A phase I/II study to assess the safety and efficacy of pazopanib (PAZ) and pembrolizumab (PEM) in patients (pts) with advanced renal cell carcinoma (aRCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4506-4506 ◽  
Author(s):  
Simon Chowdhury ◽  
David F. McDermott ◽  
Martin Henner Voss ◽  
Robert E. Hawkins ◽  
Paola Aimone ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Phase I ◽  
Liver Toxicity ◽  
Maximum Tolerated Dose ◽  
Limited Information ◽  
Safety And Efficacy ◽  
Sequential Schedule ◽  
Anti Tumor Activity ◽  
Clinical Trial Information

4506 Background: PAZ is indicated for the treatment of aRCC. The combination of an anti-angiogenic agent and immunotherapy may improve anti-tumor activity. We report preliminary safety and efficacy results of the phase I part of the study. Methods: Twenty pts were originally enrolled in cohorts A and B assessing PAZ 800 mg and 600 mg, respectively, both with 2mg/kg (Q2W and then Q3W) PEM to determine the maximum tolerated dose. Due to dose limiting liver toxicity, cohort C was opened to assess if the sequential schedule of 9 weeks PAZ run-in followed by PAZ+PEM would improve safety. Strict safety criteria for initiating PAZ+PEM were set. The data from this ongoing study are presented given the limited information available on the combination of TKI + PD-1 inhibitors in RCC. Results: Overall, 35 pts were treated; 5 out of 15 pts in cohort C received PAZ+PEM at the data cut-off. Three dose-limiting toxicities (DLT) occurred in cohort C in pts receiving PAZ+PEM; updated DLTs in all cohorts are reported in Table. G3/4 AEs were observed in 90% of pts in cohorts A and B and in 80% of pts in cohort C receiving PAZ+PEM. No G3/4 ALT/AST elevation was reported in cohort C PAZ+PEM while they were observed in 70% and 60% in cohorts A and B, respectively. Best overall response (CR+PR) was reported in 6, 2 and 1 pts receiving PAZ+PEM in cohorts A, B and C, respectively. Conclusions: Results from cohorts A and B showed significant hepatotoxicity. The sequential schedule PAZ → PAZ+PEM has shown reduced hepatotoxicity and preliminary signs of efficacy but overall limited tolerability. PAZ+PEM is not suitable to test in a larger cohort. Clinical trial information: 2013-003785-14. [Table: see text]

A phase I clinical trial of CM082 (X-82) in combination with everolimus for treatment of metastatic renal cell carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4575-4575 ◽  
Author(s):  
Xinan Sheng ◽  
Xieqiao Yan ◽  
Bixia Tang ◽  
Zhihong Chi ◽  
Chuanliang Cui ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Phase I ◽  
Cell Carcinoma ◽  
Metastatic Renal Cell Carcinoma ◽  
Renal Cell ◽  
Maximum Tolerated Dose ◽  
Cell Renal Cell Carcinoma ◽  
Multikinase Inhibitor ◽  
Expansion Cohort

4575 Background: CM082 is an oral multikinase inhibitor targeting VEGFR, PDGFR and CSF1R with a shorter half-life and limited tissue accumulation, designed to lower toxicity and enable combination with other therapies. This is a phase I study to evaluate the safety, tolerability, pharmacokinetics, and preliminary efficacy of CM082 in combination with everolimus in patients with metastatic renal cell carcinoma. Methods: A 3+3 dose escalation design with expansion cohort was utilized to determine the dose-limiting toxicities (DLT) and the maximum tolerated dose (MTD) of CM082 plus everolimus at 5 mg PO daily for patients with metastatic clear cell renal cell carcinoma. Eligibility include PS 0-1, age ≥18 y, measurable disease, adequate organ function. Results: 22 patients (M/F: 16/6; median age: 55 y [range 32-69]; 21/22 pts [95.5%] had received prior anti-VEGF treatment (tx); 2/22 pts [9.1%] had also received prior mTOR-targeted tx) were treated at 3 dose levels of CM082 (100 mg [n = 4]; 150 mg [n = 3]; 200 mg [n = 15]) in combination with everolimus 5 mg. One patient in cohort 1 was not evaluable for DLT due to consent withdrawal. DLT were observed in one patient: G4 thrombocytopenia at 200 mg. CM082 200 mg plus everolimus 5 mg did not exceed MTD, but was chosen as the optimal biological dose regimen. Median duration of tx was 24 wk (range 1-57, 7/22 [32%] pts ongoing. The most common tx-related adverse events (AEs), all grades, were proteinuria 96% (G3, 5%); leukopenia 77% (G3, 9%); neutropenia 59%, hypercholesterolemia 64%, anemia 50% (G3, 9%), hypertension 46% (G3, 14%), raised aspartate aminotransferase 41%, fatigue 45%, diarrhea 32%, hypertriglyceridemia 32% (G3, 5%) and thrombocytopenia 20% (G4, 5%). At 200mg, partial response (PR) was observed in 5/14 (36%) patients, durable stable disease (SD) (≥24 week) or PR were achieved in 10/14 (71%) patients. Median PFS was 170 days (5.7 months) at this cohort. Conclusions: CM082 200mg in combination with everolimus 5 mg appeared to be well tolerated when administered to pretreated patients with advanced RCC in this Ph1 study. The preliminary efficacy warrant further evaluationand and the follow-up Ph 2/3 study is underway. Clinical trial information: NCT02577458.

Pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors: Safety and efficacy results from a phase Id trial.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16009-e16009
Author(s):  
Dan Liu ◽  
Yingying Xu ◽  
Jifang Gong ◽  
Fen Yang ◽  
Lin Shen ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Solid Tumors ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Her2 Positive ◽  
Safety And Efficacy ◽  
Efficacy Analysis ◽  
Dose Levels ◽  
Anti Tumor Activity ◽  
Clinical Trial Information

e16009 Background: Pyrotinib (an irreversible pan-ErbB inhibitor) combined with SHR6390 (a novel oral small molecule CDK4/6 inhibitor) had shown anti-tumor activity in pyrotinib-resistant PDX models. A phase Id trial was conducted to evaluate the safety and efficacy of pyrotinib combined with SHR6390 in the treatment of refractory advanced HER2 positive gastric cancer or solid tumors (NCT03480256). Methods: A standard “3+3” design was conducted in this trial. Patients (Pts) received pyrotinib (qd, d1-28; q4w) combined SHR6390(qd, d1-21; q4w) at dose of 400/100mg (cohort A), 320/100mg (cohort E) and 400/75mg (cohort F) until disease progression or intolerable toxicity. The primary endpoint was safety and maximum tolerated dose. Results: From Sep. 2019 to Dec. 2020, 19 pts (14 gastric cancer, 3 colorectal cancer, 2 other solid tumors) were enrolled (A: n = 6; E: n = 6; F: n = 7). 15 pts received and progressed on Herceptin before enrollment. In cohort A, one DLT was observed (Grade 4 neutropenia), and another 3 pts suffered G3 neutropenia, anemia or thrombocytopenia. Considered of safety, the dose levels were decreased and designed as cohort E and F. In cohort E, one DLT was observed (G4 neutropenia). No DLT was observed in cohort F. The most common hematologic toxicities were neutropenia (95%), anemia (74%) and thrombocytopenia (74%). The most common non-hematologic toxicities were diarrhea (53%), mucositis (26%) and nausea (21%). The most common G3/4 AEs were leukopenia (37%) and anemia (16%). No G3/4 non-hematologic toxicity was observed. 18 pts were included in efficacy analysis. The overall response rate was 38.9%, with 7 PR (A: n = 3; E: n = 2; F: n = 2) and 7 SD. The median PFS was 3.83 months, with 2 pts received treatment over 12 months (A: n = 1; F: n = 1). Conclusions: Pyrotinib combined with SHR6390 had shown acceptable safety profile and encouraging efficacy in refractory advanced HER2 positive solid tumors. Further study would be carried out at the dose in cohort A. Clinical trial information: NCT03480256.

Neoadjuvant nivolumab monotherapy in patients with resectable gastric cancer: Preliminary results from a multicenter study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4026-4026
Author(s):  
Shuji Takiguchi ◽  
Kohei Shitara ◽  
Noriaki Takiguchi ◽  
Seiji Ito ◽  
Mitsugu Kochi ◽  
...  
Keyword(s):  
Gastric Cancer ◽  
Clinical Trial ◽  
Phase I ◽  
The Other ◽  
Stage I ◽  
Stage Iii ◽  
R0 Resection ◽  
Safety And Efficacy ◽  
Preliminary Results ◽  
Clinical Trial Information

4026 Background: In recent years, several studies suggest that neoadjuvant treatment improve outcomes of patients with resectable advanced gastric cancer (GC). In addition, nivolumab has demonstrated clinical efficacy in multiple types of advanced cancer, and the efficacy of neoadjuvant nivolumab monotherapy has been suggested in a past clinical trial in patients with resectable non-small cell lung cancer (NSCLC). Therefore, this phase I study was planned to evaluate the safety and efficacy of neoadjuvant nivolumab monotherapy in patients with resectable GC or NSCLC. Here we report preliminary results from GC patients. Methods: This study is a phase I, multicenter, open-label, single arm study to evaluate the safety and efficacy of neoadjuvant nivolumab monotherapy in patients with resectable GC (stage I or II [cT2 or more advanced for both], or stage III) before standard surgery. Nivolumab 240 mg was administered twice every two weeks. The primary endpoint is safety. Efficacy endpoints include major pathological response (MPR) defined as residual disease < 10% and the response of primary lesion, and surgical endpoints include proportion of patients undergoing surgery with curative intent and R0 resection rate. Biomarkers such as PD-L1 expression and MSI status are also evaluated. Results: From November 2018 to December 2019, 31 GC patients were enrolled into this study. The median age was 69 years (range, 44-84) and 21 patients (67.7%) were men. According to UICC 8th, clinical stage was stage I in 7 patients (22.6%), stage IIA in 0 patients (0%), stage IIB in 14 patients (45.2%), and stage III in 10 patients (32.3%). MSI status was high in 7 patients (22.6%), low in 4 patients (12.9%), and stable in 20 patients (64.5%). Treatment-related adverse events (TRAEs) occurred in 7 patients (22.6%). The most frequent TRAE was rash which occurred in 2 patients (6.5%); the other TRAEs occurred in 1 patient each. Asymptomatic lipase increased was the only grade 3 TRAE; the other TRAEs were all grade 1 or 2 with no new safety signal. All enrolled patients completed 2 doses of nivolumab. Five patients (16.1%) had MPRs, of whom 1 patient had pathological complete response (pCR). Four of 5 MPRs, 1 pCR included, was observed in 7 MSI-H patients (57.1%) and the remaining case of MPR was observed among 20 MSS patients (5%), whereas no MPRs was achieved in 4 MSI-L patients. Among the 31 patients, 30 patients underwent surgery. The remaining 1 patient discontinued the study before surgery due to disease progression. A total of 27 patients (90%) had R0 resection. Conclusions: Neoadjuvant nivolumab monotherapy showed acceptable safety profile and antitumor activity in patients with resectable GC. Recurrence free survival and overall survival in these patients are under follow-up. Clinical trial information: JapicCTI-183895. Clinical trial information: JapicCTI-183895.

A phase I study of an IDO inhibitor (SHR9146) plus camrelizumab and in combination with/without apatinib in patients with advanced solid tumors: Safety and efficacy analysis.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3101-3101
Author(s):  
Ying Cheng ◽  
Ying Liu ◽  
Jinhua Xu ◽  
Jing Zhu ◽  
Ying Wang ◽  
...  
Keyword(s):  
Partial Response ◽  
Phase I ◽  
Solid Tumors ◽  
Renal Cancer ◽  
Phase I Study ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label ◽  
Safety And Efficacy

3101 Background: IDO is an enzyme of interest in immuno-oncology because of the immunosuppressive effects that result from its role in tryptophan catabolism. Clinical trials of IDO inhibitors with immunotherapy are under active investigation. The addition of angiogenesis inhibitor may further enhance the anti-tumor immune responses. Here we report the safety and efficacy results of SHR9146 (IDO inhibitor) plus camrelizumab (PD-1 antibody) with/without apatinib (VEGFR-2 inhibitor) in patients (pts) with advanced solid cancers who failed standard antitumor therapies. Methods: This was an open-label, phase I study. Eligible puts would receive SHR9146 (escalated dose) plus camrelizumab (200 mg IV, q2w) alone (Cohort A) or in combination with apatinib (250 mg p.o. qd) (Cohort B). Each cohort was conducted according to a 3+3 dose escalation design. The starting dose of SHR9146 was 100mg bid, followed by 200, 400, 600 mg bid. The two primary endpoints were Dose-limiting Toxicity (DLT) and Maximum Tolerated Dose (MDT). The secondary objective was to analysis the incidence of Adverse Events (AEs) and efficacy. Results: As of Oct 31, 2020, 23 pts have been enrolled (Cohort A:14, Cohort B: 9; median age: 54 years; median prior therapies: 2 lines;). Cohort A was escalating at 600mg, and Cohort B was escalating at 400mg. Two pts experienced DLTs: one DLT (G4 hypercalcemia) was observed at 600mg in Cohort A; the other DLT (G3 rash) was observed at 400mg in Cohort B. MDT was not reached and the study was still ongoing. In Cohort A, ORR and DCR in evaluable pts were 21.4% (3/14, all confirmed) and 42.9% (6/14). Partial response was observed in 3 pts with liver cancer (1/3), renal cancer (1/3), and cervix cancer (1/3). In Cohort B, ORR and DCR in evaluable pts were 33.3%(3/9, all confirmed) and 77.8%(7/9). Partial response was observed in 3 pts with SCLC (1/3), prostate cancer (1/3) and renal cancer (1/3). The incidence of pts with TRAEs and grade>=3 TRAEs were 91.3% (21/23) and 39.1% (9/23) respectively. The most common grade>=3 TRAEs were hypercalcemia (26.1%, 6/23), fatigue (17.4%, 4/23) and nausea (13.0%, 3/23). No fatal AEs were observed. G3 nausea, G3 lipase increased and G2 GGT increased resulted in SHR9146 dose reduction in 3 pts (Cohort A). Conclusions: SHR9146 plus camrelizumab in combination with/without apatinib demonstrated promising anti-tumor activity with acceptable safety in pts with advanced solid tumors. Further study is needed to validate the efficacy and safety. Clinical trial information: NCT03491631.

Safety and efficacy outcomes with nivolumab plus ipilimumab in patients with advanced renal cell carcinoma and low Karnofsky performance status: Results from the CheckMate 920 trial.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 315-315
Author(s):  
Thomas E. Hutson ◽  
Bradley Curtis Carthon ◽  
Jeffrey Yorio ◽  
Sunil Babu ◽  
Heidi Ann McKean ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Renal Cell Carcinoma ◽  
Clinical Trials ◽  
Adverse Events ◽  
Clear Cell ◽  
Karnofsky Performance Status ◽  
Performance Status ◽  
Objective Response ◽  
Safety And Efficacy ◽  
Grade 3

315 Background: Combination therapy with nivolumab + ipilimumab (NIVO+IPI) has demonstrated long-term efficacy and tolerability for patients (pts) with previously untreated advanced renal cell carcinoma (aRCC). Most pivotal clinical trials in pts with aRCC have excluded pts with low Karnofsky performance status (KPS; < 70%). CheckMate 920 is a multi-arm, phase IIIb/IV, open-label clinical trial of NIVO+IPI treatment in pts enrolled in a community practice setting with aRCC and a high unmet medical need. We present safety and efficacy results for the cohort of pts with aRCC of any histology and KPS 50%–60% from CheckMate 920 (NCT02982954). Methods: Pts with previously untreated advanced/metastatic RCC and KPS 50%–60% received NIVO 3 mg/kg + IPI 1 mg/kg Q3W × 4 doses followed by 480 mg NIVO Q4W for ≤ 2 years or until disease progression/unacceptable toxicity. The primary endpoint was incidence of grade ≥ 3 immune-mediated adverse events (imAEs) within 100 days of last dose of study drug. Key secondary endpoints included progression-free survival (PFS) and objective response rate (ORR) by RECIST v1.1 (both per investigator). Exploratory endpoints included overall survival (OS). Results: Of 25 treated pts with KPS 50%–60%, 76% were men; median age was 67 years (range, 34–81). IMDC risk was favorable in 0%, intermediate in 32%, and poor in 68% of pts; 84% had clear cell and 16% had non-clear cell RCC histology. With a minimum follow-up of 25 months, median duration of therapy (95% CI) was 2.3 months (2.1–7.7) for NIVO and 2.1 months (2.1–2.1) for IPI. The median number of doses (range) received was 4 (1–27) for NIVO and 4 (1–4) for IPI; 76% of pts received ≥ 4 NIVO doses and 68% received all 4 IPI doses. The only grade 3–4 imAEs by category were hepatitis (4.0%) and adrenal insufficiency (4.0%). No grade 5 imAEs occurred. Overall, 4 (16%) pts discontinued due to any-grade adverse events (n = 1 each for elevated AST, malignant neoplasm progression, back pain, and acetabulum fracture). Of 18 evaluable pts, ORR was 33.3% (95% CI, 13.3–59.0); no pts had a complete response and 6 had partial response. Median time to objective response was 4.5 months (range, 2.5–24.7). Median duration of objective response was 20.6 months (range, 0.03+–24.2+). Median PFS was 4.6 months (95% CI, 2.5–14.8). Median OS was 15.6 months (95% CI, 5.3–25.1). Conclusions: NIVO+IPI demonstrated an acceptable safety profile and promising antitumor activity in pts with previously untreated aRCC and KPS 50%–60%. The combination was tolerated at a dose intensity similar to that observed in clinical trials conducted in pts with higher KPS (≥ 70%). These data support the value of NIVO+IPI in pts who may not be considered ideal candidates for this therapy and consequently may have limited treatment options. Clinical trial information: NCT02982954 .

scholarly journals First-in-human phase I trial of anti-hepatocyte growth factor antibody (YYB101) in refractory solid tumor patients

2020 ◽  
Vol 12 ◽  
pp. 175883592092679
Author(s):  
Seung Tae Kim ◽  
Jung Yong Hong ◽  
Se Hoon Park ◽  
Joon Oh Park ◽  
Young Whan Park ◽  
...  
Keyword(s):  
Growth Factor ◽  
Hepatocyte Growth Factor ◽  
Phase I ◽  
Cancer Patients ◽  
Phase I Trial ◽  
Maximum Tolerated Dose ◽  
Safety And Efficacy ◽  
Hepatocyte Growth

Background: YYB101, a humanized monoclonal antibody against hepatocyte growth factor (HGF), has shown safety and efficacy in vitro and in vivo. This is a first-in-human trial of this antibody. Materials and Methods: YYB101 was administered intravenously to refractory cancer patients once every 4 weeks for 1 month, and then once every 2 weeks until disease progression or intolerable toxicity, at doses of 0.3, 1, 3, 5, 10, 20, 30 mg/kg, according to a 3+3 dose escalation design. Maximum tolerated dose, safety, pharmacokinetics, and pharmacodynamics were studied. HGF, MET, PD-L1, and ERK expression was evaluated for 9 of 17 patients of the expansion cohort (20 mg/kg). Results: In 39 patients enrolled, no dose-limiting toxicity was observed at 0.3 mg/kg, and the most commonly detected toxicity was generalized edema ( n = 7, 18.9%) followed by pruritis and nausea ( n = 5, 13.5%, each), fatigue, anemia, and decreased appetite ( n = 4, 10.8%, each). No patient discontinued treatment because of adverse events. YYB101 showed dose-proportional pharmacokinetics up to 30 mg/kg. Partial response in 1 (2.5%) and stable disease in 17 (43.5%) were observed. HGF, MET, PD-L1, and ERK proteins were not significant predictors for treatment response. However, serum HGF level was significantly lowered in responders upon drug administration. RNA sequencing revealed a mesenchymal signature in two long-term responders. Conclusion: YYB101 showed favorable safety and efficacy in patients with refractory solid tumors. Based on this phase I trial, a phase II study on the YYB101 + irinotecan combination in refractory metastatic colorectal cancer patients is planned. Conclusion: ClinicalTrials.gov Identifier: NCT02499224

Cell-Based Regenerative Endodontics for Treatment of Periapical Lesions: A Randomized, Controlled Phase I/II Clinical Trial

2020 ◽  
Vol 99 (5) ◽  
pp. 523-529 ◽  
Author(s):  
C. Brizuela ◽  
G. Meza ◽  
D. Urrejola ◽  
M.A. Quezada ◽  
G. Concha ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Phase I ◽  
Umbilical Cord ◽  
Root Canal ◽  
Categorical Variables ◽  
Safety And Efficacy ◽  
Randomized Controlled

A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher’s exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

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