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]

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.

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.

PO-1844 Adaptive dose escalation for non-small cell lung cancer patients treated with VMAT

2021 ◽  
Vol 161 ◽  
pp. S1572-S1573
Author(s):  
N.S. Tambe ◽  
I.M. Pires ◽  
C. Moore ◽  
A. Wieczorek ◽  
S. Upadhyay ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cancer Patients ◽  
Cell Lung Cancer ◽  
Dose Escalation ◽  
Small Cell ◽  
Small Cell Lung ◽  
Lung Cancer Patients

Phase II Study of Pemetrexed and Carboplatin Plus Bevacizumab With Maintenance Pemetrexed and Bevacizumab As First-Line Therapy for Nonsquamous Non–Small-Cell Lung Cancer

2009 ◽  
Vol 27 (20) ◽  
pp. 3284-3289 ◽  
Author(s):  
Jyoti D. Patel ◽  
Thomas A. Hensing ◽  
Alfred Rademaker ◽  
Eric M. Hart ◽  
Matthew G. Blum ◽  
...  
Keyword(s):  
Lung Cancer ◽  
Small Cell Lung Cancer ◽  
Cell Lung Cancer ◽  
Objective Response ◽  
Small Cell ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Small Cell Lung ◽  
Time Curve ◽  
Grade 3

PurposeThis study evaluated the efficacy and safety of pemetrexed, carboplatin, and bevacizumab followed by maintenance pemetrexed and bevacizumab in patients with chemotherapy-naive stage IIIB (effusion) or stage IV nonsquamous non–small-cell lung cancer (NSCLC).Patients and MethodsPatients received pemetrexed 500 mg/m2, carboplatin area under the concentration-time curve of 6, and bevacizumab 15 mg/kg every 3 weeks for six cycles. For patients with response or stable disease, pemetrexed and bevacizumab were continued until disease progression or unacceptable toxicity.ResultsFifty patients were enrolled and received treatment. The median follow-up was 13.0 months, and the median number of treatment cycles was seven (range, one to 51). Thirty patients (60%) completed ≥ six treatment cycles, and nine (18%) completed ≥ 18 treatment cycles. Among the 49 patients assessable for response, the objective response rate was 55% (95% CI, 41% to 69%). Median progression-free and overall survival rates were 7.8 months (95% CI, 5.2 to 11.5 months) and 14.1 months (95% CI, 10.8 to 19.6 months), respectively. Grade 3/4 hematologic toxicity was modest—anemia (6%; 0), neutropenia (4%; 0), and thrombocytopenia (0; 8%). Grade 3/4 nonhematologic toxicities were proteinuria (2%; 0), venous thrombosis (4%; 2%), arterial thrombosis (2%; 0), fatigue (8%; 0), infection (8%; 2%), nephrotoxicity (2%; 0), and diverticulitis (6%; 2%). There were no grade 3 or greater hemorrhagic events or hypertension cases.ConclusionThis regimen, involving a maintenance component, was associated with acceptable toxicity and relatively long survival in patients with advanced nonsquamous NSCLC. These results justify a phase III comparison against the standard-of-care in this patient population.

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