criteria. Timed blood samples were collected for neratinib and paclitaxel plasma concentration determination, and PK analyses were performed using a noncompartmental method. Results: Data for 54 pts as of 30 Oct 2008 are presented (median age [range] of 51.5 [20–74] yrs; 91% female; 26 % with prior trastuzumab treatment of median duration [range] 32.5 [10–52] wks; 15% with prior lapatinib treatment). Tumor types in part 1 included breast, endometrial, cervical, colorectal and esophageal cancer. There were no dose-limiting toxicities (DLTs) at the 240 mg neratinib-80 mg/m2 paclitaxel dose, and as standard doses of neratinib and paclitaxel were reached, there was no reason for further escalation. Neratinib-related AEs, any grade in ≥10% of pts included diarrhea (50%), neutropenia (17%), rash (13%), nausea (11%) and vomiting (11%). Neratinib- related AEs, grade ≥3 in ≥2% of pts were diarrhea (20%), neutropenia (9%) and dehydration (4%). Only 2 pts (at the 240 mg neratinib-80 mg/m2 paclitaxel dose) had dose reductions due to diarrhea. In 35 efficacy evaluable pts, 5 had confirmed partial response (PR). Confirmed clinical benefit (PR and prolonged disease stabilization) was seen in 2 pts in part 1, 1 pt with endometrial cancer and 1 pt with cervical cancer. Conclusions: This combination of 240 mg neratinib and 80 mg/m2 paclitaxel was tolerable with a toxicity profile similar to that observed for neratinib, and had promising antitumor activity in pts with solid tumors and erbB-2 + breast cancer. [Table: see text]
Population pharmacokinetic (PK) analysis of ABT-869 in solid tumors and acute myelogenous leukemia (AML) patients
Authors: Gupta N. , Diderichsen P. M. , Steinberg J. , Ricker J. L. , Humerickhouse R. , Awni W. , Pradhan R. 
Published: August 2020

3567 Background: ABT-869 is an orally bioavailable, potent and specific inhibitor of all vascular endothelial growth factor and platelet derived growth factor family receptor tyrosine kinases. The objectives of this analysis were to understand the population pharmacokinetics of ABT-869 and explore the effect of several demographic/disease state covariates influencing ABT-869 disposition. Methods: A population PK analysis of 181 patients (pts) enrolled in two phase 1 (multiple types of solid tumors and AML) and three phase 2 monotherapy studies (non-small cell lung cancer, hepatocellular carcinoma [HCC] and renal cell carcinoma) was conducted. Approximately 90% of pts received ABT-869 based on body-weight dosing while the remaining pts had flat dosing. Available plasma concentrations obtained after intensive and sparse pre-dose PK sampling were analyzed by population PK using the non linear mixed effects modeling (NONMEM) approach. Potential covariates including body weight, body surface area (BSA), age, sex, creatinine clearance (CrCL) and disease state (HCC vs. non-HCC pts) were tested. Results: The mean body weight of enrolled pts was 71 kg and 57% were Asian, 36% Caucasian and 7% other races. The ABT-869 plasma concentration time profile was well described by a one-compartment model with first order absorption and elimination process. Oral clearance (CL/F) was not affected by body weight (range 35–177 kg); however, apparent volume of distribution (V/F) increased by 6L per 0.1 mg/m2 increase in BSA. CrCL (39.9–290.3 ml/min) was not a significant covariate on V/F and CL/F suggesting renally impaired pts do not require a different dose/dosing regimen. HCC pts had ∼40% lower CL/F values than pts with other malignancies suggesting a lower dose would be appropriate for HCC (Child Pugh A and B) pts. Conclusions: Population PK analysis showed that ABT-869 PK can be well described by a one-compartment model with first order absorption and elimination. Race and impaired renal function does not appear to alter PK. HCC pts had lower CL/F value therefore a lower dose may be recommended in these patients. Implications of increased V/F with increasing body size and appropriate dosing strategy are undergoing further analysis. [Table: see text]
Phase I clinical and biomarker study of BIBF 1120, an oral multitarget tyrosine kinase inhibitor, in patients with advanced solid tumors (ST): Impact of CD133- and CD117-positive cells on a biomarker of an antiangiogenic inhibitor
Authors: Okamoto I. , Kaneda H. , Satoh T. , Okamoto W. , Terashima M. , Arao T. , Nishio K. , Nakagawa K. , Konishi K. , Kaiser R. 
Published: August 2020

3572 Background: BIBF 1120 (Vargatef) is an orally bioavailable small molecule inhibitor of multiple receptor tyrosine kinases, including vascular endothelial growth factor receptors, fibroblast growth factor receptors and platelet-derived growth factor receptors. Methods: BIBF 1120 (150–250 mg) was administered orally twice-daily (bid) to heavily pre-treated solid tumor (ST) patients to determine safety, tolerability, maximum tolerated dose (MTD) and pharmacokinetics (PK). CD133- and/or CD117 (c-kit)-positive cells from CD34+CD45dim peripheral blood cells were evaluated using flow-cytometry on pre-treatment, Day 2, Day 8 and Day 29. Results: Twenty-one patients were treated at doses of 150 mg bid (n=3), 200 mg bid (n=12) and 250 mg bid (n=6). Dose-limiting toxicities (DLTs) of reversible Grade 3/4 elevated liver enzymes occurred in three of 12 patients at 200 mg bid and three of six patients at 250 mg bid; 200 mg bid was declared as the MTD. Best observed responses were stable disease in 16 (76.2%) patients and median progression-free survival was 113 days (95% CI: 77–119 days). PK analysis indicated that Cmax and AUC increased with increased dose within the dose range tested. Flow cytometry analysis revealed that BIBF 1120 treatment significantly increased the percentage of CD133+CD117- cells (p<0.001) on Day 29 compared with pre-treatment, and conversely decreased that of CD133-CD117+ cells (p<0.01). In addition, CD133+CD117+ cells tended to decrease in responders (stable disease) to a greater extent than in non- responders after treatment. Conclusions: BIBF 1120 dosed continuously at 200 mg bid was well tolerated and appeared to provide some clinical benefit. Our biomarker study provides a novel insight into CD133- and CD117-positive cells as a pharmacodynamic biomarker for an antiangiogenic inhibitor. [Table: see text]