scholarly journals Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial

2021 ◽  
Author(s):  
Frank Saran ◽  
Liam Welsh ◽  
Allan James ◽  
Catherine McBain ◽  
Rao Gattamaneni ◽  
...  
Keyword(s):  
Phase I ◽  
Dna Methyltransferase ◽  
Receptor Gene ◽  
Methylation Status ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Newly Diagnosed ◽  
Medication Regimen ◽  
Open Label

Abstract Background Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. Methods This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. Results Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. Conclusions This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. Trial registration NCT00977431 (first posted September 15, 2009).

Phase I study of AZD1775 with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) and evaluation of intratumoral drug distribution (IDD) in patients with recurrent GBM.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2005-2005
Author(s):  
Brian Michael Alexander ◽  
Manmeet Singh Ahluwalia ◽  
Arati Suvas Desai ◽  
Jorg Dietrich ◽  
Thomas Joseph Kaley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brain Tumor ◽  
Phase I ◽  
Cellular Response ◽  
Adult Brain ◽  
Dose Finding ◽  
Newly Diagnosed ◽  
Open Label ◽  
Grade 3 ◽  
Recurrent Gbm

2005 Background: The standard of care treatment for newly diagnosed GBM is maximal safe surgical resection followed by two DNA damaging agents, RT and TMZ. Cellular response to DNA damage involves checkpoints that halt the cell cycle to allow DNA repair. AZD1775 is an oral small molecular inhibitor of a nuclear tyrosine kinase Wee1, a key regulator of the G2/M checkpoint. Abrogation of the G2/M checkpoint prevents repair and pushes cells into mitosis with unrepaired DNA damage. AZD1775 was shown to enhance TMZ and RT effects in preclinical models. Methods: The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. The dose finding portion is comprised of two arms, one with AZD1775 given Monday through Friday during concurrent RT/TMZ and a second arm given with adjuvant TMZ qd x 5d/28d cycle. Each arm had standard 3+3 design. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. Results: 51 patients enrolled in the dose finding arms. For the concurrent arm, the MTD was 200 mg. At 275 mg one patient had grade 3 fatigue and another had grade 4 thrombocytopenia and neutropenia. Two of 6 total patients enrolled at 200 mg experienced DLTs (grade 4 neutropenia and grade 3 ALT elevation). The MTD for the adjuvant arm was 425 mg as 1 of 6 patients had DLT (grade 4 decrease in ANC). At 500 mg, 2 of 3 patients experienced intolerable diarrhea despite prophylaxis. Enrollment in the combination cohort is completed and evaluation of safety is underway. The drug concentration in contrast enhancing and non-enhancing brain tumor was 4-8 x and 0.5-2.6 x greater than plasma, respectively for patients on IDD portion. Conclusions: The MTD for AZD1775 in combination with RT/TMZ is 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ. IDD and PK/PD analysis is ongoing to inform the decision to proceed to phase II testing. Clinical trial information: NCT01849146.

Phase I evaluation of tipifarnib in combination with low-dose Ara-C (LDAC) in high-risk myelodysplastic syndrome (MDS) or acute myeloid leukemia (AML): Interim results

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 14014-14014
Author(s):  
J. E. Cortes ◽  
E. J. Feldman ◽  
D. Douer ◽  
A. Raza ◽  
S. Fruchtman
Keyword(s):  
Phase I ◽  
Dose Level ◽  
The Elderly ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Dose Finding ◽  
Clinical Activity ◽  
Open Label ◽  
Entire Cohort ◽  
Investigational Agent

14014 Background: Tipifarnib (T) is a farnesyltransferase inhibitor with clinical activity in MDS and AML. LDAC has utility in the elderly with MDS/AML; hence its use in combination with the investigational agent T to improve outcomes is warranted. Methods: The primary objective of this ongoing phase I, dose finding, multicenter, open-label study was to determine the maximum tolerated dose (MTD) based on dose limiting toxicities (DLT) of T+LDAC observed during the first 28 day cycle. MDS (IPSS Int 1, 2 or High) and untreated AML pts (age =75y or =65y with preceding MDS) or relapsed/refractory AML (age >18y) were included. Planned sample size was up to 57 pts with a traditional 3+3 dose escalation and a minimum of 3 pts enrolled per cohort. T (Dose Level 0) was administered initially at 200mg PO BID x 21 days in combination with LDAC 10mg SC BID x 10 days; both repeated every 28 days. Efficacy will be assessed by bone marrow and peripheral blood count studies. Results: 15 pts have been enrolled to date: 2 MDS (Int 1 n=1, High n=1) and 13 AML (7/13 pts with no previous therapy); all 15 pts were evaluable. Mean baseline characteristics for the entire cohort were: age 76.2y, 67% men, Hb 9.4 ± 0.9 g/dL, WBC 8.7 ± 11.3 x 103/μL, platelets 96.8 ± 96.6 x 103/μL. The observed DLT for T+LDAC was generalized rash seen at Dose Level 3. The MTD was therefore determined to be T 300mg and LDAC 15mg. The most common grade 3/4 adverse events were neutropenia, thrombocytopenia, anemia, and rash. Conclusions: These interim findings show the combination of T at 300mg PO BID x 21 days and LDAC at 15mg SC BID x 10 days to be the MTD in this study. Assessment for efficacy is ongoing. [Table: see text] No significant financial relationships to disclose.

Phase I study of vandetanib with radiation therapy and temozolomide for newly diagnosed glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2031-2031
Author(s):  
J. Drappatz ◽  
A. D. Norden ◽  
E. T. Wong ◽  
A. B. Lassman ◽  
L. Doherty ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Phase I Study ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Therapeutic Benefit ◽  
Newly Diagnosed ◽  
Minor Response

2031 Background: There is increasing evidence that angiogenesis inhibition may potentiate the effects of radiation therapy (RT) and chemotherapy in patients with glioblastoma (GBM). In addition, inhibition of the epidermal growth factor receptor (EGFR) may be of therapeutic benefit, as EGFR is often upregulated in GBM and contributes to radiation resistance. We conducted a phase I study of vandetanib, an inhibitor of VEGFR2 and EGFR, in patients with newly-diagnosed GBM in combination with RT and temozolomide (TMZ). Methods: Using a standard 3 + 3 dose escalation design, 13 newly-diagnosed GBM patients received vandetanib with RT (60 Gy) and concurrent TMZ 75 mg/m2 daily, followed by adjuvant TMZ for up to 12 cycles (150–200 mg/m2 on days 1–5 of each 28 day cycle). The maximum tolerated dose (MTD) was defined as the dose with ≤1/6 dose-limiting toxicities (DLT). Eligible patients were adults with newly-diagnosed GBM or gliosarcoma, Karnofsky performance status of ≥60%, normal organ function, and not taking enzyme-inducing anti-epileptic drugs. MTD was determined by evaluation of DLTs during the first 12 weeks of therapy. Results: Six patients were treated with vandetanib at 200 mg daily. 2/6 patients developed DLTs (grade 5 gastrointestinal hemorrhage and grade 3 thrombocytopenia in one patient and grade 4 neutropenia in one patient). Seven patients were treated at 100 mg daily with no DLTs observed, establishing 100 mg daily as the MTD. Of 10 evaluable patients, one had a minor response (10%), defined as 25% to <50% reduction in enhancing area for 8 weeks; eight had stable disease (80%), defined as <25% increase or decrease; and one had progressive disease (10%). Conclusions: These data suggest that vandetanib may be combined with RT and TMZ in GBM patients. A randomized phase II study in which patients receive RT and TMZ with or without vandetanib 100 mg daily is underway. [Table: see text]

scholarly journals Assessing the safety, tolerability and efficacy of PLGA-based immunomodulatory nanoparticles in patients with advanced NY-ESO-1-positive cancers: a first-in-human phase I open-label dose-escalation study protocol

BMJ Open ◽  
2021 ◽  
Vol 11 (11) ◽  
pp. e050725
Author(s):  
Jeroen H A Creemers ◽  
Inka Pawlitzky ◽  
Konstantina Grosios ◽  
Uzi Gileadi ◽  
Mark R Middleton ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase I ◽  
Cancer Immunotherapy ◽  
Dose Escalation ◽  
Competent Authority ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Dose Escalation Study ◽  
Registration Number

IntroductionThe undiminished need for more effective cancer treatments stimulates the development of novel cancer immunotherapy candidates. The archetypical cancer immunotherapy would induce robust, targeted and long-lasting immune responses while simultaneously circumventing immunosuppression in the tumour microenvironment. For this purpose, we developed a novel immunomodulatory nanomedicine: PRECIOUS-01. As a PLGA-based nanocarrier, PRECIOUS-01 encapsulates a tumour antigen (NY-ESO-1) and an invariant natural killer T cell activator to target and augment specific antitumour immune responses in patients with NY-ESO-1-expressing advanced cancers.Methods and analysisThis open-label, first-in-human, phase I dose-escalation trial investigates the safety, tolerability and immune-modulatory activity of increasing doses of PRECIOUS-01 administered intravenously in subjects with advanced NY-ESO-1-expressing solid tumours. A total of 15 subjects will receive three intravenous infusions of PRECIOUS-01 at a 3-weekly interval in three dose-finding cohorts. The trial follows a 3+3 design for the dose-escalation steps to establish a maximum tolerated dose (MTD) and/or recommended phase II dose (RP2D). Depending on the toxicity, the two highest dosing cohorts will be extended to delineate the immune-related parameters as a readout for pharmacodynamics. Subjects will be monitored for safety and the occurrence of dose-limiting toxicities. If the MTD is not reached in the planned dose-escalation cohorts, the RP2D will be based on the observed safety and immune-modulatory activity as a pharmacodynamic parameter supporting the RP2D. The preliminary efficacy will be evaluated as an exploratory endpoint using the best overall response rate, according to Response Evaluation Criteria in Solid Tumors V.1.1.Ethics and disseminationThe Dutch competent authority (CCMO) reviewed the trial application and the medical research ethics committee (CMO Arnhem-Nijmegen) approved the trial under registration number NL72876.000.20. The results will be disseminated via (inter)national conferences and submitted for publication to a peer-reviewed journal.Trial registration numberNCT04751786.

Phase I trial of PTK787/ZK222584 (PTK/ZK) in combination with carboplatin (C) and paclitaxel (T) in platinum-sensitive recurrent epithelial ovarian (EOC), fallopian tube (FT), or primary peritoneal (PPC) cancers

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 5564-5564 ◽  
Author(s):  
M. M. Juretzka ◽  
C. Aghajanian ◽  
M. L. Hensley ◽  
W. P. Tew ◽  
D. Spriggs ◽  
...  
Keyword(s):  
Growth Factor ◽  
Phase I ◽  
Tyrosine Kinases ◽  
Angiogenesis Inhibitor ◽  
Growth Factor Receptor ◽  
Liver Function Tests ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Open Label ◽  
Platinum Sensitive

5564 Background: Targeting vascular endothelial growth factor (VEGF) in patients (pts) with ovarian cancer achieves objective responses. PTK/ZK is an orally active angiogenesis inhibitor which blocks all known VEGF receptor and platelet-derived growth factor receptor tyrosine kinases. A previous study administered PTK/ZK only on days 3–21 of C and T cycle based on pre-clinical data suggesting PTK/ZK increases T levels (PROC ASCO # 5042, 2005), and recent data supports bid dosing (JCO 18:1–10, 2005). Methods: In this open label, single institution phase I study, pts with platinum sensitive recurrent EOC, FT, or PPC were treated with C and T every 21 days with increasing continuous daily doses of PTK/ZK (250 mg to 1,250mg with bid dosing). Primary endpoints were safety and maximum tolerated dose (MTD). Pharmacokinetic (PK) analysis is planned to describe C and T pharmacokinetics when combined with PTK/ZK. Results: To date, 14 pts with median age 61 (range 45–73) have been enrolled on the first 3 dose levels, including 13 EOC and 1 PPC. All patients were evaluable for toxicity and 8 were evaluable for investigator assessed response. MTD has not been reached. Febrile neutropenia was dose limiting toxicity requiring expansion at levels II and III. PK analysis is ongoing. To date, best responses are: 4 (PR), 3 (SD) and 1 (POD). Other G III toxicity included: C hypersensitivity reaction (1, gr 3), hyperglycemia (4, gr 3), hypertension (1, gr 3), diarrhea (1, gr 3), and elevated liver function tests (1, gr 3). Conclusion: PTK/ZK can be administered continuously in combination with standard doses of C and T using bid dosing. MTD is not yet reached and accrual is ongoing. PK data and MTD will be presented. Supported by Novartis and Bayer Schering Pharma. [Table: see text] No significant financial relationships to disclose.

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4084-4084
Author(s):  
H. Sheikh ◽  
J. W. Valle ◽  
K. Palmer ◽  
G. Wilson ◽  
A. Sjursen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Hand Foot Syndrome ◽  
Label Dose ◽  
Grade 3

4084 Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS. No significant financial relationships to disclose.

A TITE-CRM phase I/II study of disulfiram and copper with concurrent radiation therapy and temozolomide for newly diagnosed glioblastoma.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2033-2033 ◽  
Author(s):  
Jiayi Huang ◽  
Todd DeWees ◽  
Jian Li Campian ◽  
Milan G Chheda ◽  
George Ansstas ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase I ◽  
Methylation Status ◽  
Progression Free Survival ◽  
Maximum Tolerated Dose ◽  
Newly Diagnosed ◽  
Elevated Liver Enzymes ◽  
Significant Difference ◽  
Newly Diagnosed Glioblastoma ◽  
Recommended Phase Ii Dose

2033 Background: Disulfiram (DSF) has shown promising activity against glioblastoma in preclinical studies and is more effective when combined with copper (Cu). Our previous phase I study established the maximum tolerated dose (MTD) of DSF when combined with adjuvant temozolomide (TMZ). This phase I/II study aims to establish the MTD when disulfiram and copper are combined with concurrent radiation therapy (RT) and TMZ for newly diagnosed glioblastoma and to explore preliminary efficacy. Methods: Eligible patients were treated with standard RT and TMZ plus escalating doses of DSF (250 mg - 375 mg PO QD) and Cu (2 mg PO TID), followed by adjuvant TMZ plus DSF (500 mg/day) and Cu. The time-to-event continual reassessment method (TITE-CRM) was used to continuously estimate the probability of dose-limiting toxicity (DLT) and to assign patients to doses with an estimated DLT probability of approximately 20% with a margin of 5%. Tumor mutations were evaluated with next-generation sequencing for all patients. Results: Eighteen glioblastoma patients were treated with the study therapy: 8 with DSF of 250 mg/day and 10 with 375 mg/day. Three DLTs were observed: 1 with 250 mg/day (grade 2 urinary incontinence and ataxia), and 2 with 375 mg/day (both grade 3 elevated liver enzymes). DSF had an estimated DLT probability of 10% (95% CI: 3-29%) at 250 mg/day, and 21% (95% CI: 7-42%) at 375 mg/day. After a median follow-up of 12.3 months, 1-year progression-free survival (PFS) was 57%, and 1-year overall survival (OS) was 69%. There was no significant difference in PFS/OS when stratified by DSF doses, surgical extent, or MGMT methylation status. However, glioblastomas with IDH1 (n = 6), BRAF (n = 2), or NF1 (n = 1) mutations had significantly better PFS and OS than those without the mutations: 1-year PFS: 100% vs 22%, respectively, p = 0.001; 1-year OS: 100% vs 42%, respectively, p = 0.006. Conclusions: The MTD of DSF with RT/TMZ/Cu for glioblastoma is 375 mg/day, and the recommended phase II dose is 250 mg/day. Although confirmation with larger sample size is needed, the combination demonstrates promising preliminary efficacy for the subset of glioblastoma with IDH1, BRAF, and NF1 mutations. Clinical trial information: NCT02715609.

scholarly journals Pediatric Phase I and Pharmacokinetic Study of Erlotinib Followed by the Combination of Erlotinib and Temozolomide: A Children's Oncology Group Phase I Consortium Study

2008 ◽  
Vol 26 (30) ◽  
pp. 4921-4927 ◽  
Author(s):  
Regina I. Jakacki ◽  
Marta Hamilton ◽  
Richard J. Gilbertson ◽  
Susan M. Blaney ◽  
Jean Tersak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Pharmacokinetic Study ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Receptor Expression ◽  
Dose Finding ◽  
Pharmacokinetic Studies ◽  
Mixed Response

Purpose We conducted a phase I and pharmacokinetic study of the epidermal growth factor receptor (EGFR) inhibitor erlotinib as a single agent and in combination with temozolomide in children with refractory solid tumors. Patients and Methods Erlotinib was administered orally once daily to cohorts of three to six children for a single 28-day course. Patients then received the combination of daily erlotinib and temozolomide daily for 5 days for all subsequent 28-day courses. An oral erlotinib solution was administered during the dose-finding phase and a tablet formulation was subsequently studied at the maximum-tolerated dose (MTD). Pharmacokinetic studies and ERBB-receptor expression and signaling studies were performed. Results Forty-six patients, median age 11.5 years, received erlotinib at doses of 35, 50, 65, 85, or 110 mg/m2/d. At 110 mg/m2/d, two of four patients had dose-limiting toxicity (DLT) consisting of rash and hyperbilirubinemia, whereas one of six patients developed dose-limiting rash at 85 mg/m2/d. The most frequent non-DLTs included diarrhea, rash, and hyperbilirubinemia. The combination of erlotinib and temozolomide was well tolerated. The median apparent erlotinib clearance was 3.1 L/h/m2 and the median terminal half-life was 8.7 hours. One patient with a neurocytoma had stable disease for 19 months, two patients with neuroblastoma remained on study for 23 and 24 months, and one patient with myoepithelioma had a mixed response. Conclusion The recommended phase II dose of erlotinib in recurrent pediatric solid tumors is 85 mg/m2/d, either alone or in combination with temozolomide.

Phase I dose-escalation clinical trial with 5-imino-13-deoxydoxorubicin in cancer patients.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2575-2575
Author(s):  
Raymond J. Hohl ◽  
Robert E. Vestal ◽  
Sarah Abigail Holstein ◽  
Richard D. Olson ◽  
Karen Parrott ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Disease Progression ◽  
Solid Tumors ◽  
Rabbit Model ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Anticancer Efficacy ◽  
Number Of Patients

2575 Background: 5-imino-13-deoxydoxorubicin (DIDOX; GPX-150) is a doxorubicin (dox) analog modified in two locations to prevent formation of a) cardiotoxic metabolites and b) reactive oxygen species. In a rabbit model comparing the cardiotoxicity of dox vs. DIDOX, chronic doses of each caused similar myelosuppression, but only dox caused cardiotoxicity as assessed by echocardiography and histopathology scoring. In view of the non-cardiotoxic nature of DIDOX along with its anticancer efficacy in preclinical studies, DIDOX was entered into a Phase I, open-label, non-randomized dose-finding study in up to 30 patients with solid tumors. Methods: Inclusion criteria included progressing solid tumors and cardiac ejection fraction (CEF) 110% of lower limit of institutional normal (assessed by MUGA). There are 8 dose cohorts and up to 8 cycles/cohort, dosing (iv) once every 3 weeks with an accelerated titration dosing design at the three lowest cohorts. Cohort A =14, B=28, C=56, D=84, E=112, F=150, G=200, and H=265 mg/m2/cycle. Dose was escalated to next dose level if < 1 dose limiting toxicity (DLT) is reported. Maximum tolerated dose (MTD) will be exceeded when 2 or more patients in a cohort elicit DLT; the next lower dose is defined as the MTD. DLT occurs when a decrease in CEF is grade 2 or higher, or grade 4 neutropenia lasts > 5 days. Results: Cohorts A-G have been completed. Number of patients for the cohorts are: A=1, B=1, C=1, D=4 E=3 F=3 G=4, and H = 2 (with 4 more to be enrolled in H). No decrease in CEF occurred in any cohorts. There were no DLTs in cohorts A-G. One patient in H had neutropenia grade 4 for 11 days (a DLT). Another patient in H had neutropenia grade 4 for 4 days. There was no disease progression at the completion of dosing for 6 of the 12 patients in cohorts E-H. In contrast, all 7 patients had disease progression in cohorts A-D. Conclusions: No cardiotoxicity was observed in any patient. No DLT was observed in cohorts A-G. With one DLT in cohort H, one more DLT will define MTD for DIDOX at 200 mg/m2. At higher DIDOX doses (E-H), 6 of 12 patients showed no disease progression. (IND No. 77,051). Clinical trial information: NCT00710125.

scholarly journals Phase I open-label trial of intraperitoneal paclitaxel in combination with intravenous cisplatin and oral capecitabine in patients with advanced gastric cancer and peritoneal metastases (IPGP study): study protocol

BMJ Open ◽  
2019 ◽  
Vol 9 (5) ◽  
pp. e026732
Author(s):  
Sina Vatandoust ◽  
Tim Bright ◽  
Amitesh Chandra Roy ◽  
David Watson ◽  
Susan Gan ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Phase I ◽  
Radiation Treatment ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Good Clinical Practice ◽  
Maximum Tolerated Dose ◽  
Responsible Conduct Of Research ◽  
Open Label ◽  
The World

IntroductionGastric cancer with peritoneal metastasis has a poor outcome. Only a few studies have specifically investigated this group of patients. Japanese researchers have shown that chemotherapy with intraperitoneal paclitaxel (IPP) and oral S-1 (tegafur/gimeracil/oteracil) is active and well tolerated. These results have been achieved in a specific genetic pool (Japanese population), using regimens that may not be available in other parts of the world. We have designed this phase I trial to investigate IPP in combination with a standard chemotherapy combination in these patients.MethodsWe use a 3+3 expanded cohort dose escalation until a predefined number of dose-limiting toxicities are reached. Patients will have an intraperitoneal catheter placed surgically after trial enrolment. Chemotherapy includes a maximum of six cycles (21 days) of capecitabine (X) (1000 mg/m2two times a day, days 1–14)+cisplatin (C) (intravenous 80 mg/m2day 1) and IPP (days 1 and 8) with the following doses: cohort-1: 10 mg/m2, cohort-2: 20 mg/m2and cohort-3: 30 mg/m2. Primary endpoint is to determine the maximum tolerated dose of IPP. Secondary endpoints include determining the safety and tolerability of IPP in combination with C and X, overall response rates, ascites response rate, progression-free survival, overall survival and effects on quality of life.Important inclusion criteria include age ≥18 years, human epidermal growth factor receptor 2 non-amplified gastric adenocarcinoma with histological or cytology-proven peritoneal involvement and adequate organ function. Exclusion criteria include previous malignancy within 5 years, recent abdominal or pelvic radiation treatment, significant abdominal adhesions or sepsis.Ethics and disseminationThe study is approved by Southern Adelaide Clinical Human Research Ethics Committee. A manuscript will be prepared for publication on the completion of the trial. This study will be conducted according to the Note for Guidance on Good Clinical Practice (CPMP/ICH/135/95) annotated with TGA comments (Therapeutic Goods Administration DSEB July 2000) and in compliance with applicable laws and regulations. The study will be performed in accordance with the NHMRC Statement on Ethical Conduct in Research Involving Humans (© Commonwealth of Australia 2007), and the NHMRC Australian Code for the Responsible Conduct of Research (©Australian Government 2007), and the principles laid down by the World Medical Assembly in the Declaration of Helsinki 2008.Trial registration numberACTRN12614001063606.

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