Efficacy, safety and factors associated with disease progression in patients with unresectable (stage III) or distant metastatic (stage IV) BRAF V600-mutant melanoma: An open label, non-randomized, phase IIIb study of trametinib in combination with dabrafenib

8524 Background: Metastatic melanoma lacks effective therapy. Pazopanib is a small-molecule inhibitor of VEGFR-1,2,3, PDGFR-B and c-KIT that has antiangiogenic activity in renal cell cancer as well as inhibition of melanoma tumor xenografts. We designed a phase II single arm, open label clinical trial evaluating pazopanib in combination with metronomic paclitaxel as first line therapy for subjects with unresectable stage III and stage IV melanoma. Methods: This protocol utilizes a Simon 2-stage Minimax design, with a planned interim analysis to confirm >3 responders to move to the second stage. To date, 20 eligible patients have been enrolled with 17 evaluable for response. All subjects were treatment naïve and received paclitaxel at 80mg/m2 weekly for three weeks in a 4 week cycle and pazopanib at 800mg as a continuous daily oral dose. The primary endpoint is 6 month progression free survival. Exploratory endpoints include biomarker analysis that may be associated with treatment outcomes (serum VEGF, soluble VEGF R2, serum HIF, serum TSP1 and BRAF mutation status). An additional exploratory endpoint includes the in vitro activity of pazopanib and paclitaxel on patient biopsy material co-cultured with vascular endothelial cells. RECIST criteria were used to define treatment response. Results: For the 17 evaluable patients treated to date the following results were seen: 1 CR, 6 PR’s, 8 SD’s and 2 PD’s. The overall RR (CR+PR) was 40%. Total disease control rate was 80% (PR+SD). The most common AEs/lab abnormalities were nausea (71%), hypertension (57%), fatigue (57%) and vomiting (43%). Grade 3-4 AEs included hypertension (28%), transaminitis (21%) and neutropenia (14%). One patient discontinued for grade 4 transaminitis which subsequently resolved completely. Dose reductions were required for pazopanib in 5 patients and for paclitaxel in one patient. Conclusions: Planned interim analysis of this phase II study demonstrated that pazopanib in combination with paclitaxel was well tolerated and resulted in a 40% response rate, indicating that this combination is of further interest. Accrual will continue to reach a goal of 60 patients.

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Effects of Nintedanib on Quantitative Lung Fibrosis Score in Idiopathic Pulmonary Fibrosis

The Open Respiratory Medicine Journal ◽

10.2174/1874306402014010022 ◽

2020 ◽

Vol 14 (1) ◽

pp. 22-31

Author(s):

Lisa Lancaster ◽

Jonathan Goldin ◽

Matthias Trampisch ◽

Grace Hyun Kim ◽

Jonathan Ilowite ◽

...

Keyword(s):

Idiopathic Pulmonary Fibrosis ◽

Pulmonary Fibrosis ◽

Disease Progression ◽

Lung Fibrosis ◽

Open Label ◽

High Resolution Computed Tomography ◽

Double Blind ◽

Phase Iiib ◽

Exploratory Data ◽

Relative Change

Background: Nintedanib slows disease progression in patients with Idiopathic Pulmonary Fibrosis (IPF) by reducing decline in Forced Vital Capacity (FVC). The effects of nintedanib on abnormalities on high-resolution computed tomography scans have not been previously studied. Objective: We conducted a Phase IIIb trial to assess the effects of nintedanib on changes in Quantitative Lung Fibrosis (QLF) score and other measures of disease progression in patients with IPF. Methods: 113 patients were randomized 1:1 to receive nintedanib 150 mg bid or placebo double-blind for ≥6 months, followed by open-label nintedanib. The primary endpoint was the relative change from baseline in QLF score (%) at month 6. Analyses were descriptive and exploratory. Results: Adjusted mean relative changes from baseline in QLF score at month 6 were 11.4% in the nintedanib group (n=42) and 14.6% in the placebo group (n=45) (difference 3.2% [95% CI: −9.2, 15.6]). Adjusted mean absolute changes from baseline in QLF score at month 6 were 0.98% and 1.33% in these groups, respectively (difference 0.35% [95% CI: −1.27, 1.96]). Adjusted mean absolute changes from baseline in FVC at month 6 were −14.2 mL and −83.2 mL in the nintedanib (n=54) and placebo (n=54) groups, respectively (difference 69.0 mL [95% CI: −8.7, 146.8]). Conclusion: Exploratory data suggest that in patients with IPF, 6 months’ treatment with nintedanib was associated with a numerically smaller degree of fibrotic change in the lungs and reduced FVC decline versus placebo. These data support previous findings that nintedanib slows the progression of IPF.

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Crossover and rechallenge with pembrolizumab in recurrent patients from the EORTC 1325-MG/Keynote-054 phase 3 trial, pembrolizumab versus placebo after complete resection of high-risk stage III melanoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.9500 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 9500-9500

Author(s):

Alexander M. Eggermont ◽

Andrey Meshcheryakov ◽

Victoria Atkinson ◽

Christian U. Blank ◽

Mario Mandalà ◽

...

Keyword(s):

Disease Progression ◽

Objective Response ◽

Stage Iv ◽

Median Number ◽

Complete Resection ◽

Stage Iii ◽

Phase 3 ◽

Double Blind ◽

Grade 3 ◽

To Receive

9500 Background: The phase 3 double-blind EORTC 1325/KEYNOTE-054 trial evaluated pembrolizumab (pembro) vs placebo in stage III cutaneous melanoma patients (pts) with complete resection of lymph nodes. Pembro improved RFS (hazard ratio [HR] 0.57) and DMFS (HR 0.60) (Eggermont, NEJM 2018, TLO 2021). In the pembro group, the incidence of immune related AE (irAE) grade 1-5 was 37%, and of grade 3-5 was 7%. We present the safety profile, response rate and PFS for the subset of pts who had a recurrence and crossed over or were rechallenged with pembrolizumab, within protocol. Methods: Pts were randomized to receive iv. pembro 200 mg (N=514) or placebo (N=505) every 3 weeks for a total of 18 doses (~1 year). Upon recurrence with no brain metastases, pts with an ECOG PS 0-2 were eligible to enter part 2 of the study, i.e. to receive pembro 200 mg iv. every 3 weeks for a maximum of 2 years, for crossover (those who received placebo) or rechallenge (those who recurred ≥6 months after completing one year of pembro therapy). Treatment was stopped in case of disease progression (RECIST 1.1) or unacceptable toxicity. Results: At the clinical cut-off (16-Oct-2020), 298 (59%) pts had a disease recurrence in the placebo group; 155 pts participated in the crossover part 2 of the trial. A total of 297 (58%) pts completed the 1-yr pembro adjuvant treatment, of whom 47 had a recurrence ≥6 mths from the stop of treatment and 20 entered in the rechallenge part of the trial. Among 175 pts who started pembro in Part 2, 160 discontinued due to completion of therapy (N=24), disease progression (N=88), toxicity (N=20), investigator's decision (N=21), or other reason (N=7); 15 pts were still on-treatment. Results for the 2 groups are provided in the table. The median number of doses was 12 and 5.5, respectively (resp), and the median follow-up was 41 and 19 mts, resp. Among the 175 pts, 51 (29%) had a grade 1-4 irAE (by group: 47 [30%] and 4 [20%] resp) and 11 (6%) a grade 3-4 irAE. Conclusions: Pembrolizumab treatment after crossover yielded a 39% ORR in evaluable pts and an overall 3-yr PFS of ̃32%, but after rechallenge the efficacy was lower. Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA The median PFS (95% CI) from start of Part 2 was 14 (5-27) and 8 (5-15) mts for stage III-resected and III/IV various, resp. Among the 80 stage IV crossover pts with evaluable disease, 31 (39%) had an objective response: 14 (18%) CR, 17 (21%) PR. The 2-yr PFS rate from response was 69% (95% CI 48-83%). For these 80 pts, the median PFS was 6.1 mts and the 3-yr PFS rate was 31% (95% CI 21-41%). Among 9 stage IV rechallenged pts with an evaluable disease, 1 (11%) reached CR, 3 had SD and 5 PD. Clinical trial information: NCT02362594. [Table: see text]

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Factors associated with palliative care (PC) utilization in advanced and metastatic renal cell carcinoma (RCC).

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.6_suppl.297 ◽

2021 ◽

Vol 39 (6_suppl) ◽

pp. 297-297

Author(s):

Hiren V. Patel ◽

Joshua Sterling ◽

Arnav Srivastava ◽

Sinae Kim ◽

Biren Saraiya ◽

...

Keyword(s):

Renal Cell Carcinoma ◽

Palliative Care ◽

Cell Carcinoma ◽

Renal Cell ◽

Multivariable Analysis ◽

Stage Iv ◽

Stage Iii ◽

Clinical Factors ◽

Factors Associated ◽

To Receive

297 Background: Palliative care (PC) offers various benefits for patient with cancer that include, but are not limited to, decrease in disease-specific symptoms and improvement in functional status. Several oncological guidelines have adopted early integration of PC into oncologic care to improve quality of life among patients with advanced malignancies. However, PC utilization patterns and factors associated with its use in advanced renal cell carcinoma (RCC) remain poorly understood. Methods: Using the National Cancer Database (NCDB), we abstracted patients with stage III and IV RCC from 2004-2014 and evaluated PC utilization amongst this cohort. Socioeconomic and clinical factors were compared for patient receiving and not receiving PC for advanced RCC. Multivariable logistic regression identified factors that were associated with receipt of PC. Results: We identified 20,122 and 42,014 patients with stage III and IV RCC, respectively. Among this cohort, 329 and 9,317 patients received PC for stage III and IV RCC, respectively. From 2004 to 2014, PC utilization has been stable at ~1% for stage III RCC and has significantly increased from 17% to 20% for stage IV RCC. Multivariable analysis demonstrated that Blacks, income >$48,000, regions outside of Northeast, stage III RCC, and patients that received surgery were less likely to receive PC. Patients that were female, with more comorbidities, uninsured or with government insurance, lower educational status, treated at academic or integrated cancer program, with sarcomatoid histology, receiving systemic therapy were more likely to receive PC. Conclusions: While PC utilization has significantly increased for stage IV RCC, there are several demographic, socioeconomic, and clinical factors that predict PC usage among patients with advanced RCC. Taken together, this suggests the need for more equitable and systematic use of PC among patients with advanced RCC.

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Long-Term Efficacy and Safety of L-BLP25 Vaccine in a Multi-Centre Open-Label Study of Patients with Unresectable Stage III NSCLC

Annals of Oncology ◽

10.1016/s0923-7534(20)33763-7 ◽

2012 ◽

Vol 23 ◽

pp. ix395 ◽

Cited By ~ 1

Author(s):

C. Butts ◽

R.N. Murray ◽

C.J. Smith ◽

P.M. Ellis ◽

K. Jasas ◽

...

Keyword(s):

Stage Iii ◽

Efficacy And Safety ◽

Open Label ◽

Open Label Study ◽

Label Study ◽

Term Efficacy ◽

Unresectable Stage ◽

Stage Iii Nsclc

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Prognostic factors determining long term survival of patients with unresectable stage III and stage IV metostatic melanoma (MM) treated with combination therapy or IL-2 based biochemotherapy (BCC)

Journal of Clinical Oncology ◽

10.1200/jco.2005.23.16_suppl.7544 ◽

2005 ◽

Vol 23 (16_suppl) ◽

pp. 7544-7544 ◽

Cited By ~ 3

Author(s):

A. Y. Bedikian ◽

M. M. Johnson ◽

L. D. Broemeling ◽

N. E. Papadopoulos ◽

K. B. S. Kim ◽

...

Keyword(s):

Prognostic Factors ◽

Combination Therapy ◽

Stage Iv ◽

Stage Iii ◽

Term Survival ◽

Long Term Survival ◽

Unresectable Stage

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Dose intensive chemotherapy (Cx) in advanced thymoma: Initial report of Japan Clinical Oncology Group trials (JCOG 9605 and 9606)

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.7080 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 7080-7080

Author(s):

H. Kunitoh ◽

T. Tamura ◽

H. Fukuda ◽

K. Nakagawa ◽

K. Takeda ◽

...

Keyword(s):

Thymic Carcinoma ◽

Local Therapy ◽

Stage Iv ◽

Progression Free Survival ◽

Stage Iii ◽

Initial Report ◽

Free Survival ◽

Unresectable Stage ◽

Short Course ◽

Ecog Ps

7080 Background: Thymoma is considered to be sensitive to Cx. Dose intensive Cx might well be suitable for such tumors, especially in combination with local therapy. Objectives of the trials were to evaluate the safety and efficacy of the dose intensive CODE (cisplatin[C]- vincristine[O]- doxorubicin[D]- etoposide[E]) Cx in thymoma. The primary endpoint was progression-free survival time (PFS). Methods: Patients (pts) with 15–70 years of age with histologically documented Cx-naïve thymoma with stage IVa/IVb disease (JCOG 9605) or unresectable stage III disease (JCOG 9606) were eligible. Tumors of other histology, such as thymic carcinoma, carcinoid or lymphoma were excluded; pts were to have ample organ function and ECOG PS of 0–2. Myasthenia was allowed. Signed consent form was obtained. Pts received CODE Cx of 9 weeks (w): C 25 mg/m2 Cx day 1 on each w1–9; O 1mg/m2 d1 on w1,2,4,6,8; D 40 mg/m2 d1 and E 80 mg/m2 d1,2,3 on w 1,3,5,7,9. Cx courses were supported by GCSF. Steroids were used only for antiemesis. Those with stage III disease (JCOG 9606) went on to surgery, if judged to be resectable, and post-operative radiotherapy (RT) of 48Gy; those with unresectable disease received 60Gy RT. Results: From Jul./97 to Apr./05, 53 pts were entered to the studies. Five were found ineligible because of different histology. Pt characteristics and response to the Cx were summarized in the table . Toxicity of the Cx was mainly hematologic and generally well tolerated, with no toxic death; 70% of the pts completed planned 9 weeks. Thirteen pts in JCOG 9606 (stage III) received thoracotomy; tumor was resected in 11 pts, completely in 9 (39% of enrolled pts). Pathologic CR was observed in 3. The median PFS was 9.5m for stage IV and 4.5 y for stage III diseases. Overall survival at 2 & 5 yrs were 82% & 57% for stage IV and 96% & 77% for stage III pts. Conclusions: Short-course, dose intensive Cx was active against thymoma. Although it does not seem to bring long PFS in stage IV pts, it could improve resectability in limited disease. [Table: see text] No significant financial relationships to disclose.

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Phase I study of concomitant pemetrexed and cisplatin plus radiation in patients with locally advanced or metastatic esophageal or gastroesophageal junction (GEJ) carcinomas.

Journal of Clinical Oncology ◽

10.1200/jco.2014.32.3_suppl.145 ◽

2014 ◽

Vol 32 (3_suppl) ◽

pp. 145-145

Author(s):

Hani M. Babiker ◽

Andrew I. Kovoor ◽

Myke R. Green ◽

Tomislav Dragovich ◽

Thomas David Brown ◽

...

Keyword(s):

Phase I ◽

Dose Escalation ◽

Gastroesophageal Junction ◽

Locally Advanced ◽

Stage Iv ◽

Complete Response ◽

Stage Iii ◽

Weekly Schedule ◽

Open Label ◽

Weekly Cisplatin

145 Background: For the treatment of esophageal and GEJ carcinomas, weekly cisplatin (20-30 mg/m2 weekly; total dose approximately 100 mg/m2) has demonstrated efficacy and tolerability. Pemetrexed (PEM) in combination with carboplatin and concomitant radiation has also shown activity for treatment of esophageal or lung carcinomas on a tri-weekly schedule, despite tolerability when administered weekly. This is the first phase I trial sought to establish the MTD of bi-weekly PEM in combination with weekly cisplatin and radiation in patients with locally advanced/metastatic esophageal and GEJ carcinomas. Methods: This is a phase I single institution, open-label dose-escalation trial (Fibonacci 3+3). Patients with stage III/IV esophageal cancer received PEM on weeks 1, 3, and 5 at doses of 300, 500, 750 mg/m2 concurrently with weekly cisplatin (20 mg/m2) and 28 daily fractions of radiation (total 50.4 Gy). If 1 or fewer DLTs were observed, the next cohort of patients received an escalated dose. If two or more patients develop DLTs, then dose escalation halted. Primary endpoint was to determine MTD; secondary endpoints included tolerability and preliminary anti-tumor activity using RECIST (Version 1.0). Results: 8 patients enrolled; median age was 72 (range 56-81); 50% were male; ECOG range was 0-2; 50% of patients had adenocarcinoma (AC), remaining patients had squamous cell carcinoma (SCC); 63% and 37% of patients were stage III and IV, respectively. Dose-escalation proceeded to 750 mg/m2 dose. The MTD was determined to be 500 mg/m2 bi-weekly following grade 4 dehydration and esophagitis at 750 mg/m2. DLTs observed were grade 4 thrombosis and grade 3 neutropenia at 300 and 500 mg/m2, respectively. Complete response was observed in 50% of patients (75% stage III SCC), partial response in 25% of patients (100% Stage IV AC), and disease progression in 1 patient (Stage III AC). 38% of patients proceeded to surgery. Conclusions: The combination of bi-weekly pemetrexed 500 mg/m2 and weekly cisplatin concomitantly with radiation demonstrates efficacy in patients with advanced or metastatic GEJ carcinomas with manageable safety profile. Clinical trial information: NCT00701857.

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