Prediction of clinical efficacy by plasma concentration of apatinib in patients with solid tumor.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e15000-e15000
Author(s):  
Hongtao He ◽  
Lixing Wang ◽  
Guanglei Huang ◽  
Rongfeng Liu ◽  
Meng Yuan ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Clinical Efficacy ◽  
Solid Tumor ◽  
Trough Concentration ◽  
Peak Concentration ◽  
Venous Blood ◽  
Objective Response ◽  
Complete Response ◽  
Plasma Peak ◽  
Tumor Enlargement

e15000 Background: To explore the correlation between plasma concentration of apatinib and clinical efficacy. Methods: 42 patients were enrolled. Plasma specimens of all patients were collected. At 7:40 am, fasting blood was drawn as plasma trough concentration (Ctrough). At 8 am, apatinib mesylate (APA-M, 250mg qd) was orally administrated. At 11 am, venous blood was drawn as plasma peak concentration (Cpeak). Each patient has Ctrough and Cpeak samples. A total of 84 plasma samples were obtained. The concentration of APA-M in plasma was determined by UPLC-MS/MS. Results: 1) 42 patients were evaluable. Treatment response was assessed by RECIST1.1. 2 patients achieved complete response (CR), 16 partial response (PR), 12 stable disease (SD) (tumor shrinks), 5 SD (tumor enlargement), 7 progressive disease (PD). Objective response rate (ORR) was 42.9% (18/42) and disease control rate (DCR) was 83.3% (35/42). 2) On day 1 and 456 after oral APA-M from different patients, median trough concentration (Ctrough median) was 264.38 ng/ml (1.18 ng/ml-918 ng/ml), and median peak concentration (Cpeak median) was 543.61 ng/ml (71.11 ng/ml-1609.4 ng/ml), respectively. 3) The Ctrough median in patients with CR, PR and SD (tumor shrinks) was significantly higher than that SD (tumor enlargement) and PD ( P＜0.05). There was significantly difference between CR and PR with SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR ( P＞0.05). (Table) 4) The Cpeak median in patients with CR, PR, SD (tumor enlargement) and PD was significantly higher than that SD (tumor shrinks) ( P＜0.05). But there was no significantly difference between CR and PR with SD (tumor enlargement) ( P＞0.05). (Table). Conclusions: The plasma Ctrough of Apatinib can predict the clinical efficacy of patients with solid tumor. Perspective clinical studies with adequate sample size are required to validate our results. [Table: see text]

Avelumab treatment for metastatic urothelial carcinoma in the phase Ib JAVELIN Solid Tumor Study: Updated safety and efficacy analysis with ≥ two years of follow-up.

2019 ◽  
Vol 37 (7_suppl) ◽  
pp. 425-425 ◽  
Author(s):  
Andrea B. Apolo ◽  
John Allan Ellerton ◽  
Jeffrey R. Infante ◽  
Manish Agrawal ◽  
Michael S. Gordon ◽  
...  
Keyword(s):  
Solid Tumor ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Pooled Analysis ◽  
Clinical Activity ◽  
Efficacy Analysis ◽  
Tumor Study ◽  
Metastatic Urothelial Cancer ◽  
Duration Of Response

425 Background: Avelumab, a human anti‒PD-L1 IgG1 antibody, is approved for the treatment of metastatic urothelial cancer (mUC) progressing after platinum chemotherapy in the US, Canada, and Israel. Here, we report an updated pooled analysis of 2 cohorts of avelumab-treated patients (pts) with mUC from the JAVELIN Solid Tumor study (NCT01772004). Methods: Pts with mUC whose disease had progressed after platinum-based therapy or were cisplatin ineligible received avelumab 10 mg/kg every 2 weeks. Tumors were assessed every 6 weeks by independent review (RECIST v1.1). Endpoints included objective response rate (ORR), duration of response (DOR), progression-free survival (PFS), overall survival (OS), and safety (NCI CTCAE v4.0). Results: As of April 2018, 249 pts had received avelumab and had been followed for ≥2 years (median 2.7 years). Median treatment duration was 12.0 weeks (IQR, 6.0-32.1), and 12 pts (4.8%) remained on treatment. Confirmed ORR in all evaluable pts (n = 242) was 16.5% (95% CI: 12.1%-21.8%; complete response in 4.1%). Median DOR was 20.5 mo (95% CI: 9.7-not estimable), and the Kaplan-Meier (K-M) estimate of 12-mo DOR was 65.4% (95% CI: 47.0%-78.8%). Median PFS was 1.6 mo (95% CI: 1.4-2.7 mo), median OS was 7.0 mo (95% CI: 5.9-8.5 mo), and the K-M 12-mo and 24-mo OS rates were 35.9% (95% CI: 29.9%-42.0%) and 20.1% (95% CI: 15.2%-25.4%), respectively. Treatment-related adverse events (TRAEs) of any grade occurred in 71.1% of pts (177/249), most commonly infusion-related reactions (24.1%), fatigue (18.1%) and rash (18.1%). Grade ≥3 TRAEs occurred in 11.6% of pts (29/249), most commonly fatigue (1.6%), elevated lipase (1.6%), and pneumonitis (1.2%). Ten pts (4.0%) discontinued avelumab due to a TRAE. There was 1 treatment-related death (pneumonitis). Conclusions: Avelumab showed durable clinical activity and had a manageable safety profile in pts with mUC. A phase 3 trial of avelumab in the maintenance setting after first-line platinum-based therapy for mUC is ongoing. Clinical trial information: NCT01772004.

Assessment of objective response rate (ORR) by investigator versus blinded independent central review in pivotal trials of drugs approved for solid tumor indications.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e13570-e13570
Author(s):  
Marjorie E. Zettler ◽  
Choo H. Lee ◽  
Ajeet Gajra ◽  
Bruce A. Feinberg
Keyword(s):  
Solid Tumors ◽  
Solid Tumor ◽  
Objective Response Rate ◽  
Response Rate ◽  
Objective Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Mean Difference ◽  
Response To Treatment ◽  
The Mean

e13570 Background: Objective response rate (ORR), defined as the proportion of patients with a complete response or partial response to treatment according to Response Evaluation Criteria in Solid Tumors (RECIST), is the most common endpoint used in pivotal trials supporting FDA approval of cancer drugs for solid tumor indications. Blinded independent central review (BICR) is frequently employed in clinical trials to minimize bias in evaluation of response rate, as historically, assessment of response by investigators (INV) has been shown to overestimate treatment effect. In this study, we analyzed the variability in assessment of ORR between INV and BICR in trials supporting recent Food and Drug Administration (FDA) approvals of drugs for solid tumor indications. Methods: The FDA’s novel drug approvals (2015-2019) were reviewed to identify drugs receiving primary approval for solid tumor indications. Drug approval packages accessed via the Drugs@FDA database and primary publications for the pivotal trials accessed via PubMed were reviewed for investigator-assessed and BICR-assessed ORR. For trials reporting both assessments, the difference between INV and BICR ORR was determined across all study arms. Data are presented using descriptive statistics. Results: A total of 36 drugs received primary approval for the treatment of solid tumors between 2015 and 2019. Of the 40 supporting trials, ORR was the primary endpoint for 21 (52.5%), progression-free survival for 13 (32.5%), and overall survival for 2 (5.0%). ORR was evaluated in 35 of the 40 trials (87.5%). Eight (22.9%) of the 35 trials evaluated INV ORR only, 5 (14.3%) evaluated BICR ORR only, and 22 (62.9%) evaluated both INV and BICR ORR. Among the 22 trials (29 arms in total), the mean difference between BICR- and INV-assessed ORR was -4.3% (95% CI: -6.4, -2.3); the range was -13.1 to 5. INV-assessed ORR was greater than BICR-assessed ORR in 22 of 29 arms (75.9%). The mean difference between BICR- and INV-assessed ORR among the 6 arms representing placebo or active control was -6.0 (95% CI: -11.0, -0.9), compared with -3.9 (95% CI: -6.3, -1.5) among the 23 experimental arms. Conclusions: Compared with BICR, INV overestimated ORR in three-quarters of the trial arms, including those representing control and experimental treatments. Despite this variability, for one fifth of the trials supporting approval of drugs to treat solid tumors, INV was the only method used to assess ORR. For consistency, and the ability to make relative cross-trial comparisons of ORR between agents, BICR should be considered for evaluation of tumor response in all registrational trials.

scholarly journals NCOG-19. BEVACIZUMAB IN REAL LIFE PATIENTS WITH RECURRENT GLIOBLASTOMA: BENEFIT OR FUTILITY?

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii133-ii133
Author(s):  
Cristina Smolenschi ◽  
Emeline Colomba ◽  
Elie Rassy ◽  
Naima Lezghed ◽  
Mohamed Kettab ◽  
...  
Keyword(s):  
Clinical Benefit ◽  
Therapeutic Option ◽  
Performance Status ◽  
Objective Response ◽  
Real Life ◽  
Complete Response ◽  
Recurrent Glioblastoma ◽  
Arterial Bleeding ◽  
Substantial Clinical Benefit ◽  
Radiological Response

Abstract Angiogenesis represents a hallmark of glioblastoma but most trials disappointed and failed to change the poor outcome of this disease. However, Bevacizumab (Bev) is widely used in clinical practice by expert oncologists due to experience or efficacy in real life.We retrospectively reviewed the use of Bev and its benefit in terms of Time to treatment failure (TTF), Overall Survival(OS), Objective Response Rate (ORR) and clinical benefit. METHODS: We analyzed two hundred and two patients treated at Gustave Roussy Cancer Campus with Bev until definitive failure for recurrent glioblastoma between 2006 and 2016. Patients were treated with Bev alone or in association with radiotherapy, temozolomide, lomustine or irinotecan. RESULTS: The median duration of Bev treatment until definitive failure was 6 months. The median TTF was 7.27 months(95%CI 6.30-8.24) and the median OS from diagnosis was 22.43 months(95%CI 19.68-25.18). Two patients were still alive without active treatment at the end of study. A hundred and fourteen (56%) patients experienced symptom amelioration and seventy-five (37%) improved their Performance Status. Fifty percent of patients exhibited Partial and Complete Response on MRI, as best radiological response, within 1.6 months. No patient had anaphylactic reaction. Grade 1-2 hypertension(HT)(17%) and grade 1(10%) proteinuria were most common. Six patients presented lethal toxicity: 4 with GI perforation, 1 p with cerebral hemorrhage and 1 p with arterial bleeding. HT was correlated with treatment response in 67% of patients. A neutrophil count superior to 6000/mm³ was associated with longer TTF(mTTF 8.23m(95%CI 6.64-9.82). CONCLUSION: This retrospective study reports a substantial clinical benefit of Bev in patients with recurrent glioblastoma with an acceptable toxicity profile. As the panel of therapeutic option is still very limited in these tumors, this work supports the maintained use of Bev as a therapeutic option.

scholarly journals INNV-17. NEXT GENERATION SEQUENCING IMPACTS OUTCOMES IN RECURRENT PRIMARY GLIOBLASTOMA: A SINGLE-CENTER RETROSPECTIVE ANALYSIS

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii120-ii120
Author(s):  
Daniel Zeitouni ◽  
Michael Catalino ◽  
Jordan Wise ◽  
Kathryn Pietrosimone ◽  
Sean McCabe ◽  
...  
Keyword(s):  
Next Generation Sequencing ◽  
Cox Model ◽  
Objective Response ◽  
Complete Response ◽  
High Rate ◽  
Next Generation ◽  
Disease Response ◽  
Primary Glioblastoma ◽  
Generation Sequencing ◽  
Recurrent Gbm

Abstract BACKGROUND GBM is driven by various genomic alterations. Next generation sequencing (NGS) may reveal targetable alterations. The goal of this study was to describe how NGS can inform targeted therapy (TT) selection. METHODS The medical records of patients (pts) with GBM from 2017–2019 were reviewed. Pts with actionable mutations were included in the analysis. At first progression (PD1), two cohorts of pts were defined: cohort A received TT, while cohort B received physician’s choice chemotherapy (PCC). Regression analyses were used to determine OS and PFS between cohorts. A stratified cox model was utilized to assess the effect of TT, where KPS level (low vs high) was utilized as a stratification factor. A heat map was generated describing the landscape of mutations. Disease response in cohort A was graded per RANO criteria. RESULTS There were 38 GBM pts with actionable alterations. Cohort A had 15 (39%) pts and cohort B had 23 (61%) pts. Of the 26 common alterations, 11 (42%) were deemed actionable. Pts with higher KPS were more likely to receive TT. Pts with a KPS ≥ 70 had a longer PFS while on TT. Although not well powered, pts in cohort A had a longer median OS relative to cohort B (HR 0.37 CI 0.10–1.38). The objective response rate (ORR) was 93%, with afatinib and cabozantinib resulting in complete response, one pt had progressive disease while on TT. CONCLUSION NGS for recurrent GBM yields a high rate of actionable alterations. Pts that go on TT are often younger and with higher KPS. This likely plays into their improved survival; however, it is notable that the high ORR reflects the value of NGS in deciding on TT to match alterations that are likely to respond. In conclusion, patient selection and availability of NGS impacts outcomes in recurrent GBM.

PLASMA CONCENTRATION OF TESTOSTERONE, DIHYDROTESTOSTERONE, TESTOSTERONE-OESTRADIOL BINDING GLOBULIN, AND PITUITARY GONADOTROPHINS IN THE SYNDROME OF MALE PSEUDO-HERMAPHRODITISM WITH TESTICULAR FEMINIZATION

1972 ◽  
Vol 70 (2) ◽  
pp. 331-341 ◽  
Author(s):  
Roland R. Tremblay ◽  
Thomas P. Foley ◽  
Pierre Corvol ◽  
In-Joo Park ◽  
Avinoam Kowarski ◽  
...  
Keyword(s):  
Plasma Concentration ◽  
Reductase Activity ◽  
Venous Blood ◽  
Follicle Stimulating Hormone ◽  
Normal Subjects ◽  
Normal Male ◽  
Testicular Feminization ◽  
Peripheral Plasma ◽  
Serum Lh ◽  
High Concentrations

ABSTRACT Twenty patients with the syndrome of testicular feminization have been studied along with a group of normal subjects of both sexes and of comparable ages. Peripheral and gonadal venous blood were analysed for their content in testosterone (T), androstenedione (Δ), dihydrotestosterone (DHT), testosterone-oestradiol binding globulin (TeBG), luteinizing hormone (LH) and follicle stimulating hormone (FSH). Normal or even higher than normal male concentrations of T, Δ, and DHT were observed. An actual secretion of the three androgens by the testis was demonstrated. Elevated levels of serum LH were found despite normal male or higher levels of T, Δ, and DHT. High concentrations of TeBG presumably could alter the dynamics of plasma androgens. The gonadal production of DHT and the normal levels of DHT in peripheral plasma shows that 5α-reductase activity is definitely present in the patients.

scholarly journals Phase II trial of the IDO pathway inhibitor indoximod plus pembrolizumab for the treatment of patients with advanced melanoma

2021 ◽  
Vol 9 (6) ◽  
pp. e002057
Author(s):  
Yousef Zakharia ◽  
Robert R McWilliams ◽  
Olivier Rixe ◽  
Joseph Drabick ◽  
Montaser F Shaheen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Standard Of Care ◽  
Complete Response ◽  
Advanced Melanoma ◽  
Free Survival ◽  
Programmed Death ◽  
Evaluable Population

BackgroundThe indoleamine 2,3-dioxygenase (IDO) pathway is a key counter-regulatory mechanism that, in cancer, is exploited by tumors to evade antitumor immunity. Indoximod is a small-molecule IDO pathway inhibitor that reverses the immunosuppressive effects of low tryptophan (Trp) and high kynurenine (Kyn) that result from IDO activity. In this study, indoximod was used in combination with a checkpoint inhibitor (CPI) pembrolizumab for the treatment for advanced melanoma.MethodsPatients with advanced melanoma were enrolled in a single-arm phase II clinical trial evaluating the addition of indoximod to standard of care CPI approved for melanoma. Investigators administered their choice of CPI including pembrolizumab (P), nivolumab (N), or ipilimumab (I). Indoximod was administered continuously (1200 mg orally two times per day), with concurrent CPI dosed per US Food and Drug Administration (FDA)-approved label.ResultsBetween July 2014 and July 2017, 131 patients were enrolled. (P) was used more frequently (n=114, 87%) per investigator’s choice. The efficacy evaluable population consisted of 89 patients from the phase II cohort with non-ocular melanoma who received indoximod combined with (P).The objective response rate (ORR) for the evaluable population was 51% with confirmed complete response of 20% and disease control rate of 70%. Median progression-free survival was 12.4 months (95% CI 6.4 to 24.9). The ORR for Programmed Death-Ligand 1 (PD-L1)-positive patients was 70% compared with 46% for PD-L1-negative patients. The combination was well tolerated, and side effects were similar to what was expected from single agent (P).ConclusionIn this study, the combination of indoximod and (P) was well tolerated and showed antitumor efficacy that is worth further evaluation in selected patients with advanced melanoma.

572 Fibroblast activating protein (FAP)-targeting IL-12 (anti-FAP/IL-12) TMEkine™ potentiates anti-cancer effects in preclinical cancer models

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A606-A606
Author(s):  
Donggeon Kim ◽  
Dahea Lee ◽  
Soomin Ryu ◽  
Yeongseon Byeon ◽  
Kyoung-Ho Pyo ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Solid Tumor ◽  
Immune Modulation ◽  
Therapeutic Option ◽  
Complete Response ◽  
Tumor Burden ◽  
Tumor Growth Inhibition ◽  
Durable Response ◽  
Anti Cancer ◽  
Nih 3T3

BackgroundAlthough cancer immunotherapy showed promising results in hematological malignancies, it has come up with relatively low tumor response for many solid tumors partly due to immune-suppressive tumor microenvironment (TME). Because of the immune-suppressive nature of TME, TME has been an active area of research and therapeutic target for restoring immune system and subsequent tumor growth inhibition. Among the many components in TME, cancer-associated fibroblasts (CAFs) are one of the key cell components of TME where one of the promising solid-tumor TME marker, fibroblast-activating protein (FAP) is highly expressed. Here we have developed an antibody-cytokine fusion protein from our TMEkine™ platform containing anti-FAP and IL-12. Our TMEkine™ (anti-FAP-IL-12) molecule induced strong anti-cancer effects in preclinical solid tumor models by immune-modulation.MethodsIL-12 cytokine was mutated in TMEkine™ (anti-FAP-IL-12) to reduce systemic toxicity and its binding affinity was tested to FAP and IL-12 receptor. The anti-tumor activity of anti-FAP-IL-12 was investigated on CT26 (murine colorectal cancer) syngeneic mouse models with/without NIH-3T3 (murine fibroblast). Additionally, mice showing complete response after anti-FAP-IL-12 administration were re-injected CT26 with/without 4T1 cells for re-challenge study to monitor long-term durable response generated from the initial immune activation.ResultsWe showed that TMEkine™ (anti-FAP-IL-12) interacts with FAP and IL-12 receptor. IL-12 activity was attenuated by our IL-12 mutants. We also showed that TMEkine™ (anti-FAP-IL-12) induced IFN-γ from primary human T cells and NK cells. TMEkine™ (anti-FAP-IL-12) administration resulted in significant reduction of the tumor burden in both CT26+NIH-3T3/FAP+ and CT26/FAP+ models. In the re-challenge experiments, CT26 tumor growth was inhibited significantly compared to 4T1 tumor suggesting memory immune response was generated in TMEkine™ (anti-FAP-IL-12) treated mice.ConclusionsThese findings provide evidences that the treatment of anti-FAP/IL-12 TMEkine™ induced anti-cancer effects without serious adverse effects. Anti-FAP/IL-12 has a strong potential to provide a therapeutic option for cancer-specific immunomodulator and cancer cell eradication.

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

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

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

Exploratory circulating biomarker analyses: lenvatinib + pembrolizumab (L + P) in a phase 1b trial in unresectable hepatocellular carcinoma (uHCC).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4084-4084
Author(s):  
Andrew X. Zhu ◽  
Josep M Llovet ◽  
Masahiro Kobayashi ◽  
Masafumi Ikeda ◽  
Marc Pracht ◽  
...  
Keyword(s):  
Cox Regression ◽  
Objective Response ◽  
Rank Correlation ◽  
Study Drug ◽  
Complete Response ◽  
Rank Test ◽  
Cox Regression Analysis ◽  
Clinical Endpoints ◽  
Spearman’S Rank Correlation ◽  
Phase 1B

4084 Background: In a phase 1b trial (NCT03006926), L + P had promising antitumor activity as first-line (1L) therapy in uHCC. We present exploratory biomarker analyses of circulating angiogenic factors and cytokines/chemokines related to the mechanism of action of L + P (ie, pharmacodynamic [PD] biomarkers), as well as biomarker correlations with clinical outcomes in patients (pts) with uHCC, from this trial. Methods: Pts received lenvatinib 12 mg/d (bodyweight [BW] >60 kg) or 8 mg/d (BW < 60 kg) PO + pembrolizumab 200 mg IV Q3W. Tumors were assessed using mRECIST or RECIST v1.1 per independent imaging review. Peripheral blood samples were collected before administration of study drug at baseline, cycle (C) 2, day (D) 1, C3D1, C4D1, and off-treatment. 43 Biomarkers were assayed in serum from 100 1L uHCC pts (excluding 4 pts from the dose-limiting toxicity part of the trial with prior sorafenib). Of these 43, 31 biomarkers (for which ≤20% of samples had measurements above/below the quantification limit of the assay) were included in the analyses. Changes in biomarker levels from baseline were evaluated via 1-sample Wilcoxon signed-rank test. Associations were explored between changes in biomarker levels and maximum tumor shrinkage (MTS) via the Spearman’s rank correlation test, objective response (OR; complete response + partial response) via the Wilcoxon rank sum test, and PFS via Cox regression analysis and log rank test. Data cutoff date for clinical endpoints was 7 August 2020. Results: Levels of PD biomarkers related to angiogenic signaling (VEGF increase/ANG2 decrease), FGF signaling (increase in FGF23/FGF19), and IFNγ signaling (increase in IFNγ, CXCL9/10/11) were changed significantly (adjusted P< 0.05) with L + P (C2D1–C4D1; except for FGF19 at C3D1). Significant decreases of TIMP1 and increases of MCP1 were observed at C4D1 during treatment; these were associated with greater MTS. Greater decreases in TIMP1 and greater increases in MCP1 were observed in pts with OR vs others. Changes in levels of the PD biomarkers ANG2, IL10, and VEGFR2 were found to be associated with PFS by dichotomized analysis. With tertile 2 cutoff, median PFS for pts in the group with greater decreases of ANG2 was 13.9 months vs 9.6 months for pts in the group with lesser decreases of ANG2 (unadjusted P= 0.002; HR 2.65, 95% CI 1.39–5.08). Conclusions: These are the first exploratory biomarker analyses for the single-arm study of L + P in pts with uHCC. Changes in serum biomarkers associated with angiogenic-, FGF-, and IFNγ-signaling pathways indicated target engagement of L + P. Decreases in TIMP1 and increases in MCP1 were associated with MTS and OR. Associations were found between longer PFS and a greater decrease in levels of ANG2. Angiogenesis inhibition and modulation of cancer immune response were observed with L + P. Further validation from independent studies is warranted. Clinical trial information: NCT03006926.

Pegylated liposomal doxorubicin re-challenge in patients with ovarian cancer relapse: a multicenter retrospective study

2019 ◽  
Vol 29 (1) ◽  
pp. 153-157 ◽  
Author(s):  
Elisa Tripodi ◽  
Gennaro Cormio ◽  
Ugo De Giorgi ◽  
Giorgio Valabrega ◽  
Daniela Rubino ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Cancer Patients ◽  
Liposomal Doxorubicin ◽  
Objective Response ◽  
Pegylated Liposomal Doxorubicin ◽  
Complete Response ◽  
Recurrent Ovarian Cancer ◽  
Hematological Toxicity ◽  
Cancer Relapse ◽  
Platinum Agent

BackgroundPegylated liposomal doxorubicin (PLD) is an active and well-tolerable treatment in ovarian cancer relapse, either alone or in combination with other drugs. No data are available on the possibility to rechallenge PLD treatment in long survivor patients with recurrent ovarian cancer, as evaluated for platinum agent, paclitaxel and gemcitabine. The aim of the present study was to evaluate the anti-tumor activity and the toxicity profile of re-challenge of PLD in recurrent ovarian cancer patients.MethodsData on 27 patients with epithelial ovarian cancer treated in the last ten years (2007-2017) with palliative PLD rechallenge were included in this multicenter retrospective Italian study.ResultsThe objective response rate to PLD re-treatment were complete response in 19%, partial response in 30% and stable disease in 37%. Only 1 case of G4 hematological toxicity was reported. No patient experienced severe cardiac impairment (G2-4).ConclusionPLD rechallenge represents an active and safe possibility of treatment for long survivor ovarian cancer patients.

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