Phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib) (Cyto-KIK).

2021 ◽  
Vol 39 (6_suppl) ◽  
pp. TPS371-TPS371
Author(s):  
Karie Runcie ◽  
Eric A. Singer ◽  
Moshe Chaim Ornstein ◽  
Christopher B. Anderson ◽  
Matthew Dallos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Cytoreductive Nephrectomy ◽  
Open Label ◽  
Orthotopic Mouse Model

TPS371 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: AAAS6927 .

Cyto-KIK: A phase II trial of cytoreductive surgery in kidney cancer plus immunotherapy (nivolumab) and targeted kinase inhibition (cabozantinib).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS4598-TPS4598
Author(s):  
Karie Runcie ◽  
Eric A. Singer ◽  
Moshe Chaim Ornstein ◽  
Christopher B. Anderson ◽  
Matthew Dallos ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Phase Ii ◽  
Checkpoint Inhibitors ◽  
Recurrent Glioblastoma ◽  
Phase Iii ◽  
Cytoreductive Nephrectomy ◽  
Open Label ◽  
Orthotopic Mouse Model

TPS4598 Background: Despite recent therapeutic advancements in metastatic renal cell carcinoma (mRCC), only 5-10% of patients will achieve a complete response (CR) to therapy. Cytoreductive nephrectomy removes a large portion of the tumor which may be a source of immunosuppression driven by tumor cell-intrinsic factors in the tumor microenvironment. A pre-clinical orthotopic mouse model of aggressive metastatic triple negative breast cancer showed that neoadjuvant anti-PD-1 checkpoint inhibition generated enhanced and sustained antitumor immune responses with improved survival compared to adjuvant therapy (Liu J et al. Cancer Discov. 2016:1382). Clinical validation of improved outcomes with neoadjuvant compared to adjuvant immune checkpoint inhibitors has been demonstrated in trials for patients with non-small cell lung cancer, advanced melanoma, and recurrent glioblastoma (Forde, P.M., et al. N Engl J Med. 2018:1976; Amaria, R.N., et al Nat Med. 2018:1649; Cloughesy T.F., et al. Nat Med 2019:477). Recent data from a phase III trial in subjects with untreated mRCC, demonstrated the superiority of combination cabozantinib and nivolumab over sunitinib and established a new standard of care for mRCC (Choueiri T.K., et al. Annals of Onc, 2020;31 (suppl; abstr 6960). We hypothesize that if tumor specific immune responses to immunotherapy are greatest prior to nephrectomy, then treatment with nivolumab (nivo) and cabozantinib (cabo) prior to cytoreductive nephrectomy will lead to maximal peripheral and intra-tumoral specific immune responses and higher rates of CR during the course of treatment. Methods: This is an open label phase II, multicenter clinical trial of combination nivo and cabo prior to cytoreductive nephrectomy in patients with mRCC (NCT04322955). 48 treatment- naïve subjects with radiological or histological diagnosis of mRCC will be enrolled with the primary endpoint of CR rate according to RECIST version 1.1. Subjects will receive cabo (40mg) daily and nivo (480mg) every 4 weeks for 12 weeks prior to nephrectomy and a 3+3 design will be used to evaluate the safety of the interval (21 or 14 days) between the discontinuation of cabo and nephrectomy. Post-operatively, subjects will resume treatment with cabo and nivo until evidence of disease progression. Secondary endpoints include median size reduction of the primary tumor, response rate, PFS, OS, and surgical outcomes using the Clavien-Dindo classification system. Tissue based assays will quantify treatment related changes in the renal tumor microenvironment through polychromatic immunofluorescence, single cell RNA sequencing of the biopsy and nephrectomy specimen, and multiplex assessment of circulating serum cytokines. Dynamic contrast-enhanced MRI will be performed in a subset of subjects to assess radiologic correlates of response. The study is currently open to enrollment. Clinical trial information: NCT04322955.

REACT: A phase II study of rindopepimut (CDX-110) plus bevacizumab (BV) in relapsed glioblastoma (GB).

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. TPS2103-TPS2103 ◽  
Author(s):  
David A. Reardon ◽  
James J. Vredenburgh ◽  
Annick Desjardins ◽  
Ronald G. Steis ◽  
Erin M. Dunbar ◽  
...  
Keyword(s):  
Immune Responses ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Peptide Sequence ◽  
Phase Iii ◽  
Open Label ◽  
Term Survival ◽  
Gm Csf ◽  
Phase Ii Studies

TPS2103 Background: EGFRvIII is a constitutively active tumorigenic deletion mutation of EGFR. It is expressed in ~30% of primary GB where it is linked to poor long-term survival (Pelloski 2007). The investigational vaccine rindopepimut consists of the unique EGFRvIII peptide sequence conjugated to keyhole limpet hemocyanin (KLH), delivered intradermally (500ug with 150ug GM-CSF as an adjuvant). Remarkably consistent and promising results across 3 phase II studies in newly diagnosed, resected EGFRvIII+ GB (Lai 2011) represent a statistically significant improvement over a historical control cohort matched for major eligibility criteria (median overall survival [OS] = 24.4 - 24.6 vs. 15.2 months from diagnosis [m] and median progression-free survival [PFS] = 12.3 - 15.3 vs. 6.4 m). ACT IV, a phase III trial in this population, is ongoing. The immunosuppressive influence of residual/advanced GB presents a challenge to activation of efficacious antitumor immune responses. Anecdotal evidence (compassionate use cases, Sampson 2008) suggests that rindopepimut may induce specific immune responses and regression in multifocal and bulky residual tumors. Rindopepimut with BV, which inhibits VEGF and its immunosuppressive properties (including impaired maturation of dendritic cells and disruption of tumoral T cell infiltration [Johnson 2007, Shrimali 2010]) may further optimize EGFRvIII-specific immune response and antitumor activity. Methods: ReACT is a Phase II study of rindopepimut plus BV in patients (pts) with 1st or 2nd relapse of EGFRvIII+ GB. BV-naïve pts will be enrolled to Group 1 (n=70: randomized 1:1 to BV plus either rindopepimut/GM-CSF or control injection [low-dose KLH]) while BV-refractory patients will enter Group 2 (n=25: to receive BV plus open-label rindopepimut/GM-CSF). Concurrent with BV (10 mg/kg, q 2 wks), blinded treatment or open-label vaccine is given in priming phase (days 1, 15 and 29), then monthly until PD. Tumor response is assessed every 8 weeks, and patients are followed for survival after PD. Objectives are PFS at 6 months (primary), objective response rate, PFS, OS, safety, immunogenicity and elimination of EGFRvIII. ReACT opened to accrual in December 2011 (NCT01498328).

A randomized phase III study of immune checkpoint inhibition with chemotherapy in treatment-naive metastatic anal cancer patients: A trial of the ECOG-ACRIN cancer research group (EA2176).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS3614-TPS3614
Author(s):  
Marc Thomas Roth ◽  
Paul J. Catalano ◽  
Kristen Keon Ciombor ◽  
Al Bowen Benson ◽  
Xin Yao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Cancer Progression ◽  
Phase Ii ◽  
Anal Cancer ◽  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Phase Iii ◽  
Curative Intent ◽  
Platinum Based Chemotherapy ◽  
Treatment Naïve

TPS3614 Background: Anal cancer is growing in annual incidence globally and human papillomavirus (HPV) remains the predominant risk factor underlying its development. Due to its relative rarity, clinical trials in anal cancer have historically been difficult to conduct and treatment options for metastatic disease remain limited. Carboplatin/paclitaxel (CP) was compared to cisplatin/5-fluorouracil (historical standard of care) in a recent randomized phase II clinical trial (InterAACT; EA2133) in treatment-naïve metastatic anal cancer, finding that response rates were equivocal, but that overall survival (OS) was significantly longer in the CP arm (20 months vs 12.3 months, p = 0.014). Additionally, reduced grade 3/4 toxicities were seen in the CP arm. NCI9673, a single-arm phase II study, established safety and efficacy of nivolumab in previously-treated metastatic anal cancer. Progression-free survival (PFS) was 4.1 months (95% CI 3.0-7.9) and OS was 11.5 months (95% CI 7.1-not estimable). Multiple randomized trials in lung cancer have demonstrated efficacy of platinum-based chemotherapy combined with checkpoint inhibitors. Together these studies form the rationale behind combining CP and nivolumab in treatment-naïve metastatic anal cancer. Methods: EA2176 (NCT04444921) is the first NCTN phase III randomized clinical trial in treatment-naïve metastatic anal cancer. Stratification factors include HIV status and history of chemoradiation for curative intent. Patients will be randomized to carboplatin (AUC = 5, Day 1) plus paclitaxel (80mg/m2, Days 1, 8, 15) +/- nivolumab 240mg IV (Cycle 1 = Days 1, 15; Cycle ≥2 = Day 1, 480mg) q 28-days until disease progression or treatment intolerance. CP will be given for up to 6 cycles, while nivolumab will be continued as maintenance for up to 2 years. The primary endpoint is PFS. Secondary objectives include OS, response rate, and toxicity. Goal enrollment is 205 patients and the study continues accrual. This sample size will provide 80% power at a two-sided α of 0.05 to detect a 4.8-month improvement in PFS assuming 8 months in the control arm. Novel correlative studies include sequential quantitative tumor-derived cell-free HPV ctDNA levels (serotypes 16 and 18; Sysmex-Inostics SafeSEQ NGS assay). Correlative funding provided in part by the Farrah Fawcett Foundation and Sysmex Inostics, Inc. Clinical trial information: NCT04444921.

Immunotherapy with Y90-radioembolization for metastatic colorectal cancer (iRE-C).

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. TPS276-TPS276
Author(s):  
Pashtoon Murtaza Kasi ◽  
Beau M Toskich ◽  
Chandrikha Chandrasekharan ◽  
Dhivya Prabhakar ◽  
Saima Sharif ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Tumor Microenvironment ◽  
Mismatch Repair ◽  
Checkpoint Inhibitors ◽  
Maximum Tolerated Dose ◽  
Circulating Tumor Dna ◽  
Fixed Dose ◽  
Colorectal Cancers ◽  
Liquid Biopsies ◽  
Open Label

TPS276 Background: Immune checkpoint inhibitors have revolutionized the treatment of a number of cancers. In colorectal cancers, their efficacy is limited to mismatch repair deficient or microsatellite stability-high (dMMR/MSI-High) tumors only. These constitute only 4-5% of all metastatic colorectal cancers (mCRC). Novel approaches are needed to make immunotherapy a viable option for mismatch repair proficient or microsatellite stable (pMMR/MSS) tumors. Increasing exposure of neo-antigens to the immune system could be one potential strategy to enhance the response of immunotherapy. Yttrium 90-radioembolization (Y90-RE) in combination with immunotherapy may work synergistically to enhance efficacy of each other. Additionally, radiation can potentially make the tumor microenvironment conducive to effector T-cell recruitment and function. Therefore, we hypothesize and propose the clinical trial of combining immunotherapy with Y90-RE as a feasible and safe strategy that will improve outcomes in patients with mCRC with liver-predominant metastases. Methods: This clinical trial will be conducted as a single-center, open-label, Phase I/II trial to evaluate initially the feasibility and safety of Y90-RE in combination with a fixed dose of immunotherapy (durvalumab) in subjects with liver-predominant, mCRC (Table). It will be offered in the refractory setting. The trial will be performed in 18 subjects with mCRC with liver metastasis and the safety of immunotherapy (durvalumab) with Y90-RE will be investigated in an accelerated titration design. This would allow a maximum tolerated dose with the minimum number of subjects. Correlative studies pertaining to serial circulating tumor DNA (ctDNA - liquid biopsies) testing as well as immune-panel based profiling will be performed alongside pre- and post-biopsies to study changes in the tumor microenvironment. Clinical trial information: NCT04108481. [Table: see text]

Phase II study of nivolumab and ipilimumab in children and young adults with INI1-negative cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. TPS10055-TPS10055
Author(s):  
Suzanne J. Forrest ◽  
Joanna Yi ◽  
Cassie Kline ◽  
Thomas Cash ◽  
Alyssa Terry Reddy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Solid Tumors ◽  
Phase Ii ◽  
Immune Checkpoint ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Epithelioid Sarcoma ◽  
Objective Response ◽  
Open Label ◽  
Clinical Cancer Research

TPS10055 Background: Several aggressive pediatric and young adult cancers are characterized by SMARCB1 inactivation resulting in loss of INI1 expression, including rhabdoid tumors, epithelioid sarcoma and undifferentiated chordoma. These malignancies are associated with a poor prognosis and few effective treatment options for relapsed or refractory disease. Prior studies and emerging data suggest INI1-negative cancers may be uniquely susceptible to treatment with immune checkpoint inhibitors: Many INI1-negative pediatric tumors express PD-L1 and are infiltrated by immune cells, and there are reports of patients with advanced INI1-negative cancers with clinical responses to immune checkpoint blockade (Forrest et al. Clinical Cancer Research, 2020). We hypothesize that INI1 loss predicts tumor response to immune checkpoint inhibition (ICI). Methods: This is an ongoing multicenter, phase II, open-label clinical trial to evaluate the activity of nivolumab and ipilimumab in patients aged 6 months to 30 years with relapsed or refractory INI1-negative cancers (NCT04416568). The study enrolls patients in 2 strata: extracranial solid tumors in Stratum 1 and intracranial solid tumors in Stratum 2. Patients treated with prior ICI are excluded. Patients are treated with intravenous (IV) nivolumab 3mg/kg plus ipilimumab 1mg/kg IV every 3 weeks for 4 cycles followed by nivolumab 3mg/kg (max dose 240mg) IV every 2 weeks for up to 1-year. The primary objective is to evaluate the objective response rate (ORR) by Response Evaluation Criteria in Solid Tumors (RECIST) for Stratum 1 and by Response Assessment in Neuro-Oncology (RANO) criteria for Stratum 2. The trial has a 2-stage design targeting a 25% or greater response rate, with each stratum assessed independently. The analysis for Stage 1 in a given Stratum will be performed after 10 patients are enrolled. If a sufficient number of responders are observed, an additional 10 patients will be enrolled at Stage 2. Secondary endpoints include progression-free survival, overall survival, and disease control rate at 12 months. Correlative aims include assessing tissue and blood biomarkers associated with treatment response. Enrollment began 14 Aug 2020 and is ongoing. Clinical trial information: NCT04416568.

REGOMA: A Randomized, Multicenter, Controlled Open-Label Phase II Clinical Trial of Regorafenib Compared to Lomustine in Relapsed Glioblastoma Patients

2018 ◽  
Author(s):  
Giuseppe Lombardi ◽  
Gian Luca De Salvo ◽  
Alba Ariela Brandes ◽  
Marica Eoli ◽  
Roberta Rudà ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Clinical Trial ◽  
Open Label ◽  
Open Label Phase

scholarly journals The Effect of Herpes Simplex Virus-Type-1 (HSV-1) Oncolytic Immunotherapy on the Tumor Microenvironment

Viruses ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1200
Author(s):  
Ifeanyi Kingsley Uche ◽  
Konstantin G. Kousoulas ◽  
Paul J. F. Rider
Keyword(s):  
Herpes Simplex Virus ◽  
Herpes Simplex ◽  
Tumor Microenvironment ◽  
Immune Responses ◽  
Virus Type ◽  
Herpes Simplex Virus Type ◽  
Checkpoint Inhibitors ◽  
Significant Proportion ◽  
Simplex Virus

The development of cancer causes disruption of anti-tumor immunity required for surveillance and elimination of tumor cells. Immunotherapeutic strategies aim for the restoration or establishment of these anti-tumor immune responses. Cancer immunotherapies include immune checkpoint inhibitors (ICIs), adoptive cellular therapy (ACT), cancer vaccines, and oncolytic virotherapy (OVT). The clinical success of some of these immunotherapeutic modalities, including herpes simplex virus type-1 derived OVT, resulted in Food and Drug Administration (FDA) approval for use in treatment of human cancers. However, a significant proportion of patients do not respond or benefit equally from these immunotherapies. The creation of an immunosuppressive tumor microenvironment (TME) represents an important barrier preventing success of many immunotherapeutic approaches. Mechanisms of immunosuppression in the TME are a major area of current research. In this review, we discuss how oncolytic HSV affects the tumor microenvironment to promote anti-tumor immune responses. Where possible we focus on oncolytic HSV strains for which clinical data is available, and discuss how these viruses alter the vasculature, extracellular matrix and immune responses in the tumor microenvironment.

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