Phase II, noncomparative, open label, multicenter, study of osimertinib, in patients with locally advanced or metastatic EGFR mutated, T790M undetectable or unknown non-small cell lung cancer (Stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e21116-e21116
Author(s):  
Hector J. Soto Parra ◽  
Laura Noto ◽  
Francesco Verderame ◽  
Domenico Galetta ◽  
Vito Barbieri ◽  
...  
Keyword(s):  
Phase Ii ◽  
Null Hypothesis ◽  
Type I Error ◽  
Objective Response ◽  
Locally Advanced ◽  
Local Therapy ◽  
Attrition Rate ◽  
Type I ◽  
Open Label ◽  
Egfr Tki

e21116 Background: Osimertinib (OSI) is a potent irreversible EGFR TKI approved for 1st line therapy advanced EGFR+ NSCLC and for 2nd line T790M+ pts. The AURA trial showed promising results even in pts with T790M- NSCLC after no immediate prior OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI and subsequent chemotherapy. Methods: This phase II trial was performed to investigate the role OSI in locally advanced or metastatic EGFR+ NSCLC, T790M undetectable or unknown, after 1st line EGFR TKI (1 or 2 generation) and subsequent chemotherapy. Eligible pts (M or F, > 18 years, ECOG 0-2) received OSI (80 mg/day) until disease progression or unacceptable toxicity. Objective response rate (ORR) was the primary endopoint. Assuming a 10% attrition rate, 90 pts were planned to be enrolled according to the Optimal Simon’s 2 stage design. In the first stage, 32 pts were planned to be accrued, and if ≤ 3 responses were observed the study would be stopped. Otherwise, 49 additional pts were planned to be accrued. The null hypothesis would have been rejected if ≥ 12 responses were observed. This design yields a type I error rate of 0.05 and 80% power. Results: From May 2017 to October 2020, a total of 54 pts were enrolled (17 M and 37 F, mean age 66 years). The study was stopped early due to an extremely slow enrolment rate. However, the ORR of 31.5% (95% CI 19.5% - 45.5%) was significantly higher than the null hypothesis of 9% (p<0.0001). 17 pts obtained a partial response and 20 a stable disease with an overall disease control rate of 68.5%. Median PFS was 9 mos and median OS was 15 mos. Forty-one pts experienced at least 1 adverse event (51.8% treatment related), more than 90% Grade 1 or 2, the most common being diarrhea. Conclusions: Despite early termination and incomplete recruitment, the treatment with OSI in pts with undetectable or unknown T790M showed a significant ORR and a PFS in line with results in T790M+. Currently, OSI represents the preferred option in naïve pts with EGFR+ NSCLC, regardless of T790M status and for pts who progress the recommended subsequent therapies include local therapy, continuing OSI or chemotherapy; in this new scenario, our results confirm that OSI rechallenge in subsequent line after chemotherapy should be explored. This research was conducted with support from AstraZeneca. Clinical trial information: 2016-002555-17.

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.

An open-label phase II study comparing two doses of MK-6482 for the treatment of advanced renal cell carcinoma (RCC) following progression on prior systemic therapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS369-TPS369
Author(s):  
Michael B. Atkins ◽  
Yanfang Liu ◽  
Rodolfo F. Perini ◽  
Ananya Roy ◽  
John B. A. G. Haanen
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Systemic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Prognostic Scores ◽  
Survival Duration ◽  
Karnofsky Performance Scale ◽  
Open Label ◽  
Prior Systemic Therapy

TPS369 Background: Treatment options for RCC in the late-line setting after immunotherapy and vascular endothelial growth factor (VEGF)-targeted therapy are limited. Hypoxia-inducible factor (HIF)-2α is a transcription factor that has been established as an oncogenic driver in clear cell RCC (ccRCC). The first-in-class small molecular HIF-2α inhibitor, MK-6482, recently showed promising antitumor activity in a cohort of heavily pretreated ccRCC patients (pts) and in pts with von Hippel-Lindau–disease-associated RCC for which the FDA granted Breakthrough Therapy Designation to MK-6482. Methods: This randomized, open-label, multicenter phase II trial will evaluate the efficacy and safety of 2 doses of MK-6482 in pts with advanced RCC who have experienced progression after prior systemic therapy (NCT04489771). Eligible pts are male or female aged ≥18 years with histologically confirmed locally advanced or metastatic ccRCC (measurable disease per RECIST v1.1) who have experienced progression after 1-3 prior systemic therapies comprising an anti-PD-1/L1 agent combined with a VEGF-targeted tyrosine kinase inhibitor (TKI) or an anti-cytotoxic T lymphocyte-associated antigen-4 agent and have undergone no more than 3 prior systemic regimens; and a Karnofsky Performance Scale ≥70. Treatment progression on anti-PD-1/L1 combination therapy was defined as pts who received at least 2 doses of anti-PD-1/L1 therapy and demonstrated radiographic disease progression as assessed by the investigator. Pts who have received prior treatment with MK-6482 or another HIF-2α inhibitor, and those requiring intermittent or chronic supplemental oxygen, or with a baseline hemoglobin less than 10 g/dL, a history of human immunodeficiency virus, hepatitis B or hepatitis C infection, or active central nervous system metastases will be excluded. Approximately 150 pts will be randomly assigned 1:1 to oral MK-6482 120 mg once daily (QD) or 200 mg QD; treatment will continue until progression, unacceptable toxicity, or withdrawal. Pts will be stratified by International Metastatic RCC Database Consortium prognostic scores (0, 1-2, 3-6) and the number of prior TKI-containing therapies (0, 1, or 2-3). Imaging with computed tomography or magnetic resonance imaging will be undertaken on Week 9 from the date of randomization, every 8 weeks through Week 49, and every 12 weeks thereafter. Adverse events will be monitored throughout the study and for 30 days after treatment (90 days for serious adverse events). The primary end point is objective response rate per RECIST v1.1 by blinded independent central review (BICR). Secondary end points are progression-free survival, duration of response and clinical benefit rate per RECIST v1.1 by BICR, overall survival, pharmacokinetics, and safety. Safety will be analyzed using a tiered approach. This study is recruiting. Clinical trial information: NCT04489771 .

Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4096-4096
Author(s):  
Sophie Cousin ◽  
Carine A. Bellera ◽  
Jean Philippe Guégan ◽  
Thibault Mazard ◽  
Carlos A. Gomez-Roca ◽  
...  
Keyword(s):  
Phase Ii ◽  
Adaptive Design ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Open Label

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

scholarly journals OS4.1 MEVITEM: A European, randomized, open-label, Phase I/II study of vismodegib in combination with temozolomide versus temozolomide alone in adult patients with recurrent or refractory medulloblastoma presenting an activation of the Sonic Hedgehog (SHH) pathway

2019 ◽  
Vol 21 (Supplement_3) ◽  
pp. iii10-iii10
Author(s):  
D Frappaz ◽  
M Barritault ◽  
L Montané ◽  
F Laigle-Donadey ◽  
O Chinot ◽  
...  
Keyword(s):  
Sonic Hedgehog ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Rate ◽  
Type I ◽  
Filamin A ◽  
Open Label ◽  
Shh Pathway ◽  
Open Label Phase

Abstract BACKGROUND Vismodegib (V) suppresses sonic hedgehog (SHH) signaling. We postulated that vismodegib together with chemotherapy may be more efficient than chemotherapy alone in patients (pts) relapsing of a SHH-activated medulloblastoma (MB). MATERIAL AND METHODS Adult pts with recurrent SHH-MB not previously exposed to temozolomide (T) were randomly assigned (2:1 ratio) to Arm A (V daily 150mg/d, po) + T (D1-5: 150 mg/m2 for cycle 1 and 200 mg/m2 thereafter; n=up to 25pts) or Am B (T alone; n=up to 13pts). Identification of SHH activation was performed centrally by IHC (GAB1, β-catenin, filamin A, and YAP1). NGS analyses were performed to identify the mutations responsible for SHH activation. Primary objectives were to assess the incidence of severe toxicities (safety run-in based on a 3 + 3 design) and the 6-month non-progression rate (NPR-6m) according to WHO criteria and based on central read tumor assessment (Phase II). A Minimax Simon’s two-stage design was used to detect NPR-6m of 55% (p0: 30%, type I error rate of 5%, power of 80%). At first stage, ≥ 3/9 pts without progression at 6m were required for the accrual of 16 additional pts in Arm A. A 3rd independent and parallel arm with V as single agent (Arm C, n= up to15pts) was added for pts previously treated by T. RESULTS 24 SHH-MB pts were enrolled (Arm A: 10, Arm B: 5 and Arm C: 9; median age: 37 y [21–55]). At the end of the safety run-in; no major safety concerns were reported. At the end of Stage I: no objective response were reported and 2 pts among 10 were free of progression at 6m among in Arm A. According to statistical rules, the study was definitively closed to enrolment. NGS analyses showed a PTCH1 inactivating mutation in 6 pts (n=4 in arm A; n= 2 in arm B); a SMO activating mutation in 4 pts (n= 3 in Arm A; n=1 in Arm B). For 1 pt in each arm, no tumor sample was available for analysis, for 1 pt in Arm A DNA quality was insufficient, and for 1 patient in each arm no mutations of SMO, PTCH1, SUFU or SHH were found. Out of the 4 pts in Arm A with an inactivating PTCH1 mutation, only 1 was progression free at 6m. PFS and OS data will be presented at the meeting. CONCLUSION The combination of vismodegib with monthly T failed to demonstrate superior activity as compared with T alone. Further studies are warranted to refine therapeutic indication for vismodegib

A phase II, noncomparative, open label, multicentre, study of AZD9291 in patients with locally advanced or metastatic EGFR mutated “T790M undetectable or unknown” non-small cell lung cancer (stage IIIB-IV) after no immediate prior EGFR TKI (OSIRIS study).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9107-TPS9107 ◽  
Author(s):  
Hector J. Soto Parra ◽  
Laura Noto ◽  
Domenico Galetta ◽  
Francesco Ferraú ◽  
Vittorio Gebbia ◽  
...  
Keyword(s):  
Disease Progression ◽  
Response Rate ◽  
Mutational Analysis ◽  
Locally Advanced ◽  
Type I ◽  
Open Label ◽  
T790m Mutation ◽  
True Response ◽  
Egfr Mutated ◽  
Egfr Tki

TPS9107 Background: Osimertinib (OSI), is an oral, potent, irreversible inhibitor of both epidermal growth factor receptor (EGFR) sensitizing and resistance mutations (T790M) indicated for the treatment of pts with advanced EGFR T790M mutation-positive NSCLC. In the AURA study, OSI was associated with an ORR of 21% (13/61) among all patients with T790M negative mutation. Response rate broken down by immediate versus no immediate prior EGFR TKI was 11% (4/36 pts) versus 36% (9/25) respectively. This better activity with deferred OSI, drug able to inhibit also the EGFR sensitizing mutations, could be explained by a selection of sensitive tumor cells during chemotherapy (re-challenge strategy). Aim of the current study is prospective evaluate the efficacy of OSI in EGFR mutated, T790M “undetectable or unknown” patients as third-line therapy after a first-line EGFR TKI and a subsequent chemotherapy. Methods: OSIRIS study is a prospective single-arm, phase 2, open label, italian multicenter study. T790M “undetectable or unknown" is defined by the following conditions: inconclusive/negative tumor test result for T790M at the time of disease progression or medical inaccessible/contraindications/declined tumor biopsy or insufficient tumor tissue for testing. Pts are treated with OSI 80 mg once daily until disease progression or unacceptable toxicity. The single-arm design is appropriate, as there is no accepted standard therapy for these pts after chemotherapy. The primary endpoint is ORR according to RECIST version 1.1. The null hypothesis that the true response rate is 9% will be tested against a one-sided alternative. In the first stage, 32 pts will be accrued. If there are 3 or fewer responses in these 32 pts, the study will be stopped. Otherwise, 49 additional pts will be accrued for a total of 81. This design yields a type I error rate of 0.05 and power of 80% when the true response rate is 19%. Secondary endpoints are PFS, OS and safety. Exploratory: mutational analysis of a panel of genes involved in resistance to EGFR-TKIs is planned. Clinical trial information: 2016-002555-17.

A randomized noncomparative phase II study of maintenance therapy with multiepitope vaccine Tedopi (OSE2101) ± nivolumab or FOLFIRI after induction chemotherapy (CT) with FOLFIRINOX in patients (Pts) with advanced pancreatic ductal adenocarcinoma (aPDAC) (TEDOPaM–PRODIGE 63 GERCOR D17-01 study).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS4160-TPS4160
Author(s):  
Cindy Neuzillet ◽  
Vincent Hautefeuille ◽  
Aurélien Lambert ◽  
Marie-Line Garcia-Larnicol ◽  
Dewi Vernerey
Keyword(s):  
Maintenance Therapy ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Objective Response ◽  
Locally Advanced ◽  
Vaccine Antigen ◽  
New Combination ◽  
Ductal Adenocarcinoma ◽  
Open Label

TPS4160 Background: FOLFIRINOX (5-fluorouracil [5FU], folinic acid [FA], irinotecan [Iri], and oxaliplatin [Ox]) is a standard 1st-line treatment in fit Pts with aPDAC. Anti-PD-1/PD-L1 as single agents have failed in PDAC so far and new combination immunotherapies are needed. Tedopi (OSE2101) is a multiple neoepitope vaccine restricted to HLA-A2 positive Pts, targeting 5 tumor-associated antigens (CEA, HER2, MAGE2, MAGE3, TP53) that are frequently expressed in PDAC. This study aims to assess the efficacy and safety of Tedopi alone and in combination with anti-PD-1 nivolumab, or FOLFIRI as maintenance therapy in Pts with aPDAC after FOLFIRINOX induction CT. Methods: TEDOPaM - PRODIGE 63 is a 3-arm, Fleming 2-stage, open-label, randomized, non-comparative phase II study. 156 Pts with locally advanced or metastatic, pathologically proven PDAC; ECOG performance status 0-1; HLA-A2 genotype; controlled disease (objective response or stable disease) after 8 cycles of (modified) FOLFIRINOX; and adequate organ functions, are randomized (1:1:1, stratified on center, tumor stage, and best response to FOLFIRINOX) into 3 arms: Clinical trial information: NCT03806309. In Arms B and C, FOLFIRI is reintroduced at disease progression or unacceptable toxicity. Primary endpoint: overall survival rate at M12. Secondary endpoints: progression-free survival (CT-scan Q8W), duration of disease control, safety, objective response rate, RECIST v1.1/iRECIST comparison, HRQoL (EORTC QLQ-C30), Q-TWiST. An interim analysis is planned after inclusion of 20 Pts in each arm. Translational research will be performed on tumor tissue (initial FFPE biopsy and optional re-biopsy at inclusion): RNAseq (cancer and stroma), mutation burden, MMR status, immune infiltrates; and in blood (before and on-treatment): cytokine panel, PBMC phenotyping, vaccine-antigen specific T-cells, TCR repertoire, and extracellular vesicles, to explore biomarkers and pharmacodynamics effects of Tedopi ± nivolumab. Enrollment (12th Feb 2019): 1. ClinicalTrials Registration: NCT03806309.[Table: see text]

CaboPoint, a phase II, open-label study of cabozantinib as second-line therapy for patients with clear cell metastatic renal cell carcinoma (RCC), whose disease progressed after therapy with checkpoint inhibitors (CPIs).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS772-TPS772
Author(s):  
Laurence Albiges ◽  
Manuela Schmidinger ◽  
Naila Taguieva Pioger ◽  
David Pérol ◽  
Viktor Grünwald
Keyword(s):  
Targeted Therapy ◽  
Treatment Period ◽  
Phase Ii ◽  
Clear Cell ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Open Label ◽  
Metastatic Rcc

TPS772 Background: Cabozantinib, a tyrosine kinase inhibitor with activity against vascular endothelial growth factor (VEGF) receptors, MET and AXL, is approved for the treatment of advanced RCC (in the USA) in treatment-naïve patients with intermediate or poor risk, as well as following VEGF-targeted therapy (in Europe). Here we present the design of the CaboPoint study evaluating the efficacy and safety of cabozantinib in patients with clear-cell metastatic RCC, whose disease progressed after CPI therapy. Methods: CaboPoint is a phase II, open-label (OL), single-arm study of cabozantinib in adults with unresectable, locally advanced or metastatic RCC with a clear-cell component, whose disease progressed after CPI therapy with ipilimumab and nivolumab alone (cohort A) or in combination with VEGF-targeted therapy (cohort B). The primary endpoint is objective response rate, evaluated by independent review committee. Secondary endpoints include time to response, duration of response, disease control rate, progression-free survival and overall survival. Change in disease-related symptoms and safety/tolerability will also be assessed. During the pre-treatment period, potential participants will attend a screening visit within 15 days of treatment initiation to determine eligibility status. During the treatment period, a target of 250 eligible patients (n = 125 per cohort) at 50 sites across AT, CH, DE, ES, FR, NL and UK will receive OL cabozantinib (60 mg once daily; self-administered at home) for up to 18 months after the last recruited patient has received their first dose. Safety assessments will be conducted every 2 weeks up to week 4, and every 4 weeks thereafter. Patients may continue on cabozantinib after disease progression if clinical benefit is observed. During the post-treatment follow-up period, patients who discontinue early will be contacted at visits every 12 weeks to assess survival status and subsequent anticancer therapy. Each cohort will have an interim analysis when 60% of the patients have reached 12 months of follow-up. The study is funded by Ipsen Pharma. Clinical trial information: NCT03945773.

Phase II study of ruxolitinib in patients with pStat3+ breast cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. TPS1134-TPS1134 ◽  
Author(s):  
Nancy U. Lin ◽  
Rebecca Sue Gelman ◽  
Jane E. Brock ◽  
Aditya Bardia ◽  
Erica L. Mayer ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Tumor Tissue ◽  
Type I Error ◽  
Objective Response ◽  
Type I ◽  
Metastatic Progression ◽  
Open Label ◽  
Tumor Biopsy ◽  
T Score ◽  
Patient Reported

TPS1134 Background: Multiple lines of evidence implicate the IL-6/JAK2/Stat3 signaling pathway in metastatic progression and therapeutic resistance in breast cancer (Marotta et al, JCI2011; Britschgi et al, Cancer Cell 2012). Ruxolitinib, an oral inhibitor of JAK1 and JAK2, is approved for the treatment of intermediate or high-risk myelofibrosis, but has not been extensively tested in solid tumors. Methods: Pts with triple-negative breast cancer or inflammatory breast cancer of any subtype are eligible for prescreening of archival tumor tissue for pStat3 expression by immunohistochemistry. Pts with high (Cohort A; T-score >5) or low (Cohort B; T-score 3-4) pStat3 expression, measurable disease, adequate organ function, ECOG PS 0-2, and progression through > 1 line of prior therapy may proceed to receive ruxolitinib, 25 mg orally twice daily. Staging studies are performed at baseline (BL) and every 8 weeks (wk). Baseline tumor biopsy is required for pts who have accessible disease, with an optional biopsy at progression. Blood for IL-6, CRP, and circulating tumor cells are collected at BL, Wk 4, and off-treatment. Patient reported outcomes including EORTC QLQ C-30 and the M.D. Anderson Symptom Inventory are collected at BL, Wk 4, Wk 8, and off-treatment. Statistical Considerations: The primary endpoint of this open-label phase 2 trial is objective response by RECIST 1.1. The study is designed to distinguish between a response rate of 5% versus 20% in each cohort, separately. If > 2 responses out of 21 pts are observed in the first stage of Cohort A, a further 20 pts will be entered on that cohort; the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Cohort B will open to accrual if Cohort A passes the first stage. If > 2 responses out of 21 pts are observed in the first stage of Cohort B, a further 20 patients will be entered into Cohort B, and the agent will be deemed worthy of further study if > 5 of the total 41 pts achieve an objective response (power 0.90, type I error 0.046). Study Status: A total of 85 patients have consented for prescreening of tumor tissue. As of January 3, 2013, 5 of a planned 41 patients with high pStat3 IHC scores have been treated with ruxolitinib, and accrual is ongoing. Clinical trial information: NCT01562873.

Avelumab and cetuximab in combination with FOLFOX in patients with previously untreated metastatic colorectal cancer (MCRC): The phase II AVETUX-CRC trial (AIO KRK 0216).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS3620-TPS3620 ◽  
Author(s):  
Alexander Stein ◽  
Mascha Binder ◽  
Carsten Bokemeyer ◽  
Salah Eddin Al Batran ◽  
Axel Hinke ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Mismatch Repair ◽  
Phase Ii ◽  
Type I Error ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Type I ◽  
Translational Research Program ◽  
Clinical Trial Information

TPS3620 Background: Inhibition of the PD-1/L1 axis has shown to improve survival as single agent in a variety of tumor types. The efficacy of single agent PD-1/L1 inhibition in patients with treatment refractory MCRC seems to be limited to hypermutated tumors characterized by mismatch repair deficiency. 1st line chemotherapy (e.g. FOLFOX) with cetuximab for patients with RAS/BRAF wildtype MCRC result in objective response rates of about 60%, thus substantial antigen release will likely occur triggering immune control. Furthermore, the induction of immunogenic cell death has been recently shown for cetuximab-based regimen. Thus, the evaluation of FOLFOX and cetuximab in combination with avelumab in 1st line MCRC is of particular interest. Methods: AVETUX is a single arm exploratory phase II investigator initiated trial. Patients with RAS/BRAF wildtype MCRC will be included independent of mismatch repair status to receive mFOLFOX6 and cetuximab in combination with avelumab (10mg/kg from day 1 of cycle 2 onwards). Treatment with avelumab is limited to a maximum of 18 months. Primary endpoint is 12month progression-free survival rate, which should be increased from 40% to 57%, with type I error of 10% and 80% power, leading to a sample size of 43 patients. An early stopping rule will be applied in case of an increase in toxicity after the first 15 patients received at least two months of treatment. The trial is flanked by a large translational program including immunoprofiling to determine and correlate the respective immune response signatures with clonal dynamics (RAS/EGFR). Recruitment will start in 11 German sites early 2017. Clinical trial information: EudraCT No 2016-004434-26. Conclusion: The AVETUX trial will determine the feasibility and early efficacy of FOLFOX and cetuximab combined with avelumab in 1st line MCRC. The translational research program will shed light on the potential mode of action of this novel combination. Clinical trial information: 2016-004434-26.

Phase II study of the combination of abemaciclib and pembrolizumab in locally advanced unresectable or metastatic gastroesophageal adenocarcinoma: Big Ten Cancer Research Consortium BTCRC-GI18-149.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS461-TPS461
Author(s):  
Nataliya Volodymyrivna Uboha ◽  
Jens C. Eickhoff ◽  
Chandrikha Chandrasekharan ◽  
Shadia Ibrahim Jalal ◽  
Al Bowen Benson ◽  
...  
Keyword(s):  
Phase Ii ◽  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Locally Advanced ◽  
Open Label ◽  
Significance Level ◽  
Gastroesophageal Adenocarcinoma

TPS461 Background: Metastatic gastroesophageal adenocarcinoma (GEA) has poor prognosis. Overall survival (OS) remains around 12 months (mo) with current therapies. Pembrolizumab is approved for advanced GEA that has progressed on at least 2 prior lines of systemic therapy. However, the majority of patients progress on this treatment, and less than 15% of patients experience objective response (OR). This study will evaluate efficacy of pembrolizumab in combination with cyclin-dependent kinase 4/6 (CDK4/6) inhibitor, abemaciclib, in patients with advanced GEA. Preclinical studies have demonstrated that CDK4/6 inhibitors can increase anti-tumor immunity and can synergize with immune checkpoint inhibitors. Based on these data, we hypothesize that abemaciclib will augment response to pembrolizumab in GEA. Methods: This is a multi-institutional, single arm, open label, phase II study of abemaciclib in combination with pembrolizumab in patients with advanced GEA who have progressed or were intolerant to at least 2 prior lines of therapy. Patients previously treated with immune checkpoint inhibitors or with microsattelite unstable tumors will be excluded. Treatments will be given on a 21 day cycle until disease progression or intolerable toxicities. Pembrolizumab, 200 mg intravenously, will be given on day 1, and abemaciclib, 150 mg, will be taken orally twice a day on days 1-21. Primary endpoint is progression free survival (PFS). Secondary endpoints include PFS rate at 6 mo, disease control rate, OS and OR rate. Correlative endpoints will examine relationship between PDL1 status, genomic signature and treatment response. Saliva samples will be collected for microbiome analysis. Archival tumor tissue and blood samples will be banked for future studies. A total of 31 evaluable subjects will be enrolled to detect an anticipated increase in the median PFS from 2 months (null hypothesis) to 4 months with 80% power at the one-sided 0.05 significance level. The trial is open to enrollment. Clinical trial information: NCT03997448.

Sign in / Sign up

Export Citation Format

Share Document