Phase II trial of atezolizumab plus chemotherapy after progression on single-agent PD-1 or PD-L1 inhibitor in cisplatin ineligible patients with advanced urothelial carcinoma HCRN GU17-295.

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS587-TPS587
Author(s):  
Nabil Adra ◽  
Ralph J. Hauke ◽  
Hristos Z. Kaimakliotis ◽  
Shuchi Gulati ◽  
Neda Hashemi ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Clinical Benefit ◽  
Treatment Options ◽  
Single Agent ◽  
Progression Free Survival ◽  
Primary Objective ◽  
First Line ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Line Setting

TPS587 Background: Patients (pts) with cisplatin ineligible metastatic urothelial carcinoma (mUC) who progress after first-line PD1/PDL1 inhibition have limited treatment options. The concept of maintenance therapy with targeted agents and adding onto it at time of progression is a proven effective strategy. Preclinical data indicate that carboplatin+gemcitabine have immunomodulatory effect to potentially augment immune response. We hypothesize that in pts with cisplatin ineligible mUC, the use of atezolizumab+chemotherapy after progression on single-agent PD1/PDL1 inhibitor will result in clinical benefit. Methods: Multi-center, single arm, open label phase 2 trial of atezolizumab+carboplatin+gemcitabine in pts with cisplatin ineligible mUC. Eligible pts are adults with mUC (mixed histology allowed) who progressed after first line PD1/PDL1 inhibitor. Pts should be cisplatin ineligible based on consensus criteria. Neoadjuvant/adjuvant chemotherapy completed ≥12 months prior to enrollment is allowed. Treatment with atezolizumab will continue until disease progression or unacceptable toxicity while carboplatin+gemcitabine can be stopped after 4-6 cycles. Primary objective is progression-free survival per RECIST and secondary objectives are overall response rate, clinical benefit rate, and overall survival (OS). Exploratory endpoints include to compare OS of atezolizumab+carboplatin+gemcitabine in this trial compared to a virtual control arm of carboplatin+gemcitabine in mUC after progression on first-line PD1/PDL1 inhibitors. Other exploratory endpoints include to compare PD-L1 status at time of diagnosis and at time of enrollment (after progression on PD1/PDL1 inhibitor). Using an alternate hypothesis that atezolizumab+carboplatin+gemcitabine will have a median PFS of 9 months compared to historical control of 5 months with a platinum regimen in 2nd line setting, we plan to enroll 33 patients. This study is currently enrolling pts. A protocol amendment is under way that will allow pts with prior platinum-based chemotherapy to enroll on this trial. Clinical trial information: NCT03737123.

The prognostic impact of bone metastasis in urothelial carcinoma treated with first-line platinum-based chemotherapy.

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. 415-415
Author(s):  
Husam Alqaisi ◽  
Zachary William Neil Veitch ◽  
Carlos Stecca ◽  
Jeenan Kaiser ◽  
Scott A. North ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Performance Status ◽  
Progression Free Survival ◽  
Response To Treatment ◽  
Prognostic Impact ◽  
First Line ◽  
Ecog Performance Status ◽  
Cancer Centre ◽  
Platinum Based Chemotherapy ◽  
Line Setting

415 Background: Metastatic urothelial carcinoma (mUC) is an aggressive disease with a median overall survival (OS) of ≈ 15 months. In the first-line setting, key prognostic factors include ECOG performance status, white blood cell count, and response to treatment per the Galsky nomogram. Bone metastases (BM) in mUC are associated with morbidity and mortality but are grouped with visceral disease; hence, their impact on prognosis is not well established. We aimed to assess the survival impact of BM in mUC patients treated with first-line platinum-based chemotherapy (PBC). Methods: A retrospective collection of patient and tumor characteristics, with clinical response to treatment (complete response [CR], partial response [PR]; stable disease [SD] or progressive disease [PD]) for patients treated at Princess Margaret Cancer Centre, Tom Baker Cancer Centre, and Cross Cancer Institute from 2005-2018 was performed. Progression-free survival (PFS) and OS were estimated using the Kaplan-Meier method. Univariate (UVA) followed by multivariate analysis (MVA) of patient variables [Cox] using PFS and OS was performed. Results: Overall 376 mUC patients were included; 222 (59%) had soft-tissue metastases (STM) only, 70 (19%) had bone-only metastases, and 84 (22%) had both STM and BM. Overall, 35% had PR or CR, 19% had SD, and 39% had PD (7%: unknown response). The median PFS and OS for the whole cohort were 5.6 months (95%CI: 4.8-6.4) and 9.7 months (95% CI: 8.8-10.8) respectively. Select UVA by metastatic site showed inferior PFS for bone-only (p=0.03) and combination STM and BM (p=0.017). Only combination STM and BM were significant on UVA for OS (p=0.002). MVA showed that bone-only metastases (p=0.03) and ECOG 3-4 (p<0.0001) were associated with worse PFS (Table). Predictors of worse OS were the combination of STM and BM (p=0.02), ECOG 3-4 (p=0.001), and WBCs ≥ULN (p=0.02), (Table). Conclusions: BM are a significant predictor of worse outcomes for mUC patients treated with first-line PBC. Consideration as a treatment stratification factor for future studies is suggested. Strategies for the treatment of mUC patients with BM (ie: bone targeted agents) in the first-line setting should be addressed in future trials. [Table: see text]

Results of a Nonrandomized, Open-Label, Phase II Study of Combined Gemcitabine, Mitoxantrone, and Rituximab in Relapsed or Refractory Mantle Cell Lymphoma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4452-4452
Author(s):  
Lawrence E. Garbo ◽  
Patrick J. Flynn ◽  
Margaret A. MacRae ◽  
Mary A. Rauch ◽  
Yunfei Wang ◽  
...  
Keyword(s):  
Mantle Cell Lymphoma ◽  
Cell Lymphoma ◽  
Treatment Options ◽  
Single Agent ◽  
Stage Iv ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Open Label ◽  
Mantle Cell ◽  
Grade 3

Abstract Mantle cell lymphoma (MCL) is an aggressive type of B-cell non-Hodgkin’s lymphoma that usually presents as disseminated disease. Prognosis is poor, and responses to chemotherapy are less durable than those achieved in other types of lymphoma. New treatment options are desperately needed. Gemcitabine has shown activity in MCL as a single agent. In addition, the combination of mitoxantrone and rituximab has also been shown to be active in MCL. However, the use of these drugs in combination has not been evaluated in the treatment of MCL. The primary objective of this study was to determine the efficacy of gemcitabine+mitoxantrone+rituximab in relapsed or refractory MCL; secondary objectives were duration of response, survival at 1-year, progression-free survival (PFS), and toxicity, especially myelotoxicity. Sixteen patients were enrolled between April 2005 and December 2006, and only 15 were evaluable due to one patient’s withdrawal of consent. Patients received gemcitabine 900 mg/m2 IV (30–60 min infusion), mitoxantrone 10 mg/m2 IV (5–10 min infusion), and rituximab 375 mg/m2 IV on Day 1 (max 400 mg/hr). Patients also received gemcitabine 900 mg/m2 on Day 8 of the 21-day cycle. Medication was administered in the following order: gemcitabine→mitoxantrone→rituximab. Patients were to be treated for a maximum of 8 cycles or until the patient had evidence of a response, progressive disease, or intolerable toxicity. The median patient age was 74 years, 100% were white, and 69% were male. Of all patients, 86% had Stage IV MCL at baseline. Patients received a median of 6 cycles (range, 3 – 8). Efficacy results for the evaluable population are CR 13%, PR 27%, PD 13%, and SD 47%. Median PFS was 8.72 months (range, 1.84 – 23.49); median overall survival was 10.03 months (range, 2.50 – 23.49). Grade 3–4 treatment related toxicities reported in >1 patient were neutropenia (93%), leukopenia or thrombocytopenia (53% each), anemia (20%), and asthenia (13%). 60% of patients are currently alive as of July 2007; 9 patients discontinued study treatment due to disease progression (13%), toxicity (27%), MD request (7%), or withdrawal of consent (13%). 7 patients had normal study completion (44%). The study was closed early due to slow accrual owing to alternative treatment which became available at the time. The combination of gemcitabine, mitoxantrone, and rituximab in MCL was well-tolerated with manageable adverse events in spite of 93% neutropenia. Supplemented growth factor use was able to minimize neutropenia. No Grade 3–4 infection was reported. This regimen holds promise in patients with MCL and further studies are warranted. Updated data will be presented.

Final results of a multicenter, open-label phase II trial of dovitinib (TKI258) in patients with advanced urothelial carcinoma with either mutated or nonmutated FGFR3.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 255-255 ◽  
Author(s):  
Matthew I. Milowsky ◽  
Christian Dittrich ◽  
Ignacio Duran Martinez ◽  
Satinder Jagdev ◽  
Frederick E. Millard ◽  
...  
Keyword(s):  
Urothelial Carcinoma ◽  
Single Agent ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Response Threshold ◽  
Open Label ◽  
Mutation Status ◽  
Mutational Activation ◽  
Stage 1

255 Background: Increased signaling through mutational activation of fibroblast growth factor receptor 3 (FGFR3) contributes to tumor development and vascularization of urothelial carcinoma (UC). Dovitinib (TKI258), an oral investigational inhibitor of angiogenic factors including FGFR3, has demonstrated inhibition of tumor growth and proliferation in preclinical UC models with FGFR3-activating mutations or protein overexpression. Methods: Advanced UC patients (pts) with 1-3 prior regimens received dovitinib 500 mg/day on a 5-days-on/2-days-off schedule. Pts were stratified into 2 groups based on presence (mut) or absence (non-mut) of FGFR3 gene mutation in archival tissue (initially analyzed by SNaPshot; later by Sanger sequencing for screening and confirmation). The primary objective was overall response rate (ORR) in each group using a Simon’s 2-stage design (20 pts planned for stage 1 and 20 for stage 2 if ≥ 2 responses seen in stage 1). Results: A total of 44 pts (median age, 67 years) were treated in stage 1: 12 FGFR3 mut, 31 FGFR3 non-mut, and 1 unknown mutation status. Over-recruitment of non-mut pts was due to rapid enrollment of non-mut pts with invasive bladder tumors and some tumors initially classified as mut by SNaPshot but reclassified as non-mut after sequencing. Most pts (77%) had metastases in ≥ 2 organs. ORR (local review) was 0% in the FGFR3 mut group and 3% in the FGFR3 non-mut group (1 partial response). Median progression-free survival was 3 months in the FGFR3 mut group and 1.8 months in the FGFR3 non-mut group. There were insufficient non-mut responders to proceed to stage 2. Since most pts in the mut group did not receive > 6 months of treatment and meeting the response threshold to proceed to stage 2 was highly unlikely, the study was terminated. Common adverse events were diarrhea (73%), nausea (61%), and asthenia (50%) and were similar in both groups. Conclusions: Although there were difficulties in evaluating mutation status, dovitinib had limited single-agent activity in pts with advanced bladder cancer regardless of FGFR3 mutation status. Further studies are needed to understand the role of FGFR3 inhibition in advanced UC treatment. Clinical trial information: NCT00790426.

A phase 2 study of BGJ398 in patients (pts) with advanced or metastatic FGFR-altered cholangiocarcinoma (CCA) who failed or are intolerant to platinum-based chemotherapy.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 335-335 ◽  
Author(s):  
Milind M. Javle ◽  
Rachna T. Shroff ◽  
Andrew Zhu ◽  
Saeed Sadeghi ◽  
SuPin Choo ◽  
...  
Keyword(s):  
Phase 1 ◽  
Treatment Options ◽  
Growth Factor Receptor ◽  
Progression Free Survival ◽  
Genetic Alterations ◽  
Phase 2 ◽  
Open Label ◽  
Overall Response ◽  
Platinum Based Chemotherapy ◽  
Metastatic Setting

335 Background: CCA is a hepatobiliary malignancy with poor prognosis and few treatment options following cytotoxic therapy in the first-line metastatic setting. The fibroblast growth factor receptor (FGFR) axis may promote CCA tumorigenesis. FGFR2 fusions (in up to 17% of intrahepatic CCAs) may predict FGFR inhibitor sensitivity. A prior phase 1 trial of the selective pan-FGFR inhibitor BGJ398 showed antitumor activity in a pt with CCA harboring an FGFR2 fusion. Methods: This ongoing phase 2, open-label study is evaluating oral BGJ398 125 mg once daily on a 3-week-on/1-week-off schedule (28-day cycle) in pts with advanced or metastatic CCA with FGFR2 fusions (n ≈ 40) or other FGFR genetic alterations (n ≤ 15) who progressed after cisplatin/gemcitabine or are cisplatin intolerant (NCT02150967). The primary endpoint is investigator-assessed overall response rate (ORR) per RECIST v1.1. Secondary endpoints include progression-free survival, best overall response (BOR), disease control rate (DCR), overall survival, safety, and pharmacokinetics. Results: As of 10 July 2015, 26 pts with CCA harboring FGFR2 fusions (n = 22) or other FGFR alterations (n = 4), pretreated with 1 to ≥ 4 prior regimens, were enrolled. Common adverse events (AEs; ≥ 20% of pts), were hyperphosphatemia (50%), fatigue (42%), constipation (38%), cough (23%), and nausea (23%). Grade 3/4 AEs occurring in ≥ 2 pts were hyper/hypophosphatemia, lipase increase, and hyponatremia. AEs were manageable, reversible, and rarely led to treatment discontinuation. Among 22 pts evaluable for BOR, 3 achieved partial response and 15 had stable disease, including 10 with tumor reductions (-41%, n = 1; -2% to -29%, n = 9). Overall DCR was 82%. As of the cutoff date, 18 pts remained on therapy, of which 13 were on for > 120 days. Kaplan-Meier estimated lower limit (95% CI) of median time on study was 143 days. Conclusions: BGJ398 shows impressive anti-tumor activity and a manageable safety profile in pts with advanced FGFR-altered CCA, an indication of high unmet medical need. Updated data including additional responses post data cutoff will be presented. Clinical trial information: NCT02150967.

Effect of JAK2 SNP rs2274472 on outcome for mCRC patients treated with first-line FOLFIRI and bevacizumab: Data from FIRE-3 trial.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. 595-595
Author(s):  
Martin D. Berger ◽  
Sebastian Stintzing ◽  
Volker Heinemann ◽  
Dongyun Yang ◽  
Shu Cao ◽  
...  
Keyword(s):  
Direct Sequencing ◽  
Treatment Options ◽  
Progression Free Survival ◽  
Predictive Marker ◽  
Negative Control ◽  
Janus Kinase ◽  
Phase Iii ◽  
First Line ◽  
Angiogenic Therapy ◽  
Line Setting

595 Background: The Jak2 (Janus kinase 2) / Stat5a (signal transduction and activators of transcription 5a) pathway plays a key role in regulating cell survival, proliferation and immune function. JAK2 is a non-receptor tyrosine kinase which is stimulated by a variety of cytokines. Moreover the JAK2 / STAT5 axis is activated by hypoxia and involved in regulating angiogenesis. We therefore hypothesize that variations in the JAK2 gene may predict outcome in patients with metastatic colorectal cancer (mCRC) treated with first-line FOLFIRI and bevacizumab (bev). Methods: Theimpact of 2 functional SNPs within the JAK2 and STAT5a genes on outcome was evaluated in 295 pts with mCRC treated with first-line FOLFIRI / bev in the randomized phase III FIRE-3 trial. 227 pts receiving FOLFIRI and cetuximab (FIRE-3) served as a negative control. Genomic DNA was extracted from formalin fixed paraffin embedded tissue and the SNPs were analyzed by PCR-based direct sequencing. Results: Baseline characteristics in the FOLFIRI / bev arm were as follows: female:male ratio = 1/3:2/3; median age = 65y (31-76) andmedian PFS/OS = 10.1/24.2 months. The JAK2 rs2274472 SNP showed significant association with progression-free survival (PFS). C allele carriers had a shorter median PFS compared to those with a T/T genotype (9.9 vs 11.7 months) in both univariate (HR 1.30, 95% CI 1.00-1.69, p = 0.045) and multivariate analysis (HR 1.39, 95% CI 1.06-1.83, p = 0.018). However, this association could not be observed in patients treated with FOLFIRI and cetuximab. Here, patients harboring any C allele and T/T genotype carriers showed an equal median PFS (10.0 vs 9.9 months, HR 1.00, 95% CI 0.75-1.33, p = 1.00). Conclusions: Our results provide the first evidence that the JAK2 polymorphism rs2274472 might serve as a predictive marker in pts with mCRC treated with FOLFIRI and bev in the first line setting. Targeting the JAK2 / STAT5A axis might be a promising approach to further enlarge our treatment options against mCRC and to overcome resistance to anti-angiogenic therapy.

scholarly journals Randomized Phase II Study Investigating Pazopanib Versus Weekly Paclitaxel in Relapsed or Progressive Urothelial Cancer

2017 ◽  
Vol 35 (16) ◽  
pp. 1770-1777 ◽  
Author(s):  
Robert J. Jones ◽  
Syed A. Hussain ◽  
Andrew S. Protheroe ◽  
Alison Birtle ◽  
Prabir Chakraborti ◽  
...  
Keyword(s):  
Phase Ii ◽  
Data Monitoring Committee ◽  
Progression Free Survival ◽  
Final Analysis ◽  
Second Line ◽  
Open Label ◽  
Platinum Based Chemotherapy ◽  
Data Extract ◽  
Open Label Phase ◽  
Line Setting

Purpose Two previous single-arm trials have drawn conflicting conclusions regarding the activity of pazopanib in urothelial cancers after failure of platinum-based chemotherapy. Patients and Methods This randomized (1:1) open-label phase II trial compared the efficacy of pazopanib 800 mg orally with paclitaxel (80 mg/m2 days 1, 8, and 15 every 28 days) in the second-line setting. The primary end point was overall survival (OS). Results Between August 2012 and October 2014, 131 patients, out of 140 planned, were randomly assigned. The study was terminated early on the recommendation of the independent data monitoring committee because of futility. Final analysis after the preplanned number of deaths (n = 110) occurred after a median follow-up of 18 months. One hundred fifteen deaths had occurred at the final data extract presented here. Median OS was 8.0 months for paclitaxel (80% CI, 6.9 to 9.7 months) and 4.7 months for pazopanib (80% CI, 4.2 to 6.4 months). The hazard ratio (HR) adjusted for baseline stratification factors was 1.28 (80% CI, 0.99 to 1.67; one-sided P = .89). Median progression-free survival was 4.1 months for paclitaxel (80% CI, 3.0 to 5.6 months) and 3.1 months for pazopanib (80% CI, 2.7 to 4.6 months; HR, 1.09; 80% CI, 0.85 to 1.40; one-sided P = .67). Discontinuations for toxicity occurred in 7.8% and 23.1% for paclitaxel and pazopanib, respectively. Conclusion Pazopanib did not have greater efficacy than paclitaxel in the second-line treatment of urothelial cancers. There was a trend toward superior OS for paclitaxel.

An open-label study of sunitinib (SU) plus exemestane (E) in the first-line treatment of hormone receptor (HR)-positive metastatic breast cancer (MBC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. e12019-e12019 ◽  
Author(s):  
P. Ahlgren ◽  
M. Thirlwell ◽  
R. O’Regan ◽  
C. Mormont ◽  
L. Levesque ◽  
...  
Keyword(s):  
Kinase Inhibitor ◽  
Single Agent ◽  
Systemic Exposure ◽  
Metastatic Breast ◽  
Progression Free Survival ◽  
Dose Finding ◽  
Synergistic Activity ◽  
First Line ◽  
Open Label ◽  
Metastatic Setting

e12019 Background: SU, an oral multitargeted tyrosine kinase inhibitor of VEGFRs, PDGFRs, KIT, FLT3, CSF-1R and RET has activity in heavily pretreated pts with MBC. The aromatase inhibitor (AI), E, has proven 1st-line activity that compares favorably with tamoxifen in pts with HR+ BC in the adjuvant setting (Jones et al. 2008). Combining agents that target different signaling pathways may have additive/synergistic activity; combining the AI letrozole with the anti-VEGF agent bevacizumab prolonged progression-free survival to >14 mos as 1st-line therapy for HR+ MBC (Dickler et al. 2008). An open-label, phase I, dose-finding study of first-line SU + E was conducted in HR+ MBC pts. Methods: Eligible pts (postmenopausal; female; ≥18 yrs) had an ECOG PS ≤1, LVEF ≥50% and locally recurrent (unresectable) or MBC. Exclusion criteria included HER2+ BC (unless pt had progressed after trastuzumab) and prior treatment in the metastatic setting. Pts received SU 37.5 mg/d + E 25 mg/d on a continuous daily dosing regimen; if dose-limiting toxicities (DLTs) were experienced by >1/6 pts in the first 8 wks then further pts would be enrolled at SU 25 mg/d + E 25 mg/d. Pharmacokinetic (PK) analyses were performed for each drug and the active SU metabolite SU12662. Results: As of December 2008, enrollment was completed (N=6; mean age 59 ± 11 yrs; 50% of pts had ≥3 metastatic sites). No DLTs were observed and no dose reductions were required throughout the treatment period. An overview of key data is shown below. One death occurred on study (non treatment-related Enterobacter sepsis). No treatment-related G4/5 AEs occurred. PK parameter values determined for SU and E suggested increases in the systemic exposure of both drugs when administered concurrently. Conclusions: These data indicate that SU + E was tolerable with manageable toxicities, with increases in PK parameters and a similar AE profile to that of either single agent alone. This combination should be considered in future clinical trials. [Table: see text] [Table: see text]

Overall survival (OS) of sorafenib (So) plus interleukin-2 (IL-2) versus So alone in patients with treatment-naive metastatic renal cell carcinoma (mRCC): Final update of the ROSORC trial.

2013 ◽  
Vol 31 (6_suppl) ◽  
pp. 356-356
Author(s):  
Giuseppe Procopio ◽  
Elena Verzoni ◽  
Sergio Bracarda ◽  
Sergio Ricci ◽  
Laura Ridolfi ◽  
...  
Keyword(s):  
Overall Survival ◽  
Phase Ii ◽  
Single Agent ◽  
Interleukin 2 ◽  
Progression Free Survival ◽  
Rank Test ◽  
Combination Regimen ◽  
First Line ◽  
Open Label ◽  
Treatment Naïve

356 Background: A randomized phase II trial evaluating So plus IL-2 versus So alone as first-line treatment of mRCC, did not show any difference in progression-free survival (PFS) (primary endpoint) between the two groups. The final overall survival analysis is here reported. Methods: In this open-label phase II study, 128 patients with mRCC were randomized to receive either oral So 400 mg bid continuous dosing plus IL-2 4.5 MIU subcutaneously administered 5 times weekly for 6 weeks every 8 weeks (Arm A), or So alone (Arm B). At relapse, most patients of the two arms underwent treatment with other targeted therapies (TTs) including sunitinib, everolimus, and axitinib. Overall survival was estimated by Kaplan-Meier method and compared by two-sided log-rank test. Results: According to Motzer criteria 55 % of the patients were low risk in both arms, and 41% and 39% were intermediate risk in Arm A and B respectively. After a median follow-up time of 58 months (interquartile range: 28-63 months), the median OS was 38 and 33 months in Arm A and B, respectively (p = 0.667). Five-year OS was 26.3% (95% CI: 15.9-43.5) for the combination arm and 23.1% (95% CI: 13.2-40.5) for single agent arm. The overall number of death was 85, 42 of whom in the So monotherapy group. Median PFS survival was 7.3 and 6.9 months for Arm A and B, respectively (p = 0.109). Overall, 49 (77%) and 48 (75%) patients in Arm A and B, respectively, received at least one subsequent targeted therapy (TTs). The most common adverse events (AEs) in both arms were asthenia, hand-foot syndrome, hypertension and diarrhoea. Grade 3-4 AEs were documented in 38% of patients treated with the combination regimen and in 25% of those undergoing single agent treatment. Conclusions: The OS results suggest an improved outcome in patients with mRCC treated with TTs which appears independent of the treatment initially administered. This prospective study, regarding use of sorafenib in first line of treatment, was associated with a surprising median OS. Clinical trial information: NCT00609401.

CARSKIN: Pembrolizumab as first line therapy in patients with unresectable cutaneous squamous cell carcinoma (cSCC).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. TPS9596-TPS9596 ◽  
Author(s):  
Eve Maubec ◽  
Sabine Helfen ◽  
Isabelle Scheer-Senyarich ◽  
Marouane Boubaya ◽  
Olivier Schischmanoff ◽  
...  
Keyword(s):  
Disease Progression ◽  
Treatment Options ◽  
Locally Advanced ◽  
Immune Surveillance ◽  
Death Receptor ◽  
Progression Free Survival ◽  
The Elderly ◽  
Primary Objective ◽  
Open Label ◽  
Recist 1.1

TPS9596 Background: Treatment options are limited for patients (pts) with locally advanced or metastatic cSCCs. Cisplatin-based combinations have some efficacy but their toxicity often prohibits their use, particularly for the elderly. New therapeutic options are needed. Tumors divert the programmed death receptor 1 (PD-1) pathway suppressing immune control. Pembrolizumab (MK-3475) is a high-affinity humanized monoclonal anti-PD-1 antibody. It leads to dual PD-1 ligand (PD-L1 and PD-L2) blockade that may reactivate the immune surveillance and elicit anti-tumor response. It has antitumor activity in several tumors including head and neck SCCs. Moreover, an efficacy of pembrolizumab in cSCCs has been reported recently in a series of 6 cases. Methods: CARSKIN (ClinicalTrials.gov, NCT02883556) is a French multicenter, open-label, nonrandomized phase 2 trial, designed to evaluate the efficacy and safety of pembrolizumab in 39 pts with unresectable and/or metastatic cSCCs, naive of chemotherapy and of EGFR inhibitors. Pembrolizumab is administered (200 mg IV Q3W) for up to 24 months or until disease progression or unacceptable toxicity. Eligible pts must undergo a baseline biopsy of the tumor prior to treatment for PD-L1 evaluation. Response is to be assessed at baseline, wk 9, 15 and 24, and thereafter Q12W by central radiology review per RECIST 1.1 and per modified RECIST v1.1. The primary objective is response rate (RR) at wk 15 per RECIST 1.1. Secondary efficacy objectives are to assess whether patients with PD-L1+ tumors have a better RR than the whole sample at wk 15 and to assess in the whole sample and in PD-L1+ pts, disease control rate (DCR) at wk15, RR at wk 24, best RR, overall survival (OS), progression free survival (PFS), duration of response / control and time to disease progression. A Simon optimal two-stage design will be used. Four responders among 19 pts will be needed in the 1st step to continue the trial. Overall 9 responses will be needed to conclude the effectiveness. Kaplan-Meier statistics will assess PFS and OS. Adverse events (AEs) will be assessed throughout the study and for 30 d thereafter (6 m for serious AEs) and graded per NCI CTCAE v4.0. Clinical trial information: NCT02883556.

Checkmate 649: A randomized, multicenter, open-label, phase 3 study of nivolumab (Nivo) plus ipilimumab (Ipi) versus oxaliplatin plus fluoropyrimidine in patients (Pts) with previously untreated advanced or metastatic gastric (G) or gastroesophageal junction (GEJ) cancer.

2017 ◽  
Vol 35 (4_suppl) ◽  
pp. TPS213-TPS213 ◽  
Author(s):  
Yelena Yuriy Janjigian ◽  
Antoine Adenis ◽  
Jean-Sebastien Aucoin ◽  
Carlo Barone ◽  
Narikazu Boku ◽  
...  
Keyword(s):  
Phase 1 ◽  
Treatment Options ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Progression Free Survival ◽  
First Line ◽  
Open Label ◽  
Phase 3 ◽  
Multiple Tumor ◽  
Open Label Phase

TPS213 Background: The combination ofoxaliplatin and fluoropyrimidine is a standard-of-care (SOC) first-line treatment of pts with metastatic G/GEJ cancer, resulting in a median overall survival (OS) of 8–11 months and objective response rate (ORR) of 30%–50%. This is accompanied by up to 77% grade 3/4 toxicities. Therefore, new treatment options are needed to improve survival and decrease toxicity in G/GEJ cancer. Nivo, a fully human IgG4 monoclonal antibody (mAb) that targets programmed death 1 (PD-1) and ipi, a fully human IgG1 mAb that targets cytotoxic T-lymphocyte–associated protein 4, have demonstrated manageable safety profiles and efficacy in multiple tumor types and may have a synergistic effect. In a phase 1/2 study in chemotherapy-refractory pts with G/GEJ/esophageal cancer with or without PD-1 ligand 1 (PD-L1) expression, second-line nivo 1 mg/kg + ipi 3 mg/kg demonstrated a manageable safety profile and resulted in 26% ORR (44% ORR in pts with PD-L1+ tumors), median OS of 6.9 months, and a 34% OS rate at 12 months (Janjigian Y, et al. J Clin Oncol. 2016;34[suppl][abstract 4010]). This open-label, phase 3 trial will evaluate nivo + ipi as first-line therapy for pts with G/GEJ cancer (CheckMate 649; NCT02872116). Methods: In this study, 870 pts aged ≥ 18 years with untreated advanced or metastatic G/GEJ cancer with or without PD-L1 expression will be randomized to receive nivo + ipi (4 doses; followed by nivo monotherapy) or investigator’s choice of capecitabine/oxaliplatin (XELOX) or fluorouracil/leucovorin/oxaliplatin (FOLFOX). Tumor tissue for determination of PD-L1 status must be provided from ≤ 6 months before study treatment. Pts receiving chemotherapy or radiotherapy for G/GEJ cancer within the last 6 months or pts with suspected autoimmune disease, uncontrolled medical disorder, or active infection are excluded. Primary endpoint is OS in pts with PD-L1+ tumors. Secondary endpoints include OS in all pts and progression-free survival and time to symptom deterioration in all pts and pts with PD-L1+ tumors. Clinical trial information: NCT02872116.

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