Using Plasma Transforming Growth Factor Beta-1 During Radiotherapy to Select Patients for Dose Escalation

2001 ◽  
Vol 19 (17) ◽  
pp. 3758-3765 ◽  
Author(s):  
Mitchell S. Anscher ◽  
Lawrence B. Marks ◽  
Timothy D. Shafman ◽  
Robert Clough ◽  
Hong Huang ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Dose Escalation ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

PURPOSE: The ability to prescribe treatment based on relative risks for normal tissue injury has important implications for oncologists. In non–small-cell lung cancer, increasing the dose of radiation may improve local control and survival. Changes in plasma transforming growth factor beta (TGFβ) levels during radiotherapy (RT) may identify patients at low risk for complications in whom higher doses of radiation could be safely delivered. PATIENT AND METHODS: Patients with locally advanced or medically inoperable non–small-cell lung cancer received three-dimensional conformal RT to the primary tumor and radiographically involved nodes to a dose of 73.6 Gy (1.6 Gy twice daily). If the plasma TGFβ level was normal after 73.6 Gy, additional twice daily RT was delivered to successively higher total doses. The maximum-tolerated dose was defined as the highest radiation dose at which ≤ one grade 4 (life-threatening) late toxicity and ≤ two grade 3 to 4 (severe life-threatening) late toxicities occurred. RESULTS: Thirty-eight patients were enrolled. Median follow-up was 16 months. Twenty-four patients were not eligible for radiation dose escalation beyond 73.6 Gy because of persistently abnormal TGFβ levels. Fourteen patients whose TGFβ levels were normal after 73.6 Gy were escalated to 80 Gy (n = 8) and 86.4 Gy (n = 6). In the 86.4-Gy group, dose-limiting toxicity was reached because there were two (33%) grade 3 late toxicities. CONCLUSION: It is feasible to use plasma TGFβ levels to select patients for RT dose escalation for non–small-cell lung cancer. The maximum-tolerated dose using this approach is 86.4 Gy.

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]

Phase I/II study of amrubicin and nedaplatin in patients with untreated, advanced non-small cell lung cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 7569-7569
Author(s):  
Hiroaki Senju ◽  
Daiki Ogawara ◽  
Yoichi Nakamura ◽  
Minoru Fukuda ◽  
Katsumi Nakatomi ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Dose Level ◽  
Cell Lung Cancer ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3

7569 Background: We conducted a phase I/II study of combination chemotherapy with nedaplatin (CDGP) and amrubicin (Amr) for patients with untreated, advanced non small-cell lung cancer (NSCLC). Methods: Eligible patients were having adequate organ function and PS of 0-1. CDGP was given on day 1 and amrubicin on days 1, 2 and 3. The treatment was repeated every 3 weeks. We fixed the dose of CDGP as 100 mg/m2, and escalated the dose of amrubicin from a starting dose of 25 mg/m2 by 5mg/m2 per each levels until the maximum tolerated dose (MTD). The MTD was defined as the dose level at which at least two of three or two of six patients experienced a dose-limiting toxicity (DLT). Results: Between June 2009 and May 2011, 36 patients were enrolled. In the phase I study, two DLTs occurred in six patients at level 2; dose level 1 was therefore recommended (25 mg/m2 Amr, 100mg/m2 CDGP). DLTs included cerebral infarction and grade 4 thrombocytopenia. In the phase II study, including phase I study, a total of 36 patients were enrolled and 132 cycles of chemotherapy were conducted. Grade 3 or 4 neutropenia, grade 3 anemia and grade 3 or 4 thrombocytopenia occurred in 75%, 16.6% and 19.4% in all cycles, respectively. Febrile neutropenia occurred in 4cycles (3%) but all of them were controllable. Eighteen patients achieved a partial response and the overall response rate was 51.4%. Conclusions: Combination of CDGP and Amr was highly effective and well tolerable in patients with untreated, advanced NSCLC.

P-169 Dose and volume-dependent changes of plasma transforming growth factor-beta during radiotherapy of non-small cell lung cancer

Lung Cancer ◽  
2003 ◽  
Vol 41 ◽  
pp. S133
Author(s):  
Katrien De Jaeger ◽  
Yvette Seppenwoolde ◽  
Harm H. Kampinga ◽  
Liesbeth J. Boersma ◽  
Jose S.A. Belderbos ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Small Cell ◽  
Small Cell Lung ◽  
Growth Factor Beta

scholarly journals A Phase I Trial of Temsirolimus and Pemetrexed in Patients with Advanced Non-Small Cell Lung Cancer

Chemotherapy ◽  
2016 ◽  
Vol 61 (3) ◽  
pp. 144-147 ◽  
Author(s):  
Saiama N. Waqar ◽  
Maria Q. Baggstrom ◽  
Daniel Morgensztern ◽  
Kristina Williams ◽  
Caron Rigden ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Phase I ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Mammalian Target Of Rapamycin ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Mtor Pathway ◽  
Small Cell Lung ◽  
Grade 3

Background: Pemetrexed is an antifolate chemotherapeutic agent approved for use in non-small cell lung cancer (NSCLC). The mammalian target of rapamycin (mTOR) pathway is implicated in lung cancer development and inhibited by temsirolimus. Methods: We performed a phase I study evaluating the combination of pemetrexed and temsirolimus in advanced non-squamous NSCLC. Results: Eight patients were enrolled in this study. The dose-limiting toxicities included grade 4 thrombocytopenia, grade 3 leukopenia and grade 3 neutropenia. The maximum tolerated dose was determined to be pemetrexed 375 mg/m2 intravenously on day 1 and temsirolimus 25 mg intravenously on days 1, 8 and 15. No objective responses were noted and 3 patients had stable disease as the best response. Conclusion: The combination of pemetrexed and temsirolimus is feasible and well tolerated. This combination may be further evaluated in patients with mTOR pathway activation, particularly in those with TSC1 or STK11 mutations.

Phase I study of combination chemotherapy with amrubicin and paclitaxel in relapsed small cell lung cancer

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18206-18206
Author(s):  
J. Tanaka ◽  
H. Yoshizawa ◽  
R. Ito ◽  
Y. Hayashi ◽  
H. Kuriyama ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Combination Chemotherapy ◽  
Performance Status ◽  
Maximum Tolerated Dose ◽  
Small Cell ◽  
Small Cell Lung ◽  
Grade 3 ◽  
Level 2

18206 Background: Amrubicin (AMR) and paclitaxel (PTX) are promising agents for advanced non-small cell and small cell lung cancer (SC). However, the combination of these drugs for relapsed SC has never been reported. The aim of this study was to determine the maximum tolerated dose (MTD) of AMR and PTX, thus to investigate the recommended dose (RD) of this combination chemotherapy for relapsed SC patients. Methods: Relapsed SC patients after 1 or 2 regimens with age younger than 70 and good performance status (PS) were eligible. The treatment consisted of AMR (escalating from 30 to 40 mg/m2 by 5 mg/m2 increment) as a one- shot iv on days 1 through 3, and PTX (escalating from 70 to 90 mg/m2 by 10 mg/m2 increment) as a 60-minute infusion on days 4 and 11, repeated every 21 days. The dose-limiting toxicities (DLTs) were defined as grade 3/4 non-hematological toxicities, grade 4 thrombocytopenia, and grade 4 leukocytopenia / neutropenia for 4 days or more. Results: Nine relapsed SC patients were enrolled. All of them were sensitive-relapsed cases with mean age of 60.1 and PS of 0 - 1, and received one or more cycles of chemotherapy (mean: 2.7 cycles). Six patients were treated at level 1 (AMR 30mg/m2, PTX 70 mg/m2) with two of them on DLT of grade 4 neutropenia for 4 days or more. Three patients were treated at level 2 (AMR 35 mg/m2, PTX 70 mg/m2) with all of them on DLTs; grade 4 neutropenia for 4 days or more, grade 3 febrile neutropenia, and grade 3 pneumonia. Overall response rate was 63%. Conclusion: The MTD was identified to be level 2, and the RD for this regimen with AMR and PTX was considered to be 30 mg/m2 and 70 mg/m2, respectively. Treatment was well tolerated and the preliminary activity observed warrants further investigation. A phase II study is currently under investigation for relapsed and refractory SC patients. No significant financial relationships to disclose.

scholarly journals MiR-216b/Smad3/BCL-2 Axis Is Involved in Smoking-Mediated Drug Resistance in Non-Small Cell Lung Cancer

Cancers ◽  
2020 ◽  
Vol 12 (7) ◽  
pp. 1879 ◽  
Author(s):  
Trung Vu ◽  
Shanzhong Yang ◽  
Pran K. Datta
Keyword(s):  
Lung Cancer ◽  
Tumor Suppressor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
B Cell Lymphoma ◽  
Epidemiologic Studies ◽  
Small Cell ◽  
Small Cell Lung

Epidemiologic studies have shown that vast majority of lung cancers (85–90%) are causally linked to tobacco smoking. Although much information has been gained about the effects of smoking on various signaling pathways, little is known about how deregulation of miRNAs leads to activation of oncogenes and inhibition of tumor suppressor genes in non-small cell lung cancer (NSCLC). Our previous study showed that smoking inhibits TGF-β-induced tumor suppressor functions through downregulation of Smad3 in lung cancer cells. In order to understand the upstream mechanism of downregulation of Smad3 by smoking, we performed miRNA microarray analyses after treating human lung adenocarcinoma A549 and immortalized peripheral lung epithelial HPL1A cells with cigarette smoke condensate (CSC). We identified miR-216b as being upregulated in CSC treated cells. MiR-216b overexpression decreases Smad3 protein expression by binding to its 3′-UTR, and attenuates transforming growth factor beta (TGF-β) signaling and target gene expression. MiR-216b increases B-cell lymphoma 2 (BCL-2) expression and promotes chemoresistance of NSCLC cells by decreasing apoptosis. Increased acetylation of histones H3 and H4 in miR-216b gene promoter plays a role in CSC induced miR-216b expression. Taken together, these results suggest that smoking-mediated upregulation of miR-216b increases NSCLC cell growth by downregulating Smad3 and inhibiting TGF-β-induced tumor suppressor function, and induces resistance to platinum-based therapy.

scholarly journals Genetic variations in the transforming growth factor-beta pathway as predictors of survival in advanced non-small cell lung cancer

2011 ◽  
Vol 32 (7) ◽  
pp. 1050-1056 ◽  
Author(s):  
Moubin Lin ◽  
David J. Stewart ◽  
Margaret R. Spitz ◽  
Michelle A.T. Hildebrandt ◽  
Charles Lu ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Growth Factor ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Genetic Variations ◽  
Small Cell ◽  
Small Cell Lung ◽  
Growth Factor Beta

scholarly journals A systematic review and meta-analysis of treatment-related toxicities of curative and palliative radiation therapy in non-small cell lung cancer

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
M. Or ◽  
B. Liu ◽  
J. Lam ◽  
S. Vinod ◽  
W. Xuan ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Systematic Review ◽  
Decision Making ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Meta Analysis ◽  
Small Cell ◽  
Small Cell Lung ◽  
Cardiac Events ◽  
Grade 3

AbstractTreatment-related toxicity is an important component in non-small cell lung cancer (NSCLC) management decision-making. Our aim was to evaluate and compare the toxicity rates of curative and palliative radiotherapy with and without chemotherapy. This meta-analysis provides better quantitative estimates of the toxicities compared to individual trials. A systematic review of randomised trials with > 50 unresectable NSCLC patients, treated with curative or palliative conventional radiotherapy (RT) with or without chemotherapy. Data was extracted for oesophagitis, pneumonitis, cardiac events, pulmonary fibrosis, myelopathy and neutropenia by any grade, grade ≥ 3 and treatment-related deaths. Mantel–Haenszel fixed-effect method was used to obtain pooled risk ratio. Forty-nine trials with 8609 evaluable patients were included. There was significantly less grade ≥ 3 acute oesophagitis (6.4 vs 22.2%, p < 0.0001) and any grade oesophagitis (70.4 vs 79.0%, p = 0.04) for sequential CRT compared to concurrent CRT, with no difference in pneumonitis (grade ≥ 3 or any grade), neutropenia (grade ≥ 3), cardiac events (grade ≥ 3) or treatment-related deaths. Although the rate of toxicity increased with intensification of treatment with RT, the only significant difference between treatment regimens was the rate of oesophagitis between the use of concurrent and sequential CRT. This can aid clinicians in radiotherapy decision making for NSCLC.

Sign in / Sign up

Export Citation Format

Share Document