Treatment-Related Optimism Protects Quality of Life in a Phase II Clinical Trial for Metastatic Renal Cell Carcinoma

Abstract Background The combination of nivolumab, a programmed death-1 (PD-1) targeted monoclonal antibody, with the cytotoxic T-lymphocyte antigen-4 (CTLA-4) targeted antibody, ipilimumab, represents a new standard of care in the first-line setting for patients with intermediate- and poor-risk metastatic renal cell carcinoma (mRCC) based on recent phase III data. Combining ipilimumab with nivolumab increases rates of grade 3 and 4 toxicity compared with nivolumab alone, and the optimal scheduling of these agents when used together remains unknown. The aim of the PRISM study is to assess whether less frequent dosing of ipilimumab (12-weekly versus 3-weekly), in combination with nivolumab, is associated with a favourable toxicity profile without adversely impacting efficacy. Methods The PRISM trial is a UK-based, open label, multi-centre, phase II, randomised controlled trial. The trial population consists of patients with untreated locally advanced or metastatic clear cell RCC, and aims to recruit 189 participants. Participants will be randomised on a 2:1 basis in favour of a modified schedule of 4 doses of 12-weekly ipilimumab versus a standard schedule of 4 doses of 3-weekly ipilimumab, both in combination with standard nivolumab. The proportion of participants experiencing a grade 3 or 4 adverse reaction within 12 months forms the primary endpoint of the study, but with 12-month progression free survival a key secondary endpoint. The incidence of all adverse events, discontinuation rates, overall response rate, duration of response, overall survival rates and health related quality of life will also be analysed as secondary endpoints. In addition, the potential of circulating and tissue-based biomarkers as predictors of therapy response will be explored. Discussion The combination of nivolumab with ipilimumab is active in patients with mRCC. Modifying the frequency of ipilimumab dosing may mitigate toxicity rates and positively impact quality of life without compromising efficacy, a hypothesis being explored in other tumour types such as non-small cell lung cancer. The best way to give this combination to patients with mRCC must be similarly established. Trial registration PRISM is registered with ISRCTN (reference ISRCTN95351638, 19/12/2017). Trial status At the time of submission, PRISM is open to recruitment and data collection is ongoing.

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Phase II clinical trial of sorafenib plus interferon-alpha treatment for patients with metastatic renal cell carcinoma in Japan

BMC Cancer ◽

10.1186/s12885-015-1675-1 ◽

2015 ◽

Vol 15 (1) ◽

Cited By ~ 6

Author(s):

Masatoshi Eto ◽

◽

Yoshiaki Kawano ◽

Yoshihiko Hirao ◽

Koji Mita ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Interferon Alpha ◽

Phase Ii ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Phase Ii Clinical Trial ◽

Interferon Alpha Treatment

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Identification of biomarkers for overall survival of patients with metastatic renal cell carcinoma treated with MGN1601.

Journal of Clinical Oncology ◽

10.1200/jco.2013.31.6_suppl.468 ◽

2013 ◽

Vol 31 (6_suppl) ◽

pp. 468-468 ◽

Cited By ~ 1

Author(s):

Viktor Grünwald ◽

Steffen Weikert ◽

Ingo G.H. Schmidt-Wolf ◽

Stefan Hauser ◽

Ekaterina Weith ◽

...

Keyword(s):

Quality Of Life ◽

Clinical Trial ◽

Renal Cell Carcinoma ◽

Overall Survival ◽

Phase I ◽

Cell Carcinoma ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Local Reactions

468 Background: The cell-based therapeutic cancer vaccine MGN1601 consists of two active pharmaceutical ingredients in fixed combination. Fourfold gene-modified, allogeneic tumor cells expressing IL-7, GM-CSF, CD80, and CD154 through MIDGE gene expression vectors are combined with the DNA-based immunomodulator dSLIMas a TLR-9 agonist. In the phase I-II clinical trial (ASET trial) heavily pre-treated patients with metastatic renal cell carcinoma (mRCC) were enrolled. Methods: TheASET study has been conducted as a multicenter, open, single-arm phase I-II study. The treatment phase (TP) consisted of 8 intradermal vaccinations, administered within 12 weeks. We analysed known mRCC prognostic factors for their predictive value, i.e. safety laboratory and immunological parameters, quality of life, local reactions and other patients’ characteristics. Results: 19 patients from the ASET study, who received at least one vaccination (ITT population), were included in the biomarker evaluation. The median overall survival (mOS) in the ITT population is currently 25 weeks. mOS of patients who discontinued TP prematurely was only 10 weeks. However, mOS of those patients who completed at least TP is not yet mature for statistical calculation (NR), but is currently estimated as 69 weeks, resulting in a highly significant difference (10 weeks vs. NR, p < 0.001). Patients with an absolute lymphocyte counts (ALC) at baseline of ≥1,000/μL had increased overall survival (mOS NR vs. 16 weeks, p = 0.013), if compared to those with an ALC <1,000/μL. Neutrophil lymphocyte ratios (NLR) at baseline of >3, bone and liver metastasis, high MSKCC score were identified as risk factors associated with lower overall survival. ALC ≥1,000/μL after three MGN1601 vaccinations (week 5) was even more significantly associated with increased overall survival (mOS NR vs. 17 weeks, p = 0.007). The NLR and quality of life improvement at week 5 as well as local reactions at injection sites seem to correlate with OS. Conclusions: MGN1601 shows promising efficacy in late stage mRCC patients. The identified parameters should be further investigated as potential biomarkers for efficacy. Clinical trial information: NCT01265368.

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MP69-19 EXTENDED ANALYSES OF PHASE II CLINICAL TRIAL OF SORAFENIB PLUS INTERFERON-ALPHA TREATMENT FOR PATIENTS WITH METASTATIC RENAL CELL CARCINOMA IN JAPAN

The Journal of Urology ◽

10.1016/j.juro.2015.02.2523 ◽

2015 ◽

Vol 193 (4S) ◽

Author(s):

Masatoshi Eto ◽

Yoshiaki Kawano ◽

Yoshihiko Hirao ◽

Koji Mita ◽

Yoichi Arai ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Interferon Alpha ◽

Phase Ii ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Phase Ii Clinical Trial ◽

Interferon Alpha Treatment

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A Phase II Clinical Trial of Ixabepilone (Ixempra; BMS-247550; NSC 710428), an Epothilone B Analog, in Patients with Metastatic Renal Cell Carcinoma

Clinical Cancer Research ◽

10.1158/1078-0432.ccr-09-0379 ◽

2010 ◽

Vol 16 (5) ◽

pp. 1634-1641 ◽

Cited By ~ 24

Author(s):

Hui Huang ◽

Michael Menefee ◽

Maureen Edgerly ◽

Sen Zhuang ◽

Herb Kotz ◽

...

Keyword(s):

Clinical Trial ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Phase Ii Clinical Trial ◽

Epothilone B

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Phase II Study of Sunitinib Administered in a Continuous Once-Daily Dosing Regimen in Patients With Cytokine-Refractory Metastatic Renal Cell Carcinoma

Journal of Clinical Oncology ◽

10.1200/jco.2008.20.5476 ◽

2009 ◽

Vol 27 (25) ◽

pp. 4068-4075 ◽

Cited By ~ 153

Author(s):

Bernard Escudier ◽

Jan Roigas ◽

Silke Gillessen ◽

Ulrika Harmenberg ◽

Sandhya Srinivas ◽

...

Keyword(s):

Quality Of Life ◽

Renal Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Metastatic Renal Cell Carcinoma ◽

Renal Cell ◽

Dosing Regimen ◽

Once Daily ◽

Grade 3

PurposeSunitinib has demonstrated antitumor activity in metastatic renal cell carcinoma (mRCC) when given at 50 mg/d on a 4-weeks-on 2-weeks-off regimen. Herein, we report results of an open-label, multicenter phase II mRCC study of sunitinib administered on a continuous once-daily dosing regimen.Patients and MethodsEligibility criteria included histologically proven mRCC with measurable disease, failure of one prior cytokine regimen, and good performance status. Patients were randomly assigned to a sunitinib starting dose of 37.5 mg/d in the morning (AM) or evening (PM). RECIST-defined objective response rate (ORR) was the primary end point. Secondary end points included progression-free survival (PFS), overall survival (OS), adverse events (AEs), and quality-of-life measures.ResultsOne hundred seven patients were randomly assigned to AM (n = 54) or PM (n = 53) dosing and on study for a median 8.3 months. Eighty-three patients discontinued, 65 due to disease progression and 16 because of AEs; two patients withdrew consent. Dosing was reduced to 25 mg/d in 46 patients (43%) due to grade 3/4 AEs. The most common grade 3 treatment-related AEs were asthenia/fatigue (16%), diarrhea (11%), hypertension (11%), hand-foot syndrome (9%), and anorexia (8%). ORR was 20% with a 7.2-month median response duration. Median PFS and OS were 8.2 and 19.8 months, respectively, at median follow-up of 26.4 months. Efficacy, tolerability, and quality-of-life results were similar between patients dosed in the AM or PM.ConclusionSunitinib 37.5 mg, administered on a continuous once-daily dosing regimen, has a manageable safety profile as second-line mRCC therapy, providing flexible dosing, which can be explored in combination studies.

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