scholarly journals Investigation of spleen CXCR4 expression by [68Ga]Pentixafor PET in a cohort of 145 solid cancer patients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Richard Lewis ◽  
Stefan Habringer ◽  
Malte Kircher ◽  
Maike Hefter ◽  
Caroline Anna Peuker ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Neuroendocrine Tumors ◽  
Cell Lung Cancer ◽  
Solid Tumor ◽  
Small Cell ◽  
Cxcr4 Expression ◽  
Small Cell Lung ◽  
Tumor Patients

Abstract Background The chemokine receptor CXCR4 is frequently overexpressed and associated with adverse prognosis in most hematopoietic malignancies and solid cancers. Recently, CXCR4 molecular imaging using the CXCR4-specific positron emission tomography (PET) tracer Pentixafor ([68Ga]Pentixafor) has become a well-established method to non-invasively measure CXCR4 expression in vivo. In previous Pentixafor imaging studies, highly variable CXCR4 tracer uptake to the spleen was observed. Results We investigated the hypothesis that enhanced spleen [68Ga]Pentixafor uptake and thus CXCR4 expression in patients with solid tumors would indicate an activated spleen state and/or an association with clinical and prognostic features and survival parameters. In this retrospective study, [68Ga]Pentixafor-PET images and patient records of 145 solid tumor patients representing 27 cancer entities were investigated for an association of spleen [68Ga]Pentixafor uptake and clinical characteristics and outcome. Based on this assessment, we did not observe differences in clinical outcomes, measured by progression-free survival, overall survival and remission status neither within the entire cohort nor within subgroups of adrenal cancer, desmoplastic small round cell tumor, neuroendocrine tumors, non-small cell lung cancer, small cell lung cancer and pancreatic adenocarcinoma patients. No tumor entity showed especially high levels of spleen [68Ga]Pentixafor uptake compared to others or a control cohort. However, when investigating laboratory parameters, there was a positive correlation of high spleen [68Ga]Pentixafor uptake with leukocyte and/or platelet counts in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer. Conclusion Spleen [68Ga]Pentixafor uptake was not associated with stage of disease and clinical outcomes in solid tumor patients. We identified positively associated platelet and/or leukocyte counts with spleen [68Ga]Pentixafor uptake in neuroendocrine tumors, non-small cell lung cancer and small cell lung cancer, suggesting that splenic CXCR4 expression could possibly play a role in systemic immunity/inflammation in some types of solid tumors or a subgroup of patients within solid tumor entities.

An open-label phase 1b/2 study of surufatinib in combination with tislelizumab in subjects with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2677-TPS2677
Author(s):  
Arvind Dasari ◽  
John S. Kauh ◽  
Christopher Tucci ◽  
Shivani Nanda ◽  
Marek K. Kania ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Antitumor Activity ◽  
Adverse Events ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Neuroendocrine Tumors ◽  
Cell Lung Cancer ◽  
Primary Objective ◽  
Small Cell ◽  
Small Cell Lung

TPS2677 Background: Surufatinib (S) is an inhibitor of VEGFR1, 2, & 3; FGFR1; and CSF-1R. In two phase 3 randomized trials (SANET-ep; NCT02588170 & SANET-p; NCT02589821) S demonstrated a manageable safety profile and statistically significant efficacy. Patients (pts) with extrapancreatic neuroendocrine tumors (epNETs) achieved a median progression free survival (PFS) of 9.2 v 3.8 months (mo) (hazard ratio [HR] 0.334; p<0.0001), and pts with pancreatic NETs (pNETs) achieved a median PFS of 10.9 v 3.7 mo (HR 0.491; p=0.0011), with S v placebo, respectively. S was recently approved for the treatment of pts with epNET in China. Tislelizumab (T) is a humanized immunoglobulin G4 anti-PD-1 monoclonal antibody engineered to minimize binding to Fc-gamma-receptor on macrophages. T is approved in China in combination with chemotherapy for squamous non-small cell lung cancer and has conditional approval for Hodgkin’s lymphoma and locally advanced or metastatic urothelial carcinoma with PD-L1 high expression. The objective of this study is to evaluate the safety and efficacy of combination therapy with S and T, which may have synergistic effects, where inhibition of angiogenesis along with stimulation of an immune response may enhance the overall antitumor activity. Methods: This study (NCT04579757) will include pts, ≥18 years of age, with advanced metastatic solid tumors, who have an Eastern Cooperative Oncology Group performance status of 0 or 1 and have progressed on or are intolerant to standard therapies. The primary objective of part 1 (dose escalation) will be to evaluate the safety and tolerability of S and T to determine the recommended phase 2 dose of the combination. The starting dose in part 1 will be 250 mg of S, orally, daily, and 200mg of T, intravenously, every 3 weeks. The dose of S will be escalated during part 1, while the dose of T will remain fixed. Endpoints include dose limiting toxicities, treatment emergent adverse events, serious adverse events, adverse events leading to discontinuation, electrocardiograms, clinical laboratory abnormalities and vital signs. Antitumor activity will be evaluated as a secondary objective. Six to 12 pts will be enrolled. The primary objective of part 2 (dose expansion) will be to evaluate the objective response rate (ORR) of S in combination with T per RECIST v1.1. The endpoint will be ORR at 12 weeks. Key secondary endpoints include PFS, disease control rate, duration of response, safety endpoints, and PK parameters. Approximately 95 pts with indications of interest will be enrolled: colorectal cancer, neuroendocrine tumors (thoracic and gastroenteropancreatic), small-cell lung cancer, gastric cancer, and soft tissue sarcoma (undifferentiated pleomorphic sarcoma and alveolar soft part sarcoma). Enrollment in the United States is open and ongoing, and enrollment in Europe is planned for fourth quarter 2021. Clinical trial information: NCT04579757.

scholarly journals Phase I/II trial of pemetrexed plus nab-paclitaxel in advanced solid tumor patients with emphasis on non-small cell lung cancer

2013 ◽  
Vol 31 (6) ◽  
pp. 1587-1591 ◽  
Author(s):  
Cheryl Ho ◽  
Angela M. Davies ◽  
Randeep S. Sangha ◽  
Derick Lau ◽  
Primo Lara ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Solid Tumor ◽  
Small Cell ◽  
Advanced Solid Tumor ◽  
Small Cell Lung ◽  
Tumor Patients

A first-in-human study of mirzotamab clezutoclax as monotherapy and in combination with taxane therapy in relapsed/refractory solid tumors: Dose escalation results.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3015-3015
Author(s):  
Anthony W. Tolcher ◽  
Benedito A. Carneiro ◽  
Afshin Dowlati ◽  
Albiruni Ryan Abdul Razak ◽  
Young Kwang Chae ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Cell Lung Cancer ◽  
Dose Escalation ◽  
Lymphocyte Count ◽  
B Cell Lymphoma ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

3015 Background: Mirzotamab clezutoclax (ABBV-155) is a first-in-class antibody drug conjugate comprised of a BCL-XL (B-cell lymphoma - extra long) inhibitor, solubilizing linker, and a monoclonal anti-B7H3 antibody. Methods: Patients (pts) with relapsed and/or refractory (R/R) solid tumors were administered mirzotamab clezutoclax with or without paclitaxel. Dose escalation of mirzotamab clezutoclax was guided by Bayesian continual reassessment. Primary outcomes were to determine the maximum tolerated dose (MTD) and the recommended phase 2 dose (RP2D). Secondary outcomes: safety, pharmacokinetics, and overall response rate per RECIST v1.1. Results: As of November 6, 2020, 31 pts received mirzotamab clezutoclax monotherapy (monoTx) and 28 pts received combination therapy with paclitaxel (comboTx). Overall demographics: median age 62 years (range 25–79); 61% female; 86% white; 24% ECOG 0, 76% ECOG 1; 51% had > 3 prior systemic therapies. The median duration of mirzotamab clezutoclax exposure was 3 cycles (range 1–14) for monoTx and 5 cycles (range 1–14) for comboTx. There were no dose limiting toxicities (DLT) reported with monoTx. In comboTx, 2 pts experienced a DLT: Grade 4 neutrophil count decreased and Grade 3 lymphocyte count decreased considered related to paclitaxel. 97% of all pts had adverse events (AEs). The most common AEs (in ≥20% of pts) overall were fatigue (39%), nausea (25%), diarrhea and arthralgia (22% each), vomiting and hypokalemia (20% each). AEs in ≥5 pts related to mirzotamab cleuzutoclax were fatigue (27%), diarrhea (12%), and nausea (9%). Related Grade 3/4 AEs overall (in > 1 patient) included anemia, lymphocyte count decreased, fatigue, and diarrhea (3% each). One patient on monoTx experienced a fatal cardiac arrest. No fatal AEs occurred on comboTx. Responses were observed with comboTx as shown in the Table. Conclusions: Mirzotamab clezutoclax as monotherapy and with paclitaxel demonstrates a tolerable safety profile (MTD not reached) with anti-tumor activity in R/R solid tumors. Further investigation in prospectively-selected B7H3 positive tumors as monoTx in pts with R/R small cell lung cancer and with paclitaxel in pts with R/R breast cancer and docetaxel in pts with R/R non-small cell lung cancer in the dose expansion phase is ongoing. Clinical trial information: NCT03595059. [Table: see text]

scholarly journals 397 A phase I/II trial of intracerebroventricular 177Lu DTPA omburtamab radioimmunotherapy for leptomeningeal metastasis from solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A429-A429
Author(s):  
Elena Pentsova ◽  
Maria Düring ◽  
Charlotte Lybek Lind ◽  
John Rømer Nielsen
Keyword(s):  
Breast Cancer ◽  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Cell Lung Cancer ◽  
Leptomeningeal Metastasis ◽  
Primary Objective ◽  
Small Cell ◽  
Lobular Breast Cancer ◽  
Small Cell Lung

BackgroundLeptomeningeal metastasis (LM) from solid tumors may be diagnosed in approximately 10% of patients with metastatic cancer and can occur with virtually all malignant tumors. Median overall survival (OS) is poor and limited to a few months with LM-directed treatment, including available targeted therapy, immunotherapy and radiation therapy. Omburtamab specifically binds to B7-H3 (CD276), a transmembrane glycoprotein of the immunoglobulin superfamily. The limited expression of B7-H3 on normal cells, including normal brain, combined with the broad expression in various types of solid tumors, makes B7-H3 a target for radioimmunotherapy of LM from solid tumors. In this first-in-human trial the safety and efficacy of intracerebroventricular administration of radiolabeled omburtamab, 177Lu-DTPA-omburtamab, will be evaluated in patients with LM from ductal or lobular breast cancer, non-small cell lung cancer, or melanoma.MethodsThis is an open-label phase I/II study. Part 1 is a dose-escalation phase to be conducted at ~4 sites (US/Europe) with a primary objective of identifying the maximum tolerated dose and/or recommended phase II dose for Part 2 (RP2D). It will follow a 3+3 design with pts receiving up to five 5-week cycles of 177Lu-DTPA-omburtamab. Part 2 is a cohort-expansion phase at ~9 sites (US/Europe) in which a maximum of 48 patients in 3 cohorts (ductal or lobular breast cancer [cohort A], non-small cell lung cancer [cohort B], and melanoma [cohort C]) with up to 16 patients in each will receive up to five 5 week cycles of treatment with intracerebroventricular 177Lu DTPA omburtamab at the RP2D determined in Part 1. The primary objective of Part 2 is to establish the safety of repeat doses of 177Lu-omburtamab. Additional objectives of Parts 1/2 include the evaluation of absorbed radiation doses, PK profile, investigator-assessed response, duration of response, progression-free survival, and OS. Key inclusion criteria include diagnosis of either ductal or lobular breast cancer, non-small cell lung cancer, or malignant melanoma and diagnosis of recurrent or refractory LM; prior standard of care treatment of leptomeningeal disease; acceptable hematological, liver and kidney status; and a life expectancy of >2 months. The study has been approved by each institution’s ethics board, and patients provided informed consent before taking part.Trial RegistrationNCT04315246Ethics ApprovalThe study has been approved by each institution’s ethics board, and patients provided informed consent before taking part.

Neuroendocrine Tumors of the Lung Other Than Small Cell Lung Cancer

2018 ◽  
pp. 555-568.e6
Author(s):  
Krista Noonan ◽  
Jules Derks ◽  
Janessa Laskin ◽  
Anne-Marie C. Dingemans
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Neuroendocrine Tumors ◽  
Cell Lung Cancer ◽  
Small Cell ◽  
Small Cell Lung

A phase I study of XL228, a potent IGF1R/AURORA/SRC inhibitor, in patients with solid tumors or hematologic malignancies

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 3512-3512
Author(s):  
D. C. Smith ◽  
C. Britten ◽  
D. O. Clary ◽  
L. T. Nguyen ◽  
P. Woodard ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Solid Tumors ◽  
Cell Lung Cancer ◽  
Kinase Inhibitor ◽  
Phase 1 ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Clinical Activity ◽  
Small Cell Lung

3512 Background: XL228 is a protein kinase inhibitor targeting IGF1R, the AURORA kinases, FGFR1–3, ABL and SRC family kinases. It is being evaluated in a phase 1 trial in patients (pts) with advanced malignancies. Methods: XL228 is administered as weekly 1-hour IV infusions. Cohorts of pts with refractory solid tumors or lymphoma are evaluated for determination of the maximum tolerated dose, pharmacokinetics, and pharmacodynamic effects using FDG-PET, signal pathway analysis in tumor and normal tissue biopsies, and plasma marker analysis. MTD expansion cohorts will include pts with multiple myeloma and colorectal cancer. Results: Thirty-six pts have been treated at doses ranging from 0.45 to 8.0mg/kg. The maximum administered dose was defined as 8.0mg/kg as a result of the dose limiting toxicities of Grade (Gr) 4 neutropenia, and Gr 3 neutropenia requiring dose skipping. XL228 is generally well tolerated; one serious adverse event of drug-related Gr 3 vomiting has been observed. Common drug-related adverse events include Gr 1 nausea, fatigue, decreased appetite, and flushing, and Grade 1–2 hyperglycemia (fasting) lasting up to 4 hours post- infusion. XL228 exposure was approximately dose-proportional; the mean terminal half-life (t1/2, z) ranged from 27 to 54 hours. Low accumulation was observed after weekly administration. Protein phosphorylation measurements in skin, hair, and blood samples demonstrate inhibition of IGF1R, SRC and FGFR1 signaling by XL228, including reductions in hair follicle phospho-IGF1R and phospho-FAK1 of 39% and 42%, respectively, in a pt dosed at 5.4mg/kg. Evidence of clinical activity includes one non-small cell lung cancer pt with an unconfirmed partial response (confirmation pending) and 9 additional pts (of 30 evaluable) with stable disease (SD) lasting >3 months, including a small cell lung cancer pt on study for 13.3+ months after failing carboplatin/etoposide. For pts with SD, the median time on study is currently 5.9 months (range 3.3+ to 13.3+). Conclusions: XL228 is generally well tolerated and has shown encouraging preliminary clinical and pharmacodynamic activity. [Table: see text]

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