A phase Ib study of napabucasin plus weekly paclitaxel in patients with advanced melanoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9553-9553
Author(s):  
William Jeffery Edenfield ◽  
Carlos Becerra ◽  
Fadi S. Braiteh ◽  
Alexander I. Spira ◽  
Ryan J. Sullivan ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Weekly Paclitaxel ◽  
Combination Regimen ◽  
Clinical Safety ◽  
Grade 3 ◽  
Anti Tumor Activity

9553 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity with paclitaxel was observed in pre-clinical testing, and a favorable clinical safety profile was established in a phase I/II trial in patients (pts) with advanced solid tumors. A phase 1b trial was established to evaluate the safety and preliminary signs of anti-cancer activity of the combination regimen in pts with advanced melanoma. Methods: Pts with melanoma were enrolled after failure of standard therapies for advanced disease. Napabucasin 480 or 500 mg orally twice daily was administered with paclitaxel 80 mg/m2 IV weekly for 3 of every 4 weeks. Adverse events were evaluated using CTCAE v4.03 and objective tumor assessments were obtained every 8 weeks and evaluated per RECIST 1.1 criteria. Results: A total of 12 pts with advanced melanoma were enrolled after a median 3 prior lines of therapy (including immune checkpoint inhibitors, BRAF-inhibitor if presence of BRAF V600E mutation). Protocol therapy was well tolerated with grade 3 AEs including diarrhea (n = 3), abdominal pain (n = 1), and fatigue (n = 1). Partial response (PR) was observed in 1 pt. Stable disease of at least 24 weeks or more was achieved by 33% of patients (n = 4) and the median progression-free survival (mPFS) was 3.7 months. Prolonged survival of 1 year or more was achieved by 33% of pts (n = 4), with a median overall survival (mOS) of 10.4 months. Conclusions: Napabucasin plus weekly paclitaxel has shown clinical safety and encouraging anti-tumor activity in a cohort of pts with previously treated advanced melanoma. The RP2D in combination with weekly paclitaxel was established to 480 mg orally bid. The data suggest that targeting stemness pathways with napabucasin may be a novel therapeutic strategy for melanoma. Clinical trial information: NCT01325441.

A phase 1b study of napabucasin plus weekly paclitaxel in patients with advanced thymoma and thymic carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e20001-e20001
Author(s):  
Matthew Hitron ◽  
Aaron John Spittler ◽  
Gregory Michael Cote ◽  
Rebecca Suk Heist ◽  
Kimiko Kossler ◽  
...  
Keyword(s):  
Thymic Carcinoma ◽  
Treatment Options ◽  
Objective Response ◽  
Weekly Paclitaxel ◽  
Combination Regimen ◽  
Autoimmune Myocarditis ◽  
Clinical Safety ◽  
Phase 1B ◽  
Grade 3 ◽  
Anti Tumor Activity

e20001 Background: Napabucasin is a first-in-class cancer stemness inhibitor, identified by its ability to inhibit STAT3-driven gene transcription and spherogenesis of cancer stem cells (Li et al PNAS 112 (6):1839, 2015). Synergistic anti-tumor activity of napabucasin plus paclitaxel was observed in pre-clinical and early clinical testing. The STAT3 pathway is considered important in thymic carcinoma and thymoma, rare cancers with few treatment options. In 1st line, the objective response rate (ORR, partial response [PR] + complete response [CR] per RECIST) with carboplatin-paclitaxel was 22% in thymic carcinoma and 43% in thymoma (Gemma, 2011). A phase 1b cohort was established to evaluate safety and preliminary signs of activity of napabucasin plus paclitaxel in these patients (pts). Methods: Pts with previously-treated advanced thymoma or thymic carcinoma were enrolled with napabucasin (240 - 480 mg orally twice daily) plus paclitaxel (80 mg/m2 IV weekly for 3 of every 4 weeks). Adverse events were evaluated using CTCAE v4.03 and tumor assessments were obtained every 8 wks per RECIST 1.1. Results: A total of 9 pts (thymic carcinoma = 5, thymoma = 4) with a median 3 prior lines of systemic therapy were enrolled. In thymic carcinoma, the starting napabucasin dose was 480 mg BID (n = 2), and 240 mg BID (n = 3). Treatment was well tolerated and 1 pt required dose-reduction. There were no grade 3 AEs reported. As of data cut-off, 3 pts are off-study with progression and 2 remain on treatment. PRs were observed in 4 of 5 pts (ORR = 80%) and the median time on treatment is > 7.0 mo. In thymoma, 4 pts received napabucasin 240 mg BID. AEs included grade 3 diarrhea and dehydration in 1 pt. As of data cut-off, 1 pt was off-study with progression, 2 died (perforated bowel; autoimmune myocarditis secondary to Issac’s syndrome), and 1 pt remains on treatment. PR was observed in 1 pt (ORR 25%). Conclusions: Napabucasin plus weekly paclitaxel has demonstrated clinical safety and encouraging signs of anti-tumor activity in patients with advanced thymic carcinoma and thymoma. Further clinical evaluation of the combination regimen is warranted in this population. Clinical trial information: NCT01325441.

Everolimus in combination with paclitaxel and carboplatin in patients with advanced melanoma: A phase II trial of the Sarah Cannon Research Institute (SCRI).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8556-8556
Author(s):  
Ralph J. Hauke ◽  
Jeffrey R. Infante ◽  
Kent C. Shih ◽  
Mark S. Rubin ◽  
Edward Arrowsmith ◽  
...  
Keyword(s):  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Entire Group ◽  
Combination Regimen ◽  
Eligibility Criteria ◽  
Common Grade ◽  
Grade 3 ◽  
Ecog Ps

8556 Background: The PI3k/AKT pathway is activated in most metastatic melanomas; mTOR is a critical component of this pathway. Everolimus, an mTOR inhibitor, has demonstrated single-agent activity in patients with advanced melanoma. We evaluated the efficacy and toxicity of everolimus in combination with paclitaxel/carboplatin in patients with advanced melanoma. Methods: Eligible patients had stage IV or unresectable stage III melanoma, unselected for braf status, previously untreated with chemotherapy or targeted agents. Previous immunotherapy was allowed. Additional eligibility criteria: ECOG PS 0 or 1; measurable disease; no active brain metastases; adequate bone marrow, kidney, and liver function; informed consent. All patients received paclitaxel 175mg/m2, 1-3 hour IV infusion, and carboplatin AUC 6.0 IV on day 1 of each 21-day cycle. Everolimus 5mg PO was given daily. Patients were evaluated for response every 6 weeks; treatment continued until progression or undue toxicity. Median progression-free survival (PFS) for paclitaxel/carboplatin treatment is 4 months; we looked for a median PFS of 6 months with this novel combination. Results: Seventy patients were treated between 2/2010 and 2/2011; median age 63, 90% had stage IV melanoma. 91% of patients received at least 2 cycles of therapy; median cycles received: 4 (range: 1-25+). Twelve patients (17%) had partial responses; an additional 42 patients (60%) had stable disease at first reevaluation. After a median 13 months of followup, the median PFS for the entire group was 4 months (95% CI: 2.8 – 5.0 months); 96% had progressed during the first 12 months. Median survival was 10 months (95% CI: 7.3 – 10.9 months). Toxicity was as previously described with these agents; neutropenia was the most common grade 3/4 toxicity (27%). Only 3 patients stopped treatment due to toxicity. Conclusions: The addition of everolimus to paclitaxel/carboplatin was feasible and well-tolerated; however, efficacy results were similar to those reported with paclitaxel/carboplatin alone. Further development of this combination regimen for treatment of metastatic melanoma is not recommended.

Clinical features and response to immune checkpoint inhibitors (ICIs) in pregnancy-associated melanoma (PAM).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 9564-9564
Author(s):  
Daniel Ying Wang ◽  
Carina N. Owen ◽  
David James Palmieri ◽  
Justine Vanessa Cohen ◽  
Zeynep Eroglu ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Rna Sequencing ◽  
Checkpoint Inhibitors ◽  
Post Partum ◽  
Primary Melanoma ◽  
Progression Free Survival ◽  
Molecular Data ◽  
Advanced Melanoma ◽  
Braf V600e ◽  
Molecular Features

9564 Background: Melanoma is one of the most common malignancies diagnosed during pregnancy. Little is known about the clinical outcomes of PAM, in particular, response to ICIs. We performed a retrospective study to assess this issue. Methods: A multicenter retrospective study was performed at 4 large melanoma centers. Patients (pts) with PAM treated with ICIs were identified and examined. Clinical data and molecular data (RNA sequencing, IHC) were explored. PAM was defined as development of advanced melanoma during pregnancy or within 2 years post-partum. Results: 19 pts with PAM were treated with ICIs. Median follow-up was 11.7 months (range 1.4 – 41.9 months). Median age was 29 years (range 16-36). Most pts had a cutaneous primary (N = 17, 89%) including the extremity (N = 8) or trunk (N = 7), and 5% were occult. 11 pts (58%) had a BRAF V600E mutation and 6 (32%) pts received BRAF/MEK targeted therapy. Most pts had prior primary melanoma (N = 12, 63%) and presented with advanced melanoma in the post-partum setting (N = 11, 58%). At advanced presentation, 6 (32%) pts were stage III/M1a and 13 (68%) pts were stage M1b/c/d; 7 (41%) pts had elevated LDH and 13 (68%) had visceral involvement. Among 11 patients treated with combination ipilimumab + anti-PD-1 therapy, 7 (64%) had objective responses (OR) with a 1-year progression free survival (PFS) of 40% and 1-year overall survival (OS) of 100%. By contrast, ICI monotherapy (3 with anti-PD-1/L1 and 4 with ipilimumab) was associated with poorer outcomes (OR in 25% and 33% for ipilimumab and anti-PD-1/L1, respectively). Molecular features (RNA sequencing, immunohistochemistry) will be presented. Conclusions: Patients with PAM represent a unique population and may particularly benefit with combination ICI therapy compared with ICI monotherapy (in a limited sample size). Molecular underpinnings of PAM biology are still being elucidated.

Cobimetinib plus vemurafenib (C+V) in patients (Pts) with colorectal cancer (CRC) with BRAF V600E mutations: Results from the TAPUR Study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 122-122 ◽  
Author(s):  
Kelsey Klute ◽  
Elizabeth Garrett-Mayer ◽  
Susan Halabi ◽  
Pam K. Mangat ◽  
Reza Nazemzadeh ◽  
...  
Keyword(s):  
Objective Response ◽  
Progression Free Survival ◽  
Braf V600e ◽  
Stage Design ◽  
Elevated Liver Enzymes ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps ◽  
Stage 1 ◽  
Anti Tumor Activity

122 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of CRC pts with BRAF V600E mutation treated with C+V are reported. Methods: Eligible pts had advanced CRC, no standard treatment (tx) options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts had BRAF V600E/D/K/R mutation and no MAP2K1/2, MEK1/2, NRAS mutations. Recommended dosing was C, 60 mg orally once daily for 21 days, 7 days off and V, 960 mg orally twice daily. Simon two-stage design was used to test the null rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have disease control (DC) (objective response (OR) or stable disease at 16 weeks (wks) according to RECIST (SD16+)), 18 more pts enrolled. If ≥7 of 28 pts have DC, the tx is worthy of further study. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: Thirty pts enrolled from August 2016 to August 2018; 2 were not evaluable for efficacy. Demographics and outcomes are summarized in Table. All pts had BRAF V600E mutations. Eight PR and 8 SD16+ were observed for DC and OR rates of 57% (90% CI, 43% to 67%) and 29% (95% CI, 13% to 49%), respectively. Twelve pts had at least 1 grade 3 AE or SAE at least possibly related to C+V including elevated liver enzymes, decreased lymphocytes, dyspnea, diarrhea, fatigue, hypercalcemia, hypophosphatemia, rash, photosensitivity, upper GI hemorrhage, and vomiting. Conclusions: The combination of C+V showed anti-tumor activity in heavily pre-treated CRC pts with BRAF V600E mutations . Further study is warranted to confirm the efficacy of C+V in this population. Clinical trial information: NCT02693535. [Table: see text]

A retrospective study of efficacy and safety of mechlorethamine, vindesine, liposomal doxorubicin, and prednisone (MODP) in relapsed/refractory classical Hodgkin lymphoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e19516-e19516
Author(s):  
Min-Hang Zhou ◽  
Chunmeng Wang ◽  
Yang Liu ◽  
Wenjing Ku ◽  
Qingming Yang ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Liposomal Doxorubicin ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Response Assessment ◽  
Brentuximab Vedotin ◽  
Combination Regimen ◽  
Salvage Regimen ◽  
Heavily Pretreated ◽  
Grade 3

e19516 Background: There are few optimized therapeutic options for relapsed and/or refractory classic Hodgkin’s lymphoma (r/rCHL), especially in patients who failed in treatments of autologous stem cell transplantation (ASCT), brentuximab vedotin or even immune checkpoint blockage. Therefore, we developed a chemotherapeutic scheme to evaluate the efficacy in r/rCHL patients with previous various lines of therapies. Methods: Between January, 2014 and December, 2019, a retrospective study was performed on r/rCHL patients from Chinese PLA general hospital who were treated with MOAP regimen consisting of mechlorethamine 6mg/m2, vindesine 4mg, liposomal doxorubicin 15mg/m2 on days 1 and 8, prednisone 1mg/kg per day on days 1 to 10 (MOAP) every 4 weeks. CT or PET/CT were done every two cycles to assess the response. Patients treated with MOAP regimen and complete clinical data were included. Patients with less than two cycles of MOAT or unavailable response assessment were excluded. The primary endpoint were complete remission (CR) and progression-free survival (PFS). Results: A total of 87 patients were included and five patients were excluded, so 82 patients were eligible in the study. The median previous lines and cycles of chemotherapy was 2 (range, 1-7), and 9 (range, 3-31), respectively. All the eligible patients received MOAP regimen for a median 4 cycles (range from 2 to 8), and overall response rate (ORR) was 87.8% including 40 patients in CR (48.8%) and 32 in PR (39.0%). In patients with ≥ 3 lines or ≥ 10 cycles of chemotherapy, up to 50.0% and 41.0% of patients achieved CR, respectively. In patients with previous ASCT, 31.6% of patients also achieved CR. Patients with previous checkpoint inhibitors had even higher CR than those without checkpoint inhibitors, though not significantly (51.6% vs. 47.1%, p = 0.689). Median PFS in patients with CR, PR and SD/PD were 43.8 months, 9.6 months and 6.1 months, respectively (p = 0.000).Patients with < 3 previous lines of chemotherapy had a favorable PFS than those with ≥ 3 previous lines (not reached vs. 14.4 months, (p = 0.032). No differences in PFS were observed in terms of previous cycles of chemotherapy, ASCT and checkpoint inhibitors. Grade ≥ 3 adverse events included 37 leukopenia (45.1%), 16 lung infection (19.5%), 11 anemia (13.4%), 4 thrombocytopenia (4.9%), 3 febrile neutropenia (3.7%) and 3 increased transaminase (3.7%). Conclusions: The MOAP combination regimen produced a favorable CR in r/rCHL failing or progressing on ASCT, checkpoint inhibitors, multiple cycles or lines of chemotherapies. It is an effective salvage regimen in heavily pretreated r/r CHL.

scholarly journals Combined Therapy with Anti-PD1 and BRAF and/or MEK Inhibitor for Advanced Melanoma: A Multicenter Cohort Study

Cancers ◽  
2020 ◽  
Vol 12 (6) ◽  
pp. 1666 ◽  
Author(s):  
Sandra Huynh ◽  
Laurent Mortier ◽  
Caroline Dutriaux ◽  
Eve Maubec ◽  
Marie Boileau ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Combined Therapy ◽  
Real Life ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Advanced Melanoma ◽  
Tumor Control ◽  
Wild Type ◽  
Multicenter Cohort Study ◽  
Melanoma Patients

Despite significant progress in melanoma survival, therapeutic options are still needed in case of progression under immune checkpoint inhibitors (ICI), and resistance to targeted therapies (TT) in BRAF-mutated melanomas. This study aimed to assess the safety of combined ICI and TT as a rescue line in real-life clinical practice. We conducted a study within the prospective French multicentric MelBase cohort, including patients treated with a combination of anti-PD1 (pembrolizumab/nivolumab) and BRAF inhibitor (BRAFi: dabrafenib/vemurafenib) and/or MEK inhibitors (MEKi: trametinib/cobimetinib) for BRAF mutated or wild-type advanced melanoma. Fifty-nine patients were included: 30% received the triple combination, 34% an anti-PD1 and BRAFi, and 36% an anti-PD1 and MEKi. Grade 3–4 adverse events occurred in 12% of patients. Permanent discontinuation or dose reduction of one of the treatments for toxicity was reported in 14% and 7% of patients, respectively. In the BRAF wild-type subgroup, treatment with MEKi and anti-PD1 induced a tumor control rate of 83% and median progression-free survival of 7.1 months. The combination of anti-PD1 and BRAFi and/or MEKi was a safe rescue line for advanced melanoma patients previously treated with ICI/TT. The benefit of these combinations, specifically anti-PD1 and MEKi in BRAF wild-type melanoma patients, needs to be prospectively studied.

scholarly journals Safety and Tolerability of BRAF Inhibitor and BRAF Inhibitor-Based Combination Therapy in Chinese Patients With Advanced Melanoma: A Real World Study

2021 ◽  
Vol 11 ◽  
Author(s):  
Xing Liu ◽  
Jing-jing Li ◽  
Ya Ding ◽  
Dan-dan Li ◽  
Xi-zhi Wen ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
Braf V600e ◽  
Chinese Patients ◽  
Cancer Center ◽  
Combination Therapies ◽  
Palmoplantar Erythrodysesthesia ◽  
Grade 3 ◽  
Experienced Grade

The toxicity spectrum between Chinese and Caucasian patients with melanoma who were treated with BRAF inhibitors (BRAFi) may differ. The purpose of the present study was to assess the safety and tolerability of BRAFi and BRAFi-based combination therapies [MEK inhibitors (MEKi) or anti-programmed death-1 (PD-1) antibody] in Chinese patients with BRAF V600E/K mutation-positive metastatic melanoma. We also investigated whether treatment-related adverse events (AEs) correlated with the prognosis. This retrospective study collected data from 43 patients with BRAF V600E/K mutation-positive metastatic melanoma from a single Chinese cancer center. Of the 43 patients, 12 patients received BRAFi monotherapy, 12 patients received BRAFi+MEKi, and 19 patients received BRAFi combined with the anti-PD-1 antibody. The median follow-up time was 19 months. In the BRAFi group, the most common AEs were rashes, palmoplantar erythrodysesthesia, and arthralgia. Four out of 12 (30%) patients experienced grade 3–4 treatment-related AEs. All grades of AEs in the BRAFi+MEKi group were similar to the BRAFi group, except for higher pyrexia (58.3%) and fewer cutaneous AEs. Three out of 12 (25%) patients experienced grade 3–4 AEs, especially pyrexia (16.7%). In the BRAFi+anti-PD-1 antibody group, AEs were similar to the BRAFi group, except for an increased aminotransferase level (36.8%), increased bilirubin (31.6%), and hypothyroidism (15.8%). Eleven out of 19 (57.9%) patients experienced grade 3–4 AEs and four out of 19 (21%) patients discontinued the therapy due to AEs. Treatment-related hepatotoxicity (trHE), defined as an increase in either alanine aminotransferase (ALT), aspartate transaminase (AST), or bilirubin levels, was the only AE identified as a significant poor-prognosis indicator in this study. The median progression-free survival of patients with trHE (41.9%) was 8 months, whereas it was 18 months for those without trHE [p = 0.046, hazard ratio (HR) = 2.116]. Moreover, this association was independent of medication regimens (p = 0.014, HR = 2.971). The overall response rate of patients with trHE was significantly lower than those without trHE (44.4 vs. 60.0%, p = 0.024), and we observed a similar trend in patients treated with BRAFi, BRAFi+MEKi, and BRAFi+anti-PD-1 antibody. In conclusion, BRAFi and BRAFi-based combination therapies were tolerable with reversible AEs in Chinese patients with melanoma. The trHE in patients receiving BRAFi and BRAFi-based regimens might indicate a poor therapy-related prognosis.

A phase I trial of pembrolizumab plus vemurafenib and cobimetinib in patients with advanced melanoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21506-e21506
Author(s):  
Saba Shaikh ◽  
Yan Zang ◽  
Janel Hanmer ◽  
Hong Wang ◽  
Yan Lin ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Checkpoint Inhibitors ◽  
Progression Free Survival ◽  
Health Utility ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Advanced Melanoma ◽  
Peripheral Blood Flow ◽  
Grade 3

e21506 Background: Management of patients (pts) with advanced melanoma includes anti-PD1 with or without anti-CTLA4, and for pts with a BRAF mutation, the additional option of targeted therapy. Preclinical and translational evidence suggest BRAF/MEK inhibitors (i) modulate the tumor microenvironment, providing rationale for combination with immune checkpoint inhibitors. Phase 3 IMspire data reported improved progression-free survival (PFS) with triplet therapy (atezolizumab/vemurafenib/cobimetinib), yielding regulatory approval. However, 79% of pts experienced grade 3/4 adverse events (AE) in the triplet arm. Methods: This is an investigator-initiated, phase I trial of pembrolizumab (pembro) plus vemurafenib (vem) and cobimetinib (cobi) for pts with advanced melanoma in the first line setting. The first 4 pts received vem/pembro. The protocol was subsequently amended, and the next 5 pts received vem/cobi/pembro. Vem/cobi had an escalating dosing regimen. Pembro was 200 mg q3 weeks. Primary endpoints: safety and maximum tolerated dose of vem/cobi when administered with pembro. Secondary endpoints: overall response rate (ORR), PFS, overall survival (OS), and quality of life (QoL). We planned to accrue 30 pts; however, the trial was closed after enrollment of 9 pts due to dose-limiting toxicity (DLT). This study NCT02818023 was approved by the IRB, and all pts provided informed consent. Results: Pts received a median of 6 cycles of triplet therapy. 8 of 9 pts experienced drug-related grade 3/4 AEs, most commonly dermatitis (89%). In the vem/pembro group, DLTs included hepatitis (n = 1), dermatitis (n = 3), and arthralgias (n = 1). In the vem/cobi/pembro group, DLTs included dermatitis (n = 5), QTc prolongation (n = 1), and arthralgias (n = 1). QoL assessments identified a clinically significant decrease in average health utility at 1 year compared to baseline (0.38 v 0.43). Median PFS was 20.7 months and median OS was 23.8 months for vem/pembro, and neither was reached for vem/cobi/pembro. Overall, 4 pts had ongoing responses at the time of data analysis. 2 pts experienced a complete response, 5 had a partial response, 1 had stable disease, and 1 had progressive disease at first restaging. Peripheral blood flow cytometry identified significantly decreased PD1 expression on CD4+ T-cells at 3 and 9 weeks compared to baseline. This did not correspond to clinical response. PD-L1 testing was also performed on 6 paired tumor samples, and no significant association was identified between PD-L1 expression and clinical outcomes. Conclusions: Despite preclinical and translational evidence for tumor immunomodulation with BRAF/MEKi and improved PFS noted in IMspire150, toxicity incurred with the triplet is challenging from a practical standpoint. Our study highlights clinical efficacy of the combination and adds additional toxicity data for triplet therapy, with 8 of 9 pts experiencing at least a grade 3 AE. Clinical trial information: NCT02818023.

scholarly journals ACTR-30. UPDATED EFFICACY AND SAFETY OF DABRAFENIB PLUS TRAMETINIB IN PATIENTS WITH RECURRENT/REFRACTORY BRAF V600E–MUTATED HIGH-GRADE GLIOMA (HGG) AND LOW-GRADE GLIOMA (LGG)

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi19-vi20 ◽  
Author(s):  
Patrick Wen ◽  
Alexander Stein ◽  
Martin van den Bent ◽  
Jacques De Greve ◽  
Sascha Dietrich ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Braf Inhibitor ◽  
Progression Free Survival ◽  
High Grade Glioma ◽  
Braf V600e ◽  
Low Grade ◽  
Open Label ◽  
Ongoing Treatment ◽  
Grade 3

Abstract BACKGROUND There is a lack of treatment options for HGG and LGG patients. BRAFV600E mutations are uncommon in glioma, with a poor long-term prognosis. Combined BRAF/MEK inhibition extends progression-free survival (PFS) and overall survival (OS) in BRAF V600E–mutated melanoma, non small-cell lung cancer, and anaplastic thyroid cancer. METHODS This phase 2, open-label trial (NCT02034110) evaluated dabrafenib (BRAF inhibitor, 150mg BID) plus trametinib (MEK inhibitor, 2mg QD) in patients with BRAF V600E mutations in 9 rare tumor types, including HGG and LGG. Eligible patients had histologically-confirmed recurrent or progressive glioma (LGG:WHO grade 1 or 2; HGG:WHO grade 3 or 4), with HGG patients required to have received radiotherapy and first-line chemotherapy, or concurrent chemoradiation. Treatment continued until unacceptable toxicity, disease progression, or death. Primary endpoint was investigator-assessed objective response rate (ORR) using RANO criteria. Secondary endpoints included duration of response (DOR), PFS, OS, and safety. RESULTS Interim analysis (IA) #14 (data cutoff: April 2, 2018) reported additional 3 months follow-up, with 49 patients enrolled (HGG, n=39; LGG, n=10) and 3 patients not evaluable for response. In HGG patients, ORR was 27% (10/37; 95%CI: 13.8%-44.1%), including CR (n=1), PR (n=9), and SD (n=11), with 16 patients currently ongoing treatment. In LGG patients, ORR was 56% (5/9; 95%CI: 26.8%-79.3%), including PR (n=5) and SD (n=4), with 6 patients currently ongoing treatment. OS, PFS, and DOR will be presented (IA#15). In HGG patients, adverse events (AEs) included fatigue (33%), headache (31%), rash (28%), and pyrexia (23%); grade 3/4 AEs included neutropenia (8%) and fatigue (5%). In LGG patients, AEs included headache (70%), fatigue, pyrexia (60% each), nausea, and arthralgia (50% each); grade 3/4 AEs included fatigue (20%). CONCLUSIONS Dabrafenib plus trametinib demonstrated promising efficacy in patients with recurrent or refractory BRAF V600E‒mutated HGG or LGG, with manageable AEs and no new safety signals.

Palbociclib (P) in patients (pts) with soft tissue sarcoma (STS) with CDK4 amplification: Results from the Targeted Agent and Profiling Utilization Registry (TAPUR) study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11565-11565
Author(s):  
Scott Schuetze ◽  
Michael Rothe ◽  
Pam K. Mangat ◽  
Liz Garrett-Mayer ◽  
Funda Meric-Bernstam ◽  
...  
Keyword(s):  
Treatment Options ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Stage Design ◽  
Secondary Endpoints ◽  
Grade 3 ◽  
Ecog Ps ◽  
Stage 1 ◽  
Anti Tumor Activity

11565 Background: TAPUR is a phase II basket study evaluating anti-tumor activity of commercially available targeted agents in pts with advanced cancers with genomic alterations. Results in a cohort of STS pts with CDK4 amplification treated with P are reported. Methods: Eligible pts had advanced STS, no standard treatment options, measurable disease, ECOG PS 0-2, and adequate organ function. Genomic testing was performed in CLIA-certified, CAP-accredited site selected labs. Pts received P at 125 mg orally once daily for 21 days, followed by 7 days off until disease progression. Pts matched to P had CDK4 amplification and no RB mutations. Simon 2-stage design tested the null disease control (DC) - defined as partial (PR), complete response (CR) or stable disease at 16+ weeks (SD 16+) - rate of 15% vs. 35% (power = 0.85; α = 0.10). If ≥2 of 10 pts in stage 1 have DC, 18 more pts are enrolled. If ≥7 of 28 pts have DC, the null DC rate is rejected. Secondary endpoints are progression-free survival (PFS), overall survival (OS) and safety. Results: 29 pts (66% male) with STS with CDK4 amplification were enrolled from July 2016 to Nov 2019. 1 pt was not evaluable and excluded from efficacy analyses. Demographics and outcomes are summarized in Table. One pt with partial response (PR) and 12 pts with SD16+ were observed for DC and objective response (OR) rates of 48% (95% CI: 31%, 62%) and 3.7% (95% CI: 0.1%, 19%), respectively, and the null DC rate of 15% was rejected (p<0.001). 9/13 pts with DC continued on treatment for >32 weeks. 14 pts had at least one grade 3-4 AE at least possibly related to P with the most common being low WBC/platelets. Other grade 3 AEs included increased alanine aminotransferase, anemia, and fatigue. Conclusions: Monotherapy P demonstrated anti-tumor activity in heavily pre-treated pts with STS with CDK4 amplification. Additional study is warranted to confirm the efficacy of P in pts with STS with CDK4 amplification. Clinical trial information: NCT02693535. [Table: see text]

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