Base excision repair (BER) inhibitor TRC 102 (Methoxyamine) combined with pemetrexed (PEM)-based chemo-radiation (CRT) for locally advanced non-squamous non-small cell lung cancer (NS-NSCLC): Results of a phase I trial.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 9027-9027
Author(s):  
Tithi Biswas ◽  
Afshin Dowlati ◽  
Charles Kunos ◽  
John Pink ◽  
Nancy Oleinick ◽  
...  
Keyword(s):  
Excision Repair ◽  
Locally Advanced ◽  
Chemotherapy Resistance ◽  
Stage Iv ◽  
Similar Efficacy ◽  
Primary Objective ◽  
Phase 2 ◽  
Abasic Sites ◽  
Phase 2 Trial ◽  
Base Excision

9027 Background: About 35% of all NSCLC presents with locally advanced disease and chemo-radiation results in 5-year OS of only ~31%. PEM-platinum combination is approved in stage IV NSCLC and has similar efficacy to platinum-etoposide in stage 3 NSCLC and a favorable toxicity profile (Proclaim trial). TRC102 is an oral small molecule inhibitor of BER. TRC102 potentiates the cytotoxicity of antimetabolites and alkylators and reverses chemotherapy resistance by rapidly and covalently binding to chemotherapy-induced abasic sites in DNA. TRC102 increased radio-sensitization by PEM of NSCLC cell lines and H1299 and A549 xenografts. Methods: Between 11/2015 and 5/2019, 15 patients were enrolled in a 3+ 3 design: 12 with stage III and 3 with oligometastatic stage IV NS-NSCLC. The primary objective was to determine dose-limiting toxicities (DLT’s) and recommended Phase 2 dose (RP2D) of TRC102 in combination with PEM, cisplatin and radiotherapy. Secondary objectives were to assess toxicity, tumor response and PFS at 6 months. Based on pre-clinical data, PEM-TRC102 was given on day 1, and cisplatin/radiotherapy was initiated on day 3. This schedule was duplicated on day 21 and day 23 of the second cycle. After completion of radiotherapy, two additional cycles of PEM-cisplatin were given. Toxicities were assessed by NCI CTACAE version 4 and 5. Results: Median patient age was 69 years (45-79) and median follow up was 16.6 months (3.1-38.6). There were no DLTs or grade 5 toxicity. Hematologic and GI toxicities were the most common adverse events (Table) and radiation pneumonitis was not seen. The RP2D of TRC102 was 200 mg when given with cisplatin/radiotherapy and PEM. Of 15 evaluable patients, 3 had CR (20%) and 12 had PR (80%). The 2-year PFS rate was 49%. Conclusions: PEM-TRC102 combined with cisplatin/radiotherapy in non-squamous NSCLC was safe and well tolerated, and did not cause safety signals beyond those expected from CRT. Preliminary response data and PFS in this cohort was encouraging. A phase 2 trial, integrating post-CRT immunotherapy with this aggressive DNA-damaging regimen is warranted. Clinical trial information: NCT02535325. [Table: see text]

scholarly journals A phase 2 trial of dasatinib in patients with locally advanced or stage IV mucosal, acral, or vulvovaginal melanoma: A trial of the ECOG-ACRIN Cancer Research Group (E2607)

Cancer ◽  
2017 ◽  
Vol 123 (14) ◽  
pp. 2688-2697 ◽  
Author(s):  
Kevin Kalinsky ◽  
Sandra Lee ◽  
Krista M. Rubin ◽  
Donald P. Lawrence ◽  
Anthony J. Iafrarte ◽  
...  
Keyword(s):  
Cancer Research ◽  
Research Group ◽  
Locally Advanced ◽  
Stage Iv ◽  
Phase 2 ◽  
Phase 2 Trial

scholarly journals Abasic Sites in the Transcribed Strand of Yeast DNA Are Removed by Transcription-Coupled Nucleotide Excision Repair

2010 ◽  
Vol 30 (13) ◽  
pp. 3206-3215 ◽  
Author(s):  
Nayun Kim ◽  
Sue Jinks-Robertson
Keyword(s):  
Nucleotide Excision Repair ◽  
Excision Repair ◽  
Genome Integrity ◽  
Genetic Studies ◽  
Abasic Sites ◽  
Dna And Rna ◽  
Nucleotide Excision ◽  
Ap Sites ◽  
Base Excision ◽  
Ap Site

ABSTRACT Abasic (AP) sites are potent blocks to DNA and RNA polymerases, and their repair is essential for maintaining genome integrity. Although AP sites are efficiently dealt with through the base excision repair (BER) pathway, genetic studies suggest that repair also can occur via nucleotide excision repair (NER). The involvement of NER in AP-site removal has been puzzling, however, as this pathway is thought to target only bulky lesions. Here, we examine the repair of AP sites generated when uracil is removed from a highly transcribed gene in yeast. Because uracil is incorporated instead of thymine under these conditions, the position of the resulting AP site is known. Results demonstrate that only AP sites on the transcribed strand are efficient substrates for NER, suggesting the recruitment of the NER machinery by an AP-blocked RNA polymerase. Such transcription-coupled NER of AP sites may explain previously suggested links between the BER pathway and transcription.

A phase 2 trial of inhaled nitrous oxide for treatment-resistant major depression

2021 ◽  
Vol 13 (597) ◽  
pp. eabe1376
Author(s):  
Peter Nagele ◽  
Ben J. Palanca ◽  
Britt Gott ◽  
Frank Brown ◽  
Linda Barnes ◽  
...  
Keyword(s):  
Nitrous Oxide ◽  
Depressive Symptoms ◽  
Major Depression ◽  
Rating Scale ◽  
Similar Efficacy ◽  
Comparable Efficacy ◽  
Crossover Fashion ◽  
Phase 2 ◽  
Treatment Resistant ◽  
Phase 2 Trial

Nitrous oxide at 50% inhaled concentration has been shown to improve depressive symptoms in patients with treatment-resistant major depression (TRMD). Whether a lower concentration of 25% nitrous oxide provides similar efficacy and persistence of antidepressant effects while reducing the risk of adverse side effects is unknown. In this phase 2 clinical trial (NCT03283670), 24 patients with severe TRMD were randomly assigned in a crossover fashion to three treatments consisting of a single 1-hour inhalation with (i) 50% nitrous oxide, (ii) 25% nitrous oxide, or (iii) placebo (air/oxygen). The primary outcome was the change on the Hamilton Depression Rating Scale (HDRS-21). Whereas nitrous oxide significantly improved depressive symptoms versus placebo (P = 0.01), there was no difference between 25 and 50% nitrous oxide (P = 0.58). The estimated differences between 25% and placebo were −0.75 points on the HDRS-21 at 2 hours (P = 0.73), −1.41 points at 24 hours (P = 0.52), −4.35 points at week 1 (P = 0.05), and −5.19 points at week 2 (P = 0.02), and the estimated differences between 50% and placebo were −0.87 points at 2 hours (P = 0.69), −1.93 points at 24 hours (P = 0.37), −2.44 points at week 1 (P = 0.25), and −7.00 points at week 2 (P = 0.001). Adverse events declined substantially with dose (P < 0.001). These results suggest that 25% nitrous oxide has comparable efficacy to 50% nitrous oxide in improving TRMD but with a markedly lower rate of adverse effects.

scholarly journals Neoadjuvant and Adjuvant Pembrolizumab in Resectable Locally Advanced, Human Papillomavirus-Unrelated Head and Neck Cancer: A Multicenter, Phase 2 Trial

2020 ◽  
Author(s):  
Ravindra Uppaluri ◽  
Katie M. Campbell ◽  
Ann Marie Egloff ◽  
Paul Zolkind ◽  
Zachary L. Skidmore ◽  
...  
Keyword(s):  
Human Papillomavirus ◽  
High Risk ◽  
Head And Neck ◽  
Relapse Rate ◽  
Locally Advanced ◽  
Giant Cells ◽  
Phase 2 ◽  
Phase 2 Trial ◽  
One Year ◽  
The One

SUMMARYBackgroundPembrolizumab improved survival of patients with recurrent or metastatic head and neck squamous-cell carcinoma (HNSCC). The aims of this phase 2 trial were to determine if pembrolizumab administered to patients with resectable locally advanced, human papillomavirus (HPV)-unrelated HNSCC would be safe, result in pathologic tumor response (pTR), and lower the relapse rate.MethodsNeoadjuvant pembrolizumab (200 mg) was administered 2-3 weeks before surgery. Resection of the primary tumor and involved/at-risk nodes was performed. Post-operative (chemo) radiation was planned. Patients with high-risk pathology (positive margins and/or extranodal extension) were to receive adjuvant pembrolizumab. pTR was quantified as the proportion of the resection bed with tumor necrosis, keratinous debris, and giant cells/histiocytes: pTR-0 (<10%), pTR-1 (10-49%), and pTR-2 (≥50%). Co-primary endpoints were pTR-2 among all patients, and one-year relapse rate in patients with high-risk pathology (historical: 35%). Correlations of baseline PD-L1 expression and T-cell infiltration with pTR were assessed, and tumor clonal dynamics were evaluated. Analyses were done per protocol. This trial is registered with ClinicalTrials.gov(NCT02296684), and is ongoing but closed to accrual.FindingsBetween June 30, 2015, and March 30, 2018, 36 patients enrolled. After neoadjuvant pembrolizumab, serious (grades 3-4) adverse events and unexpected surgical delays/complications did not occur. pTR-2 occurred in eight patients (22%), and pTR-1 in eight other patients (22%). pTR ≥10% correlated with baseline tumor PD-L1 expression, immune infiltrate, and IFN-γ pathway activity. Matched sample analysis showed compensatory upregulation of multiple immune inhibitory checkpoints in patients with pTR-0, and confirmed that clonal loss occurred in some patients. The one-year relapse rate among the eighteen patients with high-risk pathology was 16.7% (95%CI: 3.6-41.4%).ConclusionsAmong patients with locally advanced, HPV-unrelated HNSCC, neoadjuvant pembrolizumab was safe, and resulted in pTR-1 or pTR-2 in 44% of patients. The one-year relapse rate in patients with high-risk-pathology was lower than historical.FundingMerck, NCI, NIDCR, NHGRI and The V Foundation.

Processing of the abasic sites clustered with the benzo[a]pyrene adducts by the base excision repair enzymes

DNA Repair ◽  
2017 ◽  
Vol 50 ◽  
pp. 43-53 ◽  
Author(s):  
Lidia V. Starostenko ◽  
Nadejda I. Rechkunova ◽  
Natalia A. Lebedeva ◽  
Alexander A. Lomzov ◽  
Vladimir V. Koval ◽  
...  
Keyword(s):  
Base Excision Repair ◽  
Excision Repair ◽  
Abasic Sites ◽  
Repair Enzymes ◽  
Base Excision

Nilotinib in locally advanced pigmented villonodular synovitis: a multicentre, open-label, single-arm, phase 2 trial

2018 ◽  
Vol 19 (5) ◽  
pp. 639-648 ◽  
Author(s):  
Hans Gelderblom ◽  
Claire Cropet ◽  
Christine Chevreau ◽  
Richard Boyle ◽  
Martin Tattersall ◽  
...  
Keyword(s):  
Locally Advanced ◽  
Pigmented Villonodular Synovitis ◽  
Villonodular Synovitis ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Pigmented Villonodular

Interim analysis of a phase II study of simultaneously integrated boost intensity modulated radiation therapy (SIB-IMRT) in combination with 5-FU and mitomycin-C among patients with locally advanced anal canal cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15501-e15501
Author(s):  
Carmen Florescu ◽  
Justine Lequesne ◽  
Jean-Michel Grellard ◽  
Aurélie Parzy ◽  
Marie-Pierre Galais ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Anal Canal ◽  
Mitomycin C ◽  
Interim Analysis ◽  
Locally Advanced ◽  
Intensity Modulated Radiation Therapy ◽  
Phase 2 ◽  
Efficacy And Safety ◽  
Intensity Modulated ◽  
Phase 2 Trial

e15501 Background: Concomitant radiochemotherapy is the standard treatment of locally advanced epidermoid anal canal carcinoma (EACC) but conventional radiotherapy (RT) frequently induces significant non-hematological toxicities, resulting in long treatment breaks. Given the numerous anatomic pelvic structures, EACC has become of interest for Intensity-Modulated Radiation Therapy (IMRT) despite the induced cutaneous toxicities responsible for RT breaks. Given the deleterious effect of treatment duration on local control and survival in other epidermoid cancers, continuous IMRT is challenging to control EACC. Several SIB-IMRT schedules provided similar results with moderate doses and schedules delivering higher doses with short breaks. Yet, standard SIB-IMRT schedule in EACC still not exists. We propose to concomitantly assess the safety and efficacy of continuous SIB-IMRT without planned breaks and concurrent chemotherapy (CT) to improve the treatment of locally advanced EACC by reducing the proportion of patients (pts) requiring RT breaks for toxicities. Methods: The CANAL-IMRT-01 phase 2 trial (NCT02701088) targets pts with histologically proven EACC candidate for concomitant RT of pelvic and inguinal nodes plus CT. Applying a two-step Bryant & Day design, the main criterion is based on both efficacy and safety. Efficacy is defined as the proportion of pts alive with no local disease progression 3 months after the end of IMRT; safety is defined as the proportion of pts with no RT breaks required by grade ≥3 toxicities. Assuming the unacceptable and acceptable proportions of pts without toxicity requiring IMRT break are 60 and 80% respectively, the unacceptable and acceptable 3-month-progression-free-survival are 80 and 90%, 14 assessable pts at first step and 46 in the second are required (alpha risk 5%, 90% power). To anticipate a 10% drop out rate, 16 pts were needed in first step, with ≥11 objective local responses and ≤6 toxicity-induced IMRT breaks to pursue. Treatment consists in 50 days of concomitant CT (2 cycles of 5FU and Mitomycin-C) and SIB-IMRT delivered by helical tomotherapy: 61.2Gy/1.7Gy to the primary tumor, 57.6Gy/1.6Gy to involved nodes, and 54/1.5Gy to elective pelvic lymph nodes. Results: From December 2015 to June 2017, 16 pts were enrolled: 11 female (73%), median age 62 [55-66]. 15 pts were assessable for efficacy and safety. All 15 pts had a 3-month locoregional response (12 complete responses, 3 partial responses). SIB-IMRT breaks were required by toxicities for 4 out of 15 pts: G1 radiodermitis, G2 inguinal and epithelitis, G1 fever, G3 anorexia and vertigo. Conclusions: The planned interim analysis of continuous SIB-IMRT plus CT allowed pursuing this phase 2 trial to assess the relevance of such schedule for locally advanced ASCC. Enrolment is still ongoing. Clinical trial information: NCT02701088.

Sign in / Sign up

Export Citation Format

Share Document