Encorafenib and binimetinib with or without nivolumab in treating patients with metastatic radioiodine refractory BRAF V600 mutant thyroid cancer.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS6085-TPS6085
Author(s):  
Matthew H. Taylor ◽  
Rom S. Leidner ◽  
Richard Bryan Bell ◽  
Bernard Fox ◽  
Hong Xiao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Thyroid Cancer ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Braf V600e ◽  
Braf Inhibitors ◽  
Multikinase Inhibitors ◽  
Braf Mutant

TPS6085 Background: Differentiated thyroid cancer is the most common endocrine malignancy and has a high frequency of actionable molecular aberrations including BRAF V600E mutations (45%), RET fusions (10%), and NTRK fusions ( < 2%). FDA approved systemic therapies for metastatic radioiodine refractory differentiated thyroid cancer (RR-DTC) include multikinase inhibitors (Lenvatinib and sorafenib), NTRK inhibitors (larotrectinib and entrectinib for NTRK fusion+ cancers), and RET inhibitors (selpercatinib and pralsetinib for RET fusion+ cancers). Previous phase II clinical trials showed clinical efficacy with first and second generation BRAF inhibitors in patients with BRAF mutant RR-DTC. BRAF inhibitors have not yet been FDA approved for treatment of BRAF mutant RR-DTC. Effective therapeutic options for patients with BRAF mutant RR-DTC remains an important unmet clinical need. BRAF mutant thyroid cancers often show elevated expression of PD-L1. Additionally, BRAF inhibition results in increased expression of PD-L1 in thyroid cancer. This clinical trial seeks to evaluate the safety and efficacy of encorafenib plus binimetinib with or without nivolumab in patients with BRAF mutant metastatic RR-DTC. Encorafenib and binimetinib are highly selective and potent oral inhibitors of BRAF and MEK, respectively. Nivolumab is a potent inhibitor of the immune co-inhibitory receptor programmed cell death protein 1 (PD-1). Methods: This is a phase II, single institution, open-label, randomized clinical trial evaluating the combinations of (Arm 1) encorafenib 450 mg/day + binimetinib 45 mg twice daily and (Arm 2) encorafenib 450 mg/day + binimetinib 45 mg twice daily + nivolumab 480 mg I.V. every 4 weeks in patients with metastatic BRAF mutant RR-DTC. The trial will enroll 20 patients in each arm and treatment will be given in 28 day cycles for up to 2 years. Eligible patients must have metastatic/unresectable BRAF mutant RR-DTC, an ECOG performance status of 0-1 and adequate bone marrow, liver and kidney function. Patients with CNS metastases are included if the metastases have been treated and remained stable or are asymptomatic and ≤10 mm in diameter. Patients may be systemic therapy naïve or have previously been treated with multikinase inhibitors. Prior therapy with BRAF, MEK or immune checkpoint inhibitors is exclusionary. The primary endpoint is confirmed objective response rate (ORR) determined by RECIST v1.1 with restaging imaging every 12 weeks. Secondary endpoints include progression free survival, overall survival, and safety/tolerability (CTCAE v5.0). Arms 1 and 2 will be evaluated independently and are not powered for direct comparison. The trial design includes continuous toxicity monitoring with a Pocock-type stopping boundary. This clinical trial is in progress and 3 patients have been enrolled. Clinical trial information: NCT04061980.

Long-term results of phase II trial of apatinib for progressive radioiodine refractory differentiated thyroid cancer

2021 ◽  
Author(s):  
Yan-Song Lin ◽  
Xin Zhang ◽  
Chen Wang ◽  
Yan-Qing Liu ◽  
Wen-Min Guan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Thyroid Cancer ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Phase Ii Clinical Trial ◽  
Braf V600e ◽  
Long Term Results

Abstract Context Radioiodine refractory differentiated thyroid cancer (RAIR-DTC) has been a global challenge due to its poor prognosis and limited treatment options. Objective To report the long-term results of the phase II clinical trial of apatinib, an anti-angiogenic tyrosine kinase inhibitor, for RAIR-DTC. Design, Setting, Participants Open-label, exploratory phase II clinical trial among progressive RAIR-DTC patients. Intervention Apatinib treatment once daily until disease progression, unmanageable toxicity, withdrawal, or death. Main Outcome Measures The primary end points were objective response rate (ORR) and disease control rate (DCR). Progression-free survival (PFS), overall survival (OS), duration of response, long-term safety and the association between patients with different tumor genotype (BRAF  V600E and TERT promotor mutation) and their PFS were also assessed. Results The ORR was 80%, and the DCR was 95%. The overall median PFS was 18.4 months (95% confidence interval [CI], 9.2-36.8 months) and median OS was 51.6 months (95%CI, 29.2-not reached [NR]). Patients with BRAF  V600E mutation (10 of 18 evaluated) had a longer median PFS compared with patients with BRAF wild-type (NR vs. 9.2 months, P=0.002). The most common adverse events included palmar-plantar erythrodysaesthesia syndrome (19/20), proteinuria (18/20) and hypertension (16/20). Conclusions In this long-term evaluation, apatinib displayed sustainable efficacy and tolerable safety profile, warranting it as a promising treatment option for progressive RAIR-DTC.

scholarly journals Cabozantinib As Salvage Therapy for Patients With Tyrosine Kinase Inhibitor–Refractory Differentiated Thyroid Cancer: Results of a Multicenter Phase II International Thyroid Oncology Group Trial

2017 ◽  
Vol 35 (29) ◽  
pp. 3315-3321 ◽  
Author(s):  
Maria E. Cabanillas ◽  
Jonas A. de Souza ◽  
Susan Geyer ◽  
Lori J. Wirth ◽  
Michael E. Menefee ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Multikinase Inhibitor

Purpose Sorafenib and lenvatinib are oral multikinase inhibitors targeting vascular endothelial growth factor receptor (VEGFR) and approved for radioiodine (RAI)-refractory differentiated thyroid cancer (DTC). However, there are no approved second- or third-line therapies. MET is implicated in resistance to VEGFR inhibitors. Cabozantinib is an oral multikinase inhibitor targeting MET in addition to VEGFR and is approved for medullary thyroid cancer. In a phase I study of cabozantinib, five of eight patients with DTC previously treated with a VEGFR-targeted therapy had an objective response to cabozantinib. Patients and Methods Patients with RAI-refractory disease with Response Evaluation Criteria in Solid Tumor (RECIST) measurable disease and evidence of progression on prior VEGFR-targeted therapy were enrolled in this single-arm phase II study. The cabozantinib starting dose was 60 mg/day orally but could be escalated to 80 mg if the patient did not experience a response. Patients underwent tumor assessment according to RECIST v1.1 every 8 weeks. In this study, if at least five of 25 response-evaluable patients had an objective response, cabozantinib would be considered a promising agent in this patient population. Results Twenty-five patients were enrolled. The median age was 64 years, and 64% of patients were men. Twenty-one patients had received only one prior VEGFR-targeted therapy (sorafenib, pazopanib, or cediranib), and four patients had received two such therapies. The most common treatment-related adverse events were fatigue, weight loss, diarrhea, palmar-plantar erythrodysesthesia, and hypertension. One drug-related death was noted. Of the 25 patients, 10 (40%) had a partial response, 13 (52%) had stable disease, and two (8%) had nonevaluable disease. The median progression-free survival and overall survival were 12.7 months and 34.7 months, respectively. Conclusion Cabozantinib demonstrated clinically significant, durable objective response activity in patients with RAI-refractory DTC who experienced disease progression while taking prior VEGFR-targeted therapy.

Anlotinib plus sintilimab in patients with recurrent advanced cervical cancer: A prospective, multicenter, single-arm, phase II clinical trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 5524-5524
Author(s):  
Qin Xu ◽  
Chuanben Chen ◽  
Yang Sun ◽  
Zhangzhou Huang ◽  
Yibin Lin ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cervical Cancer ◽  
Phase Ii ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Advanced Cervical Cancer ◽  
Median Response ◽  
Platinum Based Chemotherapy

5524 Background: It is difficult for patients with recurrent advanced cervical cancer to obtain clinical benefits after the failure of standard chemotherapy. However, antiangiogenic therapy combined with immune checkpoint inhibitors have become a promising strategy for advanced cervical cancer. Anlotinib is a novel multi-target tyrosine kinase inhibitor, inhibiting tumour angiogenesis and proliferative signalling. Sintilimab is a fully humanized, high-affinity monoclonal antibody against programmed cell death-1 (PD-1). This phase II, single-arm study (ChiCTR1900023015) aims to evaluate the efficacy and safety of anlotinib plus sintilimab in patients with recurrent advanced cervical cancer. Methods: Patients who have received at least once platinum-based chemotherapy, histopathologically confirmed recurrent advanced cervical cancer (including squamous cell carcinoma, adenocarcinoma or adenosquamous carcinoma), more than 1% PD-L1 expression, ECOG 0-1 were considered eligible for enrollment. Anlotinib was taken orally (10mg mg qd, d1-14, 21 days per cycle), and sintilimab was administered intravenously (200mg once every 3 weeks). The treatment was continued until disease progression, death or intolerant toxicity. The primary endpoint was objective response rate (ORR) and the secondary endpoints included disease control rate (DCR), progression free survival (PFS), overall survival (OS) and safety. Results: Between September 2019 and February 2021, 42 patients with a median age of 52 years (range:47-58), FIGO histopathological stage I (11.9%), II (31.0%), III (33.3%), IV (9.5%) and undiagnosed (14.3%) were enrolled. 39 of these patients were evaluable. In the efficacy-evaluable population (n = 39), the therapeutic evaluation showed that 2 and 20 patients achieved complete response and partial response respectively, yielding the ORR of 56.4% (22/39, 95% CI:40.2 to 71.5). The DCR was 94.9% (37/39, 95% CI:80.7 to 98.8). The median response time was 1.6 months. The median PFS was not reached. The most common adverse events (AEs) were grade 1 or 2, which included hypothyroidism (33.3%), hypertension (23.8%), AST (21.4%), diarrhea (19.0%), ALT (16.7%), hand-foot syndrome(14.3%), hypertriglyceridemia (14.3%) and anemia (11.9%). The grade 3 AEs were hypertension (4.8%), hyponatremia (4.8%), immune pneumonia (2.4%) and immune myocarditis (2.4%). No higher AEs and treatment-related death were observed. Conclusions: Anlotinib plus sintilimab showed a promising efficacy with a favorable toxicity profile for patients with recurrent advanced cervical cancer. We will report more data in the future. Clinical trial information: ChiCTR1900023015.

An exploratory phase II clinical trial of apatinib in progressive radioiodine refractory differentiated thyroid cancer.

2018 ◽  
Vol 36 (15_suppl) ◽  
pp. e18094-e18094 ◽  
Author(s):  
Yan-Song Lin ◽  
Xin Zhang ◽  
Yanqing Liu ◽  
Chen Wang ◽  
Teng Zhang
Keyword(s):  
Clinical Trial ◽  
Thyroid Cancer ◽  
Phase Ii ◽  
Differentiated Thyroid Cancer ◽  
Phase Ii Clinical Trial

NIVACOR: Phase II study of nivolumab in combination with FOLFOXIRI/bevacizumab in first-line chemotherapy for advanced colorectal cancer RASm/BRAFm patients.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS4118-TPS4118
Author(s):  
Angela Damato ◽  
Francesco Iachetta ◽  
Nicola Normanno ◽  
Francesca Bergamo ◽  
Evaristo Maiello ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Genetic Alterations ◽  
First Line ◽  
Flat Dose ◽  
Braf Mutant ◽  
Clinical Trial Information

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 .

Phase II study of nivolumab and ipilimumab in children and young adults with INI1-negative cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS10055-TPS10055
Author(s):  
Suzanne J. Forrest ◽  
Joanna Yi ◽  
Cassie Kline ◽  
Thomas Cash ◽  
Alyssa Terry Reddy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase Ii ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Epithelioid Sarcoma ◽  
Objective Response ◽  
Open Label ◽  
Clinical Cancer Research

TPS10055 Background: Several aggressive pediatric and young adult cancers are characterized by SMARCB1 inactivation resulting in loss of INI1 expression, including rhabdoid tumors, epithelioid sarcoma and undifferentiated chordoma. These malignancies are associated with a poor prognosis and few effective treatment options for relapsed or refractory disease. Prior studies and emerging data suggest INI1-negative cancers may be uniquely susceptible to treatment with immune checkpoint inhibitors: Many INI1-negative pediatric tumors express PD-L1 and are infiltrated by immune cells, and there are reports of patients with advanced INI1-negative cancers with clinical responses to immune checkpoint blockade (Forrest et al. Clinical Cancer Research, 2020). We hypothesize that INI1 loss predicts tumor response to immune checkpoint inhibition (ICI). Methods: This is an ongoing multicenter, phase II, open-label clinical trial to evaluate the activity of nivolumab and ipilimumab in patients aged 6 months to 30 years with relapsed or refractory INI1-negative cancers (NCT04416568). The study enrolls patients in 2 strata: extracranial solid tumors in Stratum 1 and intracranial solid tumors in Stratum 2. Patients treated with prior ICI are excluded. Patients are treated with intravenous (IV) nivolumab 3mg/kg plus ipilimumab 1mg/kg IV every 3 weeks for 4 cycles followed by nivolumab 3mg/kg (max dose 240mg) IV every 2 weeks for up to 1-year. The primary objective is to evaluate the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) for Stratum 1 and by Response Assessment in Neuro-Oncology (RANO) criteria for Stratum 2. The trial has a 2-stage design targeting a 25% or greater response rate, with each stratum assessed independently. The analysis for Stage 1 in a given Stratum will be performed after 10 patients are enrolled. If a sufficient number of responders are observed, an additional 10 patients will be enrolled at Stage 2. Secondary endpoints include progression-free survival, overall survival, and disease control rate at 12 months. Correlative aims include assessing tissue and blood biomarkers associated with treatment response. Enrollment began 14 Aug 2020 and is ongoing. Clinical trial information: NCT04416568.

scholarly journals Extended single-dose toxicity study of [211At]NaAt in mice for the first-in-human clinical trial of targeted alpha therapy for differentiated thyroid cancer

2021 ◽  
Author(s):  
Tadashi Watabe ◽  
Kazuko Kaneda-Nakashima ◽  
Kazuhiro Ooe ◽  
Yuwei Liu ◽  
Kenta Kurimoto ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Thyroid Cancer ◽  
Single Dose ◽  
General Condition ◽  
Blood Test ◽  
Differentiated Thyroid Cancer ◽  
Targeted Alpha Therapy ◽  
Evaluation Point ◽  
Alpha Therapy

Abstract Objective Astatine (211At) is a promising alpha emitter as an alternative to iodine (131I). We are preparing the first-in-human (FIH) clinical trial of targeted alpha therapy for differentiated thyroid cancer in consultation with Pharmaceuticals and Medical Devices Agency. Here, we performed an extended single-dose toxicity examination under a reliability standard, as a preclinical safety assessment of [211At]NaAt to determine the FIH dose. Methods [211At]NaAt solution was injected into normal 6-week-old mice (male (n = 50) and female (n = 50), body weight: male 33.2 ± 1.7 g, female 27.3 ± 1.5 g), which were then divided into four groups: 5 MBq/kg (n = 20), 20 MBq/kg (n = 20), 50 MBq/kg (n = 30), saline control (n = 30). The mice were followed up for 5 days (primary evaluation point for acute toxicity: n = 80) or 14 days (n = 20: evaluation point for recovery) to monitor general condition and body weight change. At the end of the observation period, necropsy, blood test, organ weight measurement, and histopathological examination were performed. For body weight, blood test, and organ weight, statistical analyses were performed to compare data between the control and injected groups. Results No abnormal findings were observed in the general condition of mice. In the 50 MBq/kg group, males (days 3 and 5) showed a significant decrease in body weight compared with the control. However, necropsy did not differ significantly beyond the range of spontaneous lesions. In the blood test, males (50 MBq/kg) and females (50 MBq/kg) showed a decrease in white blood cell and platelet counts on day 5, and recovery on day 14. In the testis, a considerable weight decrease was observed on day 14 (50 MBq/kg), and multinucleated giant cells were observed in all mice, indicating a significant change related to the administration of [211At]NaAt. Conclusions In the extended single-dose toxicity study of [211At]NaAt, administration of high doses resulted in weight loss, transient bone marrow suppression, and pathological changes in the testis, which require consideration in the FIH clinical trial.

Cabozantinib versus placebo in patients with radioiodine-refractory differentiated thyroid cancer who have progressed after prior VEGFR-targeted therapy: Results from the phase 3 COSMIC-311 trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 6001-6001
Author(s):  
Marcia S. Brose ◽  
Bruce Robinson ◽  
Steven I. Sherman ◽  
Barbara Jarzab ◽  
Chia-Chi Lin ◽  
...  
Keyword(s):  
Thyroid Cancer ◽  
Targeted Therapy ◽  
Disease Progression ◽  
Differentiated Thyroid Cancer ◽  
Statistical Significance ◽  
Phase 1 ◽  
Objective Response ◽  
Standard Of Care ◽  
Clinical Activity ◽  
Phase 3

6001 Background: Cabozantinib (C), an inhibitor of VEGFR2, MET, AXL, and RET, showed clinical activity in patients (pts) with radioiodine (RAI)-refractory differentiated thyroid cancer (DTC) in phase 1/2 studies (Cabanillas 2017; Brose 2018). This phase 3 study (NCT03690388) evaluated the efficacy and safety of C vs placebo (P) in pts with RAI-refractory DTC who had progressed during/after prior VEGFR-targeted therapy for whom there is no standard of care. Methods: In this double-blind, phase 3 trial, pts were randomized 2:1 to receive C (60 mg QD) or P, stratified by prior lenvatinib treatment (L; yes, no) and age (≤65, > 65 yr). Pts with RAI-refractory DTC must have received L or sorafenib for DTC and progressed during or following treatment with ≤ 2 prior VEGFR inhibitors. Pts randomized to P could cross over to open-label C upon disease progression per blinded independent radiology committee (BIRC). The primary endpoints were objective response rate (ORR) in the first 100 randomized pts and progression-free survival (PFS) in all randomized pts. PFS and ORR were assessed by BIRC per RECIST v1.1. The study was designed to detect an ORR for C vs P (2-sided α = 0.01) and a hazard ratio (HR) for PFS of 0.61 (90% power, 2-sided α = 0.04). A prespecified interim PFS analysis was planned for the ITT population at the time of the primary ORR analysis. Results: As of 19 Aug 2020,125 vs 62 pts had been randomized to the C and P arms, respectively; median age was 66 yr, 55% were female and 63% received prior L. Median (m) follow-up was 6.2 months (mo). At the planned interim analysis, the trial met the primary endpoint of PFS with C demonstrating significant improvement over P (HR 0.22, 96% CI 0.13–0.36; p < 0.0001). mPFS was not reached for C vs 1.9 mo for P; PFS benefit was observed in all prespecified subgroups including prior L (yes, HR 0.26; no, HR 0.11) and age (≤65 yr, HR 0.16; > 65 yr, HR 0.31). ORR was 15% for C vs 0% for P (p = 0.0281) but did not meet the prespecified criteria for statistical significance (p < 0.01). A favorable OS trend was observed for C vs P (HR 0.54, 95% CI 0.27–1.11). Treatment-emergent adverse events (AEs) of any grade with higher occurrences in the C vs P arm included diarrhea (51% vs 3%), hand-foot skin reaction (46% vs 0%), hypertension (28% vs 5%), fatigue (27% vs 8%), and nausea (24% vs 2%); grade 3/4 AEs were experienced by 57% of pts with C vs 26% with P. Dose reductions due to any grade AEs occurred in 57% of pts with C vs 5% with P. Treatment discontinuations due to AEs not related to disease progression occurred in 5% of pts with C vs 0% with P. No treatment-related deaths occurred in either arm. Conclusions: C showed a clinically and statistically significant improvement in PFS over P in pts with RAI-refractory DTC after prior VEGFR-targeted therapy with no unexpected toxicities. C may represent a new standard of care in pts with previously treated DTC. Clinical trial information: NCT03690388.

Phase II study of binimetinib with imatinib in patients with unresectable KIT-mutant melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS9594-TPS9594
Author(s):  
Katy K. Tsai ◽  
Iwei Yeh ◽  
Adil Daud ◽  
Ari Oglesby
Keyword(s):  
Phase Ii ◽  
Null Hypothesis ◽  
Response Rate ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Specific Treatment ◽  
Type I ◽  
True Response ◽  
Phase Ii Studies

TPS9594 Background: Immune checkpoint inhibitors (ICI) have transformed treatment for patients (pts) with advanced melanoma, as have BRAF/MEK inhibitors for pts with BRAF V600-mutant melanoma. However, pts with acral or mucosal melanomas are in particular need of more options given a lower objective response rate (ORR) to ICI, and lower incidence of BRAF V600 driver mutation. Such BRAF mutations are found in only 5-10% of acral/mucosal melanomas, while KIT mutations/amplifications are found in 10-20%. Even when present, a KIT alteration does not guarantee response to KIT inhibition, with only about one-third responding as previously shown in 3 phase II studies. A significant number of KIT-mutant melanomas have been shown to demonstrate NF1 or SPRED1 loss, with recent preclinical work showing that such alterations are associated with the loss of negative suppression of RAS, resulting in RAS activation and MEK dependence. We hypothesize that NF1 or SPRED1 loss cooperates with KIT mutations to drive melanomagenesis and resistance to KIT inhibition, and propose to target this vulnerability with a combination approach to targeted therapy. This phase II study will be the first to evaluate the efficacy and safety of binimetinib plus imatinib in pts with KIT-mutant melanoma. Methods: This is an investigator-initiated phase II study of binimetinib in combination with imatinib in pts with BRAF V600 WT, KIT-mutant unresectable melanoma who have progressed on or who are ineligible for ICI (NCT04598009). Pts will be ≥18 yo with performance status ECOG 0-2, and have unresectable Stage IIIB/C/D or Stage IV melanoma that is BRAF V600 WT and KIT-mutant by CLIA-certified testing platform. Pts will have progressed on prior ICI or other standard-of-care (SOC) therapies, or be ineligible for or unable to tolerate SOC therapies. Pts with brain metastasis will be eligible if clinically stable and determination made that no CNS-specific treatment is required prior to study start. Pts previously treated with a MEK inhibitor will be excluded. A Simon 2-stage Minimax design will be used; the null hypothesis that the true response rate is 0.1 will be tested against a one-sided alternative. 15 pts will be accrued in the first stage. If there are £1 responses, the study will be stopped. Otherwise, 10 additional pts will be accrued for a total of 25. The null hypothesis that the true response rate is 0.1 will be rejected if ≥6 responses are observed. This yields a type I error rate of 0.05 and power of 0.8017 when the true response rate is 0.3.Primary endpoint: ORR (RECIST). Secondary endpoints: duration of response, progression-free survival, overall survival, clinical benefit rate (CR, PR, or SD ≥16 weeks), safety profile (CTCAE). Exploratory objectives to include investigations of association between clinical response and baseline NF1 and SPRED1 status, and of pathologic correlates of acquired resistance. Study began enrolling pts in December 2020 and is ongoing. Clinical trial information: NCT04598009.

Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4598-TPS4598
Author(s):  
Karie Runcie ◽  
Eric A. Singer ◽  
Moshe Chaim Ornstein ◽  
Christopher B. Anderson ◽  
Matthew Dallos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Cytoreductive Nephrectomy ◽  
Open Label ◽  
Orthotopic Mouse Model

TPS4598 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: NCT04322955.

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