An Open-Label, Single Ascending Dose Phase I Study of F-627, a G-CSF Dimer, In Healthy Male Subjects

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4722-4722
Author(s):  
Xiao Qiang Yan ◽  
Peter G Hodsman ◽  
Zhi Hua Huang ◽  
Rou Yun Sun ◽  
Nai Chau Sun ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Conflicts Of Interest ◽  
High Dose Chemotherapy ◽  
Primary Objective ◽  
Severe Neutropenia ◽  
High Dose ◽  
Healthy Male ◽  
Open Label ◽  
Male Subjects

Abstract Abstract 4722 The management of severe neutropenia in cancer patients after high-dose chemotherapy remains a challenge, although recombinant human G-CSFs including filgrastim, lengogratim and pegfilgrastim have been widely used. We developed F-627, a mammalian expressed recombinant human G-CSF dimer to treat severe neutropenia. In a cyclophosphamide-induced neutropenia monkey model, F-627 significantly reduced the duration and lessened the severity of neutropenia compared to monkeys treated with G-CSF or pegylated G-CSF. We report the phase I results of F-627 in healthy male subjects receiving ascending single dose at 30, 60, 120 and 240 ug/kg by subcutaneous injection. The primary objective of the phase I study was to assess the safety and tolerability of F-627. The secondary objective was to evaluate the pharmacokinetics and pharmacodynamics (PK/PD) responses. F-627 was well tolerated in healthy male volunteers. Dose-dependent PD responses including increased WBC, ANC and CD34 levels in peripheral blood were demonstrated. These results indicate that the mechanism of action of F-627 is similar to the monomer recombinant hG-CSFs, while the mode of action of F-627 is different with unique PK/PD properties in human. Disclosures: No relevant conflicts of interest to declare.

A phase I study of the effect of repeated oral doses of pantoprazole on the pharmacokinetics of a single dose of fedratinib in healthy male subjects

2020 ◽  
Vol 85 (5) ◽  
pp. 995-1001 ◽  
Author(s):  
Ken Ogasawara ◽  
Bradley Vince ◽  
Christine Xu ◽  
Meng Zhang ◽  
Maria Palmisano ◽  
...  
Keyword(s):  
Single Dose ◽  
Phase I ◽  
Phase I Study ◽  
Healthy Male ◽  
Oral Doses ◽  
Male Subjects

Clinical efficacy and toxicity data on phase I study of fosbretabulin in combination with everolimus in neuroendocrine tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4114-4114 ◽  
Author(s):  
Aman Chauhan ◽  
Susanne M. Arnold ◽  
Jianrong Wu ◽  
Rashmi T Nair ◽  
Stacey A. Slone ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Phase I Study ◽  
Safety Data ◽  
Primary Objective ◽  
Water Soluble ◽  
Clinical Activity ◽  
Open Label ◽  
Gi Symptoms

4114 Background: Fosbretabulin, a synthetic, water-soluble, phosphorylated prodrug of the natural product combretastatin A4 (CA4P), initially isolated from the bark of the South African bush willow, Combretum caffrum, is the lead compound in a class of agents termed vascular disrupting agents (VDAs). Everolimus, an mTOR inhibitor, is FDA approved for the management of well-differentiated NETs. A Phase I trial combining fosbretabulin and everolimus to determine the recommended Phase II trial dose (RP2D), safety data and early clinical efficacy in metastatic GEPNET patients was conducted. Methods: An investigator-initiated, single center, open-label, phase I study involving GEPNETs incorporated partial order continual reassessment method (PO-CRM) to define the dose escalation. The primary objective was to establish the maximum tolerated dose (MTD) of the combination of everolimus and fosbretabulin in NETs that have progressed after at least one prior regimen for metastatic disease. Secondary objective included identifying the safety profile of the combination using NCI CTCAE4 reporting criteria. Patients received daily oral everolimus (2.5 mg, 5 mg, 7.5 mg, and 10 mg). Fosbretabulin was administered IV 60 mg/m2 either q3 weekly or q weekly based on PO-CRM. Patients were treated for 12 weeks with all combinations. RECIST 1.1 was used to evaluate radiological responses at 3 month. Results: Of the 17 patients enrolled, 16 completed the 12-week trial. One patient was not evaluable due to noncompliance. No DLTs were observed at day 21. The highest dose of 10 mg daily oral everolimus in combination with weekly 60mg/m2 IV fosbretabulin is the RP2D. No grade 4 or 5 toxicities were noted. Grade 3 toxicities were seen in 5 patients; abdominal pain and hyperglycemia (not related to study drug), fatigue (possibly related), decreased lymphocyte count and anemia (related). Several patients had delay in treatment due to grade 2 AE’s (GI symptoms, rash, thrombocytopenia) and one patient was unable to complete treatment due to pneumonitis. All evaluable patients except one had stable disease at 3 months. One patient showed SD but non target lesion demonstrated PD. One patient had > 30% decrease in tumor size but overall sum of lesions showed SD. A detailed table with all grade toxicities and waterfall plot of RR will be presented at the meeting. Conclusions: Ten mg PO daily everolimus plus 60 mg/m2 fosbretabulin IV weekly is the RP2D. Early clinical data suggests clinical activity and stable disease in all but one patient at 3 months. Clinical trial information: NCT0301429.

Phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with an anti-PD-1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3173-TPS3173 ◽  
Author(s):  
Colette Shen ◽  
Jessica Frakes ◽  
Jared Weiss ◽  
Jimmy J. Caudell ◽  
Trevor G Hackman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label ◽  
Open Label Phase

TPS3173 Background: Despite the past decade of transformative advances in immuno-oncology, the response rate to checkpoint inhibitors (ICIs) remains low (~15%). There is significant interest in developing strategies to overcome resistance to these treatments, thus increasing response rate. Emerging evidence suggests that radiation therapy (RT) could potentially augment the antitumor response to ICIs through synergic effect. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by direct intratumoral injection, designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing surrounding normal tissue toxicity. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: This trial [NCT03589339] is a multicenter, open-label, phase I study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of gross tumor volume (GTV). The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling. To date, three patients have been treated, one in cohort 1, two in cohort 2. Clinical trial information: NCT03589339 .

Phase I Study of Rituximab-Cyclophosphamide (R-CY) Stem Cell Mobilization and Rituximab-BEAM HDC with ASCT in Patients with Relapsed, Refractory or High Risk Intermediate Grade Non-Hodgkin’s Lymphoma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5315-5315
Author(s):  
Eileen Scigliano ◽  
Celia Grosskreutz ◽  
Steven Fruchtman ◽  
Janice Gabrilove ◽  
John Mandeli ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Phase I ◽  
Phase I Study ◽  
High Dose Chemotherapy ◽  
Stem Cell Mobilization ◽  
High Dose ◽  
Post Transplant ◽  
Cell Mobilization ◽  
Stem Cell Collection

Abstract The addition of rituximab to mobilization regimens does not adversely affect collection of adequate numbers of CD34+ PBSC and may decrease tumor cell contamination. Prior administration of rituximab may sensitize lymphoma cells to chemotherapy, but its use with high dose chemotherapy has not been studied. In this study, eligible patients had intermediate grade NHL either primary refractory, relapsed or in CR1 with an intermediate/high risk IPI score. Eight patients with a median age of 49 years (28–61) were enrolled in this study. Four patients had relapsed disease, chemosensitive to salvage in 3 patients, and untested in 1 patient. Two patients had primary refractory disease, chemosensitive to salvage. Two patients had intermediate-high risk IPI scores and were in CR-1. One patient in CR-1 declined to undergo transplant following stem cell collection. All patients had received rituximab previously. Stem cell mobilization was rituximab 375mg/M2 followed by CY 2gm/M2/day for 2 doses and filgrastim 10ug/kg/d. High dose chemotherapy consisted of rituximab 375mg/M2 on day -8, carmustine 300mg/M2 on day -7, etoposide 200mg/M2/d on days -6 to -3, cytosine arabinoside 200mg/M2 on days -6 to -3 (8 doses) and melphalan 140mg/M2 on day -2. Patients received filgrastim post transplant. RESULTS: The median CD34+ cell dose collected was 12.5 x 106/kg (1.1 to 33.2). There was one inadequate CD34+ cell collection requiring bone marrow harvesting which yielded 0.72 x 106/kg CD34+ cells. Engraftment of neutrophils and platelets occurred at a median of 8 and 11 days post transplant respectively. Infectious complications included febrile neutropenia in one patient following mobilization and in 6 patients following R-BEAM. Transient grade I–II (common toxicity criteria) hepatic enzyme elevation occurred in 2 patients following R-CY. Following R-BEAM, 3 patients developed grade II-IV LFT elevation without evidence of VOD, which resolved. One patient developed moderate hemorrhagic cystitis which resolved. One patient developed bilateral pulmonary infiltrates of unkown etiology (BAL negative for organisms) which resolved. Immunoglobulin levels remained normal in two patients, but decreased in all other patients for up to a year post transplant. Peripheral blood flow cytometry and T cell subset analysis showed absent B cell populations, decreased CD4 cells and increased CD 8 cells in all patients up to a year post transplant. Five patients are alive with no evidence of disease 381 to 676 days post transplant. Three of these patients developed PET positive lymph nodes that showed florid follicular hyperplasia on biopsy, with no evidence of lymphoma. Two patients had persistent disease following transplant. One patient underwent a non-myeloablative allogeneic transplant and died of progressive disease. CONCLUSIONS: R-CY was well tolerated as a mobilization regimen and led to adequate stem cell collection. The addition of rituximab to the high dose chemotherapy regimen did not appear to increase the incidence of infections or peritransplant complications in this Phase I study. The effect, on disease free survival, of the addition of rituximab to the collection and preparative regimens requires further investigation.

Phase I Study of Sapacitabine, an Oral Nucleoside Analogue, in Patients with Advanced Leukemias or Myelodysplastic Syndromes (MDS).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 884-884
Author(s):  
Hagop Kantarjian ◽  
Guillermo Garcia-Manero ◽  
Stefan Faderl ◽  
Jorge Cortes ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Phase I ◽  
Dose Level ◽  
Nucleoside Analogue ◽  
Phase I Study ◽  
Performance Status ◽  
Primary Objective ◽  
High Dose ◽  
Dna Breaks ◽  
Extramedullary Disease

Abstract Background: Sapacitabine, a 2′-deoxycytidine nucleoside analogue with unique ability to cause irreparable single-strand DNA breaks and as a result induce G2 cell cycle arrest, is undergoing clinical evaluation for the treatment of cancer. The recommended Phase II dose (RD) in patients with advanced solid tumors was 75 mg twice daily (b.i.d.) x 7 days orally every 21 days. The major DLT was myelosuppression. Here, we present the initial results of a Phase I study of sapacitabine in patients with advanced leukemias or MDS. The primary objective was to define the MTDs of two dosing schedules, b.i.d. x 7 days orally every 21 days or b.i.d. x 3 days per week for 2 weeks every 21 days. The secondary objectives were to characterize the PK/PD effects of sapacitabine and its major metabolite CNDAC. Methods: Eligible patients had relapsed/refractory leukemias or MDS, or untreated disease if not willing to proceed with conventional systemic chemotherapy, adequate organ functions and performance status of 0–2. At least 3 patients were enrolled at each dose level. The MTD was the highest dose level at which ≤2/6 patients experienced a DLT during the first treatment cycle. Results: Forty-seven patients received sapacitabine, including 35 treated with the 7-day schedule and 12 treated with the 3-day per week schedule. Median age was 65 (range: 36 – 91). The majority of patients had AML (n=36) or MDS (n=4). Median number of prior chemotherapies was 2 (range: 0 – 6). Cytogenetic abnormalities were present in 27; 30 had relapsed disease or were refractory to cytarabine or high-dose cytarabine regimens. MTD was reached at 375 mg b.i.d. on the 7-day schedule, and 475 mg b.i.d. on the 3-day per week x 2 schedule. DLTs consist of abdominal pain/small bowel obstruction (n=1), neutropenic colitis (n=2) and diarrhea (n=3). One patient died from complications of neutropenic colitis. Common non-hematologic adverse events (all grades, regardless of causality) included fatigue, nausea, vomiting, diarrhea, anorexia, cough, dyspnea, and abdominal pain, most of which were mild to moderate in intensity. PK and PD data are being analyzed. To date, 11 patients of 42 evaluable (9 AML, 2 MDS) had a reduction in bone marrow blast counts to ≤ 5% including 2 CRs, 2CRs with incomplete recovery of platelets, 1 CR of extramedullary disease, and 1 PR of extramedullary disease. 5/11 had relapse-resistance disease on prior cytarabine. Conclusion: The MTD of sapacitabine is 375 mg b.i.d. by the 7-day schedule and 475 mg b.i.d. by the 3-day per week schedule. The predominant DLT is gastrointestinal toxicity. Sapacitabine is well tolerated and has promising antileukemic activity in patients with relapsed or refractory AML and MDS.

Phase I Study of Forodesine (BCX1777), An Oral PNP Inhibitor In Patients with Relapsed or Refractory T/NK Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1796-1796 ◽  
Author(s):  
Kunihiro Tsukasaki ◽  
Michinori Ogura ◽  
Hirokazu Nagai ◽  
Jun Taguchi ◽  
Tatsuya Suzuki ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase I Study ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study

Abstract Abstract 1796 Background: Forodesine is a rationally designed potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to elevation of plasma deoxyguanosine (dGuo) and intracellular accumulation of dGTP levels and then apoptosis mainly in T cells. Oral forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL) (M. Duvic et al, ASH 2007). The objective of this phase I study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with recurrent or refractory T/NK malignancies in Japan. Methods: An open-label dose-escalation study of forodesine, 100 to 300 mg/body qd for 4 weeks, was conducted to evaluate safety profile (dose-limiting toxicities, DLT), tolerability and PK profile as primary endpoints. Forodesine was administered until disease progression or unacceptable toxicity is observed. Relapsed or refractory T/NK malignancies with PS 0 to 1 and without major organ dysfunction were eligible. Results: Overall, 13 Japanese patients, 8 males and 5 females, with a median age of 69 (range 30–77) years were enrolled in the study: 5 patients in the 100mg cohort, 3 in the 200mg cohort and 5 in the 300mg cohort. Patients’ histopathologic subtypes were as follows: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (6 patients), anaplastic large cell lymphoma (ALCL) (3), primary cutaneous ALCL (C-ALCL) (2) and mycosis fungoides (MF) (2). Median stage and prior treatment regimen were IIIA (range IA-IVA) and 2 (range 1, 8), respectively. No DLT was observed and a maximum tolerated dose was never defined. The most common toxicities of grade 2 or less were constipation (39 %), rash (31%), lymphopenia (31 %), neutropenia (23 %), nausea (23 %), peripheral edema (23 %), LDH elevation (23 %) and leukopenia (23 %). The toxicities of grade 3 or greater were lymphopenia (62 %), anemia (15 %), leukopenia (8 %), thrombocytopenia (8 %) and viral infection (8 %). Median baseline, nadir, and last visit lymphocytes counts (1,000/μL) were 0.69 (95% CI: 0.56, 1.18), 0.35 (95% CI: 0.14, 0.60) and 0.60 (95% CI: 0.24, 0.95), respectively. Plasma levels for forodesine showed less than dose-proportional increase in exposure as mean AUC at Day 1 was 1,948 (ng·h/mL) in the 100mg cohort, 4,608 (ng·h/mL) in the 200mg cohort, and 4,596 (ng·h/mL) in the 300mg cohort. The levels for dGuo displayed a similar trend, with mean AUC at Day 1 4,023 (ng·h/mL) in the 100mg cohort, 5,705 (ng·h/mL) in the 200mg cohort, and 6,074 (ng·h/mL) in the 300mg cohort. One patient with ALCL reached complete response (CR) in the 100mg cohort and 2 patients with MF reached partial response in the 200mg cohort. In addition, 4 patients with stable disease (SD) were observed: 1 patient with PTCL-NOS in the 100mg cohort, 1 with C-ALCL in the 200mg cohort and 2 with C-ALCL and PTCL-NOS in the 300mg cohort. As of Aug, 2010, 2 patients with ALCL (CR patient in the 100mg cohort) and PTCL-NOS (SD patient in the 300mg cohort) have continued the treatment for more than 510 days and 290 days, respectively. Conclusion: Oral forodesine was well tolerated at all the dose levels tested with similar PK findings to those in the CTCL study in USA, demonstrating potential efficacy against relapsed or refractory T/NK lymphomas including PTCL for the first time. Based on these promising data, we are planning a phase I /II study of forodesine in patients with relapsed or refractory PTCL. Disclosures: No relevant conflicts of interest to declare.

Vandetanib with mFOLFOX6 in advanced colorectal adenocarcinoma: An open-label, multicenter phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4095-4095
Author(s):  
M. Michael ◽  
N. Tebbutt ◽  
P. Gibbs ◽  
R. Smith ◽  
A. Godwood ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Day Treatment ◽  
Median Number ◽  
Primary Objective ◽  
Electrolyte Imbalance ◽  
Preliminary Evaluation ◽  
Open Label ◽  
Once Daily ◽  
Grade 3

4095 Background: Vandetanib (ZD6474) is a once-daily oral anticancer agent that selectively inhibits VEGFR- dependent tumor angiogenesis, and EGFR- and RET-dependent tumor cell proliferation. The primary objective of this Phase I study was to establish the safety and tolerability of the vandetanib + mFOLFOX6 combination in patients with metastatic colorectal cancer (CRC). Secondary objectives included an assessment of pharmacokinetic (PK) interactions between vandetanib and mFOLFOX6, and preliminary evaluation of efficacy (RECIST). Methods: Patients with CRC who were eligible for 1st- or 2nd-line chemotherapy received once-daily oral doses of vandetanib (100 mg) plus standard 14-day treatment cycles of mFOLFOX6 (oxaliplatin 85 mg/m2 and leucovorin 400 mg/m2 2-hr IV; 5-fluorouracil [5-FU] 400 mg/mg2 IV bolus and 5-FU 2400 mg/m2 46-hr IV). If <2 of 6 evaluable patients (ie, having completed 6 weeks of vandetanib treatment with associated mFOLFOX6 cycles) experienced a vandetanib-related dose-limiting toxicity (DLT), an additional cohort received vandetanib 300 mg + mFOLFOX6. Results: Seventeen patients (12 male/5 female; 7 1st-line/10 2nd-line; mean age 61 years, range 48–75) received vandetanib 100 mg (n=9) or 300 mg (n=8) + mFOLFOX6; the median number of oxaliplatin cycles was 8. Two DLTs were reported: one patient receiving 100 mg vandetanib developed diarrhea (CTC grade 2), dehydration, electrolyte imbalance and QTc prolongation, and one patient receiving vandetanib 300 mg developed diarrhea (grade 3) that responded to dose reduction. Common adverse events (AEs), irrespective of grade, were diarrhea, nausea, lethargy (all n=11), neutropenia and peripheral neuropathy (both n=10); AEs =grade 3 reported in more than one patient were diarrhea (n=4, all grade 3) and neutropenia (n=5, grade 3; n=2, grade 4). There was no apparent PK interaction between vandetanib and oxaliplatin or 5-FU. Best overall responses in the 14 patients evaluable for efficacy were partial response (n=3), stable disease =8 weeks (n=8), and progressive disease (n=3). Conclusions: In patients with advanced CRC, combining once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated. ZACTIMA is a trademark of the AstraZeneca group of companies No significant financial relationships to disclose.

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