scholarly journals Association of homogeneous inflamed gene signature with a better outcome in patients with metastatic melanoma treated with MAGE-A3 immunotherapeutic

ESMO Open ◽  
2018 ◽  
Vol 3 (5) ◽  
pp. e000384 ◽  
Author(s):  
Jean-François Baurain ◽  
Caroline Robert ◽  
Laurent Mortier ◽  
Bart Neyns ◽  
Florent Grange ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Metastatic Melanoma ◽  
Progression Free Survival ◽  
Gene Signature ◽  
Skin Lesions ◽  
Clinical Activity ◽  
Open Label ◽  
Link Type ◽  
Registration Number

PurposeThis study assessed clinical activity, safety and immunogenicity of MAGE-A3 immunotherapeutic in patients with MAGE-A3-positive metastatic melanoma.Patients and methodsIn this open-label, multicentre, uncontrolled, Phase II study (ClinicalTrials.gov NCT00896480),patients received ≤24 doses of MAGE-A3 immunotherapeutic (4-cycle schedule). At screening, two skin lesions were biopsied for MAGE-A3 expression analysis and presence/absence of a previously identified gene signature (GS) associated with favourable clinical outcome. Clinical activity was assessed in terms of clinical response, time-to-treatment failure (TTF) and progression-free survival (PFS). Adverse events (AEs) and serious AEs (SAEs) were recorded. MAGE-A3-specific immune responses were assessed. Clinical activity and immunogenicity were analysed overall and separately in patients with 2/2 (GS+/+), 1/2 (GS+/-) or 0/2 (GS-/-) biopsies presenting GS.ResultsOf 49 screened patients, 32 had MAGE-A3-positive tumours; 24 (8 GS+/+, 8 GS+/-, 8 GS-/-) were treated. Two complete (GS+/+ patients) and two partial responses (one GS+/+, one GS+/-) were reported; of note, one of the two complete responses was unlikely to be related to the study treatment. Median TTF and PFS were 14.8 and 7.2 months for GS+/+, 2.3 and 2.8 months for GS+/- and 2.4 and 2.9 months for GS-/- patients. Three grade 3 AEs and two SAEs unrelated to treatment were reported. All patients were seropositive for MAGE-A3 antibodies on vaccination with no differences between the different GS profiles. MAGE-A3-specific CD4+ and CD8+ T cell immunogenicity was detected; 12/16 (75.0%) of patients presented CD4+ T cell responses.ConclusionTreatment with MAGE-A3 immunotherapeutic showed signs of clinical activity in GS+/+ patients. Treatment was well tolerated and immunogenic. No differences in immune responses according to GS status were observed.Trial registration numberNCT00896480 (Results).

Bempegaldesleukin plus nivolumab in untreated, unresectable or metastatic melanoma: Phase III PIVOT IO 001 study design

2020 ◽  
Vol 16 (28) ◽  
pp. 2165-2175
Author(s):  
Nikhil I Khushalani ◽  
Adi Diab ◽  
Paolo A Ascierto ◽  
James Larkin ◽  
Shahneen Sandhu ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Objective Response ◽  
Progression Free Survival ◽  
Phase Iii ◽  
Clinical Activity ◽  
Open Label ◽  
Clinical Trial Registration ◽  
End Points ◽  
Free Survival ◽  
First Line Therapy

Nivolumab, a PD-1 inhibitor, has demonstrated prolonged survival benefit in patients with advanced melanoma. Bempegaldesleukin (BEMPEG; NKTR-214), a first-in-class CD122-preferential IL-2 pathway agonist, provides sustained signaling through the IL-2βγ receptor, which activates effector T and natural killer cells. In the Phase I/II PIVOT-02 trial, the combination of bempegaldesleukin plus nivolumab was well-tolerated and demonstrated clinical activity as first-line therapy in metastatic melanoma. Here, we describe the design of and rationale for the Phase III, global, randomized, open-label PIVOT IO 001 trial comparing bempegaldesleukin plus nivolumab with nivolumab alone in patients with previously untreated, unresectable or metastatic melanoma. Primary end points include objective response rate, progression-free survival and overall survival. Key secondary end points include further investigation of safety/tolerability, previously assessed in the PIVOT-02 trial. Clinical Trial Registration: NCT03635983 ( ClinicalTrials.gov )

scholarly journals 950 Final analysis: phase 1b study investigating intratumoral injection of toll-like receptor 9 agonist vidutolimod ± pembrolizumab in patients with PD-1 blockade–refractory melanoma

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A999-A999
Author(s):  
John Kirkwood ◽  
Yousef Zakharia ◽  
Diwakar Davar ◽  
Elizabeth Buchbinder ◽  
Theresa Medina ◽  
...  
Keyword(s):  
T Cell ◽  
San Francisco ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Clinical Activity ◽  
Phase 2 ◽  
Toll Like Receptor ◽  
Open Label ◽  
Link Type ◽  
Phase 1B

BackgroundThere are limited therapeutic options for patients with progressive disease (PD) on or after PD-1–blocking antibody therapy. Vidutolimod (CMP-001) is a first-in-class, immunostimulatory virus-like particle containing a CpG-A Toll-like receptor 9 (TLR9) agonist. This phase 1b study evaluated the safety and clinical activity of intratumoral vidutolimod with and without pembrolizumab in patients with refractory melanoma.MethodsThis two-part, open-label, multicenter, phase 1b study (NCT02680184) enrolled adults with histologically confirmed metastatic or unresectable cutaneous melanoma who had stable disease after ≥12 weeks or PD on anti−PD-1 treatment, measurable disease per RECIST v1.1, ECOG PS 0/1, and ≥1 lesion accessible for intratumoral injection. Part 1 evaluated vidutolimod + pembrolizumab and Part 2 evaluated vidutolimod monotherapy. Key objectives included assessment of safety and clinical activity, and exploratory analyses were performed on available tumor biopsies using immunohistochemistry and RNAseq.ResultsAt data cutoff (August 17, 2021), 159 patients had enrolled in Part 1 and 40 patients in Part 2. The median age was 64 years in Part 1 (range, 30-90) and 68 years in Part 2 (range, 30-89). Most patients had PD as their last response to prior anti–PD-1 therapy (Part 1, 93.1%; Part 2, 80.0%). Grade 3/4 treatment-related adverse events (TRAEs) occurred in 37.1% of patients treated with vidutolimod + pembrolizumab and in 22.5% of patients treated with vidutolimod monotherapy. No treatment-related deaths occurred. Based on the efficacy data presented in Table 1, vidutolimod polysorbate 20 (PS20) A was selected for further development as this formulation in combination with pembrolizumab had a best objective response rate (ORR; RECIST v1.1) of 23.5%, with a median duration of response (DOR) of 25.2 months. Vidutolimod monotherapy had an ORR of 20.0%, with a median DOR of 5.6 months. Exploratory translational analyses identified association of unique biomarkers with response among patients with T cell–inflamed versus non-T cell–inflamed tumors at baseline.Abstract 950 Table 1Safety and clinical activity of vidutolomod ± pembrolizumabConclusionsPromising clinical activity was observed with vidutolimod + pembrolizumab and vidutolimod monotherapy in patients with PD-1 blockade–refractory melanoma. A manageable safety profile was observed. The DOR with vidutolimod + pembrolizumab was substantially longer than with vidutolimod monotherapy. Clinical studies to confirm the efficacy of vidutolimod + PD-1 blockade in patients with previously untreated unresectable/metastatic melanoma (phase 2/3, NCT04695977) or PD-1 blockade–refractory melanoma (phase 2, NCT04698187) are ongoing.AcknowledgementsThis work was supported by Checkmate Pharmaceuticals. Medical writing assistance was provided by Steffen Biechele, PhD (ApotheCom, San Francisco, CA, USA), and funded by Checkmate Pharmaceuticals.Trial RegistrationNCT02680184Ethics ApprovalThis study was approved by the WCG-WIRB; WIRB approval tracking number: 20152597.

395 A first-in-human study of FS118, a tetravalent bispecific antibody targeting LAG-3 and PD-L1, in patients with advanced cancer and resistance to PD-(L)1 therapy

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A420-A420
Author(s):  
Timothy Yap ◽  
Deborah Wong ◽  
Siwen Hu-Lieskovan ◽  
Kyriakos Papadopoulos ◽  
Michelle Morrow ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Advanced Cancer ◽  
Bispecific Antibody ◽  
Acquired Resistance ◽  
Human Study ◽  
Clinical Activity ◽  
List Type ◽  
Link Type ◽  
Antibody Targeting

BackgroundUpregulation of immune checkpoints, such as LAG-3, plays an important role in promoting resistance to anti-PD-(L)1 therapy. Targeting PD-L1 and LAG-3 using a bispecific antibody may overcome resistance to PD-(L)1 blockade.1 We report initial data from a first-in-human study evaluating FS118 in patients with advanced cancer and resistance to PD-(L)1 therapy.MethodsThe ongoing Phase I FIH study (NCT03440437) is being conducted to evaluate safety, tolerability, immunogenicity, PK/PD and clinical activity of FS118 administered IV weekly to heavily pre-treated patients who had previously received anti-PD-(L)1 therapy for a minimum of 12 weeks. Adverse events were assessed using CTCAEv4.03 and tumor responses assessed using RECISTv1.1 and iRECIST. Single subject dose escalation cohorts were followed by a 3+3 ascending dose design. Three cohorts (3, 10, 20 mg/kg) were expanded to evaluate PK, PD and clinical activity. Pharmacodynamic studies examined soluble LAG-3 production and peripheral T-cell expansion.ResultsForty-three patients (median 6 lines of prior therapy, including ICB) with solid tumors received FS118 at doses from 0.8 mg up to 20 mg/kg across 8 dose levels. Weekly administration of FS118 was well tolerated and did not result in dose- or treatment-limiting toxicities. An MTD was not reached. No safety signals unexpected for the drug class of immune-checkpoint inhibitors were identified in the early study population. The majority (95%) of treatment-emergent adverse events (TEAE) considered by the Safety Review Committee (SRC) to be treatment-related were Grade 1 and 2. Grade 3 TEAEs toxicities (elevated liver enzymes) were observed in 2 patients (5%). No SAEs or deaths were attributed to FS118 treatment. Anti-drug antibodies, observed in half of patients, were typically transient in nature. The pharmacokinetic profile confirmed preclinical predictions and PD parameters included a dose-dependent increase in serum soluble LAG-3 and expansion of peripheral T cells. Long-lasting disease stabilisation (>6 months) was observed in a subset of patients with acquired resistance (defined as a CR, PR or SD ≥3 months on previous PD-(L)1 treatment), but not in patients with primary resistance. Two patients remain on FS118 treatment as of 2 Jul 2020 (duration 10 and 16 months). Retrospective IHC analysis of PD-L1 and LAG-3 co-expression in the tumor was assessed as a potential biomarker associated with clinical outcome.ConclusionsWeekly treatment with FS118 was well tolerated up to 20 mg/kg and was associated with pharmacodynamic markers of FS118 activity. Encouraging signs of clinical activity were observed in highly pre-treated patients who had acquired resistance to prior PD-(L)1 therapy.Trial RegistrationRegistered at www.clinicaltrials.gov, NCT03440437ReferenceKraman M, Faroudi M, Allen N, Kmiecik K, Gliddon D, Seal C, Koers A, Wydro M, Winnewisser J, Young L, Tuna M, Doody J, Morrow M, Brewis N. FS118, a bispecific antibody targeting LAG-3 and PD-L1, Enhances T-Cell activation resulting in potent antitumor activity. Clin Cancer Res 2020; 26:3333–3344.

Regomune: A phase II study of regorafenib + avelumab in solid tumors—Results of the biliary tract cancer (BTC) cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 4096-4096
Author(s):  
Sophie Cousin ◽  
Carine A. Bellera ◽  
Jean Philippe Guégan ◽  
Thibault Mazard ◽  
Carlos A. Gomez-Roca ◽  
...  
Keyword(s):  
Phase Ii ◽  
Adaptive Design ◽  
Objective Response ◽  
Locally Advanced ◽  
Survival Rates ◽  
Previous Treatment ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Clinical Activity ◽  
Open Label

4096 Background: Regorafenib (R) has shown promising efficacy in patients (pts) with BTC refractory to standard chemotherapy. Anti-PD1/PD-L1 antibodies have only limited clinical activity. Synergy between R and anti–PD-1/PD-L1 antibodies has been shown in pre-clinical solid tumor models. Methods: This is a single-arm open-label multicentric phase II trial (Bayesian adaptive design) assessing the efficacy and safety of R (160 mg QD 3weeks/4) + avelumab (A) (10 mg/kg every 2 weeks) combination in BTC pts. The primary endpoint was the objective response rate under treatment, based on central review according to RECIST 1.1. Secondary endpoints included: 1-year progression free survival (PFS), 1-year overall survival (OS), and Safety using NCI-CTCAE v5.0. Correlative studies were planned from pts tumor samples obtained at baseline. Results: Between Nov. 2018 and Nov. 2019, 34 BTC pts were enrolled in 4 centers. Median age was 63 (range 36 – 80). Median follow-up was 9.8 months. Median number of previous treatment lines for metastatic or locally advanced disease was: 2 (range 1 – 4). Twenty-nine (85.3%) pts experienced at least 1 dose modification or treatment interruption of R or A due to an adverse event (AE) related to the treatment. The most common grade 3/4 AEs were : Hypertension (17.6%), Fatigue (14.7%), and maculo-papular rash (11.8%). No death was related to the treatment. Among the 29 pts with at least one imaging tumor assessment, 4 (13.8%) achieved a partial response, and 11 (37.9%) demonstrated stable disease including 10 (34.5%) pts with tumor shrinkage. Fourteen pts (48.3%) had progressive disease. The median PFS and OS were 2.5 months (95%CI 1.9 – 5.5) and 11.9 months (95%CI 6.2 – NA) respectively. Baseline tumor samples were available for 27 pts. High IDO and PD-L1 expression at baseline was associated with better outcome. Conclusions: The R+A combination is associated with significant anti-tumor activity with promising survival rates in this heavily pre-treated population. Full Biomarkers analyses will be presented at the meeting. Clinical trial information: NCT03475953.

A phase 1b multicenter study of trifluridine/tipiracil (FTD/TPI) in combination with irinotecan (IRI) in patients (pts) with metastatic or unresectable gastric and gastroesophageal adenocarcinoma (mGEC) after at least one line of treatment with a fluoropyrimidine and platinum (FP) containing regimen.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e16006-e16006
Author(s):  
Farshid Dayyani ◽  
Kit Wah Tam ◽  
Edward Jae-Hoon Kim ◽  
Samuel Ejadi ◽  
Fa Chyi Lee ◽  
...  
Keyword(s):  
Primary Endpoint ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Open Label ◽  
Meaningful Improvement ◽  
Best Response ◽  
Previously Treated ◽  
Phase 1B

e16006 Background: FTD/TPI, an antimetabolite, is approved for treatment of refractory mGEC. This study sought to determine whether the combination of FTD/TPI with IRI (“TASIRI”) was safe and effective in mGEC previously treated with FP. Methods: This investigator‐initiated, multicenter, open‐label, single-dose level, single‐arm phase 1b study enrolled pts with mGEC previously treated with at least one line of FP containing regimen. FTD/TPI was given at 25 mg/m2 twice daily on days 1 to 5 with 180 mg/m2 IRI on day 1 of a 14‐day cycle. The primary endpoint was progression-free survival at six months (mo) (PFS-6). The aim was to show an improvement of PFS-6 from 15% to at least 30% based on historical controls. Results: At the time of data-cutoff (03Feb2021), 23 pts were screened and ultimately 20 pts were treated. The study met its primary endpoint. With a median follow-up of 9.8 mo (range 0.7 – 17), 8 pts are still on treatment and 4 pts have died. PFS-6 is 53.9% (lower limit of 95% CI: 28%). Median PFS and overall survival are 6.9 mo and not reached, respectively. At the time of data-cutoff, data were available for 13 pts with measurable disease by RECIST criteria and at least 1 on-treatment scan. Of those, 11 had stable disease and 2 had progressive disease as best response (5 pts had tumor shrinkage < 30%), therefore the disease control rate was 84.6%. The most common any grade (G) treatment related adverse events (TRAE) were nausea (n = 14, 70%), diarrhea (n = 9, 45%), and fatigue (n = 8, 40%). G3-4 TRAE in > 5% of pts were anemia (17%) and neutropenia (9%). 2 serious TRAE were reported: G4 febrile neutropenia (n = 1) and G3 hypotension (n = 1). There was no G5 TRAE. Conclusions: The combination of TASIRI showed encouraging clinical activity with a meaningful improvement in PFS-6 compared to historic controls. TASIRI was well tolerated and no new safety signals were seen. TASIRI warrants further investigation for patients with refractory mGEC and limited treatment options. Updated results with longer follow-up will be presented at the meeting. Clinical trial information: NCT04074343.

A prospective study of mifepristone and unlimited dosing of sublingual misoprostol for termination of second-trimester pregnancy in Uzbekistan and Ukraine

2019 ◽  
Vol 45 (3) ◽  
pp. 177-182
Author(s):  
Ingrida Platais ◽  
Tamar Tsereteli ◽  
Galyna Maystruk ◽  
Dilfuza Kurbanbekova ◽  
Beverly Winikoff
Keyword(s):  
Side Effects ◽  
Medical Abortion ◽  
Second Trimester ◽  
Open Label ◽  
Link Type ◽  
Sublingual Misoprostol ◽  
Registration Number ◽  
Second Trimester Pregnancy ◽  
A Prospective Study ◽  
At Home

IntroductionWe aimed to assess the feasibility and acceptability of a second-trimester medical abortion regimen using mifepristone and sublingual misoprostol with no maximum number of misoprostol doses in Uzbekistan and Ukraine.MethodsThis prospective open-label study enrolled 306 women with pregnancies of 13–22 weeks in Uzbekistan (n=134) and Ukraine (n=172). Women took 200 mg mifepristone at a place of their choosing, and 24–48 hours later received 400 μg sublingual misoprostol every 3 hours until the expulsion of both fetus and placenta. Study staff interviewed women about the intensity of pain, side effects, and satisfaction with the procedure. The primary outcome was the rate of complete uterine evacuation without surgical intervention or oxytocin at 15 hours after the first dose of misoprostol.ResultsThe median gestational age was 18.1 weeks, and half of the women (n=149, 48.9%) chose to take mifepristone at home. The majority of women (n=266, 86.9%, 95% CI 82.6% to 90.5%) expelled by 15 hours after the start of misoprostol treatment, and by 48 hours complete uterine evacuation was achieved in 296 (96.7%) women. Most women found pain (76.1%) and side effects (89.0%) to be acceptable or very acceptable, and reported high satisfaction (89.8%) with the procedure.ConclusionMedical abortion in pregnancies of 13–22 weeks with 200 mg mifepristone followed 24–48 hours later by 400 μg sublingual misoprostol administered every 3 hours until complete expulsion is effective, safe and acceptable to women. Women can be given the option to take mifepristone at home and return to the hospital.Clinical trials registration numberClinicalTrials.gov, www.clinicaltrials.gov, NCT02415894, NCT02235155.

scholarly journals Phase II trial of ribociclib and letrozole in patients with relapsed oestrogen receptor-positive ovarian or endometrial cancers

ESMO Open ◽  
2020 ◽  
Vol 5 (5) ◽  
pp. e000926
Author(s):  
Gerardo Colon-Otero ◽  
Valentina Zanfagnin ◽  
Xiaonan Hou ◽  
Nathan R Foster ◽  
Erik J Asmus ◽  
...  
Keyword(s):  
Phase Ii ◽  
Oestrogen Receptor ◽  
Progression Free Survival ◽  
Clinical Activity ◽  
Low Grade ◽  
Free Survival ◽  
Platinum Sensitive ◽  
Er Positive ◽  
Registration Number ◽  
Pdx Models

ObjectiveWe describe a phase II clinical trial of the combination of ribociclib and letrozole for treatment of relapsed oestrogen receptor (ER)-positive ovarian cancer (OC) and endometrial cancer (EC). The primary endpoint was the proportion of patients alive, progression-free survival (PFS), and still on treatment at 12 weeks (PFS12), with 45% or greater considered positive.MethodsPatients with measurable, relapsed ER-positive OC or EC (platinum-sensitive or resistant) were eligible and treated with 400 mg of oral ribociclib and 2.5 mg of oral letrozole daily. Patient-derived xenografts (PDXs) were created from imaging-guided tumour biopsies.ResultsForty patients (20 OC and 20 EC) were enrolled. A PFS12 of 55% was observed in the EC cohort and 50% in the OC cohort. A PFS greater or equal to 24 weeks (PFS24) was seen in 20% (4/20) of the OC cohort and 35% (7/20) of the EC cohort. The greatest benefit was seen in low-grade serous OC (LGSOC) (3/3, 100% PFS24) and grades 1 and 2 EC (5/11, 45% PFS24). All three LGSOC patients obtained at least a partial response lasting for over 2 years, with two of the three patients still on treatment. PDX tumour engraftment was feasible in 45% of patients. Positive survival effects of the combination of ribociclib and letrozole were observed in two of three EC PDX models.ConclusionRibociclib and letrozole have promising clinical activity in relapsed ER-positive OC and EC, particularly in LGSOC and relapsed ER-positive grade 1 and 2 EC. Generation of PDX models is feasible with positive survival effects observed in EC models.Trial registration numberClinicalTrials.gov registry (NCT02657928).

International multicenter phase II study of the HDAC inhibitor (HDACi) depsipeptide (FK228) in cutaneous T-cell lymphoma (CTCL): Interim report

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3063-3063 ◽  
Author(s):  
S. Whittaker ◽  
W. McCulloch ◽  
T. Robak ◽  
E. Baran
Keyword(s):  
T Cell ◽  
Clinical Activity ◽  
Open Label ◽  
Eligibility Criteria ◽  
Cell Counts ◽  
T Cell Lymphomas ◽  
The Uk ◽  
Ecog Ps

3063 Background: Depsipeptide, a unique bicyclic peptide histone deacetylase inhibitor (HDACi), has shown activity in a range of in vitro and in vivo tumor models and clinical activity in T-cell lymphomas and prostate cancer. This study seeks to confirm the CTCL activity previously reported by the NCI (Piekarz, et al., ASCO, 2004). Methods: Single-arm, open label study, in 25 centers in the UK, Germany, Poland and the US. Patients aged ≥18 years with biopsy-confirmed CTCL (centrally reviewed) who have failed at least one prior systemic treatment receive up to 6 cycles of depsipeptide as a 4-hour IV infusion on Days 1, 8 and 15 q 28 days. Eligibility criteria include: mycosis fungoides and Sézary syndrome plus variants, Stages IB - IVA, adequate organ function, ECOG PS ≤ 1. Patients with significant cardiovascular abnormalities are excluded in addition to those taking QTc-prolonging or CYP3A4-inhibiting drugs. The primary endpoint is overall reponse rate measured by a combination of imaging, circulating cell counts and a weighted skin average instrument, confirmed by standardized photography. A subset undergoes pharmacokinetic assessments. Correlative studies include acetylation status, apoptotic markers and proteomic analyses where possible. Target accrual is 76 to yield 64 evaluable patients. Results: 30 patients have received treatment with 17 evaluable for efficacy. Responses seen are 1 cCR, 4 PRs (duration 2+ to 6 months) 9 SD and 3 PD. 3 patients withdrew early for PD and 2 for other reasons. The remaining patients on study are too early to assess. Most frequent toxicities are: nausea/vomiting, fatigue, myelosuppression and asymptomatic ECG changes. No patient has withdrawn for toxicity and there have been no treatment-related deaths. Conclusions: The previously reported efficacy of depsipeptide in CTCL has also been seen in the present study. Duration of response is encouraging. Toxicity is manageable and the study continues to accrue. [Table: see text]

Randomized phase II study of the safety and efficacy of a human anti-αv integrin monoclonal antibody (CNTO 95) alone and in combination with dacarbazine in patients with stage IV metastatic melanoma: 12-month results

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9029-9029
Author(s):  
C. Loquai ◽  
A. Pavlick ◽  
D. Lawson ◽  
R. Gutzmer ◽  
J. Richards ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Research And Development ◽  
Metastatic Melanoma ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Complete Response ◽  
Open Label ◽  
Safety And Efficacy ◽  
To Receive

9029 Objectives: Evaluate the safety and efficacy of CNTO 95, a human anti-αv integrin monoclonal antibody, when administered alone or in combination with dacarbazine (DTIC). Methods: Patients with Stage IV metastatic melanoma were randomized 1:1:1:1 to receive 5 or 10mg/kg CNTO 95 alone, or DTIC (1000mg/m2) + either 10mg/kg CNTO 95 or placebo administered intravenously once every 3 weeks for 8 cycles in the absence of disease progression or unacceptable toxicity. DTIC arms were blinded; single-agent arms were open-label. The primary endpoint was progression free survival (PFS); secondary endpoints included partial response (PR), complete response (CR), stable disease (SD) and overall survival (OS). Major safety endpoints included the incidence of adverse events (AEs) and serious AEs (SAEs). Results: Patients were randomized to receive 5mg/kg CNTO 95 (n=32), 10mg/kg CNTO 95 (n=33), CNTO 95+DTIC (n=32), or placebo+DTIC (n=32). Baseline demographics were similar across groups. The median PFS for CNTO 95+DTIC was 75 days, placebo+DTIC was 54 days and both CNTO 95 alone arms were 42 days. Six patients achieved PR (2–10mg/kg CNTO 95, 1-CNTO 95+DTIC, 3-placebo+DTIC); one patient achieved CR (CNTO 95+DTIC). A higher proportion (43.3%) of patients achieved SD ≥ 12 wks in the CNTO 95+DTIC group compared with the other 3 groups (<20.0%). The median survival was 11.0 months for the patients in the CNTO 95+DTIC arm, 9.8 months and 14.9 months for the 5mg/kg and 10mg/kg arms, and 8.0 months for those in the DTIC control arm. The most common AEs were headache, nausea, fatigue, pyrexia, vomiting and transient uveitic reactions. Three patients (1–5mg/kg, 2-CNTO 95+DTIC) discontinued treatment due to AEs. A higher proportion of patients experienced SAEs in the placebo+DTIC group (29.0%) than in the 5mg/kg (12.9%), 10mg/kg (16.2%) or CNTO 95+DTIC (18.8%) groups. Conclusions: CNTO 95 alone or combined with DTIC was generally well tolerated. In patients with Stage IV metastatic melanoma, a trend toward improvement in PFS, OS and disease control was demonstrated with CNTO 95+DTIC. Centocor, Centocor Research and Development, Inc. Centocor Research and Development, Inc. Johnson & Johnson Centocor Research and Development, Inc. No significant financial relationships to disclose.

Activity of cabozantinib (XL184) in metastatic melanoma: Results from a phase II randomized discontinuation trial (RDT).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 8531-8531 ◽  
Author(s):  
Michael S. Gordon ◽  
Harriet M. Kluger ◽  
Geoffrey Shapiro ◽  
Razelle Kurzrock ◽  
Gerald Edelman ◽  
...  
Keyword(s):  
Metastatic Melanoma ◽  
Braf Mutation ◽  
Tumor Regression ◽  
Progression Free Survival ◽  
Bone Lesions ◽  
Open Label ◽  
Grade 5 ◽  
Common Grade ◽  
Grade 3 ◽  
Tumor Types

8531 Background: MET and VEGF signaling are implicated in angiogenesis, invasion, and metastasis. Cabozantinib (cabo) is an oral, potent inhibitor of MET and VEGFR2. A RDT evaluated activity and safety in 9 tumor types. Here we report on the metastatic melanoma cohort, including the ocular subtype. Methods: Eligible patients (pts) were required to have progressive measurable disease per RECIST. Pts received cabo at 100 mg qd over a 12 wk Lead-in stage. Tumor response (mRECIST) was assessed q6 wks. Treatment ≥ wk 12 was based on response: pts with PR continued open-label cabo, pts with SD were randomized to cabo vs placebo, and pts with PD discontinued. Primary endpoint in the randomized phase was progression free survival (PFS). Results: Enrollment to this cohort is complete (n = 77); all pts are unblinded. Baseline characteristics: median age 66 years; melanoma subtype: cutaneous/mucosal 70% and ocular 30%; known BRAF mutation 32%; LDH ≥ 1.1 x upper limit normal 35%; bone metastases 19%; median prior lines of therapy 1 (range 0-5). Median follow-up was 2.8 months (range 0.3 - 25). 35 pts (45%) completed the open-label Lead-in stage with 25 pts randomized to continue cabo (n=12) or to placebo (n=13). Median PFS from randomization was 5.7 months for cabo vs. 3 months for placebo (HR=0.3, p =0.055). Median PFS from Study Day 1 was 4.4 months. The estimate of PFS at month 6 (PFS6) is 44%. Evidence of objective tumor regression was observed in 39/65 pts (60%) with ≥ 1 post-baseline tumor assessment including 11/23 pts (48%) with ocular melanoma. Two bone scan evaluable pts demonstrated partial resolution of bone lesions at wk 6 accompanied by pain relief. Most common Grade 3/4 AEs were fatigue (14%), HTN (9%), constipation (4%), and diarrhea (3%); one related Grade 5 AE of diverticular perforation and peritonitis reported during Lead-in stage. Conclusions: Cabo demonstrates activity in metastatic melanoma pts, regardless of subtypes or BRAF mutation status, with improvement in PFS relative to placebo, and high rates of PFS6 and objective tumor regression. The safety profile of cabo was comparable to that of other VEGFR TKIs.

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