A phase Ib study of combination of avelumab and taxane-based chemotherapy in platinum refractory or ineligible metastatic urothelial cancer (AVETAX study).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 487-487 ◽  
Author(s):  
Rohan Garje ◽  
Timothy Ginader ◽  
Douglas Earl Laux ◽  
Kenneth Gerard Nepple ◽  
Mohammed M. Milhem ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Checkpoint Inhibitors ◽  
Standard Dose ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase 2 ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Phase 1B ◽  
Expansion Cohort

487 Background: Advanced bladder cancer is the most common malignancy of the urinary system with 5-year OS rates of 5-7%. Platinum based chemotherapy and checkpoint inhibitors are currently available treatment options but with limited benefit. We hypothesize that combining Avelumab (anti-PD-L1 immunotherapy) with Docetaxel is safe and will lead to cancer cell death releasing neoantigens with enhanced anti-tumor immune mediated cytotoxicity. Methods: This is a phase 1b, single arm, non-randomized, open label prospective clinical trial to evaluate the combination of Avelumab and Docetaxel in adult subjects with locally advanced or metastatic urothelial carcinoma with disease progression during or following platinum-containing chemotherapy, or within 12 months of neoadjuvant or adjuvant platinum-containing chemotherapy. It has two phases: Phase 1b dose de-escalation of docetaxel (Level 0: 75, Level -1: 60 or Level -2: 45 mg/m2) with standard dose avelumab (10 mg/kg) to establish phase 2 dose in the standard 3+3 design. In the dose expansion phase, the phase 2 dose of docetaxel with avelumab will be evaluated for efficacy. The combination therapy is administered every 3 weeks for 6 cycles and then avelumab alone is continued every 2 weeks. Primary endpoint is safety. Efficacy endpoints include objective response rate, progression free survival and overall survival. Results: At the cutoff date of 10/21/2019, 10 eligible patients were enrolled in the study. Only one of the six patients treated with level 0 dose of docetaxel had a dose limiting toxicity (neutropenic fever). Docetaxel at 75 mg/m2 along the avelumab was deemed safe for dose expansion cohort. Additional 4 patients were enrolled in the dose expansion cohort. Efficacy data is preliminary with 1 patient achieving CR, 2 pts had PR, 2 pts had SD, 1 pt PD and 4 pts are not yet evaluable. The most common Grade 3 or 4 AEs were febrile neutropenia, urinary tract infection and confusion. No treatment related deaths were noted. Conclusions: The combination of docetaxel in combination with avelumab is safe and the preliminary data showed promising efficacy, further data to be presented at the meeting. Clinical trial information: NCT03575013.

EV-301: Phase III study to evaluate enfortumab vedotin (EV) versus chemotherapy in patients with previously treated locally advanced or metastatic urothelial cancer (la/mUC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS497-TPS497 ◽  
Author(s):  
Daniel Peter Petrylak ◽  
Jonathan E. Rosenberg ◽  
Ignacio Duran ◽  
Yohann Loriot ◽  
Guru Sonpavde ◽  
...  
Keyword(s):  
Disease Progression ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Phase Iii ◽  
Survival Duration ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

TPS497 Background: Standard first-line treatment for patients (pts) with la/mUC is cisplatin-based chemotherapy or carboplatin-based chemotherapy for pts unfit for cisplatin. Immune checkpoint inhibitors (CPIs) are standard treatment options for pts who progressed during or after platinum-based chemotherapy. While some pts with la/mUC achieve durable responses with CPIs, less than 25% of pts respond. Following failure of a CPI, no therapies are approved. Enfortumab vedotin is a fully humanized monoclonal antibody that delivers the microtubule-disrupting agent monomethyl auristatin E to tumors expressing Nectin-4, which is expressed in 97% of mUC pt samples (Petrylak et al. ASCO, 2017). In a phase 1 study (EV-101; NCT02091999), single-agent EV 1.25 mg/kg was generally well tolerated and demonstrated a confirmed objective response rate (ORR) of 42% across the overall population of pts with mUC; in pts with prior CPI therapy or liver metastasis at baseline confirmed ORRs of 42% and 36% were observed. A pivotal phase 2 study of EV in la/mUC pts with prior CPI treatment (EV-201; NCT03219333) is ongoing. Methods: EV-301 is a global, multicenter, open-label phase 3 trial (NCT03474107) enrolling adult pts with la/mUC and an ECOG performance status score ≤1, who have received a prior platinum-containing chemotherapy, and have experienced disease progression during or following treatment with a CPI. Approximately 550 pts will be randomized (1:1) to receive EV (1.25 mg/kg) administered by IV infusion over approximately 30 minutes on Days 1, 8, and 15 of each 28-day cycle ( Arm A), or investigator choice of IV docetaxel, paclitaxel, or vinflunine (EU only) on Day 1 of each 21-day cycle ( Arm B). Treatment with the study drug will continue until radiological disease progression, intolerance, or other discontinuation criterion is met. Radiological assessments of tumor response status will be performed at baseline and every 8 weeks. The primary endpoint is overall survival; secondary endpoints include progression-free survival, duration of response, and overall response rate, as well as assessment of safety/tolerability, and quality-of-life parameters. Clinical trial information: NCT02091999.

TROPHY-u-01: A phase II open-label study of sacituzumab govitecan (IMMU-132) in patients with advanced urothelial cancer after progression on platinum-based chemotherapy and/or anti-PD-1/PD-L1 checkpoint inhibitor therapy.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS495-TPS495 ◽  
Author(s):  
Scott T. Tagawa ◽  
Daniel Peter Petrylak ◽  
Petros Grivas ◽  
Neeraj Agarwal ◽  
Cora N. Sternberg ◽  
...  
Keyword(s):  
Urothelial Cancer ◽  
Checkpoint Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Low Grade ◽  
Phase 2 ◽  
Open Label ◽  
Phase 2 Trial ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy

TPS495 Background: Patients (pts) with unresectable locally advanced or metastatic urothelial cancer (mUC) who progress after platinum-based chemotherapy and checkpoint inhibitor (CPI) therapy and pts ineligible for platinum-based chemotherapy who progress after CPI have limited treatment options and poor outcomes. Trop-2 is an epithelial cell surface antigen that is overexpressed in UC. Sacituzumab govitecan (SG) is a novel antibody-drug conjugate that targets Trop-2 and delivers the active metabolite (SN38) of the topoisomerase I inhibitor irinotecan to tumor cells. In a phase 1/2 single-arm trial, pts with advanced cancers received SG 10 mg/kg intravenously on days 1 and 8 of a 21-day cycle; preliminary results in the cohort of 41 evaluable pts with mUC and a median of 3 (range 1–6) prior therapies showed an objective response rate (ORR) of 34%. Adverse events (AE) were mostly low grade, including diarrhea (63%), nausea (56%), and fatigue (49%). Neutropenia (all grades) occurred in 49% of pts (≥ grade 3/4, 39%; treatment-related serious AE of febrile neutropenia, 5%). Median overall survival was 16.1 months, and median progression-free survival was 7.1 months. These results warrant further investigation in a dedicated phase 2 trial. Methods: TROPHY-U-01 is a single-arm, open-label, global phase 2 trial evaluating the antitumor activity and safety of SG in 140 pts with advanced UC. The primary cohort (progression after platinum chemotherapy and CPI) will enroll 100 pts in a Simon 2-stage design with > 90% power accounting for dropouts to exclude the null hypothesis or ORR < 12%, while a second cohort (40 pts) will comprise cisplatin-ineligible pts who received prior CPI. The primary objective is ORR per RECIST 1.1, assessed by central review. Secondary objectives include response duration, PFS, OS, and safety/tolerability. Enrollment began in August 2018. Clinical trial information: NCT03547973.

PIVOT-10: A phase II study of bempegaldesleukin (NKTR-214) in combination with nivolumab (NIVO) in cisplatin (cis) ineligible patients with previously untreated locally advanced or metastatic urothelial cancer (mUC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS589-TPS589
Author(s):  
Robert A. Huddart ◽  
Arlene O. Siefker-Radtke ◽  
Arjun Vasant Balar ◽  
Mehmet Asim Bilen ◽  
Thomas Powles ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Objective Response ◽  
Locally Advanced ◽  
Significant Proportion ◽  
Phase 2 ◽  
Metastatic Urothelial Cancer ◽  
Evaluable Population ◽  
Duration Of Response ◽  
New Treatment

TPS589 Background: Checkpoint inhibitors can achieve durable responses in cis-ineligible 1L mUC. However, use is restricted to patients whose tumors are PD-L1 high. Approximately 70% of cis-ineligible patients have tumors with low PD-L1 expression, leaving a significant proportion of 1L mUC patients in need of new treatment options. Bempegaldesleukin (BEMPEG; NKTR-214) is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor. NIVO is an anti-PD-1 antibody that is approved for treatment in several types of cancers, including 2L mUC after treatment with a platinum agent. Early BEMPEG plus NIVO data in 1L mUC (cis-eligible and -ineligible) patients found an objective response rate (ORR) of 48% (13/27) in the efficacy evaluable population (defined as having undergone at least one post-baseline scan) and a CR rate of 19%, prompting this further exploration of BEMPEG plus NIVO in a phase 2 study (Siefker-Radke, 2019). Methods: This Phase 2 multi-national trial evaluates BEMPEG plus NIVO in previously untreated patients with cis-ineligible mUC. Eligibility also requires tumor tissue be analyzed by central laboratory to document PD-L1 status. Approximately 205 patients will be enrolled. BEMPEG (0.006 mg/kg) and NIVO (360 mg) are given intravenously (IV) on Day 1 of each 3-week cycle. The primary endpoint is ORR assessed per RECIST 1.1 by blinded independent central review (BICR) in patients with low PD-L1 expression (defined as Combined Positive Score [CPS] < 10). Secondary endpoints include ORR and duration of response in all treated patients, safety, and tolerability. Tumor and blood samples will be collected for biomarker analyses. Enrollment is ongoing. Clinical trial information: NCT03785925.

scholarly journals Atezolizumab in locally advanced or metastatic urothelial cancer: a pooled analysis from the Spanish patients of the IMvigor 210 cohort 2 and 211 studies

2020 ◽  
Author(s):  
M. Sotelo ◽  
T. Alonso-Gordoa ◽  
P. Gajate ◽  
E. Gallardo ◽  
R. Morales-Barrera ◽  
...  
Keyword(s):  
Median Duration ◽  
Urothelial Cancer ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Pooled Analysis ◽  
Metastatic Urothelial Cancer ◽  
Platinum Based Chemotherapy ◽  
Geographical Regions ◽  
Duration Of Response

Abstract Background The studies IMvigor 210 cohort 2 and IMvigor211 evaluated the efficacy of atezolizumab in patients with locally advanced or metastatic urothelial cancer (mUC) upon progression to platinum-based chemotherapy worldwide. Yet, the real impact of this drug in specific geographical regions is unknown. Materials and methods We combined individual-level data from the 131 patients recruited in Spain from IMvigor210 cohort 2 and IMvigor211 in a pooled analysis. Efficacy and safety outcomes were assessed in the overall study population and according to PD-L1 expression on tumour-infiltrating immune cells. Results Full data were available for 127 patients; 74 (58%) received atezolizumab and 53 (42%) chemotherapy. Atezolizumab patients had a numerically superior median overall survival although not reaching statistical significance (9.2 months vs 7.7 months). No statistically significant differences between arms were observed in overall response rates (20.3% vs 37.0%) or progression-free survival (2.1 months vs 5.3 months). Nonetheless, median duration of response was superior for the immunotherapy arm (non-reached vs 6.4 months; p = 0.005). Additionally, among the responders, the 12-month survival rates seemed to favour atezolizumab (66.7% vs 19.9%). When efficacy was analyzed based on PD-L1 expression status, no significant differences were found. Treatment-related adverse events of any grade occurred more frequently in the chemotherapy arm [46/57 (81%) vs 44/74 (59%)]. Conclusion Patients who achieved an objective response on atezolizumab presented a longer median duration of response and numerically superior 12 month survival rates when compared with chemotherapy responders along with a more favorable safety profile. PD-L1 expression did not discriminate patients who might benefit from atezolizumab.

FUZE clinical trial: a phase 2 study of Debio 1347 in FGFR fusion-positive advanced solid tumors irrespectively of tumor histology.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS3157-TPS3157 ◽  
Author(s):  
David Michael Hyman ◽  
Lipika Goyal ◽  
Petros Grivas ◽  
Funda Meric-Bernstam ◽  
Josep Tabernero ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Tumor Type ◽  
Phase 2 ◽  
Alternative Treatment Option

TPS3157 Background: Dysregulation of fibroblast growth factor receptor (FGFR) signaling by FGFR fusions is implicated in many cancers. Debio 1347 is a selective oral inhibitor of FGFR 1-3 tyrosine kinases. It exhibited high antitumor activity in in vitro and in vivo tumor models with FGFR1-3 gene fusions. Preliminary data from an ongoing phase 1 trial show efficacy and tolerability in patients (pts) harboring FGFR 1-3 fusion irrespectively of tumor type. We present the design for a multicenter, basket, 2-stage, adaptive single arm Phase 2 trial investigating Debio 1347 in pts with solid tumors harboring FGFR1-3 fusion/rearrangement. Methods: Adults with locally advanced/unresectable or metastatic tumors with documented FGFR1-3 gene fusion/rearrangement who require systemic therapy and have progression after ≥1 prior standard treatment or have no satisfactory alternative treatment option are eligible. Three cohorts are included: biliary tract cancer (cohort 1), urothelial cancer (cohort 2) and all other solid tumors (cohort 3). Primary brain tumors are excluded. Other key exclusion criteria include prior treatment with FGFR1-3 selective inhibitor; clinically significant corneal/retinal disorder; history of calcium/phosphate homeostasis disorder or systemic mineral imbalance with ectopic soft tissue calcification, and symptomatic/unstable brain metastases < 1 month before enrollment. Genomic screening of tumor tissue is done at local or central laboratory with post-hoc central confirmation by RNA sequencing. Eligible pts will receive Debio 1347, 80 mg PO once daily in 28-day cycles until occurrence of progression or unacceptable toxicity. Primary Endpoint is objective response rate (ORR) based on independent central review using RECIST v.1.1. The targeted sample size (N=125) will provide approximately 90% power to reject H0: ORR ≤ 15% at an overall 5% significance level based on an expected ORR of 30% in at least one of the cohorts. Secondary endpoints are: duration of response, disease control rate, progression-free survival, overall survival, safety, tolerability, and quality of life. An interim analysis for futility and homogeneity will be performed after 27 evaluable pts. PK sparse sampling is performed to assess exposure-response relationships with efficacy and safety. Biomarkers of response and resistance will be explored. Accrual is opened in US, EU, Asia and Australia. Clinical trial information: NCT03834220.

FOENIX-CCA2: A phase II, open-label, multicenter study of futibatinib in patients (pts) with intrahepatic cholangiocarcinoma (iCCA) harboring FGFR2 gene fusions or other rearrangements.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 108-108 ◽  
Author(s):  
Lipika Goyal ◽  
Funda Meric-Bernstam ◽  
Antoine Hollebecque ◽  
Juan W. Valle ◽  
Chigusa Morizane ◽  
...  
Keyword(s):  
Disease Progression ◽  
Intrahepatic Cholangiocarcinoma ◽  
Phase 1 ◽  
Objective Response ◽  
Locally Advanced ◽  
Gene Fusions ◽  
Phase 2 ◽  
Fgfr2 Gene ◽  
Platinum Based Chemotherapy ◽  
Grade 3

108 Background: Patients (pts) with intrahepatic cholangiocarcinoma (iCCA) have a 5-year survival rate of 24%. There is no standard treatment for advanced disease after first-line chemotherapy. Fibroblast growth factor receptor-2 ( FGFR2) gene fusions occur in 10% to 20% of pts with iCCA, offering a promising therapeutic avenue for this disease. Futibatinib is a highly selective irreversible FGFR1-4 inhibitor given as a continuous once-daily (QD) oral regimen. This phase 2 registrational trial was initiated because of results from a phase 1 dose escalation/expansion study showing tolerability and preliminary efficacy of futibatinib in pts with iCCA with FGFR2 fusions. Methods: FOENIX-CCA2 (NCT02052778), a single-arm multicenter phase 2 study, enrolled pts with locally advanced/metastatic unresectable iCCA harboring FGFR2 gene fusions or other rearrangements, disease progression after ≥1 line of systemic therapy (including gemcitabine plus platinum-based chemotherapy), no prior FGFR inhibitor treatment, and an ECOG performance status of 0 or 1. Pts received futibatinib 20 mg QD until disease progression/unacceptable toxicity. The primary endpoint is objective response rate (ORR) based on independent central radiology review. Secondary endpoints include disease control rate (DCR), duration of response (DOR), and safety. Results: A total of 103 pts were enrolled. For this interim analysis, data are reported for the 67 pts (65%) with ≥6 months of follow-up. Of these, 82.1% of pts had tumors harboring an FGFR2 fusion. One, 2, or ≥3 prior therapies were received by 44.8%, 28.4%, and 26.9% of pts, respectively. ORR was 34.3% (all partial response, n = 23), and DCR was 76.1%; assessment was pending for 8 pts. Median time to response was 1.6 months (range, 1.0-4.9), and median DOR was 6.2 months (range, 2.1-14.2). The most common treatment-related adverse events (AEs; all grade, grade ≥3) were hyperphosphatemia (79.1%, 25.4%), diarrhea (37.3%, 0%), and dry mouth (32.8%, 0%). Any-cause grade ≥3 AEs were reported in 73.1% of pts. Dose delay or dose reduction was required in 65.7% and 53.7% of pts, respectively; 6.0% of pts discontinued treatment because of AEs. Conclusions: Preliminary assessment of these phase 2 data indicate efficacy and tolerability of futibatinib for treatment of pts with iCCA harboring FGFR2 fusions or other rearrangements who have progressed after chemotherapy. Continued analysis of the study population is underway. Clinical trial information: NCT02052778.

scholarly journals Nivolumab in Metastatic Adrenocortical Carcinoma: Results of a Phase 2 Trial

2019 ◽  
Vol 104 (12) ◽  
pp. 6193-6200 ◽  
Author(s):  
Benedito A Carneiro ◽  
Bhavana Konda ◽  
Rubens B Costa ◽  
Ricardo L B Costa ◽  
Vinay Sagar ◽  
...  
Keyword(s):  
Adrenocortical Carcinoma ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Progression Free Survival ◽  
Median Number ◽  
Preliminary Evidence ◽  
Comprehensive Cancer Center ◽  
Cancer Center ◽  
Phase 2 ◽  
Platinum Based Chemotherapy

Abstract Context Systemic treatment of metastatic adrenocortical carcinoma (ACC) remains limited to chemotherapy and mitotane. Preliminary evidence suggesting that antitumor immune responses can be elicited in ACC has fostered interest in checkpoint inhibitors such as anti–PD-1 nivolumab. Objective The primary endpoint was objective response rate according to the response evaluation criteria in solid tumors. Secondary endpoints were progression-free survival (PFS), overall survival, and safety. Design Single-arm, multicenter, phase 2 clinical trial with two-stage design. Setting Comprehensive cancer center. Patients Ten adult patients with metastatic ACC previously treated with platinum-based chemotherapy and/or mitotane as well as patients who declined front-line chemotherapy. Intervention Nivolumab (240 mg) IV every 2 weeks. Results Ten patients with metastatic ACC were enrolled between March and December 2016. The median number of doses of nivolumab administered was two. Three patients only received one treatment [one died of disease progression, one discontinued due to adverse events (AEs), one withdrew after beginning treatment]. The median PFS was 1.8 months. The median follow-up was 4.5 months (range, 0.1 to 25.6 months). Two patients had stable disease for a duration of 48 and 11 weeks, respectively. One patient had an unconfirmed partial response but discontinued the study due to an AE. Most AEs were grade 1/2. The most common grade 3/4 treatment-related AEs were aspartate aminotransferase and alanine aminotransferase elevations, mucositis, and odynophagia. Conclusion Nivolumab demonstrated modest antitumor activity in patients with advanced ACC. The nivolumab safety profile was consistent with previous clinical experience without any unexpected AEs in this population.

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.

Phase 1b trial of cabozantinib in combination with atezolizumab in patients with locally advanced or metastatic urothelial carcinoma (UC) or renal cell carcinoma (RCC).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. TPS541-TPS541
Author(s):  
Neeraj Agarwal ◽  
Ulka N. Vaishampayan ◽  
Bradley Alexander McGregor ◽  
Marjorie C. Green ◽  
Nehal Mohamed ◽  
...  
Keyword(s):  
Disease Progression ◽  
Dose Escalation ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Checkpoint Inhibitors ◽  
Antiangiogenic Therapy ◽  
Objective Response ◽  
Locally Advanced ◽  
Clinical Activity ◽  
Phase 1B

TPS541 Background: Cabozantinib (CABO) is an oral receptor tyrosine kinase inhibitor of MET, VEGFR, and TAM family receptors (TYRO3, AXL, and MER). It is approved for patients (pts) with RCC after prior therapy with antiangiogenic therapy, and has demonstrated clinical activity in UC. In clinical studies, CABO exposure increased circulating CD8+ T cells and reduced immune-suppressive monocytes and Tregs. In preclinical tumor models, CABO increased MHC class 1 expression on tumor cells and reduced myeloid-derived suppressor cells. CABO may facilitate an immune-permissive tumor environment and may enhance response to immune checkpoint inhibitors. Atezolizumab (ATEZO), an anti-PD-L1 mAb, is approved for: locally advanced/metastatic UC in pts who are cisplatin-ineligible or have disease progression during/following platinum-containing chemo; pts with metastatic NSCLC and disease progression during/following platinum-containing chemo. We present the study design of an ongoing phase 1b study combining CABO with ATEZO in pts with locally advanced/metastatic UC or RCC. Methods: This multicenter, phase 1b, open-label study aims to assess safety, tolerability, preliminary efficacy, and pharmacokinetics of CABO in combination with ATEZO (NCT03170960). The study will enroll pts with advanced UC (bladder, renal pelvis, ureter, urethra) or RCC. It consists of two stages: dose escalation and expansion. In the dose-escalation stage (3+3 design), a recommended CABO dose for the combination will be established. In the expansion stage, four tumor-specific cohorts will be enrolled: 1) pts with UC who have progressed on/after platinum-containing chemo; 2) chemo-naïve pts with UC who are cisplatin ineligible; 3) chemo-naïve pts with UC who are cisplatin eligible; and 4) untreated pts with RCC with clear cell histology; the primary objective is to determine the objective response rate in each cohort. Exploratory objectives include correlation of tumor and plasma biomarkers, and changes in immune cell profiles with clinical outcome. The study has been initiated and enrollment target is 120 pts across the 4 expansion cohorts. Clinical trial information: NCT03170960.

Rucaparib for recurrent, locally advanced, or metastatic urothelial carcinoma (mUC): Results from ATLAS, a phase II open-label trial.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 440-440 ◽  
Author(s):  
Petros Grivas ◽  
Yohann Loriot ◽  
Susan Feyerabend ◽  
Rafael Morales-Barrera ◽  
Min Yuen Teo ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Parp Inhibitor ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Previously Treated

440 Background: ATLAS (NCT03397394) evaluated the efficacy/safety of the PARP inhibitor (PARPi) rucaparib in patients (pts) with previously treated locally advanced/unresectable UC or mUC. Methods: Pts with measurable disease who had progressed after 1–2 prior regimens (ie, platinum-based chemotherapy [PBC] and/or immune checkpoint inhibitors [ICI]) were enrolled regardless of tumor homologous recombination deficiency (HRD) status. Prior PARPi was not allowed. Pts received rucaparib 600 mg PO BID. Baseline tumor tissue or archival tissue ≤6 mo without intervening therapy was required; serial circulating tumor DNA samples were collected. Primary endpoint was investigator-assessed objective response rate (RECIST v1.1) in the intent-to-treat and HRD-positive (defined as genomic loss of heterozygosity ≥10%) populations. Key secondary endpoints: progression-free survival (PFS) and safety. Clinical benefit rate (CBR) was defined as complete or partial response or stable disease (SD) lasting ≥16 weeks. Results: As of Oct 7, 2019, 97 pts were enrolled (median age 66 y [range, 39–87]); most were men (n=76, 78.4%) and had ECOG PS 1 (n=65, 67.0%). Sixty-six pts (68.0%) had both prior PBC and ICI. Twenty pts (20.6%) were HRD-positive, 30 (30.9%) were HRD-negative and 47 (48.5%) had unknown HRD status; 4 pts had a deleterious BRCA1/2 alteration. Median time on treatment was 54 d (range, 2–224). There were no confirmed responses. Of 96 evaluable pts, 27 (28.1%) had a best response of SD; CBR was 12.5% and median PFS was 1.8 mo. No relationship was observed between HRD status and clinical activity. Treatment was discontinued by 93 pts (95.9%), mainly due to radiologic or clinical progression (73.1%). Most frequent any grade treatment-emergent (any cause) adverse events were asthenia/fatigue (n=56, 57.7%), nausea (n=40, 41.2%), and anemia (n=34, 35.1%). Conclusions: Single agent rucaparib did not show activity in pts with previously treated advanced UC and enrollment was suspended at the first interim analysis. The safety profile was consistent with that observed in pts with ovarian cancer. Next generation sequencing–based characterization of the genomic landscape of mUC will be presented. Clinical trial information: NCT03397394.

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