Preclinical efficacy evaluation of ixabepilone (BMS-247550) in combination with cetuximab or capecitabine in human colon and lung carcinoma xenografts

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 12017-12017 ◽  
Author(s):  
F. Y. Lee ◽  
A. Camuso ◽  
S. Castenada ◽  
C. Flefleh ◽  
I. Ingio ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Lung Carcinoma ◽  
Therapeutic Potential ◽  
Single Agent ◽  
Human Colon ◽  
Maximum Tolerated Dose ◽  
Antitumor Efficacy ◽  
Efficacy Evaluation ◽  
Multiple Tumor ◽  
Tumor Types

12017 Background: Ixabepilone belongs to a class of structurally novel, microtubule-stabilizing agents that exert their antimitotic action by binding to tubulin with a binding mode that is distinct from the taxanes. Preclinical findings that ixabepilone has antitumor activity in a broad spectrum of tumor types, including taxane-resistant tumors, is borne out by Phase II clinical trials where ixabepilone has demonstrated activities in multiple tumor types including breast, renal, pancreatic, prostate and lymphoma. The aim of this series of studies was to further characterize the therapeutic potential of ixabepilone in combination with currently approved chemotherapy agents. Methods: Antitumor activity was evaluated in the GEO human colon and L2987 human lung carcinoma xenografts. Therapeutic synergism of the combination was defined as the attainment of efficacy that was significantly better than the best response of the individual single agents administered at their maximum-tolerated dose (MTD) or optimal dose (OD). Results: In the GEO tumors, single-agent ixabepilone produced 1.1 log cell kill (LCK) at its MTD. Cetuximab at its OD yielded 0.8 LCK. The combination of ixabepilone and cetuximab produced 1.7 LCK which was significantly superior to ixabepilone alone (P=0.0173) and cetuximab alone (P=0.0002). Similar synergistic efficacy was observed in the L2987 tumors. The combined efficacy of capecitabine plus ixabepilone was evaluated in the GEO tumors. In this tumor, single-agent ixabepilone was modestly active (LCK = 0.8) at its MTD. Single-agent capecitabine was not effective (LCK = 0.4) at its MTD. However, the combination of the two agents produced therapeutic synergism, yielding antitumor efficacy (1.9 LCK) that was superior to either of the agents alone at their MTDs (P=0.035 and 0.0004, respectively). Conclusions: Ixabepilone demonstrates robust synergistic antitumor efficacy when used in combination with cetuximab or capecitabine in human xenografts providing a biologic rationale for these combinations in the treatment of cancer. [Table: see text]

NKP-1339: Maximum tolerated dose defined for first-in-human GRP78 targeted agent.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 3033-3033 ◽  
Author(s):  
Dana Shelton Thompson ◽  
Glen J. Weiss ◽  
Suzanne Fields Jones ◽  
Howard A. Burris ◽  
Ramesh K. Ramanathan ◽  
...  
Keyword(s):  
Phase I ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Unknown Primary ◽  
Multiple Tumor ◽  
Anti Cancer ◽  
Targeted Agent ◽  
Adequate Organ Function ◽  
Tumor Types ◽  
Post Therapy

3033 Background: NKP-1339 is a first-in-class small molecule anti-cancer compound that down-regulates GRP78, a key regulator of misfolded protein processing and tumor survival/anti-apoptosis. GRP78 up-regulation occurs in many tumors, and is associated with intrinsic and chemotherapy-induced resistance. Preclinically, single agent NKP-1339 demonstrates activity against multiple tumor types, including chemoresistant lines. This phase I trial evaluates the safety, tolerability, maximum tolerated dose (MTD), pharmacokinetics, and pharmacodynamics (PD) of NKP-1339. Methods: Patients (pts) with advanced solid tumors, adequate organ function, ECOG 0-1 are enrolled. NKP-1339 is infused on day 1, 8, and 15 of 28 day cycles. Single pt cohorts are enrolled until grade 2 toxicity, then adjusted to standard 3+3 design. Doses from 20-780 mg/m2 are evaluated. PD samples for plasma GRP78 are collected. At MTD, an expanded cohort of 25 pts is enrolled. Results: 34 pts are enrolled for dose escalation: 30 evaluable for dose determination; 4 replaced due to tumor progression in cycle 1. Demographics: 19M/15F; median age 62 yrs (range 28 to 79). Tumor types: colorectal (CRC, 10), non-small cell lung (NSCLC, 8); neuroendocrine (NET, 5); head and neck (H&N, 3); and other cancer (8). Dose limiting toxicity of grade (gr) 2-3 nausea, with gr 2 creatinine in 1 pt, occurred at 780 mg/m2; MTD is 625 mg/m2. Gr 1 fever/chills is observed above 420 mg/m2, but is prevented by steroid premedication. The most common drug-related events are gr 1 nausea, gr 1-2 vomiting, and gr 1-2 fatigue. No lab abnormalities were noted except reversible creatinine elevation in 4 pts: 3 pt with gr 1; 1 pt with gr 2 secondary to DLT. Partial response was in 1 pt (NET); stable disease in 7 pts, including NET (2), NSCLC (2), CRC (1), sarcoma (1), and unknown primary (1). Therapy duration 14+-88+ weeks. Soluble GRP78 is detected in the plasma of patients at baseline. Conclusions: NKP-1339is well tolerated with manageable side effects. Single agent activity is noted in multiple tumors including NET. Results from the expanded cohort and pre/post-therapy PD will be presented. Phase II single agent NKP-1339 and phase I NKP-1339 combination trials are planned.

Phase I and Pharmacokinetic Study of Irinotecan and Docetaxel in Patients With Advanced Solid Tumors: Preliminary Evidence of Clinical Activity

2000 ◽  
Vol 18 (5) ◽  
pp. 1116-1116 ◽  
Author(s):  
Alex A. Adjei ◽  
Cheri E. Klein ◽  
Helen Kastrissios ◽  
Richard M. Goldberg ◽  
Steven R. Alberts ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Intravenous Infusion ◽  
Maximum Tolerated Dose ◽  
Preliminary Evidence ◽  
Clinical Activity ◽  
Clinically Significant ◽  
Grade 3 ◽  
Recommended Phase Ii Dose ◽  
Tumor Types ◽  
Dose Levels

PURPOSE: The goals of this study were to determine the maximum-tolerated dose and describe the toxicities of the combination of irinotecan and docetaxel administered every 3 weeks to patients with advanced malignancies and, also, to evaluate the effect of irinotecan on the disposition of docetaxel and describe preliminary evidence of antitumor activity. PATIENTS AND METHODS: Eighteen patients received 85 courses (median, two courses; range, one to 15 courses) of treatment with irinotecan, administered over 90 minutes by intravenous infusion, followed by docetaxel, administered over 60 minutes by intravenous infusion. Four escalating dose levels of irinotecan/docetaxel (160/50 mg/m2, 160/65 mg/m2, 200/65 mg/m2, and 200/75 mg/m2) were studied. Pharmacokinetic analyses were performed to evaluate the effect of irinotecan on the disposition of docetaxel. RESULTS: The most common and dose-limiting toxicity was myelosuppression, which consisted of neutropenia that was severe (National Cancer Institute common toxicity criteria [NCI CTC] grade 4) but brief (< 5 days) in 11 patients, with three episodes of febrile neutropenia. Nonhematologic toxicities of anorexia, nausea, and stomatitis were mild to moderate (NCI CTC grades 1 and 2), but there was one incidence each of both CTC grade 3 anorexia and nausea. All patients had total alopecia. Diarrhea was dose-dependent and severe in four patients who failed to take adequate antidiarrhea therapy. Five out of 16 assessable patients, one with cholangiocarcinoma, one with leiomyosarcoma, and three with non–small-cell lung cancer, achieved partial remissions. CONCLUSION: The combination of irinotecan and docetaxel causes significant reversible myelosuppression, which was dose limiting but led to no serious sequelae. There was no evidence of a clinically significant interaction using these two agents in this sequence. The combination showed antitumor activity at all the dose levels tested and should be further studied in a number of tumor types. The recommended phase II dose on this schedule is irinotecan 160 mg/m2 and docetaxel 65 mg/m2.

Pemetrexed in combination with paclitaxel: A phase I clinical and pharmacokinetic trial in patients with solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2051-2051 ◽  
Author(s):  
T. Graefe ◽  
C. Bolling ◽  
C. Lubbing ◽  
J. Latz ◽  
J. Blatter ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Thyroid Carcinoma ◽  
Phase Ii ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Recommended Dose ◽  
Clinical Activity ◽  
Best Response ◽  
Recommended Phase Ii Dose

2051 Background: Pemetrexed (Alimta [AL]) and paclitaxel (P) are clinically active in a variety of tumors. The primary objective of this trial was to determine the maximum tolerated dose (MTD) of the ALP combination; secondary objectives were: determination of dose-limiting toxicities (DLTs), definition of a recommended phase II dose, pharmacokinetic (PK) characterization and the anecdotal collection of antitumor activity. Methods: Escalating doses of P (3h infusion, d1 and d8) and AL (10 min infusion, d8 prior to P) were given in a 21d cycle. Results: 59 patients (pts) were enrolled. DLTs occurred at the following ALP (mg/m2) doses: 400/30 [G3 bilirubin (b), G3 and G4 thrombocytopenia (plts)]; 500/30 (G4 plts); 500/40 (G3 b); 500/75 (G4 ANC); 500/100 (G4 leukopenia, G4 ANC). With G4 leukopenia and G4 ANC in 4/6 pts and febrile neutropenia in 1 pt, the MTD was reached at the ALP (mg/m2) dose of 500/120. To confirm safety at the recommended dose-level, another 6 patients were treated at the ALP (mg/m2) dose of 500/100. 18 pts [mesothelioma (3), esophagus (2), lung (1), liver (1), renal (1), stomach (1), thyroid (9)] showed stable disease as best response. 4/14 (29%) pts with thyroid carcinoma showed long lasting partial responses [duration (months) 29+, 22, 18, 15]. One additional PR (2) was observed in a pt with penile carcinoma. AL PK when administered with P were consistent with those for AL administered as a single-agent. Conclusions: The ALP combination is safe and shows broad clinical activity. 500/100 mg/m2 is the recommended dose for further studies. Promising antitumor activity was observed in thyroid cancer. A phase II trial in thyroid carcinoma will be conducted. [Table: see text]

Assessment of safety with abbreviated, weight-based bevacizumab infusions in a variety of solid tumors

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 19674-19674
Author(s):  
J. W. Hart ◽  
J. R. Murillo ◽  
M. S. Oholendt ◽  
H. A. Preti
Keyword(s):  
Solid Tumors ◽  
Single Agent ◽  
Central Nervous System Involvement ◽  
Minimal Risk ◽  
Phase I Clinical Trials ◽  
Multiple Tumor ◽  
Humanized Monoclonal Antibody ◽  
Number Of Patients ◽  
Infusion Schedule ◽  
Tumor Types

19674 Background: Bevacizumab (BEV), a humanized monoclonal antibody that neutralizes vascular endothelial growth factor, has shown improved responses in patients with colorectal cancer (CRC) and non-small cell lung cancer (NSCLC) while displaying activity in a variety of other solid tumors. Phase I clinical trials with BEV utilized standard 90- 60-, and 30-minute infusions for 1st, 2nd, and subsequent infusions, as tolerated; initial doses reported less than 3% incidence of infusion-related adverse events (AEs), with 0.2% grade III/IV reactions. Recommended infusion rates for BEV remain unchanged despite the minimal risk of infusion-related AEs. Saltz and colleagues recently reported novel data supporting the safety and tolerability of abbreviated BEV infusions in CRC patients within a single institution. Our objective was to replicate previously reported safety profiles while utilizing abbreviated infusions of BEV in multiple tumor types. Methods: An internal retrospective analysis revealing minimal infusion AEs with standard infusions facilitated this current study. BEV- naïve and previously-treated patients were consented for the study utilizing the following weight-based infusion times: 5, 10, and 15 mg/kg doses over 10, 20, or 30 minutes, respectively, for all doses. Patients were assessed throughout and immediately following the infusion for any infusion-related AE. Results: A variety of tumor types are represented in 26 enrolled patients including CRC, NSCLC, breast, ovarian, pancreatic, and brain. Central nervous system involvement accounted for 35% of patients [primary brain (23%) and metastatic disease (12%)]. A considerable number of patients (19%) were treated with single-agent BEV. Nine BEV-naïve patients were initiated on abbreviated infusions, while 16 were converted from the standard infusion schedule. Seventy-seven total doses utilizing the abbreviated infusions failed to produce infusion-related AEs. Conclusion: These results support previous data affirming the safety and tolerability of abbreviated BEV infusions in CRC patients, while also reporting promising safety of abbreviated infusions in a variety of additionally unreported solid tumors types. No significant financial relationships to disclose.

Phase I study of MK-3475 (anti-PD-1 monoclonal antibody) in patients with advanced solid tumors.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 2512-2512 ◽  
Author(s):  
Amita Patnaik ◽  
Soonmo Peter Kang ◽  
Anthony W. Tolcher ◽  
Drew Warren Rasco ◽  
Kyriakos P. Papadopoulos ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Preliminary Evidence ◽  
Open Label ◽  
Dose Escalation Study ◽  
Advanced Malignancy ◽  
Multiple Tumor ◽  
Label Dose ◽  
Grade 3 ◽  
Tumor Types

2512 Background: Programmed death-1 (PD-1) is an inhibitory T-cell coreceptor that may lead to suppression of antitumor immunity. MK-3475 is a humanized monoclonal IgG4 antibody against PD-1. Preclinically, MK-3475 has shown antitumor activity in multiple tumor types. This first-in-human phase I trial explored safety, PK, PD, and antitumor activity of MK-3475. Methods: An open-label, dose escalation study was conducted in patients with advanced malignancy refractory to standard therapy. Cohorts of 3-6 patients were enrolled (3+3 design) at escalating IV doses of 1, 3, and 10 mg/kg. Following an initial dose and 28-day Cycle 1, patients were allowed to subsequently receive multiple doses given every 2 wks. Radiographic assessment was conducted every 8 wks using RECIST 1.1 guidelines. Results: Nine patients, 3 at each dose level, completed the dose-limiting toxicity (DLT) period (28 d). Patients had non–small cell lung cancer (NSCLC, n=3), rectal cancer (n=2), melanoma (MEL, n=2), sarcoma (n=1), or carcinoid (n=1). To date, a total of 63 doses were administered (median 7/patient; max 12) without DLT. Drug-related adverse events (AEs) across all doses included Grade 1 fatigue (n=3), nausea (n=2), diarrhea (n=1), dysgeusia (n=1), breast pain (n=1), and pruritus (n=1). One drug-related Grade 2 AE of pruritus was reported. No drug-related AEs ≥ Grade 3 were observed. PK data are shown in the table. Based on RECIST, 1 patient with MEL on therapy >6 mths had a partial response, and preliminary evidence of tumor size reduction (stable disease) was observed in 3 additional patients with advanced cancer. Conclusions: MK-3475 was well-tolerated without DLT across 3 tested dose levels. Evidence of antitumor activity was observed. Enrollment continues to obtain additional safety, PK, and efficacy data; updated data will be presented at the meeting. [Table: see text]

Phase Ib/IIa study of GC1118 in combination with irinotecan or FOLFIRI in patients with metastatic solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3592-3592
Author(s):  
Keun Wook Lee ◽  
Sae-Won Han ◽  
Ji-Won Kim ◽  
Dae-Won Lee ◽  
Yong Sang Hong ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Solid Tumors ◽  
Skin Rash ◽  
Single Agent ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Stage Design ◽  
Phase 1B ◽  
Grade 3 ◽  
Stage 1

3592 Background: GC1118 is a novel anti-EGFR monoclonal antibody which has a unique binding epitope and superior ligand inhibition potential. It showed promising antitumor activity as a single agent in the phase I study. This study aimed to determine the maximum tolerated dose (MTD) and recommended phase 2 dose (RP2D) of GC1118 in combination with irinotecan or FOLFIRI in metastatic solid tumors and evaluate the efficacy of GC1118 plus FOLFIRI as a second line therapy for RAS and BRAF wild-type metastatic colorectal cancer. Methods: Phase 1b part was designed to evaluate weekly GC1118 (starting from 3 mg/kg) in combination with biweekly irinotecan (180mg/m2) or FOLFIRI (irinotecan 180mg/m2, leucovorin 400mg/m2, 5-FU 400 mg/m2 bolus, and 5-FU 2400mg/m2 over 46hrs) in a 3+3 design. In the phase 2a part, the RP2D of GC1118 is administered in combination with FOLFIRI in a Simon’s two stage design with objective response rate (ORR) as the primary endpoint. Results: 13 pts were enrolled in phase 1b and received 3mg/kg of GC1118 with irinotecan (N = 6) or FOLFIRI (N = 7). DLT occurred in 2 pts (G4 neutropenia, G2 rash) in irinotecan arm and 1pt (G3 neutropenia) in FOLFIRI arm with 3mg/kg of GC1118 and it was determined as MTD and RP2D. Adverse events (AE) of grade ≥ 3 included neutropenia (61.5 %), skin rash (15.4 %) and diarrhea (15.4%). Dose reductions due to GC1118-related AE were required in 6 (46.2%) patients. Among 10 response-evaluable pts in phase 1b, best overall response was PR in 3 and SD in 6, and median PFS was 12 months. In stage 1 of phase 2a (N = 9), 4 PR and 5 SD were observed (ORR 44.4%, 95% CI 13.7 – 78.8). We moved to stage 2, and are currently enrolling additional 20 pts. AE of grade ≥ 3 included neutropenia (66.7%), skin rash (22.2%) and diarrhea (11.1%). Updated data of the phase 2a part will be presented at the meeting. Conclusions: The MTD and RP2D of weekly GC1118 in combination with irinotecan or FOLFIRI was 3mg/kg. Preliminary results of GC1118 and FOLFIRI as a 2nd line treatment in mCRC suggests promising antitumor activity and acceptable safety profile. Clinical trial information: NCT03454620 .

A first-in-human phase I study of the CDK4/6 inhibitor, LY2835219, for patients with advanced cancer.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2500-2500 ◽  
Author(s):  
Geoffrey Shapiro ◽  
Lee S. Rosen ◽  
Anthony W. Tolcher ◽  
Jonathan Wade Goldman ◽  
Leena Gandhi ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Ovarian Cancer ◽  
Antitumor Activity ◽  
Advanced Cancer ◽  
Human Cancer ◽  
Phase 1 ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Ca 125 ◽  
Clinical Activity

2500 Background: Cyclin dependent kinases 4 and 6 (CDK4/6) act with D-type cyclins to inactivate the retinoblastoma (Rb) tumor suppressor protein and enable cell cycle progression from G1 to S phase. LY2835219 is a selective inhibitor of CDK4/6 that shows antitumor activity in preclinical models of human cancer and also distributes efficiently to the brain. We performed a phase 1 study to evaluate safety, pharmacokinetics, pharmacodynamics, and antitumor activity of LY2835219. Methods: 3+3 dose escalation was followed by expansions in 5 tumor types (brain metastases permitted): non-small cell lung cancer (NSCLC), glioblastoma, breast cancer, melanoma, and colorectal cancer. LY2835219 was taken orally every 12 or 24 hours (in escalation) and every 12 hours (in expansions) on days 1-28 of a 28-day cycle. Results: 55 patients (pts) received LY2835219. In escalation, 33 pts received LY2835219 on 1 of 2 schedules: 50, 100, 150, 225 mg every 24 hours (Q24H) or 75, 100, 150, 200, 275 mg every 12 hours (Q12H). On the Q24H schedule, the maximum tolerated dose (MTD) was not identified. On the Q12H schedule, the MTD was 200mg Q12H with dose limiting toxicity of G3 fatigue at 200 mg (1/6 evaluable pts) and 275 mg (2/3 evaluable pts). At 200mg Q12H, the mean Cmax and AUC0-24hr at steady state were 285 ng/mL and 5502 ng-hr/ml, respectively. In skin, LY2835219 induced pharmacodynamic inhibition of both Rb phosphorylation and topoisomerase IIα expression. In the ongoing expansions, 22 pts have received LY2835219. Across the study, the most common related adverse events were diarrhea (52%, including 5% G3), nausea (30%, 4% G3), fatigue (21%, 7% G3), vomiting (18%, 2% G3), and neutropenia (16%, 7% G3). 15 pts have reached ≥4 cycles for stable disease or better with 3 pts achieving 8, 16, and 26 cycles. One pt with ovarian cancer had a durable CA-125 response with >50% decrease for 16 cycles. One pt with KRAS mutant NSCLC had a 27% decrease by RECIST. One pt with CDKN2A-/- NRAS mutant melanoma had a confirmed partial response. Early clinical activity has been observed in ovarian cancer, NSCLC, breast cancer, and melanoma. Conclusions: LY2835219 shows acceptable safety and early clinical activity as a single agent for patients with advanced cancer. Clinical trial information: NCT01394016.

Association of LRP1B pathogenic genomic alterations with favorable outcomes with immune checkpoint inhibitors across multiple tumor types.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3007-3007 ◽  
Author(s):  
Landon Carter Brown ◽  
Ramy Sedhom ◽  
Eric B Schwartz ◽  
Jason Zhu ◽  
Chester Kao ◽  
...  
Keyword(s):  
Immune Checkpoint ◽  
Immune Checkpoint Inhibitors ◽  
Checkpoint Inhibitors ◽  
Single Agent ◽  
Objective Response ◽  
Density Lipoprotein ◽  
Primary Objective ◽  
Missense Mutations ◽  
Multiple Tumor ◽  
Tumor Types

3007 Background: Low-density lipoprotein receptor-related protein 1b (LRP1b) is a putative tumor suppressor and one of the most frequently altered genes in cancer. Our prior single-center work suggested that LRP1B alterations may enrich for responses to immune checkpoint inhibitors (ICI) in solid tumors including prostate cancer; however, validation of these findings is needed. Methods: We conducted a multicenter, retrospective analysis of patients with LRP1B alterations (on tissue-based next-generation sequencing panels) treated with ICI at Duke, Johns Hopkins (JHU), and University of Michigan (UM). The primary objective was to assess the association between objective response rate (ORR) to ICI and pathogenic LRP1B alterations, defined as deletions or truncating alterations, when compared with LRP1B variants of undetermined significance (VUS), defined as missense mutations not predicted to be pathogenic in COSMIC. Missense changes with a COSCMIC FATHMM score of > 0.8 were categorized separately as likely pathogenic. Summary statistics, ORR, progression free survival (PFS), and overall survival (OS) were calculated. Results: 101 patients (44 Duke, 35 JHU, 22 UM) with LRP1B alterations were treated with ICI. Median age was 61 (range 32-82). The most common tumor types by alteration (pathogenic or likely pathogenic/VUS%) were lung (33/47%), GI (17/13%), prostate (11/7%), sarcoma (2/9%), melanoma (11/0%), and others (26/24%). 93% of patients received single-agent PD-(L)1 inhibition. The ORR for patients with either pathogenic/likely pathogenic alterations, or VUS alterations was 57% and 18%, respectively. After excluding MSI-high or TMB-high ( > 10 mut/Mb) tumors, ORR was 14/25 (56%) and 6/36 (17%), respectively. Pathogenic or likely pathogenic LRP1B alterations were associated with longer PFS (HR 0.39, 95% CI 0.24-0.63) and OS (HR 0.58, 95% CI 0.36-0.95). Conclusions: This multicenter study shows impressive and durable objective response rates to ICI for patients harboring pathogenic LRP1B alterations when compared to those with LRP1B VUS, independent of TMB/MSI status. Further mechanistic insights and prospective validation studies are warranted. [Table: see text]

scholarly journals Agnostic Evaluation of Ipilimumab and Nivolumab Association: A Metanalysis.

2020 ◽  
Author(s):  
Paolo Marchetti ◽  
Andrea Botticelli ◽  
Antonio Paolo Ascierto ◽  
Giuseppe Curigliano ◽  
Diana Giannarelli
Keyword(s):  
Meta Analysis ◽  
Single Agent ◽  
Objective Response ◽  
Progression Free Survival ◽  
Added Value ◽  
Combination Strategy ◽  
Free Survival ◽  
Multiple Tumor ◽  
Single Agent Therapy ◽  
Tumor Types

Abstract Background. Ipilimumab and Nivolumab, targeting the molecules CTLA-4, PD-1, respectively, have shown efficacy against several types of cancer. Despite these results, only a small percentage of patients maintain a long-lasting effect. Even Ipilimumab, in combination with nivolumab, has demonstrated a significant clinical benefit in multiple tumor types. However, no trial has been designed with the primary endpoint to compare the efficacy of nivolumab plus ipilimumab combined, compared to nivolumab alone. Hence, the added value of ipilimumab in the combination has not clearly been established yet. The aim of this study was to demonstrate the superiority of the combination strategy compared to single agent therapy.Materials and methods. We performed a meta-analysis of Phase I-II-III Clinical Trials, published from 2010 up to 2020, in which the combination of ipilimumab plus nivolumab was compared to nivolumab alone. We extracted ORR, OS and PFS HR on the basis of treatment from the subgroup analysis of each trial. Results. A total of 8 trials were included in the present meta-analysis. Overall, 1313 patients were treated with the nivolumab plus ipilimumab combination compared to 1110 patients treated with nivolumab alone. All trials reported the Objective response rate (ORR) (Table 2), no heterogeneity was found and the pooled Odds Ratio (Figure 1) was highly in favor of the nivolumab plus ipilimumab combination with respect to nivolumab alone (1.683; 95% CI: 1.407-2.012; P<0.0001). Three studies were considered for Progression free survival (PFS) analysis (Table 3), no heterogeneity was found and the pooled Hazard Ratio (Figure 2) favored the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.807; 95% CI: 0.719-0.907; P<0.0001). The Overall survival (OS) endpoint was considered only in 2 trials (Table 4), no heterogeneity was found and the pooled HR (Figure 3) favored, also in this case, the combination of nivolumab plus ipilimumab with respect to nivolumab alone (0.87; 95% CI: 0.763-0.997; P=0.045).Conclusions. The combination of ipilimumab plus nivolumab seems to be superior to nivolumab alone in cancer patients, regardless of histology.

CTNI-55. THE CDK4/6 INHIBITOR ABEMACICLIB IN PATIENTS WITH RECURRENT MENINGIOMA AND OTHER PRIMARY CNS TUMORS

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi72-vi73
Author(s):  
Elizabeth Coffee ◽  
Katherine Panageas ◽  
Robert Young ◽  
Tara Morrison ◽  
Ahmad Daher ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Single Agent ◽  
Pituitary Tumors ◽  
Molecular Characteristics ◽  
Multiple Cancer ◽  
Who Grade ◽  
Multiple Tumor ◽  
Primary Brain Tumors ◽  
Basket Trial ◽  
Tumor Types

Abstract BACKGROUND Medical therapies for recurrent brain tumors are limited. Abemaciclib is a small molecule CDK4/6 inhibitor that has demonstrated antitumor activity in multiple cancer types and crosses the blood-brain barrier. METHODS We conducted a phase II trial of single-agent abemaciclib in patients with recurrent primary brain tumors utilizing a novel CNS basket trial design with multiple tumor types accrued to separate cohorts including patients with recurrent IDH-wildtype gliomas (Cohort A), any recurrent gliomas requiring cytoreductive surgery (Cohort B), and any other recurrent primary brain tumors (Cohort C) including IDH-mutant gliomas, meningiomas, and other tumor types. In all patients, abemaciclib was administered orally at 200mg twice daily for each 28-day cycle. In cohort B abemaciclib was administered 4-7 days prior to surgery then resumed after recovery. Neuroimaging disease assessments were performed every two cycles. Cohorts were individually assessed for efficacy, tumoral molecular characteristics, and exploratory biomarker analyses. Next generation sequencing was performed on patients who had prior surgery. RESULTS To date, a total of 61 patients have enrolled and initiated treatment with abemaciclib. Cohort A enrolled 9 patients with IDH-wildtype WHO grade II and III astrocytomas. Cohort B enrolled 10 patients with astrocytomas of varying IDH-status. Cohort C is a diverse group of 42 patients including 22 treatment-refractory meningiomas, 10 IDH-mutant gliomas (5 astrocytomas, 5 oligodendrogliomas), 3 ependymomas, 3 primary CNS lymphomas, 2 pituitary tumors, 1 glioneuronal rosette forming tumor, and 1 diffuse midline glioma. A total of 7 grade 3 toxicities occurred in 6 patients: fatigue (3), neutropenia (2), colitis (1) and seizure (1); no grade 4 toxicities occurred. CONCLUSIONS We present the results of a novel CNS basket trial looking at the efficacy of abemaciclib across multiple recurrent primary brain tumors. Efficacy results will be presented, highlighting an update on promising results in the 22 patients with recurrent meningiomas.

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