Apatinib for Chemotherapy-Refractory Advanced Metastatic Gastric Cancer: Results From a Randomized, Placebo-Controlled, Parallel-Arm, Phase II Trial

Purpose Patients with metastatic gastric cancer (mGC) who do not respond to or who experience progression with second-line chemotherapy have no treatment options that clearly confer a survival benefit. This trial investigated the safety and efficacy of apatinib, an inhibitor of vascular endothelial growth factor receptor, as a treatment option for heavily pretreated patients with mGC. Patients and Methods Patients who experienced treatment failure with at least two chemotherapeutic regimens were randomly assigned to receive placebo (group A), apatinib 850 mg once daily (group B), or apatinib 425 mg twice daily (group C). Results We enrolled 144 patients onto this study. In groups A, B, and C, the median overall survival (OS) times were 2.50 months (95% CI, 1.87 to 3.70 months), 4.83 months (95% CI, 4.03 to 5.97 months), and 4.27 months (95% CI, 3.83 to 4.77 months), respectively, and the median progression-free survival (PFS) times were 1.40 months (95% CI, 1.20 to 1.83 months), 3.67 months (95% CI, 2.17 to 6.80 months), and 3.20 months (95% CI, 2.37 to 4.53 months), respectively. There were statistically significant differences between the apatinib and placebo groups for both PFS (P < .001) and OS (P < .001 and P = .0017). Nine patients had a partial response (three patients in group B and six patients in group C). Toxicities were tolerable or could be clinically managed. The most common grade 3 to 4 adverse events were hand-foot syndrome and hypertension. Hematologic toxicities were moderate, and grade 3 to 4 hematologic toxicities were rare. Conclusion Apatinib showed improved PFS and OS in heavily pretreated patients with mGC who had experienced treatment failure with two or more chemotherapy regimens.

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An Exploration of Trifluridine/Tipiracil in Combination with Irinotecan in Patients with Pretreated Advanced Gastric Cancer

10.21203/rs.3.rs-1143619/v1 ◽

2021 ◽

Author(s):

Takuro Mizukami ◽

Keiko Minashi ◽

Hiroki Hara ◽

Tomohiro Nishina ◽

Yusuke Amanuma ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Treatment Options ◽

Progression Free Survival ◽

Maximum Tolerated Dose ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Recommended Phase Ii Dose

Abstract Background: Trifluridine/tipiracil (FTD/TPI) and irinotecan are treatment options for heavily pretreated patients with advanced gastric cancer but with limited efficacies. We investigated the combination of FTD/TPI and irinotecan for such patients.Methods: Patients who refractory to fluoropyrimidine, platinum and taxane were enrolled into four cohorts (Level 1A/1B/2A/2B) used an escalated dose of irinotecan [100 (Level 1) or 125 mg/m2 (Level 2) on days 1 and 15] with 2 schedules of FTD/TPI 35 mg/m2/dose: twice daily, on days 1-5 and 8-12 (Level A) or on days 1-5 and days 15-19 (Level B) of a 28-day cycle. The primary and secondary objectives were determination of maximum tolerated dose, dose-limiting toxicities (DLTs), and recommended phase II dose (RP2D) , and evaluation of disease control rate (DCR), respectively. Results: Eleven patients were enrolled; 2 at Level 1A, 3 at Level 1B and 6 at Level 2B. DLTs occurred in 2/2 patient at Level 1A, and 2/6 patients at Level 2B. Grade 3 or higher treatment-related adverse events were neutropenia (90.9%), leukopenia (54.5%), anemia (45.5%) and febrile neutropenia (18.2%). One patient at Level 2B achieved partial response and the DCR was 72.7% (95% CI 39.0- 94.0%). The median progression-free survival and overall survival was 3.0 months (95% CI 0.92- not reached) and 10.2 months (95% CI 2.2- not reached), respectively.Conclusion: The RP2D of FTD/TPI combined with irinotecan was determined to be Level 1B with manageable hematologic toxicities and feasible non-hematologic toxicities. Further evaluation for its efficacy in the RP2D is necessary. Mini-abstract: A phases Ib study of trifluridine/tipiracil in combination with irinotecan for advanced gastric cancer determined the recommended dose with manageable hematologic toxicities and feasible non-hematologic toxicities.

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Oxaliplatin and irinotecan chemotherapy in advanced gastric cancer. Final results of a multicenter phase II trial

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.4070 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 4070-4070 ◽

Cited By ~ 1

Author(s):

E. Woell ◽

T. Kühr ◽

W. Eisterer ◽

K. Gattringer ◽

R. Greil ◽

...

Keyword(s):

Gastric Cancer ◽

Advanced Gastric Cancer ◽

Treatment Options ◽

Locally Advanced ◽

Sensory Neuropathy ◽

Metastatic Gastric Cancer ◽

Female Ratio ◽

Multiple Metastases ◽

Grade 3 ◽

Gastric Cancer Patients

4070 Background: There are only limited treatment options for advanced gastric cancer. Development of new treatment options is therefore warranted. The aim of this study was to evaluate the safety, feasibility and efficacy of an outpatient Oxaliplatin/Irinotecan combination in patients suffering from unresectable, locally advanced and/or metastatic gastric cancer. Methods: The combination of Oxaliplatin 85 mg/m2 biweekly with Irinotecan 125 mg/m2 biweekly was chosen since it has been shown in colorectal cancer that a biweekly dose of at least 85 mg/m2 oxaliplatin is superior to a lower dose and toxicity of Irinotecan is much lower if given fractionated into two doses. Furthermore the Irinotecan dose below MTD considers concerns about increased toxicity in gastric cancer patients. Results: 43 patients with histologically proven unresectable and/or metastatic gastric adenocarcinoma and no previous palliative chemotherapy and/or immunotherapy were selected. Median age: 61 years (range 32–81 years), male/female ratio: 24/19, PS 0:11 patients, PS <3:32 patients, locally advanced cancer 5 patients, single metastatic site: 19 patients, multiple metastases: 19 patients, previously adjuvant radiochemotherapy: 4 patients. This outpatient regimen was generally well tolerated. Frequently reported adverse events (more than 20% of patients) were grade 1 or 2 and included neutropenia (44% of patients), thrombocytopenia (30%), anemia (77%), nausea 67%), diarrhea (51%), alopecia (35%). Grade 3 and 4 toxicities included neutropenia in 2/43 pts., anemia in 3/43 pts., nausea in 2/43 pts., and diarrhea in 4/43pts. 5 patients were taken off-study due to toxicity (asthenia, nausea, reversible renal failure, diarrhea). Sensory neuropathy occurred only as grade 2 in 14%, no grade 3/4 neurotoxicity was observed. For response 38 patients are assessable with 3 pts. (8%) showing a CR, PR in 19 pts. (50%), SD in 11 pts. (29%), PD in 5 pts. (13%). Median TTP was 5.3 months and median OS 9.5 months. Conclusions: The outpatient combination of a biweekly Oxaliplatin/Irinotecan chemotherapy is well tolerated and shows a response rate within the range of other combination therapies. The favourable toxicity profile makes it an alternative 1st line regimen. [Table: see text]

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Phase II Study of Temsirolimus (CCI-779), a Novel Inhibitor of mTOR, in Heavily Pretreated Patients With Locally Advanced or Metastatic Breast Cancer

Journal of Clinical Oncology ◽

10.1200/jco.2005.66.130 ◽

2005 ◽

Vol 23 (23) ◽

pp. 5314-5322 ◽

Cited By ~ 347

Author(s):

Stephen Chan ◽

Max E. Scheulen ◽

Stephen Johnston ◽

Klaus Mross ◽

Fatima Cardoso ◽

...

Keyword(s):

Breast Cancer ◽

Metastatic Breast Cancer ◽

Adverse Events ◽

Dose Level ◽

Locally Advanced ◽

Metastatic Breast ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Time To Tumor Progression

Purpose In this study, two doses of temsirolimus (CCI-779), a novel inhibitor of the mammalian target of rapamycin, were evaluated for efficacy, safety, and pharmacokinetics in patients with locally advanced or metastatic breast cancer who had been heavily pretreated. Patients and Methods Patients (n = 109) were randomly assigned to receive 75 or 250 mg of temsirolimus weekly as a 30-minute intravenous infusion. Patients were evaluated for tumor response, time to tumor progression, adverse events, and pharmacokinetics of temsirolimus. Results Temsirolimus produced an objective response rate of 9.2% (10 partial responses) in the intent-to-treat population. Median time to tumor progression was 12.0 weeks. Efficacy was similar for both dose levels but toxicity was more common with the higher dose level, especially grade 3 or 4 depression (10% of patients at the 250-mg dose level, 0% at the 75-mg dose level). The most common temsirolimus-related adverse events of all grades were mucositis (70%), maculopapular rash (51%), and nausea (43%). The most common, clinically important grade 3 or 4 adverse events were mucositis (9%), leukopenia (7%), hyperglycemia (7%), somnolence (6%), thrombocytopenia (5%), and depression (5%). Conclusion In heavily pretreated patients with locally advanced or metastatic breast cancer, 75 and 250 mg temsirolimus showed antitumor activity and 75 mg temsirolimus showed a generally tolerable safety profile.

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Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.11545 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 11545-11545

Author(s):

Daniel Pink ◽

Dimosthenis Andreou ◽

Anne Flörcken ◽

Alexander Golf ◽

Stephan Richter ◽

...

Keyword(s):

Phase Ii ◽

Single Agent ◽

Primary Efficacy ◽

Primary Efficacy Endpoint ◽

Efficacy And Safety ◽

Disease Stabilization ◽

Group A ◽

Pretreated Patients ◽

Grade 3 ◽

Group B

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.

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Clinical Response in Heavily Pretreated Mycosis Fungoides with Pembrolizumab: A Case Report

Acta Haematologica ◽

10.1159/000518815 ◽

2021 ◽

pp. 1-3

Author(s):

Ginevra Lolli ◽

Beatrice Casadei ◽

Lisa Argnani ◽

Alessandro Pileri ◽

Cinzia Pellegrini ◽

...

Keyword(s):

Mycosis Fungoides ◽

Assessment Tool ◽

Therapeutic Option ◽

Rapid Responses ◽

Duration Of Response ◽

Heavily Pretreated ◽

Stage Ia ◽

Pretreated Patients ◽

Grade 3 ◽

The Moment

Mycosis fungoides (MF) is a disease almost impossible to cure. In the context of heavily pretreated patients, the anti-programmed cell death protein 1 (anti-PD-1) pembrolizumab is a valid therapeutic option. The alteration of the PD-1-PD ligand 1 (PD-L1) axis is often present in MF, and this aspect explains the feasibility of this therapy. We report the case of a 60-year-old woman diagnosed with MF in 2003, Olsen stage IA (T1M0NXBO). Since the moment of the diagnosis, she received 10 lines of therapy, with a short duration of response after each one of them. In April 2020, our patient started pembrolizumab 2 mg/kg every 3 weeks, and she achieved a partial response after the 4th cycle, consistent with the modified severity assessment tool (mSWAT) 1, which she is still maintaining after 10 cycles. No grade ≥3 adverse events were recorded. We conclude that pembrolizumab can induce extremely rapid responses in MF, with very low toxicity.

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New drug developments in metastatic gastric cancer

Therapeutic Advances in Gastroenterology ◽

10.1177/1756284818808072 ◽

2018 ◽

Vol 11 ◽

pp. 175628481880807 ◽

Cited By ~ 6

Author(s):

Aaron C. Tan ◽

David L. Chan ◽

Wasek Faisal ◽

Nick Pavlakis

Keyword(s):

Gastric Cancer ◽

Clinical Trials ◽

Targeted Therapies ◽

Immune Checkpoint ◽

Immune Checkpoint Inhibitors ◽

Checkpoint Inhibitors ◽

Treatment Options ◽

Predictive Biomarkers ◽

Metastatic Gastric Cancer ◽

New Era

Metastatic gastric cancer is associated with a poor prognosis and novel treatment options are desperately needed. The development of targeted therapies heralded a new era for the management of metastatic gastric cancer, however results from clinical trials of numerous targeted agents have been mixed. The advent of immune checkpoint inhibitors has yielded similar promise and results from early trials are encouraging. This review provides an overview of the systemic treatment options evaluated in metastatic gastric cancer, with a focus on recent evidence from clinical trials for targeted therapies and immune checkpoint inhibitors. The failure to identify appropriate predictive biomarkers has hampered the success of many targeted therapies in gastric cancer, and a deeper understanding of specific molecular subtypes and genomic alterations may allow for more precision in the application of novel therapies. Identifying appropriate biomarkers for patient selection is essential for future clinical trials, for the most effective use of novel agents and in combination approaches to account for growing complexity of treatment options.

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Pomalidomide-Dexamethasone in the Management of Heavily Pretreated Multiple Myeloma

Blood ◽

10.1182/blood-2020-143143 ◽

2020 ◽

Vol 136 (Supplement 1) ◽

pp. 1-1

Author(s):

Claudio Cerchione ◽

Lucio Catalano ◽

Davide Nappi ◽

Anna Emanuele Pareto ◽

Gerardo Musuraca ◽

...

Keyword(s):

Oral Administration ◽

Oral Treatment ◽

Novel Agents ◽

Hematologic Toxicity ◽

Salvage Regimen ◽

Good Compliance ◽

Impressive Result ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3

Background Pomalidomide is a new generation IMID, with a very good compliance, thanks to oral administration, which can be used also in heavily pretreated patients, in a domestic setting. Aims In this retrospective observational trial, It has been evaluated efficacy and tolerance of pomalidomide plus dexamethasone (PD) as salvage regimen in heavily pretreated patients with relapsed and refractory MM (rrMM), whose prognosis is particularly severe. Methods 57 patients (31 M/26 F), with rrMM, median age at diagnosis 69 years (r. 52-86), and median age at start of treatment 76 years (r.56-90) treated with several lines of treatments (median 7, r. 2-11), every refractory to all the drugs previously received (also Bortezomib, Thalidomide and Lenalidomide), received Pomalidomide-Dexamethasone (Pomalidomide 4 mg for 21 days, Dexamethasone 40 mg days 1,8,15,22, pegfilgrastim day +8) every 28 days, until progression. ISS was equally distributed, and cytogenetic at relapse was evaluable in 14 patients. All the patients had previously been treated with schedule containing bortezomib and IMIDs. 63% (36/57) had undergone at least to a single ASCT. All patients were relapsed and refractory to last therapies received before PD. Results Pomalidomide was well tolerated, with grade 3-4 transfusion-dependent anemia in 58% (33/57) of patients, 44% (23/57) grade 3-4 neutropenia (pegfilgrastim in primary prophylaxis was given, no hospitalization was required, no septic shocks were observed), 40% (23/57) grade 3-4 thrombocytopenia without hemorrhagic events and transfusion-dependence. No severe extra-hematologic toxicity was observed. According to IMWG, ORR1 (≥PR) was 47.3% (27/57: 5 CR, 11 VGPR, 7 PR, 4 MR), but, considering that we are evaluating a cohort of heavily pretreated patients, with poor prognosis, another parameter should be considered, ORR2 (≥SD), considering stable disease as a successful result in progressive MM. ORR2 was 77.1% (17 SD). These can be considered as impressive result in this subset of patients. Oral treatment gives a really good compliance, in frail and unfit patients, and response, when present, is always really fast (median time to response: 2 months (r.1-6)), median OS from diagnosis was 94 months (range 21-234), median OS from start of pomalidomide was 9 months (range 1-25). Nine patients have surprisingly achieved a notable response (3 VGPR, 4 PR, 2 MR) after failure of novel agents (i.e. Carfilzomib, Daratumumab and Pomalidomide). Conclusions Pomalidomide-dexamethasone has shown significant efficacy and a very good compliance, thanks to oral administration, in a particularly severe setting of heavily pretreated patients, relapsed and refractory to all available therapeutic resources, also after failure of novel agents. Disclosures Lucchesi: Novartis: Honoraria; Pfizer: Honoraria; Incyte: Honoraria.

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CTIM-32. IMMUNE CHECKPOINT INHIBITOR NIVOLUMAB IN PEOPLE WITH RECURRENT SELECT RARE CNS CANCERS: RESULTS OF INTERIM ANALYSIS IN A HEAVILY PRETREATED COHORT

Neuro-Oncology ◽

10.1093/neuonc/noab196.224 ◽

2021 ◽

Vol 23 (Supplement_6) ◽

pp. vi57-vi58

Author(s):

Marta Penas-Prado ◽

Ying Yuan ◽

Kathleen Wall ◽

Elizabeth Vera ◽

Ukeme Ikiddeh-Barnes ◽

...

Keyword(s):

Safety Profile ◽

Interim Analysis ◽

Cns Tumors ◽

Myxopapillary Ependymoma ◽

Investigational Drugs ◽

Heavily Pretreated ◽

Pretreated Patients ◽

Grade 3 ◽

Total Accrual ◽

Immune Profiling

Abstract INTRODUCTION Standard and experimental therapies for patients with rare CNS tumors are scarce. Nivolumab (PD-1 inhibitor) is approved for several non-CNS cancers. This ongoing Phase II trial (NCT03173950) will determine the efficacy of nivolumab in adults with recurrence/progression of one of 11 selected rare primary CNS tumors. Efficacy is measured by Disease Control Rate (DCR; confirmed CR/PR or durable SD for ≥ 6 months) in 2 cohorts: heavily and non-heavily pretreated patients (heavily pretreated: ≥ 3 prior therapies; non-heavily pretreated: ≤ 2). We report efficacy and safety results of a preplanned interim analysis in the heavily pretreated cohort. METHODS Eligibility includes recurrence/progression of an eligible tumor; age ≥ 18 years; tumor tissue available for histopathology, molecular and immune profiling; KPS ≥ 70; and no steroids at study entry. A total of 150 evaluable patients will be enrolled (75 to each cohort). Prior therapies include radiation and/or standard or investigational drugs. Nivolumab treatment is 240 mg IV every 2 weeks (4 doses); then 480 mg every 4 weeks (14 additional doses). Interim analysis was planned when sample size reached 32 in each cohort. RESULTS As of March 10, 2021, DCR exceeded the minimum required for interim analysis in the heavily pretreated cohort. Among 30 patients, 4 achieved SD > 6 months (medulloblastoma, anaplastic ependymoma, myxopapillary ependymoma, metastatic atypical meningioma). Safety profile (related AEs): grade 3 = 7; grade 4 = 1. Most frequent grade 3-5 AEs regardless of attribution: tumor progression (6); anemia, hydrocephalus, lymphopenia (3 each); cerebral edema, headache (2 each). CONCLUSION DCR exceeded the “go” boundary (i.e., > 2) in the heavily pretreated cohort. Nivolumab showed safety profile consistent with other studies. This cohort will continue to stage 2 and complete total accrual of 75 patients. The trial is currently being expanded to 10 additional sites across the BTTC/NCI-CONNECT consortium.

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