Intravenous Topotecan Research Articles

Tazemetostat in combination with topotecan and pembrolizumab in patients with recurrent small cell lung cancer.

TPS8130 Background: Small-cell lung cancer (SCLC) is the most fatal type of lung cancer characterized by exquisite chemo-sensitivity at diagnosis and chemoresistance at relapse. Despite a highly mutated genome, patients with SCLC derive little benefit from immunotherapy. EZH2 (enhancer of zeste homolog 2) is a master epigenetic regulator of SCLC neuroendocrine cell fate and plasticity. EZH2 inhibition 1) promotes upregulation of Schlafen 11 (SLFN11) which irreversibly blocks replication in response to DNA damaging agents and 2) enhances intrinsic immune signaling, leading to constitutive MHC I recovery, sensitizing resistant SCLC models to DNA damaging chemotherapy and immunotherapy. Tazemetostat is a selective oral EZH2 inhibitor. Methods: This is an investigator-initiated, NCI Cancer Therapy Evaluation Program (CTEP) sponsored, phase I dose escalation and dose expansion study which will evaluate safety and tolerability of combination of tazemetostat with topotecan, a selective TOP1 inhibitor, and programmed cell death protein 1 (PD-1) inhibitor antibody pembrolizumab. Adult patients with relapsed/recurrent SCLC after at least platinum doublet (limited stage-SCLC) or chemo-immunotherapy (extensive stage-SCLC) and ECOG performance 0-1 are eligible. The regimen design involves a 7-day “run-in” of oral tazemetostat BID followed by 21-day cycles of tazemetostat (1-21 days), intravenous (IV) topotecan (day 1-5) and IV pembrolizumab (Day 1). The dose escalation cohort aims to determine safety and optimal doses of tazemetostat and topotecan (with standard dose of pembrolizumab) using a 3+3 design by assessing for dose limiting toxicities. The dose expansion cohort aims to assess safety, tolerability and preliminary efficacy of the combination in 15 additional patients with relapsed SCLC. The study involves collection of mandatory biopsies at pre-treatment and post-treatment (cycle 1) to gain insights into mechanism of action and resistance of the combination using single cell and spatial transcriptomic approaches. For more questions regarding enrollment and eligibility please contact Rasa.vilimas@nih.gov or anish.thomas@nih.gov . Clinical trial information: NCT05353439 .

Combination lurbinectedin and doxorubicin versus physician's choice of chemotherapy in patients with relapsed small-cell lung cancer (ATLANTIS): a multicentre, randomised, open-label, phase 3 trial

Lurbinectedin is a synthetic marine-derived anticancer agent that acts as a selective inhibitor of oncogenic transcription. Lurbinectedin monotherapy (3·2 mg/m2 every 3 weeks) received accelerated approval from the US Food and Drug Administration on the basis of efficacy in patients with small-cell lung cancer (SCLC) who relapsed after first-line platinum-based chemotherapy. The ATLANTIS trial assessed the efficacy and safety of combination lurbinectedin and the anthracycline doxorubicin as second-line treatment for SCLC. In this phase 3, open-label, randomised study, adult patients aged 18 years or older with SCLC who relapsed after platinum-based chemotherapy were recruited from 135 hospitals across North America, South America, Europe, and the Middle East. Patients were randomly assigned (1:1) centrally by dynamic allocation to intravenous lurbinectedin 2·0 mg/m2 plus doxorubicin 40·0 mg/m2 administered on day 1 of 21-day cycles or physician's choice of control therapy (intravenous topotecan 1·5 mg/m2 on days 1-5 of 21-day cycles; or intravenous cyclophosphamide 1000 mg/m2, doxorubicin 45·0 mg/m2, and vincristine 2·0 mg on day 1 of 21-day cycles [CAV]) administered until disease progression or unacceptable toxicity. Primary granulocyte-colony stimulating factor prophylaxis was mandatory in both treatment groups. Neither patients nor clinicians were masked to treatment allocation, but the independent review committee, which assessed outcomes, was masked to patients' treatment allocation. The primary endpoint was overall survival in the intention-to-treat population. This trial is registered with ClinicalTrials.gov, NCT02566993, and with EudraCT, 2015-001641-89, and is complete. Between Aug 30, 2016, and Aug 20, 2018, 613 patients were randomly assigned to lurbinectedin plus doxorubicin (n=307) or control (topotecan, n=127; CAV, n=179) and comprised the intention-to-treat population; safety endpoints were assessed in patients who had received any partial or complete study treatment infusions (lurbinectedin plus doxorubicin, n=303; control, n=289). After a median follow-up of 24·1 months (95% CI 21·7-26·3), 303 patients in the lurbinectedin plus doxorubicin group and 289 patients in the control group had discontinued study treatment; progressive disease was the most common reason for discontinuation (213 [70%] patients in the lurbinectedin plus doxorubicin group vs 152 [53%] in the control group). Median overall survival was 8·6 months (95% CI 7·1-9·4) in the lurbinectedin plus doxorubicin group versus 7·6 months (6·6-8·2) in the control group (stratified log-rank p=0·90; hazard ratio 0·97 [95% CI 0·82-1·15], p=0·70). 12 patients died because of treatment-related adverse events: two (<1%) of 303 in the lurbinectedin plus doxorubicin group and ten (3%) of 289 in the control group. 296 (98%) of 303 patients in the lurbinectedin plus doxorubicin group had treatment-emergent adverse events compared with 284 (98%) of 289 patients in the control group; treatment-related adverse events occurred in 268 (88%) patients in the lurbinectedin plus doxorubicin group and 266 (92%) patients in the control group. Grade 3 or worse haematological adverse events were less frequent in the lurbinectedin plus doxorubicin group than the control group (anaemia, 57 [19%] of 302 patients in the lurbinectedin plus doxorubicin group vs 110 [38%] of 288 in the control group; neutropenia, 112 [37%] vs 200 [69%]; thrombocytopenia, 42 [14%] vs 90 [31%]). The frequency of treatment-related adverse events leading to treatment discontinuation was lower in the lurbinectedin plus doxorubicin group than in the control group (26 [9%] of 303 patients in the lurbinectedin plus doxorubicin group vs 47 [16%] of 289 in the control group). Combination therapy with lurbinectedin plus doxorubicin did not improve overall survival versus control in patients with relapsed SCLC. However, lurbinectedin plus doxorubicin showed a favourable haematological safety profile compared with control. PharmaMar.

Trametinib versus standard of care in patients with recurrent low-grade serous ovarian cancer (GOG 281/LOGS): an international, randomised, open-label, multicentre, phase 2/3 trial

SummaryBackgroundLow-grade serous carcinoma of the ovary or peritoneum is characterised by MAPK pathway aberrations and its reduced sensitivity to chemotherapy relative to high-grade serous carcinoma. We compared the MEK inhibitor trametinib to physician's choice standard of care in patients with recurrent low-grade serous carcinoma.MethodsThis international, randomised, open-label, multicentre, phase 2/3 trial was done at 84 hospitals in the USA and UK. Eligible patients were aged 18 years or older with recurrent low-grade serous carcinoma and measurable disease, as defined by Response Evaluation Criteria In Solid Tumors version 1.1, had received at least one platinum-based regimen, but not all five standard-of-care drugs, and had received an unlimited number of previous regimens. Patients with serous borderline tumours or tumours containing low-grade serous and high-grade serous carcinoma were excluded. Eligible patients were randomly assigned (1:1) to receive either oral trametinib 2 mg once daily (trametinib group) or one of five standard-of-care treatment options (standard-of-care group): intravenous paclitaxel 80 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; intravenous pegylated liposomal doxorubicin 40–50 mg/m2 by body surface area once every 4 weeks; intravenous topotecan 4 mg/m2 by body surface area on days 1, 8, and 15 of every 28-day cycle; oral letrozole 2·5 mg once daily; or oral tamoxifen 20 mg twice daily. Randomisation was stratified by geographical region (USA or UK), number of previous regimens (1, 2, or ≥3), performance status (0 or 1), and planned standard-of-care regimen. The primary endpoint was investigator-assessed progression-free survival while receiving randomised therapy, as assessed by imaging at baseline, once every 8 weeks for 15 months, and then once every 3 months thereafter, in the intention-to-treat population. Safety was assessed in patients who received at least one dose of study therapy. This trial is registered with ClinicalTrials.gov, NCT02101788, and is active but not recruiting.FindingsBetween Feb 27, 2014, and April 10, 2018, 260 patients were enrolled and randomly assigned to the trametinib group (n=130) or the standard-of-care group (n=130). At the primary analysis, there were 217 progression-free survival events (101 [78%] in the trametinib group and 116 [89%] in the standard-of-care group). Median progression-free survival in the trametinib group was 13·0 months (95% CI 9·9–15·0) compared with 7·2 months (5·6–9·9) in the standard-of-care group (hazard ratio 0·48 [95% CI 0·36–0·64]; p<0·0001). The most frequent grade 3 or 4 adverse events in the trametinib group were skin rash (17 [13%] of 128), anaemia (16 [13%]), hypertension (15 [12%]), diarrhoea (13 [10%]), nausea (12 [9%]), and fatigue (ten [8%]). The most frequent grade 3 or 4 adverse events in the standard-of-care group were abdominal pain (22 [17%]), nausea (14 [11%]), anaemia (12 [10%]), and vomiting (ten [8%]). There were no treatment-related deaths.InterpretationTrametinib represents a new standard-of-care option for patients with recurrent low-grade serous carcinoma.FundingNRG Oncology, Cancer Research UK, Target Ovarian Cancer, and Novartis.

Topotecan plus Platinum-Based Chemotherapy versus Etoposide plus Platinum-Based Chemotherapy for Small-Cell Lung Cancer: A Systematic Review and Meta-Analysis of Randomized Controlled Trials

Background: Whether topotecan plus platinum-based chemotherapy (TP) can achieve better results than etoposide plus platinum-based chemotherapy (EP) for small-cell lung cancer (SCLC) treatment is still controversial in clinical applications. We compared the effectiveness and toxicity of TP versus EP in this meta-analysis. Methods: We searched PubMed, ScienceDirect, Cochrane Library, Scopus, Ovid MEDLINE, Embase, Web of Science, and Google Scholar databases for completeness one by one to find articles that met the conditions. Overall survival (OS) and progression-free survival (PFS) were analyzed as primary endpoints, and the objective response rate (ORR), disease control rate (DCR), and adverse events (AEs) were analyzed as secondary endpoints. Results: In total, 2,480 articles were retrieved, and 6 randomized controlled trials (RCTs) contained results based on 1,924 patients. EP suggested conspicuously better OS (hazard ratio [HR]: 1.24 [1.02, 1.50], p = 0.03) and PFS (HR: 1.39 [1.17, 1.64], p = 0.0001) in SCLC treatment than TP, and ORR (54.1% vs. 60.2%, risk ratio [RR]: 0.77 [0.57, 1.06], p = 0.11), and DCR (74.9% vs. 84.4%, RR: 0.89 [0.79, 1.00], p = 0.06) tended to favor EP. Subgroup analysis of subsistence showed that EP had prominent benefit in the following subgroups: Asian, median age > 60, first-line treatment, ECOG 0–2, intravenous topotecan, and cisplatin. AEs illustrated that EP had conspicuously more anemia and alopecia than TP. Conclusions: Compared with TP, EP was noticeably better in OS and PFS, but EP was toxic in terms of anemia and alopecia. More multicenter, better planned RCTs are needed.

Selinexor in combination with topotecan in patients with advanced or metastatic solid tumors: Results of an open-label, single-center, multi\u2010arm phase Ib study

SummaryBackground Selinexor, a first-in-class, oral selective inhibitor of nuclear export (SINE) compound inhibits Exportin-1(XPO1), had demonstrated synergistic activity with many chemotherapies and conferred in vivo antitumor efficacy in hematologic as well as solid tumors. Methods This open-label, single-center, multi-arm phase 1b study used a standard 3 + 3 design and a “basket type” expansion. Selinexor with intravenous topotecan was given in one of the 13 parallel arms. Patients with advanced or metastatic relapsed/refractory solid tumors following prior systemic therapy, or in whom the addition of selinexor to standard chemotherapy deemed appropriate, were eligible. Results Fourteen patients with the median age of 61 years (range, 22–68years) were treated, and the most common cancer types were gynecological cancers; ovarian (n = 5), endometrial (n = 2), and 1 each with fallopian tube and vaginal cancers. Of the 14 patients treated, 12 (86 %) had at least one treatment-related adverse event (TRAE). The most common TRAEs were anemia (71 %), thrombocytopenia (57 %), hyponatremia (57 %), vomiting (57 %), fatigue (50 %), nausea (50 %), and neutropenia (36 %). Two patients had dose limiting toxicities. One patient dosed at selinexor 80 mg had grade 3 nausea and vomiting and one patient dosed at selinexor 60 mg experienced grade 4 neutropenia and thrombocytopenia. Of the 13 efficacy evaluable patients, one (8 %) with endometrial cancer achieved unconfirmed partial response (uPR) and the time-to-treatment failure (TTF) was 48 weeks, whereas 6 of the 13 (46 %) patients had stable disease (SD) contributing to the clinical benefit rate of 46 %. The median TTF for all patients was 9 weeks (range, 2–48weeks). Conclusions Once weekly selinexor in combination with topotecan was viable and showed some preliminary tumor efficacy. The recommend phase 2 dose of selinexor was 60 mg once weekly in combination with IV topotecan.Trial registration: NCT02419495. Registered 14 April 2015, https://clinicaltrials.gov/ct2/show/NCT02419495

RESILIENT part II: an open-label, randomized, phase III study of liposomal irinotecan injection in patients with small-cell lung cancer who have progressed with platinum-based first-line therapy.

TPS9081 Background: Although small cell lung cancer (SCLC) is often sensitive to established first-line therapies, many patients relapse and develop drug resistance, and second-line therapies are limited. RESILIENT (NCT03088813) is a two-part phase 2/3 study assessing the safety, tolerability, and efficacy of liposomal irinotecan monotherapy in patients with SCLC who progressed with platinum-based first-line therapy. Preliminary data from the dose-ranging part of the study (part 1) showed that liposomal irinotecan 70 mg/m2 administered every 2 weeks was well tolerated and had promising antitumor activity (Paz-Ares et al. ASCO 2019; poster 318). Here, we present the design of the second, larger part of the study, which will evaluate the efficacy and safety of liposomal irinotecan versus topotecan in the same patient population. Methods: Part 2 of RESILIENT is a phase 3, open-label study with a planned sample size of 450. Patients are randomly allocated 1:1 to intravenous liposomal irinotecan or intravenous topotecan. Liposomal irinotecan is administered every 2 weeks at 70 mg/m2 (free-base equivalent) and topotecan is administered for 5 consecutive days every 3 weeks at 1.5 mg/m2. As of January 2020, 80 patients have been enrolled in part 2 of the trial. Tumor assessments are performed using the Response Evaluation Criteria in Solid Tumors version 1.1 and the Response Assessment in Neuro-oncology criteria for CNS lesions; symptom improvement is measured using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30. Safety assessments include monitoring for adverse events. The primary endpoint is overall survival (OS) and secondary endpoints are progression-free survival (PFS), objective response rate, and proportion of patients reporting symptom improvement. Patients will continue study treatment until disease progression, unacceptable toxicity or study withdrawal and will then be followed for survival until death or study end (when all patients have died, withdrawn consent or are lost to follow-up). Clinical trial information: NCT03088813.

PCN137 COST COMPARISON OF ADVERSE EVENTS AND TREATMENT ADMINISTRATION OF LURBINECTEDIN VERSUS INTRAVENOUS TOPOTECAN FOR RELAPSED SMALL CELL LUNG CANCER IN SPAIN AND THE UNITED KINGDOM

To conduct an economic analysis comparing the costs of managing adverse events (AEs) and treatment administration in patients with relapsed small cell lung cancer (SCLC) treated either with lurbinectedin or intravenous (IV) topotecan. A cost analysis was conducted comparing the costs of managing Grade ≥3 AEs and treatment administration with lurbinectedin and topotecan. The incidence of AEs was obtained from the Basket trial for lurbinectedin (n=105) and from three randomised controlled trials (RCTs) for topotecan (1.5mg/m2/day): Von Pawel 1999 (n=107), Von Pawel 2001 (n=54) and Eckardt 2007 (n=151). Trials were identified via targeted literature review; RCTs permitting granulocyte-colony stimulating factor and/or antibiotic as primary prophylaxis were excluded. AEs affecting >1% of patients in either treatment were included in the analysis and the time horizon was in line with median treatment duration (4 cycles). Where AEs were reported as percentage of cycles (this was the case for febrile neutropenia in von Pawel 2001 and Eckardt 2007) they were converted to percentage of patients. Spanish and UK costs were obtained from the literature and local costs databases. In the UK and Spain, the mean total costs per patient were higher for topotecan than lurbinectedin. In Spain, mean total costs: lurbinectedin = €3,042 and topotecan = €11,447 (range: €11,155- €11,727). In UK, mean total costs: Lurbinectedin = £3,973 and topotecan = £14,383 (range: £13,697 - £15,271). This resulted in a total cost saving of €8,406 in Spain and £10,409 in the UK for lurbinectedin vs topotecan. Spain disaggregated results showed a cost saving of €5,103 and €3,302 for administration and AEs, respectively. UK disaggregated results showed a cost saving of £4,629 and £5,780 for administration and AEs, respectively. Lurbinectedin demonstrated consistent cost savings in terms of both treatment administration and management of AEs in Spain and the UK.

Risk-adapted therapy for young children with medulloblastoma (SJYC07): therapeutic and molecular outcomes from a multicentre, phase 2 trial

Young children with medulloblastoma have a poor overall survival compared with older children, due to use of radiation-sparing therapy in young children. Radiotherapy is omitted or reduced in these young patients to spare them from debilitating long-term side-effects. We aimed to estimate event-free survival and define the molecular characteristics associated with progression-free survival in young patients with medulloblastoma using a risk-stratified treatment strategy designed to defer, reduce, or delay radiation exposure. In this multicentre, phase 2 trial, we enrolled children younger than 3 years with newly diagnosed medulloblastoma at six centres in the USA and Australia. Children aged 3-5 years with newly diagnosed, non-metastatic medulloblastoma without any high-risk features were also eligible. Eligible patients were required to start therapy within 31 days from definitive surgery, had a Lansky performance score of at least 30, and did not receive previous radiotherapy or chemotherapy. Patients were stratified postoperatively by clinical and histological criteria into low-risk, intermediate-risk, and high-risk treatment groups. All patients received identical induction chemotherapy (methotrexate, vincristine, cisplatin, and cyclophosphamide), with high-risk patients also receiving an additional five doses of vinblastine. Induction was followed by risk-adapted consolidation therapy: low-risk patients received cyclophosphamide (1500 mg/m2 on day 1), etoposide (100 mg/m2 on days 1 and 2), and carboplatin (area under the curve 5 mg/mL per min on day 2) for two 4-week cycles; intermediate-risk patients received focal radiation therapy (54 Gy with a clinical target volume of 5 mm over 6 weeks) to the tumour bed; and high-risk patients received chemotherapy with targeted intravenous topotecan (area under the curve 120-160 ng-h/mL intravenously on days 1-5) and cyclophosphamide (600 mg/m2 intravenously on days 1-5). After consolidation, all patients received maintenance chemotherapy with cyclophosphamide, topotecan, and erlotinib. The coprimary endpoints were event-free survival and patterns of methylation profiling associated with progression-free survival. Outcome and safety analyses were per protocol (all patients who received at least one dose of induction chemotherapy); biological analyses included all patients with tissue available for methylation profiling. This trial is registered with ClinicalTrials.gov, number NCT00602667, and was closed to accrual on April 19, 2017. Between Nov 27, 2007, and April 19, 2017, we enrolled 81 patients with histologically confirmed medulloblastoma. Accrual to the low-risk group was suspended after an interim analysis on Dec 2, 2015, when the 1-year event-free survival was estimated to be below the stopping rule boundary. After a median follow-up of 5·5 years (IQR 2·7-7·3), 5-year event-free survival was 31·3% (95% CI 19·3-43·3) for the whole cohort, 55·3% (95% CI 33·3-77·3) in the low-risk cohort (n=23) versus 24·6% (3·6-45·6) in the intermediate-risk cohort (n=32; hazard ratio 2·50, 95% CI 1·19-5·27; p=0·016) and 16·7% (3·4-30·0) in the high-risk cohort (n=26; 3·55, 1·66-7·59; p=0·0011; overall p=0·0021). 5-year progression-free survival by methylation subgroup was 51·1% (95% CI 34·6-67·6) in the sonic hedgehog (SHH) subgroup (n=42), 8·3% (95% CI 0·0-24·0%) in the group 3 subgroup (n=24), and 13·3% (95% CI 0·0-37·6%) in the group 4 subgroup (n=10). Within the SHH subgroup, two distinct methylation subtypes were identified and named iSHH-I and iSHH-II. 5-year progression-free survival was 27·8% (95% CI 9·0-46·6; n=21) for iSHH-I and 75·4% (55·0-95·8; n=21) for iSHH-II. The most common adverse events were grade 3-4 febrile neutropenia (48 patients [59%]), neutropenia (21 [26%]), infection with neutropenia (20 [25%]), leucopenia (15 [19%]), vomiting (15 [19%]), and anorexia (13 [16%]). No treatment-related deaths occurred. The risk-adapted approach did not improve event-free survival in young children with medulloblastoma. However, the methylation subgroup analyses showed that the SHH subgroup had improved progression-free survival compared with the group 3 subgroup. Moreover, within the SHH subgroup, the iSHH-II subtype had improved progression-free survival in the absence of radiation, intraventricular chemotherapy, or high-dose chemotherapy compared with the iSHH-I subtype. These findings support the development of a molecularly driven, risk-adapted, treatment approach in future trials in young children with medulloblastoma. American Lebanese Syrian Associated Charities, St Jude Children's Research Hospital, NCI Cancer Center, Alexander and Margaret Stewart Trust, Sontag Foundation, and American Association for Cancer Research.

Inhalation delivery of topotecan is superior to intravenous exposure for suppressing lung cancer in a preclinical model

Intravenous (IV) topotecan is approved for the treatment of various malignancies including lung cancer but its clinical use is greatly undermined by severe hematopoietic toxicity. We hypothesized that inhalation delivery of topotecan would increase local exposure and efficacy against lung cancer while reducing systemic exposure and toxicity. These hypotheses were tested in a preclinical setting using a novel inhalable formulation of topotecan against the standard IV dose. Respirable dry-powder of topotecan was manufactured through spray-drying technology and the pharmacokinetics of 0.14 and 0.79 mg/kg inhalation doses were compared with 0.7 mg/kg IV dose. The efficacy of four weekly treatments with 1 mg/kg inhaled vs. 2 mg/kg IV topotecan were compared to untreated control using an established orthotopic lung cancer model for a fast (H1975) and moderately growing (A549) human lung tumors in the nude rat. Inhalation delivery increased topotecan exposure of lung tissue by approximately 30-fold, lung and plasma half-life by 5- and 4-folds, respectively, and reduced the maximum plasma concentration by 2-fold than the comparable IV dose. Inhaled topotecan improved the survival of rats with the fast-growing lung tumors from 7 to 80% and reduced the tumor burden of the moderately-growing lung tumors over 5- and 10-folds, respectively, than the 2-times higher IV topotecan and untreated control (p < .00001). These results indicate that inhalation delivery increases topotecan exposure of lung tissue and improves its efficacy against lung cancer while also lowering the effective dose and maximum systemic concentration that is responsible for its dose-limiting toxicity.

Combined chemotherapy with cisplatin, etoposide, and irinotecan versus topotecan alone as second-line treatment for patients with sensitive relapsed small-cell lung cancer (JCOG0605): a multicentre, open-label, randomised phase 3 trial

Etoposide and irinotecan are key drugs in the treatment of small-cell lung cancer. We did this study to investigate whether combined chemotherapy with cisplatin, etoposide, and irinotecan was superior to topotecan monotherapy as second-line chemotherapy in patients with sensitive relapsed small-cell lung cancer. We did this open-label, multicentre, randomised phase 3 trial at 29 institutions in Japan. Patients with small-cell lung cancer that responded to first-line treatment but showed evidence of disease relapse or progression at least 90 days after completion of the first-line treatment were eligible to participate. Enrolled patients were randomly assigned (1:1) to receive combination chemotherapy with cisplatin plus etoposide plus irinotecan or topotecan alone. Randomisation was done via the minimisation method with biased-coin balancing for Eastern Cooperative Oncology Group performance status, disease stage at enrolment, and institution. Combination chemotherapy consisted of five 2-week courses of intravenous cisplatin 25 mg/m(2) on days 1 and 8, intravenous etoposide 60 mg/m(2) on days 1-3, and intravenous irinotecan 90 mg/m(2) on day 8, with granulocyte colony-stimulating factor given by hypodermic injection every day starting from day 9 of the first course (except on the days anticancer drugs were given). Topotecan therapy consisted of four courses of intravenous topotecan 1·0 mg/m(2) on days 1-5, every 3 weeks. The primary endpoint was overall survival in the intention-to-treat population, which was analysed with a one-sided α of 5%, and safety was assessed in all patients who received at least one dose of study drug. The trial is registered with University Hospital Medical Information Network Clinical Trials Registry, number UMIN000000828. Between Sept 20, 2007, and Nov 30, 2012, 180 patients were enrolled, with 90 assigned to each treatment group. The median follow-up for censored patients was 22·7 months (IQR 20·0-35·3). Overall survival was significantly longer in the combination chemotherapy group (median 18·2 months, 95% CI 15·7-20·6) than in the topotecan group (12·5 months, 10·8-14·9; hazard ratio 0·67, 90% CI 0·51-0·88; p=0·0079). The most common grade 3 or 4 adverse events were neutropenia (75 [83%] patients in the combination chemotherapy group vs 77 [86%] patients in the topotecan group), anaemia (76 [84%] vs 25 [28%]), and leucopenia (72 [80%] vs 46 [51%]). Grade 3 or 4 febrile neutropenia was more common in the combination chemotherapy group than in the topotecan group (28 [31%] vs six [7%]), as was grade 3 or 4 thrombocytopenia (37 [41%] vs 25 [28%]). Serious adverse events were reported in four (4%) patients in the topotecan group and nine (10%) in the combination chemotherapy group. Two treatment-related deaths (one each of pneumonitis and pulmonary infection) occurred in the topotecan group and one (febrile neutropenia with sepsis) occurred in the combination chemotherapy group. Combination chemotherapy with cisplatin plus etoposide plus irinotecan could be considered the standard second-line chemotherapy for selected patients with sensitive relapsed small-cell lung cancer. National Cancer Center and the Ministry of Health, Labour and Welfare of Japan.

Safety of topotecan monotherapy for relapsed small cell lung cancer patients with pre-existing interstitial lung disease.

To investigate the safety of intravenous topotecan monotherapy for relapsed small cell lung cancer (SCLC) patients with pre-existing interstitial lung disease (ILD). A total of 77 patients who received topotecan for the treatment of relapsed SCLC between April 2007 and April 2014 were reviewed. Patients with pre-existing ILD were identified using the pretreatment chest computed tomography. The safety of intravenous topotecan for SCLC patients with ILD was retrospectively examined, particularly focusing on topotecan-induced acute exacerbation of ILD (AE-ILD). Twenty-three patients were identified as having pre-existing ILD [median age 74 (range 55-85) years; 21 men]. At the first topotecan administration, two-thirds (65.2%) had an Eastern Cooperative Oncology Group performance status 0 or 1. Topotecan was administered intravenously as second-line (n = 11) or later chemotherapy (n = 12). The median number of treatment cycles was two (range 1-7). The most common adverse events with grade 3 or 4 were neutropenia in 13 patients (56.5%) and thrombocytopenia in 10 patients (43.5%). Febrile neutropenia was observed in six patients (26.1%) and resulted in one death. AE-ILD occurred in five patients (21.7%; 95% confidence interval 4.9-38.5 %) 5-18 days after the last administration of topotecan and was fatal in three cases. Intravenous topotecan monotherapy can be unsafe for relapsed SCLC patients with pre-existing ILD. Clinicians should be cautious regarding topotecan-induced AE-ILD as a lethal complication.

Second-Line Therapy of Small-Cell Lung Cancer: Topotecan Compared to a Combination Treatment with Adriamycin, Cyclophosphamide And Vincristine (ACO) - a Single Center Experience.

Background: Randomized trials established topotecan and the combination of adriamycin, cyclophosphamide and vincristine (ACO) as second-line therapy options for small-cell lung cancer. We retrospectively evaluated the outcome of SCLC patients undergoing second-line chemotherapy.Patients and Methods: 92 consecutive patients with a diagnosis of SCLC between 2000 and 2010 were analyzed.Results: 86 patients (93.5%) were evaluable for outcome analysis. All patients diagnosed with limited disease (LD) SCLC received platinum-based chemotherapy as first-line treatment. 69 patients (98.6%) diagnosed with extensive disease (ED) SCLC received first-line palliative chemotherapy. In the total cohort, the median overall survival (OS) was 10.3 months (19.2 months and 9.2 months for LD-SCLC and ED-SCLC, respectively). 42 patients received second-line therapy (ACO in 47.6% and topotecan in 31.0% of patients, respectively). Eight patients (19.0%) were re-challenged with platinum/etoposide. Neither the overall response rate (52.9% vs. 22.2%; p=0.128) nor progression-free survival (2.4 vs. 2.4 months; p=0.794) or OS (5.5 vs. 5.0 months; p=0.997) were significantly different between ACO and topotecan. ACO-treated patients showed a trend towards a longer duration of inpatient care.Conclusion: We showed similar outcomes as reported in clinical trials. Second-line combination chemotherapy with ACO did not show superiority to intravenous topotecan, but was associated with a clinically relevant longer hospitalization time.

Interaction between riboflavin and BCRP‐mediated drug transport in the mammary gland (844.2)

Breastfeeding provides numerous benefits to a child’s growth and development. However, in a lactating mother, expression of Breast Cancer Resistance Protein (BCRP) is significantly increased in the mammary gland. BCRP is an efflux transporter and is responsible for the transport of many different substrates from natural carcinogens (ex. PhIP found in charred meats) to chemotherapeutic drugs. As a result, this poses a risk of exposure to potentially harmful BCRP substrates from a mother’s milk to her child. We hypothesized that riboflavin, a vitamin substrate for BCRP, can act as a potential competitor for BCRP‐mediated excretion of drugs/toxins into milk. We used intravenous topotecan and cimetidine at a dose of 1 and 5 mg/kg as model BCRP substrates in lactating mice. In mice pretreated with 5 mg/kg riboflavin, excretion of topotecan and cimetidine into milk at 30 min postdose was significantly reduced. Mean topotecan levels in the milk were 883 ng/ml (SD: ±465; n=10) in the control and 682 ng/ml (SD: ±316; n=10; p&lt;0.01) in the riboflavin treatment group. For cimetidine, the mean milk levels were 1941 ng/ml (SD: ±387; n=7) in the control, compared to 1555 ng/ml (SD: ±192; n=7; p&lt;0.05) in the riboflavin‐pretreated mice. The milk‐to‐plasma ratios of topotecan and cimetidine in riboflavin‐pretreated mice also showed a significant 35% and 26% decrease respectively. In conclusion, our findings indicate that riboflavin administration does reduce the excretion of other BCRP substrates into a mother’s milk.Grant Funding Source: Supported by CIHR

Phase I dosage finding and pharmacokinetic study of intravenous topotecan and oral erlotinib in adults with refractory solid tumors

Topotecan is widely used for refractory solid tumors but multi-drug resistance may occur due to tumor expression of ATP-binding cassette (ABC) transporters. Since erlotinib, an inhibitor of the epidermal growth factor receptor, also inhibits several ABC transporters, we performed a phase I study to evaluate the safety, efficacy, and pharmacokinetics of intravenous topotecan given in combination with erlotinib. Patients received 150 mg of oral erlotinib daily and a 30 min intravenous infusion of topotecan on days 1-5 of a 21-day cycle. Dosage escalation of topotecan occurred with a starting dosage of 0.75 mg/m(2). The pharmacokinetics of topotecan was evaluated on day 1 of cycle 1 without erlotinib and on day 1 of cycle 2 or 3 with erlotinib. Twenty-nine patients were enrolled. The maximum tolerated dosage was determined to be 1.0 mg/m(2). Dose-limiting toxicities included neutropenia and thrombocytopenia. The average duration of treatment was 97 days. Two partial responses were observed. Topotecan clearance and exposure were similar with and without erlotinib. The combination of topotecan and erlotinib is tolerable at clinically effective doses. Erlotinib does not affect the disposition of topotecan to a clinically significant extent.

Intra‐arterial chemotherapy is more effective than sequential periocular and intravenous chemotherapy as salvage treatment for relapsed retinoblastoma

Treatment of eyes with retinoblastoma failing systemic chemoreduction and external beam radiotherapy is seldom efficacious. This study compares the efficacy and toxicity of intra-arterial ophthalmic artery chemotherapy (IAO) to our historical cohort of sequential periocular and systemic chemotherapy in such patients. Eighteen eyes (15 consecutive patients) were retrospectively evaluated. Eight eyes received IAO for a median of four cycles (range: 2-9) including melphalan alone (n = 3) or after topotecan and carboplatin (n = 4) or topotecan and carboplatin without melphalan (n = 1). Ten eyes received a median of two cycles (range: 1-3) of periocular topotecan (n = 9) or carboplatin (n = 1) followed by intravenous topotecan and cyclophosphamide in three patients if at least stable disease was achieved. Both groups were comparable for disease extension and prior therapy. No extraocular dissemination or second malignancy occurred and all patients are alive. The probability of enucleation-free eye survival at 12 months was 0.87 (95% CI: 0.42-0.97) for the IAO group, compared to 0.1 (95% CI: 0.06-0.35) for the periocular group (P < 0.01). Ocular toxicity was mild and similar in both groups (mostly mild orbital edema). Systemic toxicity was low for IAO and periocular injection, but children who received sequentially intravenous chemotherapy (n = 12 cycles) had five episodes of grade 4 neutropenia, three of which resulted in hospitalizations. No case in the IAO group presented these complications. IAO is significantly superior to sequential periocular-intravenous topotecan-containing regimens in eyes with relapsed intraocular retinoblastoma with a more favorable toxicity profile.

Étude post-autorisation de mise sur le marché sur le topotécan dans le cancer bronchique à petites cellules. Utilisation du topotécan dans un service de pneumologie universitaire

Lung cancer is the leading cause of cancer related death in France and Europe. Small-cell lung carcinoma (SCLC) represents 15-20% of cases. International standards of care recommend the use of first-line chemotherapy, which has a high response rate. However, tumour recurrence occurs after a variable disease-free period. If the first-line treatment cannot be repeated during the relapse, intravenous topotecan may be used according to its market authorization (MA). We report the first French postmarketing surveillance study on the use of topotecan in the SCLC. Between August 2005 to December 2009, 26 SCLC patients received at least one cycle of intravenous topotecan in our department. All patients were treated in accordance with MA. Seventeen patients received this treatment as second line, as in the MA study, while nine patients where treated beyond the second line. In the first group, we showed that the anti-tumour efficiency of topotecan is similar to that observed in the MA study (24% response) while grade 3 to 4 haematological toxicities were less frequent. In the second group of patients, who could not have been included in the MA study, the tumour response rate was equal to 11% without an increase in severe toxicity compared to the first group. Specific or overall survival was not different between the two groups. Our study provides original public health data on the target population, the anti-tumor efficiency and the toxicity of topotecan in the treatment of SCLC.

A phase I study of concurrent weekly topotecan and cisplatin chemotherapy with whole pelvic radiation therapy in locally advanced cervical cancer: A gynecologic oncology group study

PurposeTo determine the maximum tolerated dose (MTD) and acute dose-limiting toxicities (DLT) of intravenous topotecan administered with weekly cisplatin during pelvic radiation therapy in patients with locally advanced cervical cancer. MethodsPatients were treated at one of two dose levels receiving intravenous topotecan at 0.5mg/m2 and cisplatin at either 30 or 40mg/m2 given weekly for 6weeks concurrently with pelvic radiation and intracavitary brachytherapy. The primary endpoint for the escalation study was acute dose-limiting toxicities occurring within 30days of completing radiation therapy. ResultsEleven patients were enrolled. Dose-limiting toxicity consisting of Grade 3 nausea and vomiting lasting >24h in one patient and grade 3 febrile neutropenia in another patient occurred at the first dose level of weekly topotecan 0.5mg/m2 and cisplatin 40mg/m2. This necessitated de-escalation to weekly cisplatin 30mg/m2 in combination with topotecan 0.5mg/m2 and pelvic radiation. This dose level was tolerable in 6 evaluable patients with only one DLT consisting of grade 4 thrombocytopenia, grade 3 abdominal pain and grade 3 elevated gamma glutamyl transpeptidase (GGT). ConclusionsIn women with locally advanced cervical cancer, intravenous topotecan 0.5mg/m2 and cisplatin 30mg/m2 given weekly for 6weeks with concurrent pelvic radiation and intracavitary brachytherapy were tolerable. Further expansion of the feasibility cohort of this study was suspended based on the results of a phase 3 trial comparing the efficacy of platinum combinations in advanced and recurrent cervical cancer.

A prospective clinical trial of lenalidomide with topotecan in women with advanced epithelial ovarian carcinoma

Lenalidomide is an anti-angiogenic IMiD(®) immunomodulatory drug. The objective of this study was to determine the maximum tolerated dose (MTD), overall safety profile, and activity of oral lenalidomide in combination with topotecan in women with advanced epithelial ovarian or primary peritoneal carcinoma. In this Phase I/II open-label, dose-escalation study, patients with histologically or cytologically confirmed advanced ovarian or primary peritoneal carcinoma with disease progression or recurrence following first-line therapy with a platinum agent and paclitaxel were eligible. The Phase I trial utilized a standard dose-escalation design to define the MTD and evaluate the safety profile of lenalidomide and topotecan. The starting doses were lenalidomide 5 mg, days 1-14, and intravenous topotecan 1.25 mg/m(2), days 1-5 of a 21-day cycle. Only the lenalidomide dose was escalated, in 5-mg increments up to 25 mg. Toxicity was graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events. The Phase II portion was designed to evaluate the antitumor activity based on objective response rate of lenalidomide and topotecan. Five women with advanced epithelial ovarian carcinoma were enrolled, each receiving 5 mg oral lenalidomide and 1.25 mg/m(2) topotecan. Four patients discontinued because of dose-limiting toxicity, most commonly grade 4 neutropenia (n = 3). One patient discontinued because of lack of therapeutic effect. The study was terminated early for reasons of toxicity. The addition of lenalidomide to topotecan is not a feasible drug combination in women with advanced epithelial ovarian carcinoma because of dose-limiting toxicity.

OUR EXPERIENCE WITH TOPOTECAN AS SECOND- LINE TREATMENT OF PATIENTS WITH RELAPSED SMALL CELL LUNG CANCER

RESUME: Objectives: Single agent intravenous Topotecan is an effective treatment for small cell lung cancer /SCLC/ after failure of first- line chemotherapy. The aim of this study was to evaluate the efficacy and toxicity of intravenous Topotecan in recurrent SCCC. Methods: In the period 20082009 seventeen consecutive patients with relapsed SCLC entered the study. The treatment schedule consists of Topotecan 1,5 mg/ m2 i.v. for five consecutive days, with repetition every 21 days. Results: Overall response rate was 23,5%. Median survival was 6,4 months. Nausea, vomiting and neutropenia were most common side effects. Conclusion: Intravenous Topotecan is effective as second- line therapy for patients with relapsed SCCC with good tolerability.

A phase II study of two topotecan regimens evaluated in recurrent platinum-sensitive ovarian, fallopian tube or primary peritoneal cancer: A Gynecologic Oncology Group Study (GOG 146Q)

Objective. To evaluate the efficacy and safety of topotecan in patients with recurrent ovarian, primary peritoneal, and fallopian tube carcinomas. Methods. A randomized phase II analysis of platinum-sensitive patients with measurable disease was performed independently assessing intravenous topotecan 1.25 mg/m 2 daily × 5 every 21 days (regimen I) and topotecan 4.0 mg/m 2/day on days 1, 8, and 15 of a 28-day cycle (regimen II). All patients were treated until disease progression, unmanageable toxicity, or patient refusal. Insufficient accrual related to regimen I resulted in a redesign of the study as a single arm phase II trial assessing only regimen II. More complete efficacy data is presented for regimen II as enrollment on regimen I was insufficient for some analyses. Results. A total of 81 patients were enrolled. One patient was ineligible. Fifteen patients received regimen I, while 65 patients were treated with regimen II. The response rate on regimen I (daily × 5) was 27% (90% CI: 10–51%) and 12% (90% CI: 6–21%) on regimen II (weekly). The median PFS and OS were 4.8 and 27.8 months, respectively, for regimen II. Grade 3/4 neutropenia rate was 93% with daily × 5 dosing and 28% for weekly treatment. Febrile neutropenia was very low in both groups. Conclusion. The weekly regimen of topotecan appeared less active but resulted in less toxicity than the daily regimen in platinum-sensitive recurrent ovarian cancer patients.