A phase 1b study of avelumab plus DCC-3014, a potent and selective inhibitor of colony stimulating factor 1 receptor (CSF1R), in patients with advanced high-grade sarcoma.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11549-11549
Author(s):  
Evan Rosenbaum ◽  
Sujana Movva ◽  
Ciara Marie Kelly ◽  
Mark Andrew Dickson ◽  
Mary Louise Keohan ◽  
...  
Keyword(s):  
Dose Level ◽  
Peripheral Blood ◽  
Cytotoxic T Cells ◽  
Objective Response ◽  
Myeloid Cells ◽  
Suppressor Cells ◽  
Open Label ◽  
Blood Samples ◽  
Pleomorphic Sarcoma ◽  
High Grade Sarcoma

11549 Background: Select sarcomas are infiltrated with immunosuppressive myeloid cells. DCC-3014 is an inhibitor of the CSF1R kinase that decreases tumor infiltrating myeloid cells in preclinical models. We hypothesized that DCC-3014 combined with the anti-PDL1 inhibitor avelumab would be safe and tolerable, decrease immunosuppressive myeloid cells, and increase cytotoxic T cells. Methods: This investigator initiated, open label, single center, phase I study of DCC-3014 plus avelumab in patients (pts) with unresectable or metastatic sarcoma utilized a standard 3+3 dose escalation design. DCC-3014 was administered on days 1-3 (loading dose of 20, 30, or 50 mg) followed by oral daily maintenance (10, 14, or 20 mg) in 28-day cycles; 800 mg of IV avelumab was administered q2weeks. The primary endpoint was to determine the recommended phase 2 dose (RP2D). Secondary endpoints defined the adverse event (AE) profile and assessed clinical efficacy. Peripheral blood CD14+Lin-HLA-DRlo myeloid-derived suppressor cells (MDSCs) were measured by flow cytometry. Results: 13 pts were treated; median age was 61 (range 32 – 71), 8 were female, and median prior lines of therapy was 5 (range 2 – 10). Histologic subtypes included leiomyosarcoma (LMS, n = 7), undifferentiated pleomorphic sarcoma (2), dedifferentiated liposarcoma (LPS, 2), synovial sarcoma (1), and pleomorphic LPS (1). The Table lists treatment-related AEs (TRAEs) of any grade (G) occurring in ≥ 10% of pts and all G ≥ 3 TRAEs, sorted by frequency. All pts had at least 1 TRAE. Seven pts (54%) had a G ≥ 3 TRAE. Most TRAEs were either G ≤ 2 or expected on-target effects of CSF1R inhibition. 1 of 6 pts on the highest dose level had a dose limiting toxicity (G4 elevated AST with abdominal pain) that resolved with treatment cessation. The highest dose level was declared the RP2D. Best objective response by RECIST 1.1 was stable disease in 3 pts; 2 had LMS and were treated at the highest dose level. At baseline, the mean proportion of monocytes in peripheral blood samples with an MDSC phenotype was 12.2% (range 7.1 – 19.9). 5 of 7 pts with serial blood samples had decreased circulating MDSCs (mean decrease of 26.9% from baseline to last time point). Conclusions: DCC-3014 combined with avelumab was safe and tolerable. Study therapy decreased circulating MDSCs in select patients; T cell analyses will be reported. Study expansion at the RP2D is ongoing. Clinical trial information: NCT04242238. [Table: see text]

A phase II, multicenter, randomized, open-label study to evaluate the safety and tolerability of proxalutamide (GT0918) in subjects with metastatic castrate-resistant prostate cancer (mCRPC).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 108-108
Author(s):  
Tie Zhou ◽  
Dingwei Ye ◽  
Zhongquan Sun ◽  
Qinggui Meng ◽  
Dalin He ◽  
...  
Keyword(s):  
Dose Level ◽  
Response Rate ◽  
Objective Response ◽  
Specific Antigen ◽  
Stage Iv ◽  
Study Drug ◽  
Progression Free Survival ◽  
Open Label ◽  
Significant Difference ◽  
Psa Progression

108 Background: GT0918 is a 2nd generation of AR antagonist and capability to down-regulate AR level. This study is an open-label, randomized, multicenter, Ph II study to evaluate the safety and efficacy in patients with mCRPC, and to determine the optimal dose for Ph III study. Methods: Patients with historically confirmed mCRPC who progressed after/intolerant to/reluctant to receive Docetaxel and previously treated with abiraterone or enzalutamide were excluded. All the patients received up to 6 cycles or, unacceptable toxicity, or loss of clinical benefit as recommended by PCWG3. Primary endpoint was prostate-specific antigen (PSA) reduction from baseline. Secondary endpoints included time to PSA progression (TTPP), objective response rate (ORR), progression free survival (PFS), disease control rate (DCR) and safety profiles. Results: As of June 30, 2019, 108 treated with GT0918 at three dose levels: 100 mg (n =37), 200 mg (n = 35) and 300 mg (n = 36), the median age of patients was 70.0 years (range 63-77), 88% of patients had stage IV disease at the initial diagnosis and 69.4% had Gleason score ≥ 8. The median duration of disease was 2.88 years. All received prior endocrine therapy, 35.2% received prior chemotherapy, 29.6% received Docetaxel. The median PSA at baseline was 35.285ng/ml, PSA response rate (≥50 % reduction from baseline) was 41.9%. The median time to PSA progression was not reached. There was no significant difference among three arms. Of 19 evaluable patients with target lesions at baseline, the ORR was 15.8% (all were PR) assessed by IRC with RECIST v 1.1, with 20.0% (1/5), 22.2% (2/9), 0 (0/5) at 100, 200, 300 dose level, respectively. The DCR assessed by IRC was 78.9% (CR 0+PR15.8%+SD 63.2%). Of 26 evaluable patients with target lesions at baseline, the ORR was 19.2% assessed by investigators (CR 3.8%+PR 15.4%), with 11.1% (1/9), 20.0% (2/10), 28.6% (2/7) at 100, 200, 300 dose level, respectively. Overall, AEs were experienced by most of patients (94.4 %, n=102). AEs leading to drug interruption were reported in 13 patients (12.0%), 9 (8.3%)of them were suspected to be drug related. AEs leading to discontinuation were reported in 6 patients (5.6%), 3(2.8%) were possibly related to GT0918. 14 patients (13.0%) experienced Grade 3 and 4 AEs. 17 patients (15.7%)experienced SAE, 5(4.6%) of them were suspected to be related to study drug. Most of AEs were mild or moderate. The common suspected AE (≥10%) were asthenia (17.6%, n=19), anemia (14.8%, n=16), AST increased (14.8%, n=16), ALT increased (13.0%, n=14), decreased appetite (13.0%, N=14), white blood cell count decreased (12.0%, n=13), proteinuria (12.0%, n=13). Conclusions: GT0918 showed a manageable safety profile. This study provided preliminary anti-tumor activity in patients with mCRPC. 200mg/day is recommended dose for Ph III trial. Clinical trial information: CTR20170177.

Final results of PEANUT: Pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 5017-5017
Author(s):  
Patrizia Giannatempo ◽  
Giuseppina Calareso ◽  
Marco Bandini ◽  
Laura Marandino ◽  
Daniele Raggi ◽  
...  
Keyword(s):  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Open Label ◽  
Ecog Performance Status ◽  
Repair Gene ◽  
Good Tolerability ◽  
Blood Samples ◽  
Disease Response

5017 Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigated their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts received 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nab-paclitaxel on D1 and D8, every 3 weeks, until disease progression (PD) or unacceptable toxicity. Inclusion criteria were: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response was evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers included PD-L1 combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint was the progression-free survival (PFS). The target was to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 12/2019, PEANUT study enrolled 65 pts: 24% were female, median age was 69 yrs (IQR: 61-73); 25% had failed > 1 prior systemic therapies; 35% had ECOG-performance status 1; 33% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up (FUP) of 5.5 months, 34 pts have relapsed (52.3%). The median PFS was 5 months (95%CI: 3-not reached). The 3-month PFS was 60.7% (95%CI: 49.8-74.1). The confirmed objective response-rate (ORR) was 47.7% (95%CI: 35.2-60.4): 22 partial responses and 9 complete responses (13.8%). The median duration of response was not reached, and 4 pts (6.1%) are long-term responders ( > 12 months). Grade 3 treatment-related adverse events (TRAE) were seen in 20 pts (30.7%). Most common any-grade TRAE included alopecia (76%), neutropenia (33.3%) and asthenia (33%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. In matched tumor/blood samples, objective responses were seen in 8/10 pts with PI3KCA mutations (80%); 6/10 pts with RB1 alterations (60%); 5/12 pts with DNA damage repair gene alterations (41.7%). Conclusions: Pembro-nab-paclitaxel, the first salvage CT-immunotherapy combination in UC, demonstrated a good tolerability, promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. As more mature data on biomarker selection emerges, this combination warrants additional studies in either second-line or earlier disease settings. Clinical trial information: NCT03464734 .

Phase I pilot study of RRx-001 + nivolumab in patients with traditionally non-checkpoint inhibitor-responsive cancers (PRIMETIME).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. e15119-e15119
Author(s):  
Corey Carter ◽  
Scott Caroen ◽  
Bryan Oronsky ◽  
Mary Flanagan Quinn ◽  
Jeannie Williams ◽  
...  
Keyword(s):  
Adverse Event ◽  
Pilot Study ◽  
Dose Level ◽  
Phase 1 ◽  
Objective Response ◽  
Evaluation Criteria ◽  
Preliminary Evidence ◽  
Open Label ◽  
Voluntary Withdrawal ◽  
Main Adverse Event

e15119 Background: RRx-001 is a minimally toxic small molecule that downregulates CD47 via Myc inhibition and repolarizes tumor-associated macrophages (TAMs). A phase 1 pilot study was undertaken to determine the safety and feasibility of RRx-001 and nivolumab in patients with advanced traditionally non-immunogenic cancers and no standard options. Methods: This single arm, open-label pilot study (NCT02518958) was designed to evaluate the safety profile of RRx-001 + nivolumab in patients with advanced malignancies. A 3+3 trial design was used to establish safety of the combination at each dose level and guide the decision to escalate dose. RRx-001 is infused once weekly while nivolumab is given at 3mg/kg once every 2 weeks. RRx-001 starting dose was 2 mg IV weekly with 4 dose level escalations up to 16 mg IV weekly. From January 2015 to November 2015, 12 patients received treatment for 4 cycles (total 12 weeks) with the combination due to unavailability of nivolumab, which was not supplied to the Sponsor. Treatment-emergent (all cause, TEAEs) and treatment-related (TRAEs) adverse events occurring within 16 weeks of the first dose of RRx-001 + nivolumab were characterized according to CTCAE v4.03. Results: 12 patients received > 1 dose of RRx-001 and nivolumab. One discontinuation occurred due to pneumonitis and one to voluntary withdrawal after a post-procedural infection. There were no dose-limiting toxicities. The main adverse event related to RRx-001 was pain on infusion (33.3%). The main adverse event related to the combination was pseudoprogression (larger tumors in symptomatically improved patients) (25%). The most common immune-related treatment-emergent AEs were pneumonitis (8.3%), and hypothyroidism (8.3%). Objective response rate at 12 weeks was 25% and the disease control rate (DCR) consisting of > SD was 67% by Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1. 25% of the patients progressed on the combination. Conclusions: RRx-001 + nivolumab was well-tolerated with preliminary evidence of anti-cancer activity in non-immunogenic cancers. Further analyses with a larger sample size are required to confirm activity. Clinical trial information: NCT02518958 .

Phase I study investigating the safety of stereotactic body radiotherapy (SBRT) with anti-PD-1 and anti-IL-8 for the treatment of multiple metastases in advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS2681-TPS2681
Author(s):  
Lilit Karapetyan ◽  
Adam C. Olson ◽  
William E. Gooding ◽  
Riyue Bao ◽  
Steven J. Chmura ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase 1 ◽  
Objective Response ◽  
Suppressor Cells ◽  
Neutralizing Antibody ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Multiple Metastases ◽  
Organ Site

TPS2681 Background: Anti-PD-(L)1 immunotherapy improves outcomes for patients across various cancers; however, many patients do not benefit. Previous studies combining multi-site SBRT with anti-PD1 have confirmed feasibility and revealed induction of interferon signaling by SBRT. Elevated levels of serum IL8 (sIL8) associate with lack of response to anti-PD1 and we have observed that elevated IL8 is strongly associated with lack of response to immunotherapy and SBRT combinations. Overcoming IL8 induced epithelial-mesenchymal transitioning and trafficking of myeloid derived suppressor cells in tumor microenvironment therefore represents a promising strategy to overcome resistance. BMS-986253 is a fully human neutralizing antibody that binds to sIL8. The combination of BMS-986253 and nivolumab was safe in patients with advanced solid tumors. The present study aims to evaluate safety and preliminary efficacy of combining BMS-986253 with nivolumab and SBRT in patients with advanced solid tumors, Melanoma (MEL) and Renal Cell Carcinoma (RCC). Methods: This is a phase 1 open label single arm study (CT.gov: NCT04572451) which will include safety and efficacy cohorts. Patients will receive SBRT in 1-4 tumor lesions, in 3 or 5 fractions, at the total of 30 or 45 or 50 Gy based on the irradiated organ site. This will be followed by intravenous (IV) nivolumab (480mg q4 weeks (W)) and IV BMS-986253 (2400mg q2W) within seven days of completing SBRT. In the initial safety portion of the clinical trial, we will include 30 patients with advanced/metastatic solid tumors in order to evaluate safety. The primary endpoint of dose limiting toxicity will be assessed by continual Bayesian monitoring. The toxicities will be attributed to combination of SBRT/Immunotherapy as opposed to individual components. The secondary objective of the study is efficacy with an endpoint of objective response rate (ORR) as assessed by RECIST v1.1 in Mel and RCC. We will include 20 patients with MEL and RCC and compare against a historical benchmark of 20% ORR as sufficient signal of activity for further study. ORR will be assessed for association with serum IL-8 levels and radiation-induced changes in peripheral blood T cell populations. Clinical trial information: NCT04572451.

ENVASARC: A pivotal trial of envafolimab, and envafolimab in combination with ipilimumab, in patients with advanced or metastatic undifferentiated pleomorphic sarcoma or myxofibrosarcoma who have progressed on prior chemotherapy.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS11581-TPS11581
Author(s):  
Sandra P. D'Angelo ◽  
Steven Ian Robinson ◽  
Joelle Lam ◽  
Bonne J. Adams ◽  
James L. Freddo ◽  
...  
Keyword(s):  
Confidence Interval ◽  
Objective Response Rate ◽  
Response Rate ◽  
Single Agent ◽  
Objective Response ◽  
Locally Advanced ◽  
Primary Objective ◽  
Open Label ◽  
Undifferentiated Pleomorphic Sarcoma ◽  
Pleomorphic Sarcoma

TPS11581 Background: Metastatic undifferentiated Pleomorphic Sarcoma (UPS) and the genetically related myxofibrosarcoma (MFS) are soft tissue sarcoma (STS) subtypes with poor prognoses. While responses to front line chemotherapy can approach 20%, efficacy remains limited in the 2nd line setting and beyond. Pazopanib, the only approved treatment in the refractory setting, has demonstrated an objective response rate (ORR) of 4%. Envafolimab is a single domain PD-L1 antibody administered rapidly by subcutaneous (SQ) injection that is being studied in two additional pivotal trials: microsatellite instability-high (MSI-H) cancer and biliary tract cancer. The activity of envafolimab appears to be similar to other PD-1 antibodies administered i.v. Envafolimab demonstrated a 32% objective response rate (ORR) in MSI-H colorectal cancer patients who failed three approved chemotherapeutics, similar to the ORR of 28% and 33% with nivolumab and pembrolizumab in these patient populations, respectively. The rationale for the ENVASARC trial is based on the previously reported activity of checkpoint inhibition in UPS/MFS. Single agent pembrolizumab demonstrated a 23% ORR, while the combination of nivolumab and ipilimumab demonstrated a 29% ORR in refractory UPS/MFS. Methods: ENVASARC (NCT 04480502) is a pivotal multicenter (at ̃25 U.S. centers) open-label, randomized, non-comparative, parallel cohort study of treatment with envafolimab 300 mg every 3 weeks by SQ injection (cohort A; n = 80) or envafolimab 300 mg every 3 weeks by SQ injection combined with ipilimumab 1 mg/kg every 3 weeks i.v. for four doses (cohort B; n = 80) in patients with locally advanced, unresectable or metastatic UPS/MFS who have progressed on one or two lines of prior therapy. The primary objective of each of parallel cohort is to demonstrate an ORR with a lower limit of the 95% confidence interval that excludes 5.0% in each cohort. If ≥ 9 responders are observed of the 80 patients enrolled in each cohort, then the lower bound of the 95% confidence interval will exclude 5.0%. Secondary endpoints include duration of response (DOR), PFS and OS. Key inclusion criteria: ≤ 2 prior lines of therapy (neoadjuvant and adjuvant therapy excluded), ECOG ≤ 1. Clinical trial information: NCT 04480502.

scholarly journals PC3 - 151 Toca 5: A Phase 2/3 Randomized, Open-Label Study of Toca 511, a Retroviral Replicating Vector, Combined with Toca FC versus Standard of Care in Patients Undergoing Planned Resection for Recurrent Glioblastoma (GBM) or Anaplastic Astrocytoma (AA) (NCT02414165)

2016 ◽  
Vol 43 (S4) ◽  
pp. S17-S17
Author(s):  
G. Zadeh ◽  
D. Bota ◽  
D. Cachia ◽  
J. Landolfi ◽  
D. Schiff ◽  
...  
Keyword(s):  
Phase 1 ◽  
Objective Response ◽  
Unmet Need ◽  
Suppressor Cells ◽  
Standard Of Care ◽  
Immune Monitoring ◽  
Recurrent Glioblastoma ◽  
Phase 2 ◽  
Open Label ◽  
Dismal Prognosis

Recurrent GBM and AA have a dismal prognosis and a high unmet need for effective therapies. Toca 511 (vocimagene amiretrorepvec) is an investigational retroviral replicating vector that encodes the transgene cytosine deaminase (CD). Toca 511 selectively infects, persists and spreads in tumor. Subsequent oral administration of 5-fluorocytosine (Toca FC) produces 5-fluorouracil (5-FU) by CD within infected cells. 5-FU kills cancer cells and myeloid derived suppressor cells, inducing robust antitumor immune responses in animal models. Clinical data from phase 1 trials are consistent with this mechanism of action, and show extended survival compared to historical controls. Toca 5 is a multicenter, randomized, open-label Phase 2/3 trial of Toca 511 and Toca FC versus standard of care administered to patients undergoing resection for first or second recurrence of GBM or AA. Phase 2 will enroll 170 patients. Primary endpoint is overall survival (OS). Key secondary endpoints are safety, objective response rate, clinical benefit rate, progression-free survival, and landmark OS. Key inclusion criteria are age 18-75 years, histologically proven GBM or AA, measurable disease preoperatively of less than 5cm, candidate for equal or greater 80% resection of enhancing tumor based on pre-operative evaluation, and KPS equal or greater to 70. Assays for immune monitoring will be performed and molecular profiling of resected tumor samples will be correlated efficacy.

Serial changes in PD1/PDL1 expression in metastatic urothelial carcinoma (mUC) patients (pts) treated with immune checkpoint blockade (CPB).

2018 ◽  
Vol 36 (5_suppl) ◽  
pp. 109-109
Author(s):  
Alice Tzeng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Jin Sub Kim ◽  
Paul G Pavicic ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Mixed Model ◽  
Mononuclear Cells ◽  
Suppressor Cells ◽  
Immune Checkpoint Blockade ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples ◽  
Immune Marker ◽  
Marker Expression ◽  
Median Change

109 Background: Since CPB may alter immune marker expression in key immunomodulatory populations such as myeloid-derived suppressor cells (MDSC) and CD8+ cytotoxic T lymphocytes (CTL), we evaluated PD1/PDL1 expression in longitudinal samples from mUC pts treated with CPB. Methods: Serial peripheral blood samples were collected from mUC pts who received CPB. PD1/PDL1 and VISTA expression was measured in MDSC (CD33+HLADR−) and CTL (CD8+CD4−) from live peripheral blood mononuclear cells using flow cytometry. MDSC subsets were further defined as (G)ranulocytic (CD15+CD14−), (M)onocytic (CD15−CD14+), and (I)mmature (CD15−CD14−). PD1/PDL1 and VISTA expression was presented as % of each MDSC subset or CTL. Wilcoxon signed-rank tests and mixed-model regression analyses were performed to assess changes in immune marker expression after CPB. Results: Of 30 CPB-treated pts with ≥ 2 blood samples for analysis, 21 received anti-PDL1 (20 atezolizumab/1 avelumab; [A]) and 9 received anti-PD1 (pembrolizumab [P]). Median age at diagnosis was 69.5 (46–81), 77% men, 33% never smokers, 63% pure UC, 70% bladder primary, 20% prior intravesical BCG, 37% prior neoadjuvant chemotherapy, 63% prior cystectomy. Best overall responses to CPB were 3 PR/13 SD/5 PD (A) and 1 CR/1 PR/4 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC, while those of P correlated with decreased %PD1+ M- and I- MDSC (Table). No significant changes in VISTA expression were detected. In 11 A-treated pts with samples before/after the 1st dose, %PDL1+ M- and I- MDSC decreased (median change −25.5 and −5.7; p = 0.02 and 0.03) and %PD1+ CTL increased (median change +2.4; p = 0.02) between 1st and 2nd samples. Conclusions: In this mUC pt cohort, distinct post-tx changes in %PD1/PDL1 in MDSC subsets and CTL occurred based on CPB (anti-PD1 vs anti-PDL1). Further analysis of correlations between CPB, immune marker expression, clinicopathologic factors, and outcomes is ongoing in a larger cohort. Mean absolute change in marker expression per dose in pts treated with CPB. [Table: see text]

Immunological correlates of response to immune checkpoint inhibitors (ICI) in metastatic urothelial carcinoma (mUC) patients (pts).

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 454-454
Author(s):  
Alice Tzeng ◽  
C. Marcela Diaz-Montero ◽  
Patricia A. Rayman ◽  
Jin Sub Kim ◽  
Paul G Pavicic ◽  
...  
Keyword(s):  
T Cells ◽  
Peripheral Blood ◽  
Mixed Model ◽  
Mononuclear Cells ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Suppressor Cells ◽  
Peripheral Blood Mononuclear ◽  
Blood Samples ◽  
Never Smokers

454 Background: Identification of biomarkers predictive of response to ICI could help guide treatment (tx) decisions. We assessed the correlation between PD1/PDL1 expression in key immunomodulatory subsets (myeloid-derived suppressor cells [MDSC]; CD8+ T cells) and tx response in mUC pts treated with ICI. Methods: Serial peripheral blood samples were collected from mUC pts treated with ICI. Flow cytometry was used to quantify PD1/PDL1 expression in MDSC (CD33+HLADR−) and CD8+ T cells (CD8+CD4−) from live peripheral blood mononuclear cells. MDSC were subdivided into monocytic (M)-MDSC (CD14+CD15−), polymorphonuclear (PMN)-MDSC (CD14− CD15+), and immature (I)-MDSC (CD14− CD15−). Mixed-model regression and Wilcoxon rank-sum tests were performed to assess post-ICI changes in immune marker expression and identify correlations between PD1/PDL1 expression and best overall response (BOR) to ICI. Results: Of 36 ICI-treated pts with ≥2 blood samples, 24 received anti-PDL1 (22 atezolizumab/2 avelumab; [A]) and 12 received anti-PD1 (pembrolizumab [P]). 78% were men, median age 69 (46–81), 28% never smokers, 19% had prior intravesical BCG, 39% prior neoadjuvant chemotherapy, and 64% prior cystectomy. BOR to ICI included 3 PR/14 SD/7 PD (A) and 1 CR/2 PR/6 SD/3 PD (P). Successive doses of A correlated with decreased %PDL1+ M-MDSC (mean change −5.26/dose; p = 0.009), while those of P correlated with decreased %PD1+ M- and I- MDSC (mean change −1.55 and −1.14/dose; p = 0.04 and 0.02, respectively). Though pre-tx %PD1+ CD8+ T cells did not predict BOR, greater PD1 expression by CD8+ T cells within 12 weeks after ICI initiation correlated with BOR (Table). Conclusions: ICI tx correlated with distinct changes in PD1/PDL1 expression by specific peripheral immune cell subsets. Responders to ICI had higher % of PD1+ CD8+ T cells after ICI than non-responders, though pre-tx % were comparable between groups. Further validation of these and other potential blood/tissue biomarkers is ongoing. [Table: see text]

Interim results of PEANUT: pembrolizumab and nanoparticle albumin-bound paclitaxel (nab-paclitaxel) as salvage therapy for metastatic urothelial carcinoma (UC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. 494-494
Author(s):  
Andrea Necchi ◽  
Daniele Raggi ◽  
Marco Bandini ◽  
Elena Farè ◽  
Patrizia Giannatempo ◽  
...  
Keyword(s):  
Performance Status ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Study Endpoint ◽  
Open Label ◽  
Ecog Performance Status ◽  
Blood Samples ◽  
Disease Response ◽  
Line Setting

494 Background: Pembrolizumab (pembro) is a new standard of care in chemotherapy (CT) pre-treated patients (pts) with metastatic UC. Nab-paclitaxel (nPtx) demonstrated preliminary activity in advanced UC. In the PEANUT study (NCT03464734) we investigate their combination in advanced UC after CT failure. Methods: In an open-label, single-arm, phase 2 trial, pts receive 200 mg pembro, intravenously (IV), on D1 and 125 mg/m2 IV nPtx on D1 and D8, every 3 weeks, until disease progression (PD) or onset of unacceptable toxicity. Key inclusion criteria are: predominant UC histology, failure of ≤2 platinum-based CT for metastatic disease. Response is evaluated by RECIST v.1.1 criteria every 2 cycles. Biomarkers include PD-L1 expression with the combined positive score (CPS) and comprehensive genomic profiling on tumor and blood samples (FoundationONE and FoundationACT assay). The primary endpoint of the study is the progression-free survival (PFS). The target is to detect an improvement in the median PFS from ≤3.0 months (H0) to ≥5.0 months (H1). Results: Between 01 and 08/2019, PEANUT enrolled 46 pts evaluable for the study endpoint: 26% female, median age 66 y (range 43-78); 70% had failed 1 prior systemic therapy vs 30% 2 prior therapies; 24% had ECOG-performance status 1; 28% had liver metastases. The median TMB was 6.9 mut/Mb. After median follow-up of 5 months, 18 pts have relapsed (39%). The projected median PFS was 7 months (95%CI: 4-not achieved). The confirmed objective response-rate (ORR) was 47.8% (95%CI: 32.9-63.1): 18 partial responses and 4 complete responses (8.7%). Grade 3 treatment-related adverse events (TRAE) were seen in 6 pts (13%). Most common any-grade TRAE included alopecia (91%), asthenia (21.7%), and neutropenia (15%). Neither TMB nor CPS were significantly associated with PFS on univariable analyses. 7/8 pts with PI3KCA mutations in matched tumor/blood samples had an objective response (87.5%). Conclusions: Preliminary results from PEANUT study demonstrated a promising PFS and a clinically meaningful ORR in II-III line setting of advanced UC. Updated data, including mature PFS, duration of response and biomarkers will be presented. Clinical trial information: NCT03464734.

Phase II study of sitravatinib in combination with nivolumab in patients undergoing nephrectomy for locally-advanced clear cell renal cell carcinoma (ccRCC).

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. TPS686-TPS686
Author(s):  
Jose A. Karam
Keyword(s):  
Immune Response ◽  
Immune Cell ◽  
Kinase Inhibitor ◽  
Objective Response ◽  
Locally Advanced ◽  
Suppressor Cells ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Cell Renal Cell Carcinoma

TPS686 Background: Sitravatinib is a receptor tyrosine kinase inhibitor (RTKI) that targets multiple closely related RTK pathways including VEGFR, PDGFR, KIT, MET and the TAM receptors (TYRO3, AXL and MERTK) Nivolumab is a monoclonal antibody against PD-1 and releases PD-1-mediated inhibition of T-cell proliferation and cytokine production. Together, sitravatinib and nivolumab may cooperate to elicit greater anti-tumor activity than either agent alone, as sitravatinib is predicted to enhance several steps in the cancer immunity cycle that may augment nivolumab’s efficacy. Mechanisms by which sitravatinib may augment an antitumor immune response include enhanced antigen presentation; depletion of immunosuppressive regulatory T-cells (Tregs) and myeloid-derived suppressor cells (MDSCs) via inhibition of split kinases VEGFR and KIT; and shifting tumor-associated macrophages from an immunosuppressive M2 to a pro-immunogenic M1 phenotype via inhibition of TAM RTKs. Each of these factors converge on promoting T effector cell expansion, tumor infiltration and an antigen-specific anti-tumor immune response. Methods: This open-label, non-randomized, preoperative window of opportunity Phase 2 study evaluates tolerability and clinical activity of sitravatinib in combination with nivolumab in pts with locally-advanced ccRCC undergoing nephrectomy. Study treatment consists of 2 weeks of sitravatinib monotherapy followed by 4 weeks of the combination. Sitravatinib is administered orally daily at 120 mg; nivolumab intravenously every 2 weeks at 240 mg. The primary objective is to evaluate clinical activity using percentage of pts achieving a presurgical point-in-time objective response. Secondary objectives include evaluation of safety and tolerability, and determination of the immune effects of sitravatinib monotherapy and the combination through serial tissue and blood collections (temporal changes in PD-L1 expression, selected cytokines and immune cell populations including MDSCs, Tregs and ratio of M1:M2 macrophages). The study is open for enrollment and recruitment is ongoing. Clinical trial information: NCT03680521.

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