First-in-human phase I trial of a cyclodextrin-containing polymer-camptothecin nanoparticle in patients with solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14078-14078 ◽  
Author(s):  
Y. Yen ◽  
T. Synold ◽  
T. Schluep ◽  
J. Hwang ◽  
J. Oliver ◽  
...  
Keyword(s):  
Phase I ◽  
Surface Charge ◽  
Stable Disease ◽  
Animal Studies ◽  
De Novo ◽  
Pancreatic Cancer Patient ◽  
Polymer Chains ◽  
Disease Rate ◽  
Neutral Surface ◽  
Tumor Accumulation

14078 Background: IT-101 is a de novo designed experimental therapeutic comprised of linear, cyclodextrin(CD)-containing polymer conjugates of camptothecin(CPT) that assemble into ca. 40 nm diameter nanoparticles via polymer-polymer interactions that involve inclusion complex formation between the CPT and the CD. Particle size, near neutral surface charge and CPT release rate were specifically designed into IT-101. Published pre-clinical animal studies show extended circulation times (t1/2 of ca. 20 h in rodents), tumor accumulation, slow release of the CPT and anti-tumor efficacy that directly correlate to the properties of the nanoparticle. Release of CPT can disassemble the nanoparticle into individual polymer chains that have size ca. 10 nm that are capable of renal clearance (t1/2 of several minutes in rodents). Methods: Patients with relapsed or refractory cancer were evaluated every two cycles of therapy (90 minute IV infusions of IT- 101 in D5W on days 1, 8 and 15 of a 28 day cycle). Three dose levels of 6, 12 and 18 mg CPT eq./m2 have been tested. Results: At the time of this interim analysis, eight patients have been enrolled and five evaluated. In general, IT-101 is well tolerated and pancytopenia is the DLT. The expected MTD is 12 mg/ m2.Three out of five patients demonstrated stable disease on CT scan evaluation. One pancreatic cancer patient remains stable for 6 months. PK data are available from the first 5 patients. Total and free CPT display biphasic elimination from plasma with mean terminal elimination half lives of 38±3.7 and 61±43 hours, respectively. The mean Vd and CLsys of total CPT are 6.1±1.4 L and 0.1±0.03 L/h and are unrelated to dose over the range tested, with a mean total-to-free AUC ratio of 10.7±3.7. Conclusions: These first in human PK data for IT-101 confirm that 40 nm particles with near neutral surface charge provide favorable PK properties. The stable disease rate, although not yet conclusive, is consistent with promising efficacy. The preliminary results of this phase I study warrant continued enrollment that is ongoing. No significant financial relationships to disclose.

A phase I study of bortezomib in combination with 5FU/LV plus oxaliplatin in patients (pts) with advanced colorectal cancer (CRC): EORTC 16029

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4090-4090 ◽  
Author(s):  
D. A. Lacombe ◽  
F. Caponigro ◽  
A. Anthoney ◽  
J. Bauer ◽  
A. Govaerts ◽  
...  
Keyword(s):  
Phase I ◽  
Stable Disease ◽  
Phase I Study ◽  
Sensory Neuropathy ◽  
Reversible Inhibitor ◽  
Disease Rate ◽  
Clinical Activity ◽  
Starting Dose ◽  
Proteasome Pathway ◽  
Dose Levels

4090 Background: Bortezomib is a potent and reversible inhibitor of the ubiquitin-mediated proteasome pathway, whose inhibition results in the stabilization of p53, p21Cip1, p27Kip1, Bax, in cell-cycle dysregulation and, finally, apoptosis. A phase I study of the combination of 5FU/LV and bortezomib has shown a significant stable disease rate in advanced CRC (Iqbal, ASCO 2004). Methods: In this phase I study bortezomib was given as an IV push over 3 to 5 seconds on days 1, 8 and 15 in combination with standard FOLFOX-4 every 28 days in chemo-naïve pts with advanced CRC. Bortezomib starting dose level was 1.3 mg/m2. A 3+3 study design was utilized at predefined dose levels (DL). Dose-limiting-toxicity (DLT) was assessed during cycle 1. Exploratory pharmacogenetics research was conducted. Results: 15 pts were treated and 46 cycles given. At DL2 (1.6 mg/m2), 2/4 pts experienced a DLT: G3 febrile neutropenia causing treatment delay and bortezomib dose reduction in 1pt and one bortezomib dose skipped due to persistent G2 peripheral neuropathy and myalgia in 1pt. At DL1 (1.3 mg/m2), 2/6 pts had a DLT. Both pts experienced a G3 neutropenia on day 15, which prevented treatment from being given as scheduled. DL-1 (1 mg/m2) was therefore investigated and no DLT was observed among 5 pts. The most frequently reported toxicities in cycle 1 were γGT (64%), nausea, fatigue and sensory neuropathy (53%), pain (33%), diarrhea and fever (27%), vomiting (20%), anorexia, dyspnea and mucositis (13%) and neutropenia 29% (G2,3). 12 pts are currently evaluable for response; 6 had a partial response, 3 stable disease and 3 disease progression. Conclusion: The toxicity profile of this combination is predictable and early evidence of clinical activity has been observed. The recommended bortezomib dose for further investigation within this regimen is 1 mg/m2. No significant financial relationships to disclose.

Open-Label, Multi-Center Phase I Dose Escalation Study with Lenalidomide In Patients with Acute Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3297-3297
Author(s):  
Marie-Luise Huetter ◽  
Walter Fiedler ◽  
Andrea Kuendgen ◽  
Juergen Krauter ◽  
Marie von Lilienfeld-Toal ◽  
...  
Keyword(s):  
Phase I ◽  
Dose Level ◽  
Stable Disease ◽  
Progressive Disease ◽  
De Novo ◽  
Concomitant Disease ◽  
Monosomy 7 ◽  
Induction Type ◽  
Grade 3 ◽  
Sensory Polyneuropathy

Abstract Abstract 3297 Background: Lenalidomide is an immunomodulatory drug, which has antiangiogenic and antineoplastic properties. There have been some case reports and small phase I/II trials showing clinical efficacy of lenalidomide in AML. However, dosage and duration of lenalidomide treatment in patients with AML are unclear. Aim: To define dose-limiting toxicities (DLT) and the maximally tolerated dose (MTD) for single agent treatment with lenalidomide in AML patients. Methods: A phase-I trial was initiated in March 2009 for younger patients in second or higher relapse, patients above the age of 60 years with refractory or relapsed AML, and patients not eligible for intensive chemotherapy. The trial followed a modified (3+3) Fibonacci design. The starting dose of lenalidomide was 25mg per day for a maximum of 56 days in an induction-type dosing schedule. Additional cycles of 28 days duration were possible for responding patients. DLT was defined as hematological (grade ≥4) or non-hematological (grade ≥3) toxicity or a shift of CTC graded toxicity by 2 grades from baseline in the first cycle attributable to study drug. Results: 11 patients have so far been enrolled (7 males and 4 females). Median age was 72 years (range 36–83). 4 patients had previously untreated AML, 7 patients suffered from relapsed or refractory disease. Type of AML was de novo in 3, secondary AML after a preceding MDS in 6, and therapy-related AML in 2 patients. Initial median blast counts in bone marrow were 64% (range 40–75%) and 36,5% in the peripheral blood (range 0–65,4%); 5 patients showed a complex karyotype (including del(5q) in 4 of them), 2 had a single monosomy 7, one patient had a t(1;3) and a monosomy 7, 3 revealed a normal karyotype. In the first dose level of 25mg/day, 4 patients were treated and 3 were evaluable for DLT. One patient dropped out due to rapidly progressive disease. No DLT was observed in these patients. Therefore, dose was escalated to 50mg and 7 patients were treated in this dose level, 3 were evaluable for DLT assessment. DLT occurred in two patients, both developed CTC-grade 3 sensory polyneuropathy at day 15 and day 20, respectively. According to the design of the study, dose level was decreased back to 25mg/day for the next cohort. Toxicities not classifying as DLT were fever in neutropenia (n=6), anemia (n=6), dyspnea (n=4). Seven patients were evaluable for response on day 22. The other 4 patients dropped out due to rapidly progressive AML or severe concomitant disease. Five of the evaluable patients had refractory or relapsed disease, two had de novo AML. In one patient a short partial remission of 34 days and in 4 patients a short-lasting stable disease was observed (8-36 days of stable disease). However, all patients eventually experienced progressive disease. All but one of the 11 patients have died between 16 and 144 days after entry into the study. Conclusion: Sensory polyneuropathy is the dose limiting toxicity in induction type dosing of lenalidomide in AML. In this phase I study using an induction-type dosage regimen, limited clinical activity was seen. Disclosures: Fiedler: Pfizer: Consultancy, Research Funding.

scholarly journals A Safety Study of the Addition of Omacetaxine to the Standard-of-Care Induction Regimen of Cytarabine and Idarubicin in Newly-Diagnosed AML Patients

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5218-5218
Author(s):  
Sonia Christian ◽  
Kelley E. Kozma ◽  
Stephanie Barath ◽  
Ardaman Shergill ◽  
Damiano Rondelli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Dose Escalation ◽  
De Novo ◽  
Standard Of Care ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Induction Regimen ◽  
Dose Levels

Abstract Background: Omacetaxine mepesuccinate (OM) is a semi-synthetic form of Homoharringtonine (HH), a cephalotaxine alkaloid. OM induces cell apoptosis by inhibiting peptide bond formation during mRNA translation, with rapid loss of short-lived proteins, such as MCL-1, c-MYC, and Cyclin D1 (Lu, J Hematol Oncol. 2014, 7: 2). Notably, cytarabine synergizes with HH in causing apoptosis of leukemia cells in vitro. A phase III RCT in China of 620 patients with de novo AML demonstrated superior CR and 3-yr survival rates upon addition of HH to a standard 2-drug AML induction therapy ('7 + 3'; Jin, Lancet Oncol. 2013, 14:599). Thus, we hypothesized that OM, at an appropriate dose, would similarly enhance the efficacy of a 7 + 3 regimen. OM is FDA-approved for the treatment of TKI-resistant CML. The MTD of 1.25 mg/m2/d SQ for 14 days every 28 days, as determined in a phase I/II CML trial of OM (Quintás-Cardama, Cancer 2007, 109: 248), served as a basis for the dose escalation used in this study. Methods: The primary endpoint of this phase I safety trial was to determine the optimally safe and active dose (OD) of OM when added to a standard 7 + 3 induction regimen, cytarabine and idarubicin. OM was administered SQ q12h d1-7 with cytarabine (100mg/m2 CIV) d1-7 and idarubicin (12mg/m2 IV) d1-3. Four dose levels were tested, starting with OM 0.625 mg/m2 q12h (further dose levels: 1.25, 2.0, 3.0, and 4.2 mg/m2 q12h). All newly diagnosed, untreated de novo or secondary AML patients, aged 18-70y with ECOG PS of 0-3 were eligible for this study. Secondary endpoints included overall response rate (ORR) and overall and event free survival (OS, EFS). Hematologic toxicity (HT) was defined as incomplete hematologic recovery; ANC < 1.0 x 109/L or platelet count < 100 x 109/L present at d49, with the bone marrow documented to be free of leukemic infiltration. Dose escalation was based on the EffTox design (Biometrics 2004, 60:684), a Bayesian adaptive design which considers the trade-off between efficacy and toxicity in determining the OD for Phase II trials. Results: Twenty-two patients, median age 58 (range 25-69) years were enrolled from June 2015 to June 2018. 12 patients (54.5%) had adverse cytogenetics, 6 (27%) intermediate risk, 3 (13.7%) favorable risk and 1 patient's cytogenetic risk was unknown (fibrotic BM). Eight patients demonstrated disease evolution from myelodysplastic syndrome (MDS). Altogether 16 of the 22 patients (73%) were deemed high risk based on cytogenetics or MDS-AML evolution. The EffTox design was implemented until cohort 4 (3 mg/m2 q12h), where 2 of 3 patients experienced a grade 5 non-hematologic toxicity (NHT), resulting in a dose-limiting toxicity (DLT). Since no DLTs were observed in cohort 3, an additional 5 patients were thus enrolled at this dose level to ensure safety. The OD was determined to be the dose level used in cohort 3: OM 2 mg/m2. No HTs were observed in 21 of 22 patients, (one patient not evaluable). The most common non-hematologic treatment emergent adverse events (TEAEs) of any grade were fever (68%), nausea (64%), vomiting (55%), hyperglycemia (41%), diarrhea (41%), mucositis (36%), headache (36%), sinus tachycardia (32%), rash/dermatitis (32%), and abdominal pain (32%). The most prevalent non-hematologic grade 3/4 TEAEs were febrile neutropenia (23%), hypoxia (18%), hyperglycemia (18%), and dyspnea (18%). ORR (CR and CRi) was 45.5%. Median OS was 605 days and EFS was 100 days. Conclusion: In this population with predominantly high-risk AML, the combination of OM with a standard 7 + 3 regimen demonstrates a manageable safety profile with acceptable efficacy. As ~ 25% of patients achieving CR with '7 + 3' do so after a second induction (based on meta-analysis of 6 trials, n = 1980, see Cancer 2010, 116: 5012), the ORR here is comparable to those receiving a single standard of care induction. The results in this high-risk group are therefore promising and warrant further investigation in a phase II trial. At present, we are assessing leukemic blast MCL protein expression in stored pre-treatment samples to determine if this predicts OM efficacy. NCT02440568. Teva has performed a Medical Accuracy Review of this abstract. Figure. Figure. Disclosures Khan: Teva: Speakers Bureau. Patel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Successful Implementation of the Randomized Discontinuation Trial Design: An Application to the Study of the Putative Antiangiogenic Agent Carboxyaminoimidazole in Renal Cell Carcinoma—CALGB 69901

2005 ◽  
Vol 23 (16) ◽  
pp. 3726-3732 ◽  
Author(s):  
Walter M. Stadler ◽  
Gary Rosner ◽  
Eric Small ◽  
Donna Hollis ◽  
Brian Rini ◽  
...  
Keyword(s):  
Stable Disease ◽  
Renal Cell ◽  
Performance Status ◽  
Cell Cancer ◽  
Objective Response ◽  
Disease Rate ◽  
Successful Implementation ◽  
Evaluation Point ◽  
Randomized Discontinuation Trial ◽  
A Performance

Purpose To assess the disease-stabilizing activity of carboxyaminoimidazole (CAI) in patients with metastatic renal cell cancer (RCC) using a randomized discontinuation trial (RDT) design. Patients and Methods Recruited patients had a performance status of 0 to 2, minimal neuropathy or cerebellar dysfunction, measurable disease, and normal organ function. Treatment with 250 mg/d CAI was initiated in all patients and continued until disease progression in those with an objective response. Protocol treatment was discontinued for unacceptable toxicity or progressive disease; patients with stable disease at the 16-week evaluation point were randomly assigned in a double-blind manner to continued CAI or placebo. The primary end point was the stable disease rate in the randomized groups. Results A total of 368 patients were accrued and received therapy. Ninety percent had a performance status of 0 or 1, 80% underwent a prior nephrectomy, and 41% had received no prior systemic therapy. Serious or life-threatening toxicity was experienced by 34%, with asthenia (15%) and neuropsychiatric difficulties (7%) being most common. At the randomization point, 51% of patients had progressed, 30% withdrew, 1% experienced a partial response, and 17% had stable disease and were randomly assigned. A Bayesian futility analysis utilizing the first 49 randomly assigned patients suggested that the probability of demonstrating a higher stable disease rate in the experimental group was less than 9% even under the most optimistic a priori assumptions, and further trial accrual was halted. Conclusion CAI is inactive in RCC. The RDT design should be further explored for evaluating activity of putative disease stabilizing agents.

Low-dose metronomic topotecan and pazopanib in children with recurrent or refractory solid tumors: A C17 Canadian phase I trial (TOPAZ).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 10020-10020
Author(s):  
Arif Manji ◽  
Daniel A. Morgenstern ◽  
Yvan Samson ◽  
Rebecca Deyell ◽  
Donna Johnston ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Stable Disease ◽  
Low Dose ◽  
Pediatric Patients ◽  
Novel Approach ◽  
Best Response ◽  
Grade 3 ◽  
Relapsed Disease

10020 Background: Low-dose metronomic topotecan (mTP) represents a novel approach to chemotherapy delivery which, in preclinical models, may work synergistically with pazopanib (PZ) in targeting angiogenesis. This study was designed to determine the recommended phase 2 dose (RP2D) of mTP/PZ in pediatric patients with solid tumors, while describing the safety and toxicity of this regimen. Methods: A phase I dose-escalation, pharmacokinetic (PK) and pharmacodynamic (PD) study of mTP/PZ was conducted at ten sites across Canada, enrolling pediatric patients aged 2-21 years with relapsed/refractory solid tumors. Patients were treated with oral mTP and PZ suspension daily without interruption in 28-day cycles, with dose escalation in accordance with the rolling-six design. Five dose levels (0.12/125, 0.16/125, 0.22/125, 0.22/160, and 0.3/160 mg/m2/day of mTP/PZ) were evaluated. PK studies were performed on day 1 and at steady state, and PD studies included circulating angiogenic factors VEGFR1, VEGFR2, VEGF, endoglin and placental growth factor. Results: Thirty patients (pts) were enrolled, of whom 26 were evaluable for dose-limiting toxicity (DLT), with median age 12 years (3-20). The most common diagnoses included osteosarcoma (8), neuroblastoma (NB, 7), Ewing sarcoma/PNET (4), and rhabdomyosarcoma (4). The most common grade 3/4 adverse events (AEs) related to protocol therapy were neutropenia (18%), thrombocytopenia (11%), lymphocytopenia (11%), AST elevation (11%), and lipase elevation (11%). Only 2 cycle-1 DLTs were observed on study, both at the 0.3/160 mg/m2 mTP/PZ dose level (2/5 pts) comprising persistent grade 3 thrombocytopenia and grade 3 ALT elevation. No AEs experienced beyond cycle-1 required treatment discontinuation. Best response was stable disease in 10/25 pts (40%) for a median duration of 6.4 months (1.7-45.1). One patient with refractory NB achieved stable disease for 45 months and continued on mTP/PZ via compassionate access after study closure. PK and PD results are pending at this time. Conclusions: The combination of oral mTP and PZ is safe and tolerable in pediatric patients with solid tumors, with a RP2D of mTP 0.22 mg/m2/day and PZ suspension 160 mg/m2/day. Ten patients achieved stable disease for a median of 6 months. The lack of objective responses suggests that this combination is likely of limited benefit for relapsed disease, but may play a role as maintenance therapy. Clinical trial information: NCT02303028.

scholarly journals Phase I and Pharmacologic Study of SNS-032, a Potent and Selective Cdk2, 7, and 9 Inhibitor, in Patients With Advanced Chronic Lymphocytic Leukemia and Multiple Myeloma

2010 ◽  
Vol 28 (18) ◽  
pp. 3015-3022 ◽  
Author(s):  
Wei-Gang Tong ◽  
Rong Chen ◽  
William Plunkett ◽  
David Siegel ◽  
Rajni Sinha ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Chronic Lymphocytic Leukemia ◽  
Phase I ◽  
Clinical Efficacy ◽  
Stable Disease ◽  
Single Agent ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
Clinical Activity ◽  
Dose Escalation Study

Purpose SNS-032 is a highly selective and potent inhibitor of cyclin-dependent kinases (Cdks) 2, 7, and 9, with in vitro growth inhibitory effects and ability to induce apoptosis in malignant B cells. A phase I dose-escalation study of SNS-032 was conducted to evaluate safety, pharmacokinetics, biomarkers of mechanism-based pharmacodynamic (PD) activity, and clinical efficacy. Patients and Methods Parallel cohorts of previously treated patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) received SNS-032 as a loading dose followed by 6-hour infusion weekly for 3 weeks of each 4-week course. Results There were 19 patients with CLL and 18 with MM treated. Tumor lysis syndrome was the dose-limiting toxicity (DLT) for CLL, the maximum-tolerated dose (MTD) was 75 mg/m2, and the most frequent grade 3 to 4 toxicity was myelosuppression. One patient with CLL had more than 50% reduction in measurable disease without improvement in hematologic parameters. Another patient with low tumor burden had stable disease for four courses. For patients with MM, no DLT was observed and MTD was not identified at up to 75 mg/m2, owing to early study closure. Two patients with MM had stable disease and one had normalization of spleen size with treatment. Biomarker analyses demonstrated mechanism-based PD activity with inhibition of Cdk7 and Cdk9, decreases in Mcl-1 and XIAP expression level, and associated CLL cell apoptosis. Conclusion SNS-032 demonstrated mechanism-based target modulation and limited clinical activity in heavily pretreated patients with CLL and MM. Further single-agent, PD-based, dose and schedule modification is warranted to maximize clinical efficacy.

scholarly journals Phase I trial evaluating safety and efficacy of intratumorally administered inflammatory allogeneic dendritic cells (ilixadencel) in advanced gastrointestinal stromal tumors

2020 ◽  
Vol 69 (11) ◽  
pp. 2393-2401
Author(s):  
Robin Fröbom ◽  
Erik Berglund ◽  
David Berglund ◽  
Inga-Lena Nilsson ◽  
Jan Åhlén ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Phase I ◽  
Stable Disease ◽  
Phase I Trial ◽  
Second Line ◽  
Clinical Trial Registration ◽  
Safety And Efficacy ◽  
Recist 1.1 ◽  
Choi Criteria ◽  
Third Line

Abstract Background The majority of patients with advanced gastrointestinal stromal tumor (GIST) develop resistance to imatinib, and subsequent treatments have limited efficacy. Ilixadencel (allogeneic inflammatory dendritic cells) is a cell-based immune primer injected intratumorally that previously has been clinically investigated in metastatic renal cell carcinoma and hepatocellular carcinoma. Methods The trial was a single arm phase I trial assessing safety and efficacy of ilixadencel in subjects with progressing advanced/metastatic GIST despite ongoing treatment with second or later lines of tyrosine kinase inhibitors (TKI). Three patients were progressing while on sunitinib (second line), one on regorafenib (third line), and two on pazopanib (fourth line). TKI treatment was maintained throughout, while two intratumoral injections of ilixadencel (10 × 106 viable and HLA-DR expressing cells per dose) were administered. Results No severe adverse events were found to be related to ilixadencel administration. Four patients showed continued tumor progression at 3 months per RECIST 1.1 and Choi criteria. One patient (on third line regorafenib) had stable disease for 9 months and another patient (on second line sunitinib) had stable disease at end of study (12 months) as per RECIST 1.1. These two patients developed a partial response as per Choi criteria with a duration of 3 and 6 months, respectively. The median progression-free survival (PFS) was 4.0 months. Conclusion Ilixadencel treatment presented an acceptable safety profile among advanced GIST patients who developed resistance to TKI. Encouraging radiological tumor responses were detected in 33% of treated patients, supporting further investigation. Clinical trial registrationwww.clinicaltrials.gov; NCT: 02432846; registration date: February 22, 2016.

scholarly journals Phase I study of DFP-11207, a novel oral fluoropyrimidine with reasonable AUC and low Cmax and improved tolerability, in patients with solid tumors

2020 ◽  
Vol 38 (6) ◽  
pp. 1763-1773
Author(s):  
Jaffer A. Ajani ◽  
Milind Javle ◽  
Cathy Eng ◽  
David Fogelman ◽  
Jackie Smith ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Stable Disease ◽  
Phase I Study ◽  
Potent Inhibitor ◽  
Pharmacokinetic Analysis ◽  
Gastrointestinal Cancers ◽  
Chemotherapy Treatment ◽  
Favorable Safety ◽  
Combination Regimens

Summary 5-fluorouracil (5-FU) and 5-FU derivatives, such as capecitabine, UFT, and S-1, are the mainstay of chemotherapy treatment for gastrointestinal cancers, and other solid tumors. Compared with other cytotoxic chemotherapies, these drugs generally have a favorable safety profile, but hematologic and gastrointestinal toxicities remain common. DFP-11207 is a novel oral cytotoxic agent that combines a 5-FU pro-drug with a reversible DPD inhibitor and a potent inhibitor of OPRT, resulting in enhanced pharmacological activity of 5-FU with decreased gastrointestinal and myelosuppressive toxicities. In this Phase I study (NCT02171221), DFP-11207 was administered orally daily, in doses escalating from 40 mg/m2/day to 400 mg/m2/day in patients with esophageal, colorectal, gastric, pancreatic or gallbladder cancer (n = 23). It was determined that DFP-11207 at the dose of 330 mg/m2/day administered every 12 hours was well-tolerated with mild myelosuppressive and gastrointestinal toxicities. The pharmacokinetic analysis determined that the 5-FU levels were in the therapeutic range at this dose. In addition, fasted or fed states had no influence on the 5-FU levels (patients serving as their own controls). Among 21 efficacy evaluable patients, 7 patients had stable disease (33.3%), of which two had prolonged stable disease of >6 months duration. DFP-11207 can be explored as monotherapy or easily substitute 5-FU, capecitabine, or S-1 in combination regimens.

scholarly journals Phase I Study of ATR Inhibitor M6620 in Combination With Topotecan in Patients With Advanced Solid Tumors

2018 ◽  
Vol 36 (16) ◽  
pp. 1594-1602 ◽  
Author(s):  
Anish Thomas ◽  
Christophe E. Redon ◽  
Linda Sciuto ◽  
Emerson Padiernos ◽  
Jiuping Ji ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Dose Escalation ◽  
Stable Disease ◽  
Phase I Study ◽  
Small Cell ◽  
Small Cell Lung ◽  
Platinum Refractory

Purpose Our preclinical work identified depletion of ATR as a top candidate for topoisomerase 1 (TOP1) inhibitor synthetic lethality and showed that ATR inhibition sensitizes tumors to TOP1 inhibitors. We hypothesized that a combination of selective ATR inhibitor M6620 (previously VX-970) and topotecan, a selective TOP1 inhibitor, would be tolerable and active, particularly in tumors with high replicative stress. Patients and Methods This phase I study tested the combination of M6620 and topotecan in 3-week cycles using 3 + 3 dose escalation. The primary end point was the identification of the maximum tolerated dose of the combination. Efficacy and pharmacodynamics were secondary end points. Results Between September 2016 and February 2017, 21 patients enrolled. The combination was well tolerated, which allowed for dose escalation to the highest planned dose level (topotecan 1.25 mg/m2, days 1 to 5; M6620 210 mg/m2, days 2 and 5). One of six patients at this dose level experienced grade 4 thrombocytopenia that required transfusion, a dose-limiting toxicity. Most common treatment-related grade 3 or 4 toxicities were anemia, leukopenia, and neutropenia (19% each); lymphopenia (14%); and thrombocytopenia (10%). Two partial responses (≥ 18 months, ≥ 7 months) and seven stable disease responses ≥ 3 months (median, 9 months; range, 3 to 12 months) were seen. Three of five patients with small-cell lung cancer, all of whom had platinum-refractory disease, had a partial response or prolonged stable disease (10, ≥ 6, and ≥ 7 months). Pharmacodynamic studies showed preliminary evidence of ATR inhibition and enhanced DNA double-stranded breaks in response to the combination. Conclusion To our knowledge, this report is the first of an ATR inhibitor-chemotherapy combination. The maximum dose of topotecan plus M6620 is tolerable. The combination seems particularly active in platinum-refractory small-cell lung cancer, which tends not to respond to topotecan alone. Phase II studies with biomarker evaluation are ongoing.

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