Auswahl der wissenschaftlichen Literatur zum Thema „NIVACOR Trial“

TPS4118 Background: FOLFOXIRI (fluorouracil, leucovorin, oxaliplatin, and irinotecan) plus bevacizumab has been shown to be one of the therapeutic regimens in first line with the highest activity profile in patients (pts) with metastatic colorectal cancer (mCRC) unselected for biomolecular alterations. Tumors co-opt the PD-1/PD-L1 signaling pathway as one key mechanism to evade immune destruction. Anti-PD-1 monoclonal antibodies are FDA approved only for DNA mismatch repair deficient/microsatellite instability-high (MMRd/MSI-H), which are only about 5% among all mCRC. Nowadays, there are no data demonstrating anti-PD1 activity in stable and proficient (MMRp/MSS) disease. Another critical therapeutic target is the Vascular Endothelial Growth Factor A (VEGF-A), which acts on endothelial cells to stimulate angiogenesis; his inhibition with bevacizumab increase immune cell infiltration, giving a strong rationale for combining VEGF targeted agents with immune checkpoint inhibitors. Based on evidence, we explore the combination of triplet chemotherapy (FOLFOXIRI) with bevacizumab and nivolumab in pts with mCRC all- RAS/BRAF mutant regardless of microsatellite status. Methods: This is a prospective, open-label, multicentric phase II trial where pts with mCRC RAS/BRAF mutant in first line will receive nivolumab in combination with FOLFOXIRI/Bevacizumab every 2 weeks for 8 cycles followed by maintenance with bevacizumab plus nivolumab every 2 weeks. Bevacizumab will be administered intravenously at dose of 5 mg/kg every 2 weeks and nivolumab intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint is the overall response rate (ORR) and our hypothesis is that the treatment is able to improve the ORR from 66% to 80%. Secondary endpoints include overall survival, safety, time to progression, duration of response. Collateral translational studies evaluate the tumor mutational burden, and genetic alterations by circulating free DNA (cfDNA) obtained from plasma samples. The trial is open to enrollment, 4 of planned 70 pts have been enrolled. Clinical trial information: EudraCT Number: 2018-002893-38. Clinical trial information: NCT04072198 .

37 Background: NIVACOR trial is an open-label, multicentric Italian phase II trial of FOLFOXIRI/bevacizumab in association with an anti-PD1 antibody, nivolumab, in patients (pts) with metastatic colorectal cancer (mCRC). We report preliminary safety analysis by an Independent Monitoring Committee. Methods: Pts with mCRC RAS or BRAF mutated, regardless microsatellite status and eligible to receive a first line treatment will be enrolled. FOLFOXIRI/bevacizumab (BEV) in association with nivolumab (NIV) was administered every 2 weeks for 8 cycles (induction) followed by BEV plus NIV every 2 weeks (maintenance) until PD or unacceptable toxicities. BEV was administered intravenously at dose of 5 mg/kg and NIV intravenously as a flat dose of 240 mg every 2 weeks. The primary endpoint was the ORR. The safety is assessed after the inclusion of the 10th patient, receiving ≥1 dose. Results: As of September 20, 2020, 25/70 pts are enrolled. The first 10 pts were evaluated for preliminary safety analysis. Median age was 58 years (32-66), 60% of pts were male, median cycles of treatment was 5.5 (1-9). 100% were KRAS G12D mut and BRAF wild type, respectively, and 2% MSI-H/dMMR. 7/10 pts experienced at least one AE related to FOLFOXIRI/BEV and 2/10 related to NIV. The most frequent grade 1-2 AEs related to FOLFOXIRI/BEV were nausea and vomiting 4(57%), fatigue 5(71%), and diarrhea 5(71%); 3(43%) pts had grade 3-4 neutropenia, and 1(14%) febrile neutropenia. Only 2 pts developed grade 1-2 AEs related to NIV represented by rash (50%) and salivary gland infection (50%); no grade 3-4 was reported. One of pts with dose delay because of serious AES (proteinuria) BEV related, and one patient discontinued due to serious AEs (ileo-urethral fistula) not related to NIV. Conclusions: Combination of FOLFOXIRI/BEV and NIV was generally well tolerated and showed an acceptable toxicity profile. The final analysis will be scheduled at the end of enrollment. Clinical trial information: NCT04072198.

Abstract Background: Patients treated for early stage breast cancer (BC) have a 30% lifetime risk of developing metastatic disease. Numerous studies have demonstrated that dormant bone marrow disseminated tumor cells (DTCs) are independently associated with risk of recurrence and death, yet interventions targeting these cells are lacking. The PENN-SURMOUNT (Surveillance Markers of Utility for Recurrence after (Neo)adjuvant Therapy) Screening Study was launched in 2016 to screen high risk BC survivors for DTCs using bone marrow aspirate (BMA) and identify eligible DTC positive patients for clinical trials. Given the novelty of this approach, we concurrently developed and pilot tested a PRO measurement strategy to study how the screening method of BMA and disclosure of DTC results impacts early-stage BC patients. Methods: PENN-SURMOUNT is a single center prospective, longitudinal cohort study examining BM and blood biomarkers of MRD among patients within 5 years of BC diagnosis who have high risk criteria (positive axillary nodes, triple negative biology, ER+ with Oncotype Dx ≥ 25 and/or high risk Mammaprint, or pathologic residual disease after neoadjuvant chemotherapy). From May 2019 – August 2021, we recruited patients on SURMOUNT to complete PRO surveys at baseline (T0), after BMA (T1), and after disclosure of DTC results (T2). Surveys were administered in paper form initially, then electronic form starting Feb 2021. PRO survey instruments were selected through literature review, followed by consensus among multidisciplinary clinical and research experts and patient advocates. PRO measures assess recurrence distress (Quality of Life in Adult Cancer Survivors, QLACS), illness intrusiveness (Illness Intrusiveness Ratings Scale, IIRS), and decision making (Decision Regret Scale). Additional survey items assess tolerability of the BMA and patients’ risk perception and cognitive understanding after DTC results disclosure. Descriptive statistics summarize PRO survey compliance and responses at T0, T1, and T2 in the total population and the population who reported longitudinal data for T2. Results: 61 of 66 eligible patients on the SURMOUNT trial enrolled in the PRO pilot study and completed a baseline survey, of which 47 (77%) tested negative for DTCs. Mean completion rates were 0.92 at T0, 0.85 at T1, and 0.56 at T2. After electronic survey implementation, completion rates increased to 0.94 (T0), 0.97 (T1) and 0.81 (T2). At T0, 36 (59%) patients reported a high risk perception of developing BC recurrence at 5 years and 42 (69%) during their lifetime. Mean T0 recurrence distress using the QLACS subscale was 14.6 (SD 6.3) out of possible score 4-28, compared to an expected mean of 11.42 (SD 5.48) in a general survivorship population. Mean T0 illness intrusiveness was 27.3 (SD 13.9) out of possible score 13-91. At T1, approximately 85% of patients agreed that they correctly understood the purpose of the bone marrow procedure and what the procedure would entail. 44 (72%) of patients reported a maximum pain score <= 4 in the week post-procedure and 42 (69%) reported the BMA was same or better than expected tolerability. Exploratory subset analysis of patients with complete longitudinal data at T2 (n = 34) showed average scores of 13.4 (SD 6.0), 30.1 (SD 14.0), and 2.8 (SD 6.2) for recurrence distress, illness intrusive, and decision regret scores (scale 0-100), respectively. At T2, 26 (76%) of patients reported no decision regret for undergoing testing for DTCs; 27 (79%) reported feeling less anxious after DTC results disclosure. Conclusions: Participants of PENN-SURMOUNT perceived risk of recurrence as high. The BMA procedure was well-tolerated and better than expected among the majority of this cohort, and most did not regret having undergone BMA after DTC status disclosure. Longitudinal completion rates were low, limiting assessment of PROs at later time points, a major focus of future work in this setting. Citation Format: Tara Kaufmann, Patrick Chang, Shoshana Rosenberg, Elizabeth Frank, Brian Hobbs, Lauren J. Bayne, Isoris Nivar, Brooke L. Goodspeed, Killian M. Rohn, Emily M. Kugler, Kevin Fox, Susan Domchek, Angela Bradbury, Payal Shah, Hayley Knollman, Rachel C. Jankowitz, Igor Makhlin, Amy S. Clark, Lewis A. Chodosh, Angela DeMichele, Katherine Goodfellow. Pilot study of a patient-reported outcome (PRO) measurement strategy to determine impact of screening for minimal residual disease (MRD) in high-risk breast cancer survivors [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr P5-08-01.

The NIVACOR trial is a phase II study assessing the efficacy and safety of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line setting in patients affected by metastatic colorectal cancer (mCRC) RAS/BRAF mutated. We report safety run-in results in the first 10 patients enrolled. Patients received triplet chemotherapy with FOLFOXIRI scheme plus bevacizumab, in association with nivolumab every 2 weeks for 8 cycles (induction phase) followed by bevacizumab plus nivolumab every 2 weeks (maintenance phase), until progression of disease or unacceptable toxicities. The first ten patients were evaluated: 7 experienced at least one adverse event (AE) related to FOLFOXIRI/bevacizumab and 2 related to nivolumab. The most frequent grade 1–2 AEs related to FOLFOXIRI/bevacizumab were diarrhea and fatigue (71%), nausea and vomiting (57%); 3 (43%) had grade 3–4 neutropenia, and 2 (20%) patients developed grade 1–2 AEs nivolumab related: skin rash and salivary gland infection. Two patients delayed the dose because of serious AEs, proteinuria and salivary gland infection; one patient discontinued experimental treatment due to the ileo-urethral fistula and concurrent Clostridium infection diarrhea. No treatment- related death occurred. The safety run-in analysis of NIVACOR trial reassured using co-administration of FOLFOXIRI/bevacizumab and nivolumab was well tolerated with an acceptable toxicity profile.Clinical Trial Registrationhttps://clinicaltrials.gov/, (NCT04072198).

The phase II NIVACOR trial, an open-label, multicenter study, was designed to assess in the first-line setting, the efficacy and safety in patients affected by mCRC RAS/BRAF mutated, an anti-PD-1 antibody, nivolumab, in combination with chemotherapy triplet scheme (FOLFOXIRI) plus an anti-VEGF antibody, bevacizumab. The preliminary safety run-in analysis performed by an Independent Monitoring Committee (IDMC), after the 10th patient enrolled was conducted. The main grade 1-2 adverse events (AEs) related to FOLFOXIRI/bevacizumab affect mainly diarrhea and fatigue (71%), nausea and vomiting (57%), followed by grade 3-4 neutropenia (43%) and febrile neutropenia (14%). Grade 1-2 immune-related AEs were reported in two patients as skin rash and salivary gland infection. Two serious AEs have been reported both related to FOLFOXIRI/bevacizumab. Overall, these toxicities appear to be manageable and no major safety concerns arose. In mCRC, the coexistence of immune cell infiltration and persistent neo-angiogenesis might develop an atypical response pattern and fail the conventional criteria to detect the atypical patterns of tumor response. In the preliminary analysis in 47 patients, different exploratory criteria (RECIST 1.1., iRECIST, Choi) were performed to assess whether there was concordance. Although in a small sample of patients, these results show that there is concordance from the use of RECIST 1.1 and iRECIST criteria to evaluate the percentage variation in the sum of the diameters of the target lesions and consequently the response to treatment. More significative differences were highlighted using the Choi criteria considering the percentage variation of density in target lesions showing a higher prevalence of partial response compared to stable disease compared to RECIST Criteria.