Phase I Study of Cladribine (2-chlorodeoxyadenosie), Cytarabine and G-CSF Based Induction Therapy (CLAG) with ATRA (All-trans retinoic acid) and Midostaurin for Relapsed/Refractory AML,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3609-3609
Author(s):  
Giridharan Ramsingh ◽  
Andrew Sprau ◽  
Peter Westervelt ◽  
Ali McBride ◽  
Keith E. Stockerl-Goldstein ◽  
...  
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Induction Therapy ◽  
Kinase Inhibitor ◽  
Pulmonary Hemorrhage ◽  
Salvage Chemotherapy ◽  
Hematological Toxicity ◽  
Grade 3 ◽  
Refractory Aml

Abstract Abstract 3609 Patients with relapsed or refractory AML have poor outcomes after conventional salvage chemotherapy with long-term remissions likely only with allogeneic stem cell transplantation. Hence, there is a need for better treatment options for these patients. Since it is known that multiple pathways are dysregulated in AML, combination therapy that targets multiple pathways may improve remission rates. The combination of salvage chemotherapy (CLAG), a multi-targeted tyrosine kinase inhibitor (midostaurin) and a differentiation inducing agent (ATRA) was investigated in patients with relapsed refractory AML in this study, to assess its tolerability and to identify the maximum tolerated dose (MTD) of midostaurin in the combination. Midostaurin is a multi-targeted kinase inhibitor that has been shown to inhibit FLT-3 (FMS like tyrosine kinase 3) mutations and wild type and other molecular targets thought to be important for the pathogenesis of AML including VEGFR-1, PDGFR, c-kit, H-ras, K-ras and MDR. FLT-3 mutations are seen in about 25–30% of patients with AML and is associated with poor long term survival. FLT-3 is highly expressed even in patients without FLT-3 mutations making FLT-3 a promising target in AML. In vitro studies have suggested that ATRA induces differentiation not only in AML-M3 but also in AML other than AML-M3. In AML cell lines ATRA has been shown to increase sensitivity to cytarabine. Addition of ATRA to induction therapy has shown to produce superior results in AML patients over 60 years of age. Here we conducted this single institutional phase I trial with the combination of midostaurin, ATRA and CLAG in patients with relapsed refractory AML. Patients ≥ 18 years of age with relapsed/refractory AML were included in the study. The treatment regimen consisted of CLAG (cladribine 5 mg/m2 IV days 2–6, cytarabine 2 g/m2 IV days 2–6, GCSF 300 mcg SC days 1–6), ATRA 15 mg/m2 PO days 7–20, midostaurin 25 mg (cohort 1) or 50 mg (cohort 2) PO BID days 7–20. Response was assessed by a bone marrow examination done at day 28–45. A total of 11 patients were enrolled in the study (4 in cohort 1 and 7 in cohort 2) of which 9 (3 in cohort 1 and 6 in cohort 2) were evaluable for the planned end points. The median age was 52 years (range 32–71) and male: female ratio was 45:55. FLT-3 mutation was positive in 6 patients, negative in 1 and unknown in the rest. 4 patients had complex karyotype cytogenetics. 7 patients were in enrolled at first relapse, 2 at second relapse and 2 after refractory disease following the first induction therapy. The ECOG performance score was 0 for all enrolled patients. No dose limiting toxicities was observed in either cohort. Grade 3/4 hematological toxicity was seen in 100% of patients as expected. Grade 3/4 non-hematological toxicity was seen in 2 patients: 1 patient died of pulmonary hemorrhage which was attributed to severe thrombocytopenia and another patient developed grade 4 hyperglycemia. No significant hepatotoxicity occurred in our two dosing cohorts with midostaurin and ATRA likely as echinocandins were used instead of azoles for antifungal therapy. Overall 3/9 (33.3%) evaluable patients achieved complete remission/ complete remission with incomplete count recovery. Five patients died, 4 of progressive disease and one from pulmonary hemorrhage. The levels of midostaurin and ATRA were measured at pretreatment, 1 hour, 4 hours, 8 hours, 12 hours, 7 days, 14 days and 20 days on treatment. The median levels of midostaurin were 2150 ng/ml (range 641–7210) in the 25 mg cohort and 1820 ng/ml (range 850–8930) in the 50 mg cohort. In summary CLAG+ midostaurin+ATRA regimen has an acceptable toxicity profile for relapsed refractory AML and the MTD of midostaurin defined in this trial is 50 mg. Additional phase 2 studies to assess the effectiveness of this regimen in relapsed refractory AML are warranted. Disclosures: Off Label Use: The purpose of the study is to investigate the use of midostaurin and ATRA in relapsed refractory AMl in compbination with chemotehrapy. Westervelt:Novartis: Speakers Bureau. Abboud:novartis: Consultancy, Research Funding, Speakers Bureau.

A Phase 1 Study of Concomitant High Dose Lenalidomide and 5-Azacytidine Induction in the Treatment of Acute Myeloid Leukemia,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3616-3616
Author(s):  
Giridharan Ramsingh ◽  
Peter Westervelt ◽  
Amanda Cashen ◽  
Geoffrey L. Uy ◽  
Keith Stockerl-Goldstein ◽  
...  
Keyword(s):  
Complete Remission ◽  
Progressive Disease ◽  
Phase 1 ◽  
Hematological Toxicity ◽  
High Dose ◽  
Phase 2 ◽  
Elderly Aml ◽  
Grade 3 ◽  
Induction Cycle ◽  
Refractory Aml

Abstract Abstract 3616 Novel therapies for elderly and relapsed AML are needed. We recently published an institutional phase 2 trial using high dose (50mg/day × 28 days) single agent lenalidomide (HDL) followed by maintenance of 10 mg daily for 12 months in responders in elderly untreated AML patients (≥ 60 years) showing a complete remission (CR)/complete remission with incomplete blood count recovery (CRi) of 30% (Fehniger et al, Blood, 2011). Azacitidine (AZA) given IV or SC has also shown significant response in patients with MDS and AML. Recently Pollyea et al (JCO 29: 2011 (suppl; abstr #6505) reported on a phase 1 trial combining AZA and escalating doses of lenalidomide repeated sequentially in 6 week cycles in patients with untreated AML. Here, we report on a phase 1 single institutional study to evaluate the toxicities and feasibility of combining HDL and AZA concurrently as induction followed by a less intensive lenalidomide and AZA maintenance schedule in untreated elderly AML (≥60 years) or relapsed/refractory AML ≥18 years. Treatment schedule: 2 cycles of induction (each 28 days) of lenalidomide 50 mg PO days 1–28 and AZA at 3 dose cohorts 25 mg/m2 (cohort 1), 50 mg/m2 (cohort 2) and 75 mg/m2 (cohort 3) given IV days 1–5. Thereafter patients were given maintenance cycles (every 28 days) with lenalidomide 10 mg PO days 1–28 and AZA 75 mg/m2 days 1–5 for a total of 12 cycles. The median age was 74 (range 63–81); 7 males, 8 females; 6 with newly diagnosed elderly AML and 9 with relapsed or refractory AML. The median WBC count was 2600 (range 300–13100). The median bone marrow blast percentage was 22% (range 2–90%),with normal cytogenetics in 7 (63.6%), monosomy 7 in 3 (20%), trisomy 8 in 1 (6.7%), and other in 4 (26.6%). 8 patients were enrolled in cohort 1, 4 patients in cohort 2 and 3 patients in cohort 3. 2 patients in cohort 1 and 1 patient in cohort 2 who received less than 1 induction cycle (2 withdrew consent and 1 had progressive disease) were replaced. 11 (73.3%) of patients completed 1 induction cycle and 7 (46.7%) of patients completed 2 induction cycles and 5 (30%) patients went on to maintenance therapy. Patients remained on therapy for a median of 2 months (range 0.5–13 months). Dose limiting toxicities (DLT) observed included grade 3 rash in cohort 1 leading to expansion of the cohort to include 3 additional patients. To date grade 3/4 non-DLT hematological toxicity was seen in 6/11 (54.1%) patients. The most common 3/4 non-DLT non-hematological toxicity was neutropenic fever seen in 5/11 (45.4%). The most common grade 1/2 toxicity was fatigue in 7/11 (63.6%). 40% (6/15) of patients died, all due to progressive disease. Of the 11 evaluable patients 7 (63.6%) responded to treatment with CR/CRi in 3 (27.3%) and partial remission (PR) in 4 (36.4%) with the median duration of response of 3 months (range 0.5–11 months). In summary combination of lenalidomide with AZA appears to be a feasible regimen with acceptable toxicities. A phase 2 multicenter extension of this study with untreated elderly AML at the maximum tolerated dose of AZA and HDL will be initiated soon. Disclosures: Off Label Use: Here we discuss the use of lenalidomide and azacytidine in relapsed refractory or elderly AML. Stockerl-Goldstein:Celgene: Speakers Bureau. Vij:Celgene: Consultancy, Research Funding, Speakers Bureau.

A phase I trial of erlotinib (E), cisplatin (C) and radiotherapy (RT) for patients with locally advanced squamous cell cervical cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13081-13081
Author(s):  
C. G. Ferreira ◽  
M. Salgado ◽  
R. Lima ◽  
C. Viegas ◽  
I. A. Small ◽  
...  
Keyword(s):  
Cervical Cancer ◽  
Phase I ◽  
Squamous Cell ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Locally Advanced ◽  
Hematological Toxicity ◽  
Study Cohort ◽  
Duration Of Treatment ◽  
Grade 3

13081 Background: Pre-clinical data indicates that inhibition of epidermal growth factor receptor (EGFR) potentiates the effect of RT. This phase I trial aims to determine the maximal tolerated dose (MTD) of erlotinib, an oral EGFR tyrosine kinase inhibitor, when administered concurrently with standard chemoradiation (CRT) for cervical cancer. Methods: In a modified Fibonacci design, two cohorts of three patients received escalating doses of E (50 mg/100 mg) one week before and combined with C (40 mg/m2, weekly, 5 cycles) and RT (external beam RT - 5040 cGy in 28 fractions, followed by 4 fractions/700 cGy/weekly of brachytherapy). Eligibility criteria included histologically proven squamous cell cervical carcinoma, stage III; no prior therapy; ECOG PS <3 and adequate end-organ functions. Patients were allowed four additional weeks of toxicity observation after CRT + E before proceeding to the next cohort. Frozen tissue for molecular studies was collected before treatment. Results: Considering the first two cohorts, patients presented median age 48 (36–59), stage IIIB (all patients). Median duration of treatment was 71 (70–104) days. Most common non-hematological toxicity were mild to moderate rash, fatigue, diarrhea (grade 3 in one patient), nausea and dysuria. Grade 3 leukopenia was observed in only one patient. Dose limiting toxicities have not been reported so far. Five patients had complete response and one patient had partial response (MRI). Of note, 5/6 patients reported clinical benefit (bleeding cessation) after one week on E alone. The third study cohort (E = 150 mg) is ongoing. Conclusions: This is the first report of a combination of erlotinib, cisplatin and pelvic RT. The addition of E to standard CRT does not appear to increase in-field or systemic toxicities. MTD has not been defined so far. Final results of the phase I will be presented at the meeting. [Table: see text]

scholarly journals A Phase I/II, Open-Label, Multicentre 2-Part Study to Assess the Safety, Tolerability, Pharmacokinetics, and Efficacy of AZD2811 Nanoparticle As Monotherapy or in Combination in Treatment-Naïve or Relapsed/Refractory Acute Myeloid Leukaemia/Myelodysplastic Syndrome Patients Not Eligible for Intensive Induction Therapy

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4064-4064
Author(s):  
William B. Donnellan ◽  
Ehab L. Atallah ◽  
Adam S. Asch ◽  
Manish R Patel ◽  
Julie Charlton ◽  
...  
Keyword(s):  
Phase I ◽  
Continuous Infusion ◽  
Disease Progression ◽  
Induction Therapy ◽  
Dose Escalation ◽  
Adaptive Design ◽  
Kinase Inhibitor ◽  
Treatment Naïve ◽  
Grade 3

Abstract Background: Aurora kinases represent potential targets for anticancer therapy in solid tumors and hematological malignancies. In a phase I/II study, the aurora B kinase inhibitor AZD1152 (barasertib) showed benefit (35% CR/CRi) in patients (pts) with untreated AML when given as a 7-day continuous infusion (Lowenberg B et al, Blood 2011, Kantarjian HG et al., Cancer 2013). AZD2811 nanoparticle is a novel, encapsulated slow-release inhibitor of Aurora kinase B offering several advantages compared with AZD1152, including prolonged drug release in vivo. AZD2811 nanoparticle mimics the AZD1152 7-day continuous infusion when given as a 2-hr infusion on Day 1 and 4, and resulted in increased efficacy and decreased toxicity in vivo. We report the first-in-man dose-escalation of AZD2811 nanoparticle in pts with relapsed AML/MDS or treatment-naïve patients not eligible for intensive induction therapy. The objectives were to determine the safety profile, MTD, PK, dosing schedule and preliminary efficacy of AZD2811 nanoparticle. Methods: Patients received a single 2-hour IV infusion on Day 1 and 4 of each 28-day cycle. Based on the previous experience with AZD1152 in the same patient population, the expected MTD is in a range of 1,200 mg per cycle. In the ongoing dose escalation, cohorts of 3-6 patients have been sequentially enrolled in 4 cohorts ranging from 100 mg to 600 mg per infusion on Day 1 and 4 every 28 days, i.e. from 200 mg to 1,200 mg per cycle. Patients were allowed to continue to receive AZD2811 until disease progression, tolerability, or discontinuation criteria have been met. The study uses a Bayesian adaptive design approach to dose escalation to improve the efficiency and precision of the MTD estimation compared to a traditional 3+3 design. Results: Currently, 10 pts with age ranges from 56 to 86 years have completed DLT assessment period for the first 3 cohorts. 9 patients had relapsed/refractory secondary AML/MDS after failure of hypomethylating agents and 1 patient had a relapsed, therapy-related AML. Cohort 4 (600 mg per infusion D1 and D4) is currently under evaluation. Of the 10 pts in cohorts 1-3, 7 pts discontinued due to disease progression, 1 discontinued due to subject decision/consent withdrawal, 1 discontinued due to physician decision, and 1 pt is active and ongoing. AEs assessed as related to AZD2811 that occurred in one or more patients were Grade 3/4 neutropenia/thrombocytopenia, Grade 3 anemia and Grade 1 fatigue, rash and stomatitis. Thus far, no DLTs and no fatal AEs related to AZD2811 have been observed. 2 deaths have been reported, 1 due to the underlying disease and 1 due to a Serious Adverse Event of Gr 5 Sepsis (not related to study drug). AZD2811 total blood PK appears dose proportional with a t1/2 of 30-50 hours. Conclusion: AZD2811 nanoparticle is safe and well tolerated at a dose up to 400 mg on Day 1 and 4 every 28-days. The monotherapy dose escalation is ongoing and updated results including preliminary efficacy data and supporting preclinical data will be presented. Additional dose finding and expansion cohorts of AZD2811 nanoparticle in combination with azacytidine and venetoclax are planned. Disclosures Atallah: Novartis: Consultancy; Abbvie: Consultancy; BMS: Consultancy; Jazz: Consultancy; Pfizer: Consultancy. Charlton:AstraZeneca: Employment. MacDonald:AstraZeneca: Employment. Young:AstraZeneca: Employment. Sainsbury:AstraZeneca: Employment. Overend:AstraZeneca: Employment. Adelman:AstraZeneca: Employment. Travers:AstraZeneca: Employment. Smith:AstraZeneca: Employment. Pease:AstraZeneca: Employment. Brugger:AstraZeneca: Employment.

scholarly journals Efficacy of Long-Term Decitabine Treatment Combined with Sequential Priming Regimen for Acute Myelocytic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5287-5287
Author(s):  
Miao Miao ◽  
Wu Depei ◽  
Aining Sun ◽  
Ting Xu ◽  
Song Jin ◽  
...  
Keyword(s):  
Side Effects ◽  
Complete Remission ◽  
Induction Therapy ◽  
Chromosomal Abnormality ◽  
Gene Mutations ◽  
Half Cycle ◽  
First Time ◽  
Refractory Aml ◽  
Sequential Priming

Abstract Introduction The Sequential priming regimen has been used for newly diagnosed and relapsed/refractory patients with acute myeloid leukemia unfit for intensive chemotherapy. Unfortunately, the rate of CR is not hopeful. Hypomethylating agent, decitabine is active in eldly patients with AML. Long-term decitabine combined with sequential priming regimen treats these patients, its efficacy and side effects and optimal dose are unknown. Methods A total of 14 inpatients with AML during the period from February 2013 through May 2014 were enrolled in this study, including 8 men and 6 women. The subjects had a median age of 56 years (range, 25–71 years), with 10 cases at ages of over 50 years. Of all participants, transformation of myelodysplastic syndromes (MDS) into AML occurred in 6 cases; 8 cases received treatment for the first time, 5 cases had refractory AML, and 1 case had relapsed AML. Normal chromosome was detected in 9 cases, and chromosomal abnormality +8, t(1;9), -y,t(8;21), t(8;21),mar and complex chromosomal abnormality occurred in one case each; 6 cases (42.9%) had gene mutations, including NPM1/DNMT3, CEBPA, FLT3-ITD/NPM1/DNMT3, FLT3-ITD/NPM1, DEK/CAN and U2AF1, of one case for each mutation. There were 12 cases with concomitant diseases. There were 5 cases with an Eastern Cooperative Oncology Group (ECOG) score of 4 and 7 cases with an ECOG score of 3. The chemotherapy regimen was decitabine at a dose of 20 mg/m2 on days 1 to 6 or 8, and the IAG priming regimen was used in 5 cases, CAG regimen in 5 cases, and HAG regimen in one case. There were 5 cases undergoing a half cycle of the induction therapy (7 days) and 9 cases undergoing a whole cycle of the induction therapy (14 days). A cycle of therapy achieved complete response in 12 cases (85.7%) and no response in 2 cases, including one recurrent case with FLT3-ITD mutation following autologous stem cell transplantation and a refractory case with DEK/CAN mutation. Results A half cycle ofinduction therapy resulted in completed remission in 4 out of 5 cases, and the whole cycle of therapy resulted in 8 out of 9 cases. All 8 cases receiving therapy for the first time achieved complete remission, and 3 out of 5 refractory cases achieved complete remission. The median time for nonerythroid cell (NEC) count of < 0.5 × 105/L and platelet blood cell (PBC) count of < 20 × 109/L was 12 (range, 0–37) and 18 (range, 0–37) days, respectively. During the half cycle of induction therapy, the median time for NEC count of < 0.5 × 105/L and platelet blood cell (PBC) count of < 20 × 109/L was 17 (range, 6–37) and 18 (range, 7–38) days, respectively, whereas being 11 (range, 0–30) and 12 (range, 0–28) days during the whole cycle of induction therapy, respectively. There were 6 cases with side effects, including 4 cases achieving complete remission. Post-chemotherapy complications included infections, bleeding, and liver function impairment. Of the 10 cases complicated with infections at the first diagnosis, 2 cases developed aggravated pulmonary infection and 4 cases developed new infections at the stage of bone marrow suppression, including one case with infection at the perianal region, one case with infection at pharynx, one case with influenza A, and one case with skin infection. No therapy-induced death was observed. Conclusions Long-term decitabine treatment in combination with sequential priming regimen is effective for the AML patients undergoing treatment for the first time and recurrent and refractory AML, which is comparable to the standard "7 + 3" remission-induction therapy. In addition, it may improve the prognosis of AML patients with chromosomal abnormality and gene mutations, particularly for patients with DNMT3 and FLT3-ITD mutations. Further multi-center, prospective clinical trials are required to evaluate the efficacy of the new regimen for AML and optimize the treatment regimen. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy and Safety of Blinatumomab for Relapsed or Refractory Pediatric ALL Patients: A Systematic Review

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 22-23
Author(s):  
Anam Khan ◽  
Atif Irfan Khan ◽  
Sana Irfan Khan ◽  
Sobia Aamir ◽  
Usman Ali Akbar ◽  
...  
Keyword(s):  
Systematic Review ◽  
Overall Survival ◽  
Clinical Trials ◽  
T Cells ◽  
Complete Remission ◽  
Adverse Outcomes ◽  
Term Survival ◽  
Paediatric Patients ◽  
Grade 3

Background Most children with Acute Lymphoblastic Leukaemia achieve complete remission and subsequent cure after chemotherapy. But, ALL relapse is the leading cause of treatment failure in paediatric patients, causing long term survival to below. Chemotherapy along with targeted therapies have been explored in relapsed/refractory ALL (R/R ALL) patients. One such targeted therapy is Blinatumomab (Blin), a bi-specific T-cell engagers (BiTEs) antibody, it binds to CD3 receptors on T-cells and CD19 receptors on B-cells thereby re-directing T-cells to exert their cytotoxic effect on malignant as well as non-malignant B-cells. Blin was approved by FDA in March 2018 for the treatment of B-cell precursor ALL in first or second complete remission with minimal residual disease (MRD) ≥0.1%. This approval was based on BLAST trial conducted on ≥18-year-old ALL patients. The drug has been studied in children (1-18 years) with five clinical trials exclusively in children of which two have reported their results and three are ongoing. In this systematic review, we evaluated the safety and efficacy of Blin as a monotherapy in paediatric R/R ALL patients. Material/Methods We performed a search on PubMed, Embase, Clinical Trials, Web of Science and Cochrane. We used Mesh Terms "ALL" and "Blinatumomab" without any filters. After screening of 1199 articles, 5 clinical trial, 3 retrospective studies and 1 case series were included. These studies included only paediatric patients (&lt;18yrs) evaluating the role of Blin as monotherapy in R/R ALL. We followed the PRISMA guidelines for literature search and selection of studies RESULTS: A total number of patients who received Blin was 320, all were &lt;18 years. The preceding treatment regimens included multi-agent chemotherapy with or without hematopoietic stem cell transplant (HSCT). Five studies included only those patients with more than ≥5% bone marrow blasts. Though many combination monoclonal antibody therapies are available, we included only patients given Blin as monotherapy. Blin therapy was a 4 weeks continuous infusion at a dosage of 5 or 15μg/m2/day followed by 2 weeks of treatment-free interval as one cycle, in the studies, the number of treatment cycles ranged from 1-18. A median follow up in the studies ranged from 6 months to 5 years. Overall, complete response (CR) was found to be 58% (n=184) ranging between 31% to 100%. Following CR with Blin relapse rate was 40% (n=66). The overall median survival ranged from 4.3 to 22 months amongst 5 of the nine studies, while it was reported to be 80% (n=9) survival at the end of 12 months by Elitzur et al and 33.3% (n=3) at the end of two cycles of blin by Schlegel, P et al, the remaining two studies did not mention the duration of overall survival. The cumulative hematologic adverse outcomes of ≥grade 3 amongst the studies reported were neutropenia 22% (n=70), Anemia 27.7%(n=55), thrombocytopenia as reported in four studies was 21.5% (n=30). Fuster J et al. reported a cumulative non-hematologic adverse outcome of 40%(n=6) while other studies reported ≥ grade 3 non-hematologic adverse outcomes with increased liver enzymes, neurologic problems and fever to be most common. Cumulative cytokine release syndrome was reported as 4.7% (n=14) in 6 out of 9 studies. Elitzur et al. reported no non-hematologic adverse effect. We found total cumulative death reported as 17% of cases (n=34). Conclusion Blinatumomab use for R/R ALL paediatric patients treatment showed promising outcomes with more than half of the patients achieving CR. Overall survival has been good with median patient surviving disease-free between 4 to 22 months at large. Though, low mortality indicated long term survival, a high relapse rate points that Blin with combination therapy may show better outcomes. Fifteen ongoing clinical trials are testing Blin currently, three of which are on paediatric R/R ALL group. One trial is testing a combination of Blin and pembrolizumab. The results of these trials will further provide information on its effectiveness in combination therapy. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.:Honoraria, Research Funding, Speakers Bureau.

scholarly journals Efficacy of combination-chemotherapy with pirarubicin, ifosfamide, and etoposide for soft tissue sarcoma: a single-institution retrospective analysis

BMC Cancer ◽  
2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Shiro Saito ◽  
Hisaki Aiba ◽  
Satoshi Yamada ◽  
Hideki Okamoto ◽  
Katsuhiro Hayashi ◽  
...  
Keyword(s):  
Soft Tissue ◽  
Soft Tissue Sarcoma ◽  
Adverse Events ◽  
Combination Chemotherapy ◽  
Progressive Disease ◽  
Treatment Phase ◽  
Hematological Toxicity ◽  
Single Institution ◽  
Grade 3

Abstract Background The standard chemotherapy regimens for soft tissue sarcoma are doxorubicin-based. This retrospective study aimed to assess the efficacy and safety of pirarubicin, ifosfamide, and etoposide combination therapy for patients with this disease. Methods Between 2008 and 2017, 25 patients with soft tissue sarcoma were treated with pirarubicin (30 mg/m2, 2 days), ifosfamide (2 g/m2, 5 days), and etoposide (100 mg/m2, 3 days) every 3 weeks. The primary endpoint was overall response, and the secondary endpoint was adverse events of this regimen. Results Responses to this regimen according to RECIST criteria were partial response (n = 9, 36%), stable disease (n = 9, 36%) and progressive disease (n = 7, 28%). During the treatment phase, frequent grade 3 or worse adverse events were hematological toxicities including white blood cell decreases (96%), febrile neutropenia (68%), anemia (68%), and platelet count decreases (48%). No long-term adverse events were reported during the study period. Conclusion This regimen was comparable to previously published doxorubicin-based combination chemotherapy in terms of response rate. Although there were no long-lasting adverse events, based on our results, severe hematological toxicity should be considered.

scholarly journals Beneficial Treatment Management with Trifluridine/Tipiracil in a Patient with Metastatic Colorectal Cancer and Pronounced Hematological Event History during Previous Treatments

2018 ◽  
Vol 11 (1) ◽  
pp. 43-48 ◽  
Author(s):  
Volker Kaechele ◽  
Jürgen Hess ◽  
Wolfgang Schneider-Kappus
Keyword(s):  
Colorectal Cancer ◽  
Metastatic Colorectal Cancer ◽  
Dose Reduction ◽  
Performance Status ◽  
Recommended Dose ◽  
Hematological Toxicity ◽  
Ecog Performance Status ◽  
History Of ◽  
Grade 3

Trifluridine/tipiracil (FTD/TPI) significantly improves overall survival in patients with metastatic colorectal cancer (mCRC). The most common treatment-related event (grade ≥3) was hematological toxicity. We here report long-term disease-stabilizing FTD/TPI treatment of an mCRC patient (KRAS wild-type, ECOG performance status 1 at baseline and at the end of FTD/TPI therapy) with multifocal synchronous metastases and a longstanding history of extensive hematological events during previous treatments. Finally, this 62-year-old male patient was treated for 10 months with FTD/TPI by consecutive alteration of treatment parameters: (i) initial daily dose reduction to 80 mg (72% of the recommended dose), (ii) 20 days dose delay, (iii) a second and later third dose reduction to 70 mg and 60 mg (about 64% and 55%, respectively, of the recommended dose), and (iv) 30 µg per day of granulocyte colony-stimulating factor administration first for 3 days, and later for 5 days, for each treatment cycle.

Long-term follow-up with ABDIC salvage chemotherapy of MOPP-resistant Hodgkin's disease.

1983 ◽  
Vol 1 (7) ◽  
pp. 432-439 ◽  
Author(s):  
N Tannir ◽  
F Hagemeister ◽  
W Velasquez ◽  
F Cabanillas
Keyword(s):  
Complete Remission ◽  
Median Survival ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Survival Curve ◽  
Salvage Chemotherapy ◽  
Significant Prognostic Factor ◽  
Long Term Follow Up

Thirty-six consecutive patients with advanced recurrent Hodgkin's disease resistant to chemotherapy with mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) were treated with doxorubicin (Adriamycin), bleomycin, (dacarbazine) DTIC, (lomustine) CCNU, and prednisone (ABDIC). Among the 34 patients evaluable for response, complete remission occurred in 35% and partial remission in 35%. The achievement of complete remission during primary MOPP induction was a statistically significant prognostic factor that predicted complete remission with ABDIC (p less than 0.01). The median time to complete remission was 2 months (range 1-11 mo). The median relapse-free survival time for complete responders is 47 months, and an estimated 53% of all patients who achieve complete remission are projected to be alive, free of disease off therapy at 3 years from initiation of ABDIC. The median survival of all patients is 24 months. The median survival of complete responders, partial responders, and nonresponders is 70, 17, and 4 months, respectively. The survival curve for complete responders is significantly different from that for partial responders (p less than 0.01); the survival curve for partial responders is also significantly different from that of nonresponders (p less than 0.01). Toxicity of ABDIC was acceptable; only one patient died from complications of myelosuppression. Our results indicate that ABDIC is a potentially curative regimen for a fraction of patients with MOPP-resistant Hodgkin's disease who achieve complete remission with prior MOPP therapy. It also prolongs the survival of patients who do not achieve complete remission with prior MOPP therapy.

scholarly journals Preclinical and phase I clinical studies of KW-2450, a dual IGF-1R/IR tyrosine kinase inhibitor, in combination with lapatinib and letrozole

2018 ◽  
Vol 10 ◽  
pp. 175883591878685 ◽  
Author(s):  
Hiroshi Umehara ◽  
Yoshimi Maekawa ◽  
Fumito Koizumi ◽  
Makiko Shimizu ◽  
Toshio Ota ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Drug Combination ◽  
Phase I Trial ◽  
Kinase Inhibitor ◽  
Her2 Positive ◽  
Grade 3 ◽  
Mcf 7

Background: KW-2450 is an oral dual insulin-like growth factor-1 receptor/insulin receptor tyrosine kinase inhibitor. We investigated the in vitro and in vivo preclinical activity of KW-2450 plus lapatinib and letrozole and conducted a phase I trial of the triple-drug combination in one male and 10 postmenopausal female patients with advanced/metastatic hormone receptor-positive, human epidermal growth factor receptor 2 (HER2)-positive breast cancer. Methods: A series of in vitro and in vivo animal studies was undertaken of KW-2450 in combination with lapatinib and hormonal agents. The phase I trial was conducted to establish the safety, tolerability, and recommended phase II dose (RP2D) of KW-2450 administered in combination with lapatinib and letrozole. Results: Preclinical studies showed KW-2450 and lapatinib act synergistically to induce in vitro apoptosis and inhibit growth of HER2-positive MDA-MB-361 and BT-474 breast cancer cell lines. This combined effect was confirmed in vivo using the MDA-MB-361 xenograft model. KW-2450 showed synergistic in vitro growth inhibition with letrozole and 4-hydroxytamoxifen in ER-positive MCF-7 breast cancer cells and MCF-7-Ac1 aromatase-transfected MCF-7 cells. In the phase I study, dose-limiting toxicity (DLT; grade 3 rash and grade 3 hyperglycemia, respectively) occurred in two of three patients at the dose of KW-2450 25 mg/day plus lapatinib 1500 mg/day and letrozole 2.5 mg/day. The RP2D of the triple-drug combination was established as KW-2450 25 mg/day, lapatinib 1250 mg/day, and letrozole 2.5 mg/day with no DLT at this dose level. Conclusions: The proposed phase II study of the RP2D for the triple-drug combination did not progress because of anticipated difficulty in patient enrollment and further clinical development of KW-2450 was terminated.

Phase I/II Study of Clofarabine Combined with Standard Dose Cytarabine as Remission Induction Therapy of De Novo AML in Elderly Patients ≥60 Years.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4635-4635
Author(s):  
James M. Foran ◽  
Angeline S. The ◽  
Marcel Devetten ◽  
Sreelatha Meleth ◽  
Jeff Worrell ◽  
...  
Keyword(s):  
Complete Remission ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
De Novo ◽  
Standard Dose ◽  
Level I ◽  
De Novo Aml ◽  
To Receive ◽  
Dose Limiting Toxicity

Abstract Despite significant advances in the treatment of acute myeloid leukemia (AML) in younger adults, there has been little progress in the treatment of older patients (age≥60 years), who comprise the majority of those with the disease. Clofarabine is a purine nucleoside analog with single agent activity in patients with relapsed AML. In addition, clofarabine potentiates Ara-C cytotoxicity in vitro through increased intracellular Ara-CTP accumulation, making this an attractive combination. A phase I/II study has therefore been initiated combining clofarabine with standard dose cytarabine (100mg/m2/day x 7) in pts age ≥60 years with de novo AML. The starting dose of clofarabine was 30mg/m2/day x 5 beginning on day 2 (Dose level I). Patients were accrued in cohorts of 3–6 to establish dose limiting toxicity (DLT); cohort expansion at the maximum tolerated dose (MTD) is planned in phase II using a Simon 2-stage design. Detailed plasma and intracellular pharmacokinetics were performed during induction therapy with Ara-C alone (day 1), and following the addition of clofarabine (day 2) to determine the effect of clofarabine on intracellular Ara-CTP accumulation. Pts with residual AML on d14–21 restaging bone marrow (BM) biopsy were eligible to receive Re-Induction with 5 days of clofarabine & Ara-C. Those achieving complete remission were also eligible to receive 1–2 cycles of consolidation with Ara-C (d1–5) & clofarabine (total 3 cycles of planned therapy). Dose limiting toxicity was encountered at dose level I (see Table 1). 2/4 pts achieved CR, in 1 case with residual cytogenetic abnormality, and there were 2 treatment-related deaths from infxn (culture neg sepsis, n=1; Candida tropicalis, n=1). In the latter case (pt 4), BM aplasia was achieved, but the pt died on d25 prior to hematologic recovery. In view of the DLT, the protocol has therefore been amended to allow 25% dose de-escalation of clofarabine to Dose Level -I (22.5mg/m2/day x 5), and to limit eligibilty to pts age 60–75 yrs inclusive. Routine use of aggressive pre-hydration and antibiotic and antifungal prophylaxis is now mandated. Clofarabine & cytarabine is a highly active induction regimen in older adults age ≥60 yrs with de novo AML, but has significant myelosuppressive and infectious toxicity. The study is proceeding in phase I at Dose Level -I to establish the MTD. Phase I, Dose Level I PT AGE, GENDER FAB CYTOGENETICS F/U BM TOXICITY (Gr.III/IV) OUTCOME MLD - multilineage dysplasia; F&N - fever & neutropenia; CR - complete remission 1 66M M2 Diploid D21: residual AML renal, infxn Death 2 61M M2 Complex D14: aplastic F&N CR 3 69M M2 with MLD Intermediate Risk D21: recovering F&N CR 4 77F M2 Diploid D14: aplastic renal, infxn, capillary leak Death

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