Impact of Performance Status on Response and Survival Among Patients Receiving Checkpoint Inhibitors for Advanced Solid Tumors

2021 ◽  
pp. OP.20.01055
Author(s):  
Mridula Krishnan ◽  
Pooja Kasinath ◽  
Robin High ◽  
Fang Yu ◽  
Benjamin A. Teply
Keyword(s):  
Overall Survival ◽  
Solid Tumors ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Hospital Death ◽  
Advanced Solid Tumors ◽  
Referral Rates ◽  
Overall Response ◽  
Hospice Referral ◽  
Ecog Ps

PURPOSE Clinical trials, which led to the approval of immune checkpoint inhibitors (ICI), have been almost exclusively performed in patients with good Eastern Cooperative Oncology Group performance status (ECOG PS of 0-1). However, ICI remains an attractive option for patients with advanced tumors and poor PS. We hypothesized that patients with ECOG PS ≥ 2 would have worse outcomes with ICI. METHODS We retrospectively identified patients with advanced solid tumors who were treated with ICI at our institution. The log-rank test compared the survival among patients with different ECOG PS. We used a proportional hazards model to assess association between ECOG PS and overall survival (OS) with adjustment for covariates including age, sex, malignancy type, time from advance disease diagnosis, and line of therapy. We compared overall response rates between groups with Pearson chi-square exact test. We also analyzed in-hospital mortality and hospice referral rates. RESULTS We identified 257 patients treated with ICI. One hundred eighty-two patients had ECOG PS 0-1, and 75 had ECOG PS ≥ 2. The median overall survival was 12.6 months for the ECOG PS 0-1 group compared with 3.1 months for the ECOG PS ≥ 2 group ( P < .001). The overall response rate for patients with ECOG PS 0-1 was 23% compared with 8% for those with poor PS ( P = .005). Patients with poor PS treated with ICI had similar hospice referral rates (67% for ECOG PS ≥ 2 v 61.9% for ECOG PS 0-1, P = .50) but were more likely to have in-hospital death as compared with the good PS group (28.6% v 15.1%, P = .035). CONCLUSION Despite the appeal of ICI in patients with advanced malignancy and poor PS, outcomes in this cohort were poor. Prospective trials defining the activity and role of ICI in poor PS are urgently needed.

Outcomes of patients (pts) with metastatic urothelial cancer (mUC) and poor performance status (PS) receiving anti-PD(L)1 agents.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 4525-4525
Author(s):  
Ali Raza Khaki ◽  
Leonidas Nikolaos Diamantopoulos ◽  
Ang Li ◽  
Michael Edward Devitt ◽  
Alexandra Drakaki ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Wholesale Price ◽  
Poor Performance ◽  
Wald Test ◽  
Median Number ◽  
Hospital Death ◽  
Poor Performance Status ◽  
Metastatic Urothelial Cancer ◽  
Ecog Ps

4525 Background: Anti-PD(L)1 immune checkpoint inhibitors (ICI) prolong overall survival (OS) after platinum chemotherapy in mUC. However, clinical outcomes in pts with poor PS at time of ICI initiation are unknown. We hypothesized that ICI initiation in pts with ECOG PS 2-3 would be associated with worse outcomes vs. pts with ECOG PS < 2, and impact death location. Methods: A retrospective cohort study in 8 institutions identified pts with mUC who received ICI. Demographic, clinicopathologic, treatment (tx) patterns, tx response, and outcomes were collected. Primary endpoint: overall response rate (ORR). Secondary endpoints: median (m) OS in pts receiving ICI as 1st and 2nd line (1L, 2L); odds of dying in hospital (vs elsewhere) for pts receiving ICI (vs no tx) within 30 days of death; and estimated drug cost for pts with ICI within 30 days of death based on average wholesale price. Unadjusted logistic regression was used to assess association between ORR and ECOG PS (2-3 vs < 2) and wald test was used to compare mOS between ECOG PS (2-3 vs < 2). Results: 194 consecutive pts (30% women, 41% never smokers, median age at diagnosis 69) treated with ICI for mUC were identified. Median number of total tx lines was 2; all pts received ≥1 ICI line (6 pts received 2 ICI lines); 97, 79, 17 and 7 pts received ICI in 1L, 2L, 3L and 4L, respectively; 26% pts with ICI in 1L and 2L had ECOG PS 2-3. ORR and mOS are shown in table. Among 106 pts who died, 96 had available death location; of those, 8% received ICI within 30 days of death. Starting ICI within 30 days of death (vs no tx) was associated with higher odds of hospital death (OR 6.05, 95%CI 1.3-27.6). Estimated average ICI cost/pt within 30 days of death was $1400.58. Conclusions: Pts with ECOG PS 2-3 at time of ICI initiation had similar ORR vs ECOG PS < 2 but worse mOS. ICI initiation within 30 days from death was associated with higher likelihood of hospital death. ICI may not circumvent the negative prognostic role of poor PS, so biomarker-based pt selection is critical. Limitations include lack of adjustment for selection bias and other confounders at time of ICI initiation; data validation is ongoing. [Table: see text]

SWOG 1609 (DART): A phase II basket trial of dual anti-CTLA-4 and anti-PD-1 blockade in rare tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2658-TPS2658 ◽  
Author(s):  
Sandip Pravin Patel ◽  
Megan Othus ◽  
Young Kwang Chae ◽  
Frank Giles ◽  
Jourdain Hayward ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Overall Survival ◽  
Solid Tumors ◽  
Phase Ii ◽  
Overall Response Rate ◽  
Response Rate ◽  
Alternative Hypothesis ◽  
Performance Status ◽  
Overall Response ◽  
Rare Tumors

TPS2658 Background: Immune checkpoint blockade, in particular anti-CTLA-4 and anti-PD-1-directed approaches, have improved outcomes in various tumor types. However, little is known about the efficacy of these agents in advanced rare solid tumors. We sought to investigate the activity of ipilimumab and nivolumab in previously unstudied rare solid tumors, with planned biomarker evaluation pending including whole exome sequencing, RNAseq, and multiplex immune profiling via the NCI CIMACs. Methods: We performed a prospective, open-label, multicenter phase II clinical trial of ipilimumab (1mg/kg iv q6weeks) plus nivolumab (240mg iv q2weeks) across 37 cohorts of rare tumors. Eligible patients had incurable rare cancer, defined histologically with an incidence of less than 6 in 100,000 per year, and did not have an approved or standard therapy available that had been shown to prolong overall survival. Patients were required to be 18 years of age or older, have a Zubrod performance status of 0-2, with absolute neutrophil count ≥ 1,000/mcL, platelets ≥ 75,000/mcL, hemoglobin ≥ 8 g/dL, creatinine clearance ≥ 50 mL/min, total bilirubin ≤ 2.0 x institutional upper limit of normal (IULN), AST and ALT ≤ 3.0 x IULN, TSH or free T4 serum ≤ IULN, and normal adrenocorticotropic hormone (ACTH) ≤ IULN. The primary endpoint was overall response rate (ORR) by RECIST v1.1 (complete (CR) and partial responses (PR)); secondary endpoints included progression-free (PFS) and, overall survival (OS), stable disease (SD) ≥ 6 months, and toxicity. The primary objective of this Phase II trial was to evaluate the overall response rate (ORR, confirmed complete and partial responses [CR and PR]) by RECIST v1.1. Our objective was to distinguish between a true ORR 15% (null hypothesis) versus 30% (alternative hypothesis). A Simon’s two-stage design was used, which required an analysis on the first 6 eligible patients who received therapy. If 1 or more of the 6 patients had a response (confirmed CR or PR), an additional 10 patients were to be accrued. The study was activated on 1/13/17 with the first patient treated on 3/1/17. The trial is currently open at 862 sites across the NCTN (with 352 sites having enrolled patients) and 554 patients enrolled to date. Clinical trial information: NCT02834013.

287 Safety and antitumor activity of indoleamine 2,3-dioxygenase 1 (IDO-1) inhibitor KHK2455 in combination with anti-CCR4 monoclonal antibody mogamulizumab in patients with advanced solid tumors

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A313-A314
Author(s):  
Solmaz Sahebjam ◽  
Jameel Muzaffar ◽  
Timothy Yap ◽  
David Hong ◽  
Olivier Rixe ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Overall Survival ◽  
Antitumor Activity ◽  
Combination Therapy ◽  
Adverse Events ◽  
Solid Tumors ◽  
Ex Vivo ◽  
Advanced Solid Tumors ◽  
Grade 3 ◽  
Dose Dependent

BackgroundIDO-1 inhibitors have shown antitumor activity in combination with immunotherapeutic agents in multiple cancers. KHK2455 is a novel and selective oral IDO-1 inhibitor. KHK2455 inhibits IDO-1 apo-enzyme, with long-lasting and potent activity. Mogamulizumab is an anti-C-C chemokine receptor 4 (CCR4) monoclonal antibody that has shown synergy with KHK2455 in preclinical models. Mogamulizumab is approved in the US and EU for treatment of mycosis fungoides and Sézary syndrome.MethodsIn this first-in-human study, patients with advanced solid tumors received escalating oral doses of KHK2455 alone (0.3, 1, 3, 10, 30 and 100 mg once daily) for 4 weeks (Cycle 0), followed by combination with 1 mg/kg weekly of IV mogamulizumab for 4 weeks (Cycle 1), and then on Days 1 and 15 (from Cycle 2 onward) in a standard 3+3 Phase I design. Safety, tolerability, pharmacokinetics and IDO activity (kynurenine [Kyn] and tryptophan [Trp] levels and ex vivo Kyn production) were evaluated.ResultsThirty-six patients were enrolled across all cohorts. One patient with lower esophageal cancer in the 100 mg cohort exhibited dose-limiting toxicity (Grade 3 gastrointestinal necrosis). The most frequent (≥10%) treatment-emergent adverse events (TEAEs) are presented in table 1. Overall numbers of TEAEs, ≥Grade 3 TEAEs, and serious TEAEs related to KHK2455 and mogamulizumab are presented in table 2. Serious KHK2455-related TEAEs included gastrointestinal necrosis (KHK2455 monotherapy), and nausea and drug eruption (combination therapy). In addition, five drug-related TEAEs in combination therapy led to discontinuation; there were no fatal outcomes related to either study drug. Plasma KHK2455 concentrations reached steady state by Day 8 (Cycle 0) and increased dose-dependently. Potent dose-dependent inhibition of IDO activity was demonstrated by plasma Kyn concentration and Kyn/Trp ratio (median inhibition 70.5% and 70.8%, respectively, at 100 mg dose on Day 15, compared to baseline) and ex vivo Kyn production (>95% inhibition at ≥10 mg KHK2455), confirming target modulation. Six of 26 evaluable patients from all dosing groups achieved durable disease stabilization (≥6 months, RECIST 1.1), and one patient with bevacizumab-resistant glioblastoma demonstrated confirmed partial response (43.5% tumor reduction over a 2-year observation period). Median overall survival was 13.4 months, with 30% of subjects surviving for 2 years or longer (figure 1).Abstract 287 Table 1Study 2455-001: Treatment-Emergent Adverse Events (≥10% by Preferred Term)Abstract 287 Table 2Abstract 287 Figure 1Study 2455-001: Overall SurvivalConclusionsKHK2455 in combination with mogamulizumab was well-tolerated and manageable at all doses tested, suppressed Kyn production in a dose-dependent and sustained manner, and demonstrated signals of antitumor activity. These data support the continued development of this combination.AcknowledgementsMedical writing assistance was provided by Susan E. Johnson, PhD, S.E. Johnson Consulting, LLC, New Hope, PA, USA.Trial RegistrationNCT02867007 (www.clinicaltrials.gov)Ethics ApprovalThis study was approved by Ethics Committees at all participating study institutions.

scholarly journals Melanoma Brain Metastases in the Era of Targeted Therapy and Checkpoint Inhibitor Therapy

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1489
Author(s):  
John M. Rieth ◽  
Umang Swami ◽  
Sarah L. Mott ◽  
Mario Zanaty ◽  
Michael D. Henry ◽  
...  
Keyword(s):  
Overall Survival ◽  
Brain Metastases ◽  
Checkpoint Inhibitor ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Multivariable Analysis ◽  
Treatment Strategies ◽  
Poor Performance Status ◽  
Poor Overall Survival ◽  
Melanoma Brain Metastases

Brain metastases commonly develop in melanoma and are associated with poor overall survival of about five to nine months. Fortunately, new therapies, including immune checkpoint inhibitors and BRAF/MEK inhibitors, have been developed. The aim of this study was to identify outcomes of different treatment strategies in patients with melanoma brain metastases in the era of checkpoint inhibitors. Patients with brain metastases secondary to melanoma were identified at a single institution. Univariate and multivariable analyses were performed to identify baseline and treatment factors, which correlated with progression-free and overall survival. A total of 209 patients with melanoma brain metastases were identified. The median overall survival of the cohort was 5.3 months. On multivariable analysis, the presence of non-cranial metastatic disease, poor performance status (ECOG 2–4), whole-brain radiation therapy, and older age at diagnosis of brain metastasis were associated with poorer overall survival. Craniotomy (HR 0.66, 95% CI 0.45–0.97) and treatment with a CTLA-4 checkpoint inhibitor (HR 0.55, 95% CI 0.32–0.94) were the only interventions associated with improved overall survival. Further studies with novel agents are needed to extend lifespan in patients with brain metastases in melanoma.

Preliminary results of a phase II study of alrizomadlin (APG-115), a novel, small-molecule MDM2 inhibitor, in combination with pembrolizumab in patients (pts) with unresectable or metastatic melanoma or advanced solid tumors that have failed immuno-oncologic (I-O) drugs.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2506-2506
Author(s):  
Anthony W. Tolcher ◽  
James Andrew Reeves ◽  
Meredith McKean ◽  
Bartosz Chmielowski ◽  
Joseph Thaddeus Beck ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Solid Tumors ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Performance Status ◽  
Nerve Sheath Tumor ◽  
Advanced Solid Tumors ◽  
Antitumor Effects ◽  
Ecog Performance Status ◽  
Multiple Tumor

2506 Background: Alrizomadlin (APG-115) restores TP53 function, activating p53-mediated apoptosis in tumor cells with wild-type TP53 and/or MDM2 amplification. Alrizomadlin also functions as a host immunomodulator and hence may restore antitumor activity in pts with cancers failing PD-1/PD-L1 blockade. Methods: This US multicenter trial assessed alrizomadlin combined with pembrolizumab in pts with unresectable/metastatic melanoma or advanced solid tumors that had failed I-O drugs; or pts with malignant peripheral nerve sheath tumor (MPNST), liposarcoma, or ATM mutant solid tumors that had failed any standard therapy. Eligible pts had ECOG performance status of 0-2 and no CNS metastases. The phase II study cohorts included pts with melanoma, NSCLC, solid tumor with ATM mutation, well-differentiated/dedifferentiated liposarcoma, urothelial carcinoma, and MPNST. Alrizomadlin was administered orally at 150 mg once every other day for 2 consecutive weeks with 1 week off and pembrolizumab at 200 mg via IV infusion for 30 minutes on Day 1 of a 21-day cycle. Results: As of December 25, 2020, 84 pts had been treated in 6 cohorts: melanoma (n = 26), NSCLC (n = 23), ATM mutation (n = 9), liposarcoma (n = 14), urothelial (n = 9), and MPNST (n = 3). In the PD-1/PD-L1 inhibitor-failed melanoma cohort, there was 1 confirmed partial response (PR) out of 5 pts with uveal melanoma, 2 PR (1 confirmed and 1 unconfirmed) of 5 pts with mucosal melanoma, and 1 confirmed PR of 11 pts with cutaneous melanoma. ORR in the melanoma cohort was 17.4% (4/23 evaluable pts), and the disease control rate was 60.9% (14/23). In the MPNST cohort, 1 of 3 pts had an unconfirmed ongoing PR. In I-O drug-failed NSCLC (n = 14 evaluable) and urothelial (n = 5 evaluable) cohorts, each reported 1 confirmed PR. Common treatment (alrizomadlin or pembrolizumab)-related adverse events (TRAEs) (≥ 10%) were nausea (63.1%), thrombocytopenia (36.9%), vomiting (33.3%), fatigue (31.0%), decreased appetite (27.4%), diarrhea (21.4%), neutropenia (15.4%), and anemia (11.9%). Grade ≥ 3 TRAEs (≥ 5%) included thrombocytopenia (20.2%), neutropenia (14.2%), and anemia (8.3%). Eleven pts discontinued treatment due to AEs: 5 were treatment related, including 2 grade 4 thrombocytopenia, and 1 each of grade 2 vomiting, grade 2 fatigue, and grade 2 posterior reversible encephalopathy syndrome (PRES). Three treatment-related SAEs were PRES, pyrexia, and asthenia. Conclusions: Alrizomadlin combined with pembrolizumab is well tolerated and may restore antitumor effects in pts with cancer resistant to or intolerant of I-O drugs, as suggested by preliminary antitumor activities in multiple tumor types. Internal study identifiers: APG-115-US-002; Keynote MK-3475-B66. Clinical trial information: NCT03611868.

Toxicity, response, and survival in older adults with metastatic melanoma treated with checkpoint inhibitors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 9544-9544
Author(s):  
Nienke A De Glas ◽  
Esther Bastiaannet ◽  
Frederiek van den Bos ◽  
Simon Mooijaart ◽  
Astrid Aplonia Maria Van Der Veldt ◽  
...  
Keyword(s):  
Older Adults ◽  
Overall Survival ◽  
Metastatic Melanoma ◽  
Older Patients ◽  
Regression Models ◽  
Checkpoint Inhibitors ◽  
Performance Status ◽  
Toxicity Response ◽  
Grade 3 ◽  
The Impact

9544 Background: Checkpoint inhibitors have strongly improved survival of patients with metastatic melanoma. Trials suggest no differences in outcomes between older and younger patients, but only relatively young patients with a good performance status were included in these trials. The aim of this study was to describe treatment patterns and outcomes of older adults with metastatic melanoma, and to identify predictors of outcome. Methods: We included all patients aged ≥65 years with metastatic melanoma between 2013 and 2020 from the Dutch Melanoma Treatment registry (DMTR), in which detailed information on patients, treatments and outcomes is available. We assessed predictors of grade ≥3 toxicity and 6-months response using logistic regression models, and melanoma-specific and overall survival using Cox regression models. Additionally, we described reasons for hospital admissions and treatment discontinuation. Results: A total of 2216 patients were included. Grade ≥3 toxicity did not increase with age, comorbidity or WHO performance status, in patients treated with monotherapy (anti-PD1 or ipilimumab) or combination treatment. However, patients aged ≥75 were admitted more frequently and discontinued treatment due to toxicity more often. Six months-response rates were similar to previous randomized trials (40.3% and 43.6% in patients aged 65-75 and ≥75 respectively for anti-PD1 treatment) and were not affected by age or comorbidity. Melanoma-specific survival was not affected by age or comorbidity, but age, comorbidity and WHO performance status were associated with overall survival in multivariate analyses. Conclusions: Toxicity, response and melanoma-specific survival were not associated with age or comorbidity status. Treatment with immunotherapy should therefore not be omitted solely based on age or comorbidity. However, the impact of grade I-II toxicity in older patients deserves further study as older patients discontinue treatment more frequently and receive less treatment cycles.[Table: see text]

Primary Splenic Diffuse Large B-Cell Lymphoma (PS-DLBCL): Splenectomy Improves Survival

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4439-4439 ◽  
Author(s):  
Osnat Bairey ◽  
Lev Shvidel ◽  
Chava Perry ◽  
Eldad J Dann ◽  
Rosa Ruchlemer ◽  
...  
Keyword(s):  
Overall Survival ◽  
Performance Status ◽  
B Cell Lymphoma ◽  
Stage I ◽  
Event Free Survival ◽  
Ecog Performance Status ◽  
Free Survival ◽  
Large B Cell Lymphoma ◽  
The Mean ◽  
Ecog Ps

Abstract Introduction: Although the spleen is involved in about a third of patients with non-Hodgkin's lymphoma (NHL), primary splenic diffuse large B-cell lymphoma (PS-DLBCL) is rare having a reported incidence of less than 1% of all NHL. Most of the described series include small numbers of patients before the rituximab era and the role of splenectomy treatment in addition to immuno-chemotherapy is unknown. Methods: Data were retrospectively collected for 87 patients (pts) with PS-DLBCL treated in 7 medical centers in Israel during the years 1982-2013. Patients presenting with systemic disease with splenic involvement or those having a diagnostic biopsy from other nodal or extranodal disease were excluded. Results: The mean age was 59.6 years (range, 24-89 years); 57.5% were male. Abdominal pain was reported in 61 pts (81%), B symptoms in 49 pts (59%), ECOG performance status 0 - 1 in 85%. Stage I disease was recorded in 28%, II in 33%, III in 18%, and IV in 21%. Thrombocytopenia (<100,000/µl) was recorded in only 6 pts. Lactic dehydrogenase levels (LDH) were elevated in 69 pts (84%). Favorable International Prognostic Index (IPI) 0-2 was recorded in 62 pts (72%). The mean splenic length was 17.34±6 cm (range 7- 37 cm) and the mean splenic weight was 1216 gm±1243 gm (range 180-6000 gm). A splenic mass was found in 97% of pts, and its mean size was 9.26 cm (range 3-18 cm). The diagnostic procedure was core needle biopsy in 46 pts and splenectomy in 39 pts: 27 underwent open splenectomy and 12 laparoscopic splenectomy. Splenectomized pts had lower IPI (p<0.05) and lower stage (p<0.05) compared to non-splenectomized pts. Treatment: The CHOP regimen was given to 80 pts (92%), DA-EPOCH was given to 2 pts (2%) and 5 pts (6%) received other regimens. Rituximab was given to 68 pts (78%). Complete response was achieved in 67 pts (80%) and partial response in 8 (9%). Relapse occurred in 17 pts (22%). Survival: The median follow-up time was 7 years (range 0-19.4 years). During this period 24 pts died (27.5%). The 5-year overall survival (OS) was 76.6±4.9% and 5-year event-free survival (EFS) 67.2±5.5%. Splenectomy at diagnosis improved survival: the 5-year EFS was 85.4±6% and 54.7±8% for splenectomized and non-splenectomized pts respectively (p=0.02) and the 5-year OS was 91.2±5% and 67.9±7% respectively (p=0.08). For the 53 pts with stage I-II disease, both 5-year EFS and OS were better in the splenectomized pts (p<0.02, Fig 1). The 5-year EFS and OS in pts with stage I and II disease that were splenectomized at diagnosis was 89.6±6% and 96.4±3.5% as compared with 50.5±11% and 63.2±11% in pts who were not splenectomized (p=0.012 and 0.009). The EFS and OS were not influenced by the stage of the disease. Overall survival was associated with B symptoms (p=0.02), weight loss (p=0.04) and ECOG performance status (p=0.03). In a multivariate model, low ECOG PS and splenectomy independently predicted a better EFS (p=0.03 and 0.02 respectively), however for OS, low ECOG PS independently predicted better OS (p=0.03), while splenectomy had only marginal effect on the OS (p=0.056). Conclusions: In our group of pts, PS-DLBCL generally presented with abdominal pain, high LDH and a splenic mass. We demonstrate for the first time that splenectomy at diagnosis improves survival in early stages of PS-DLBCL. Our study is a retrospective one. Therefore, until prospective studies prove that early splenectomy in PS-DLBCL is beneficial in terms of overall survival, the risk and benefit of performing splenectomy should be weighed for each patient. Fig 1: (A) Event-free survival and (B) Overall survival in patients with primary splenic DLBCL and stages I - II disease who did or did not undergo splenectomy at diagnosis. Fig 1:. (A) Event-free survival and (B) Overall survival in patients with primary splenic DLBCL and stages I - II disease who did or did not undergo splenectomy at diagnosis. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Safety and pharmacokinetics of intravenous VEGF Trap plus irinotecan, 5-fluorouracil, and leucovorin (I-LV5FU2) in a combination phase I clinical trial of patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 13161-13161 ◽  
Author(s):  
O. Rixe ◽  
C. Verslype ◽  
J. B. Méric ◽  
S. Tejpar ◽  
J. Bloch ◽  
...  
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Angiogenesis Inhibitor ◽  
Maximum Tolerated Dose ◽  
Vegf Receptor ◽  
Advanced Solid Tumors ◽  
Colon Cancers ◽  
Ecog Ps ◽  
Dose Levels ◽  
Vegf Trap

13161 Background: VEGF Trap is a potent angiogenesis inhibitor comprising portions of human VEGF receptor VEGFR1 (Flt-1) and VEGFR2 (Flk-1) extracellular domains fused to the Fc portion of human IgG. VEGF Trap binds VEGF and neutralizes all VEGF-A isoforms plus placental growth factor. I-LV5FU2 is an approved chemotherapy regimen for the first-line treatment of metastatic colorectal cancer. This study was designed to evaluate the safety and pharmacokinetics (PK) of VEGF Trap plus I-LV5FU2 administered intravenously. Methods: Successive cohorts of 3–6 patients (pts) with relapsed or refractory solid tumors received intravenous VEGF Trap plus I-LV5FU2 every 2 weeks. Study endpoints included safety, PK, and immunogenicity. Antitumor activity was assessed by CT scan. Results: Ten pts (3 male/7 female), median age 59 (34–67), ECOG PS 0/1/2: 8/2/0, with a variety of advanced solid tumors, including 5 colorectal and 2 ovarian, have received a total of 50 cycles of VEGF Trap plus I-LV5FU2 across 2 VEGF Trap dose levels (2.0 mg/kg, 4.0 mg/kg) to date. Only 1 dose-limiting toxicity (G3 proteinuria >2 wks with normal plasma creatinine levels) has been encountered so far (4.0 mg/kg, Cycle 2). This pt also had controlled G2 HTN (renal biopsy pending). No other G3/4 VEGF Trap-related AEs have been reported so far. Preliminary free VEGF Trap clearance was 15.4 mL/kg/day. Three pts (synovial sarcoma, ovarian and colon cancers) achieved partial responses. Conclusions: VEGF Trap may be safely combined with I-LV5FU2 at the dose levels studied. Preliminary free VEGF Trap clearance did not differ significantly from that seen with single-agent exposure; chemotherapy PK analysis is pending. The maximum tolerated dose has not yet been reached, and dose escalation continues. Updated safety, pharmacokinetic, and preliminary efficacy results from this ongoing study will be presented. [Table: see text]

Phase I trial of patupilone (P) and RAD001 in patients (pts) with advanced solid tumors

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2529-2529
Author(s):  
M. N. Stein ◽  
B. Knox ◽  
E. Wesolowsky ◽  
M. Levitt ◽  
R. Moss ◽  
...  
Keyword(s):  
Prostate Cancer ◽  
Colon Cancer ◽  
Phase I ◽  
Solid Tumors ◽  
Clinical Activity ◽  
Advanced Solid Tumors ◽  
Clinical Models ◽  
Adequate Organ Function ◽  
Ecog Ps ◽  
Tumor Types

2529 Background: P is an epothilone with activity in solid tumors including docetaxel (D) resistant prostate cancer. R is an oral mTOR inhibitor that demonstrates synergy with P in pre-clinical models, possibly by decreasing resistance to apoptosis. This on-going phase I study is assessing the tolerability of P in combination with R in pts with advanced solid tumors. Methods: Eligible patients with ECOG PS 0–2, adequate organ function and no more than 3 prior chemotherapy treatment received P every 21 days and weekly R using a standard 3+3 dose escalation schema in a 21 day(d) cycle starting at 50% of the phase II dose of P and 60% of the standard weekly dosing of R. Dosing levels are (1) P 5mg/m2 D1, R 30mg D1; (2) P 7.5mg/m2 D1, R 30mg D1 (3) P 7.5mg/m2 D1 R 30mg D1, D8 (3A) P 7.5mg/m2 D1 R 30mg D1, D8, D15 (3B) P 8mg/m2 D1 R 50mg D1, D8 (4) P 10 mg/m2 D1, D8 R 30mg D1, D8 (5) P 10 mg/m2 D1, D8 R 50mg D1, D8. Pharmacokinetic (PK) levels of R were obtained D1, D2 and PBMC were obtained to assess phospho-S6 and to assess markers of apoptosis and autophagy. Results: A total of 24 pts have been enrolled and 23 pts are evaluable for toxicity (tumor types: colon-7, prostate-6, lung-3, ampulla-3, leiomyosarcoma-2, cervical cancer-1). DLTs of grade(g) 3 diarrhea, g3 colitis and g3 fatigue were observed in dose levels 5, 4 and 1 pt in cohort 3A with a colostomy. Cohorts 1–3 were well tolerated with the common AEs of g1 diarrhea, g2 neuropathy after cycle 7, g1/g2 anemia, g1 triglycerides. In pts with prostate cancer (all previously pretreated with D) PSA declines of >50% occurred in 3/5 pts treated with >2 cycles; 1/7 pts with colon cancer had a PR and 3/7 pts with colon cancer had stable disease (SD) > 8 cycles; 1/3 pts with ampullary ca had a PR and a pt with cervical ca had SD x10 cycles. Conclusions: P 7.5mg/m2 and R 30mg D1, D8 is safe and well tolerated. Encouraging evidence of clinical activity is observed in prostate, colon and other tumor types. Enrollment to cohort 3A is ongoing. [Table: see text]

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