A phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated classical Kaposi sarcoma (CKS).

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 11518-11518
Author(s):  
Alona Zer ◽  
Oded Icht ◽  
Lilach Joseph ◽  
Dana Avram ◽  
Oded Jacobi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Interim Analysis ◽  
Phase Ii Study ◽  
Gene Transcript ◽  
Copy Number Loss ◽  
Immune Gene ◽  
Mesenchymal Neoplasm ◽  
Previously Treated ◽  
Clinical Trial Information

11518 Background: CKS is a mesenchymal neoplasm associated with HHV8 infection. Though recombinant INFa is approved for treatment of AIDS-related KS, data is limited regarding the role of immune modulation in CKS therapy. Based on favorable responses in viral-induced cancers, we hypothesized that CTLA-4 and PD-1 blockade can induce tumor regression in CKS. We present pre-planned interim analysis of a phase II study of Nivo/Ipi in previously treated progressive CKS. Methods: CKS pts with progressive disease after > 1 line of systemic therapy and measurable disease received nivolumab 240mg d1,15,28 and ipilimumab 1mg/kg d1 q42 days until progression or toxicity. The primary endpoint was overall response rate (ORR) evaluated clinically, radiologically (RECIST) and metabolically (FDG-PET). Secondary endpoints include 6-months progression free survival rate (PFS) and safety. Exploratory endpoints included PD-L1/MMR by IHC, DNAseq (596 genes)/RNAseq (whole transcriptome) of tumor and matched blood specimens to explore CKS genomic traits and IO correlates: TMB and MSI status, MMR and PD-L1 protein expression, and immune gene transcript expression (PD-1, PD-L1, CTLA-4, and others) (Tempus Labs, Chicago, IL, USA). Results: Fifteen patients were enrolled and evaluable (Apr18-Jan20). Median age 72.5 (61-81), all male. At a median FU of 15.7 mo ORR as per RECIST was 66% (9 pts PR, 1 pt CR, 2 pts SD, 3 pts NE). Clinical ORR was 87% and metabolic ORR was 60%. Median PFS was not reached, 6mo PFS rate was 85% and 1y PFS rate was 75%. The safety profile was as expected with all pts experiencing G1 toxicity, 3 pts with G2 toxicity (1 hepatic, 2 asymptomatic lipase increase) and 2 pts with G3 toxicity (1 colitis, 1 asymptomatic lipase increase). One SAE was reported (TIA considered not related to therapy) and treatment was discontinued in 3 pts. Correlative results are available for 8 pts showing a trend for copy number loss in genes with tumor-suppressive activity (FOXA1, ELF3), no PDL1 expression, low TMB, microsatellite stability, but marked overexpression of CTLA-4, PD-1, PDL-1, CD40, OX40 and LAG3 RNA immune transcripts. Conclusions: The interim analysis of this prospective phase II study of nivolumab and low-dose ipilimumab demonstrates promising activity in progressive CKS, with 66% ORR and a 6mo PFS rate of 85%. Toxicity profile is as expected in this class of drugs. Correlative studies are preliminary, but warrant further investigation into genomic traits and immune gene expression profiles. Clinical trial information: NCT03219671. Clinical trial information: NCT03219671 .

A phase II single-arm study of nivolumab and ipilimumab (Nivo/Ipi) in previously treated Classic Kaposi sarcoma (CKS).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 11064-11064 ◽  
Author(s):  
Alona Zer ◽  
Oded Icht ◽  
Lilach Joseph ◽  
Dana Avram ◽  
Oded Jacobi ◽  
...  
Keyword(s):  
Phase Ii ◽  
Interim Analysis ◽  
Immune Modulation ◽  
Phase Ii Study ◽  
Tumor Regression ◽  
Progression Free Survival ◽  
Serum Samples ◽  
Human Herpes Virus 8 ◽  
Mesenchymal Neoplasm ◽  
Previously Treated

11064 Background: CKS is an angioproliferative mesenchymal neoplasm causatively associated with human herpes virus 8 infection. Though recombinant IFNa is approved for treatment of AIDS-related KS, data is limited regarding the role of immune modulation in CKS therapy. Based on favorable responses in viral-induced cancers, we hypothesized that CTLA-4 and PD-1 blockade can induce tumor regression in CKS. We present pre-planned interim analysis of a phase II study of Nivo/Ipi in previously treated progressive CKS (NCT03219671). Methods: CKS pts with progressive disease after ≥ 1 line of systemic therapy and measurable disease by PET/CT and/or physical exam received nivolumab 240mg d1,15,28 and ipilimumab 1mg/kg d1 q42 days until progression or toxicity. The primary endpoint was overall response rate (ORR), secondary endpoints include 6-months progression free survival rate (PFS) and safety. Correlative studies in tumor and serum samples are ongoing using an NGS panel for DNA and RNA and proteomic staining (Tempus Labs Inc). A pre-planned interim analysis was conducted after the first ten enrolled patients for efficacy and toxicity evaluation. Results: Ten patients were enrolled and evaluable between April2018 and February2019. Median age 72 (61-79), all male. At a median FU of 3.1 months (1.5-8.1) ORR was 50% (4 patients PR, 1 patient CR, 5 patients SD). Median PFS was not reached however no progression of disease was documented so far. The safety profile was as expected with all patients experiencing G1 toxicity and four patients with G2 toxicity (1 ALT/AST increase, 2 asymptomatic lipase increase). One SAE was reported (TIA considered not related to therapy) and treatment was discontinued in one patient (G2 LFT increase. maintaining CR 4 months after treatment discontinuation). Correlative results are pending. Conclusions: The interim analysis in this prospectively designed phase II study of nivolumab and low-dose ipilimumab demonstrate promising activity in progressive CKS, with 50% ORR and no events of progression thus far. We expect to report the updated efficacy and correlative data. Clinical trial information: NCT03219671.

RECIST and iRECIST criteria for the evaluation of nivolumab + ipilimumab combination in patients (pts) with microsatellite instability-high/mismatch repair-deficient (MSI/dMMR) metastatic colorectal cancer (mCRC): Results of the GERCOR NIPICOL phase II study.

2020 ◽  
Vol 38 (4_suppl) ◽  
pp. 101-101 ◽  
Author(s):  
Romain Cohen ◽  
Jaafar Bennouna ◽  
Julie Henriques ◽  
Christophe Tournigand ◽  
Christelle De La Fouchardiere ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Checkpoint Inhibitors ◽  
Low Frequency ◽  
Progression Free Survival ◽  
Primary Objective ◽  
Free Survival ◽  
Previously Treated ◽  
Grade 3 ◽  
Clinical Trial Information

101 Background: Immune checkpoint inhibitors (ICKi) are highly effective for MSI/dMMR mCRC pts. RECIST1.1 criteria are reported to underestimate response to ICKi. The GERCOR NIPICOL phase II study aimed to evaluate disease control rate (DCR) using RECIST1.1 and iRECIST for MSI/dMMR mCRC pts treated with nivolumab (NIVO) and ipilimumab (IPI). Methods: MSI/dMMR mCRC pts previously treated with fluoropyrimidines (FP), oxaliplatin (OX) and irinotecan (IRI) ± targeted therapies received NIVO 3 mg/kg + IPI 1 mg/kg Q3W for 4 cycles then NIVO 3 mg/kg Q2W until progression or a maximum of 20 cycles. CT-scan tumor assessments were done every 6 weeks during 24 weeks and then every 12 weeks. Primary objective was DCR at 12 weeks (12wDCR) according to RECIST1.1 and iRECIST by central review. Response rates and progression-free survival (PFS) by central review were secondary objectives. A one-stage Fleming design was used with a targeted improvement of 12wDCR from 70% to 85%. Results: Of 57 pts included between Dec 2017 and Nov 2018, 43.9% had received ≥ 3 prior lines including FP (100%), OX (100%), IRI (95.5%), antiangiogenics (57.9%) and anti-EGFRs (45.6%). 17.5% of pts had BRAF mutation and 27.5% Lynch syndrome. Grade 3-4 treatment-related adverse events were reported in 49.1% of pts, mainly hepatitis (12.3%). 12wDCR was 86.0% and 87.7% using RECIST1.1 and iRECIST respectively, with only 1 pseudo-progression (1.8%) observed during the first 12 weeks, and one later. Kappa coefficient between RECIST and iRECIST 12wDCR was 0.92 (95%CI 0.77-1.0). Best observed responses with RECIST1.1/iRECIST were: 2/2 complete responses (3.5/3.5%), 19/19 partial responses (33.3/33.3%), 30/31 stable diseases (52.6/54.4%) and 3/2 disease progressions (5.3/3.5%), with 3 pts not evaluable (cancer-related deaths before first evaluation). Conclusions: Combination of NIVO and IPI in MSI/dMMR mCRC is associated with a low frequency of pseudo-progression and high DCR rate. PFS will be evaluated in Dec 2019, with all pts having completed the predefined 1-year of ICKi therapy. Clinical trial information: NCT033501260.

Neonax (AIO-PAK-0313): Neoadjuvant plus adjuvant or only adjuvant nab-paclitaxel plus gemcitabine for resectable pancreatic cancer: A phase II study of the AIO Pancreatic Cancer Group.

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS497-TPS497 ◽  
Author(s):  
Thomas Jens Ettrich ◽  
Andreas W. Berger ◽  
Rainer Muche ◽  
Manfred P. Lutz ◽  
Nicole Prasnikar ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Tumor Tissue ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Tumor Surgery ◽  
Resectable Pancreatic Cancer ◽  
Post Surgery ◽  
Clinical Trial Information

TPS497 Background: Resectable pancreatic cancer still has an unfavourable prognosis. Neoadjuvant or perioperative therapies might improve the prognosis of these patients. Recently, two phase III trials demonstrated for the first time, a substantial improvement in overall response, PFS and OS in patients with metastatic pancreatic cancer compared to standard gemcitabine (FOLFIRINOX and nab-paclitaxel/gemcitabine). The combination of nab-paclitaxel/gemcitabine has a more favourable toxicity profile compared to the FOLFIRINOX protocol and appears applicable in a perioperative setting. Methods: NEONAX is a study for patients (to be enrolled: n=166) with resectable ductal adenocarcinoma of the pancreas ≤ T3 in two arms: Arm A (perioperative arm): 2 cycles nab-paclitaxel (125 mg/m2)/gemcitabine (1000 mg/m2, d1, 8 and 15 of an 28 day-cycle) - tumor surgery - 4 cycles nab-paclitaxel/gemcitabine, Arm B (adjuvant only arm): tumor surgery - 6 cycles nab-paclitaxel/gemcitabine. NEONAX is an interventional, prospective, randomized, controlled, open label, two sided phase II study with an unconnected analysis of the results in both experimental arms against a fixed survival probability (38% at 18 month with adjuvant gemcitabine). The randomization (1:1) is eminent to achieve two comparable patient groups. Primary objective is DFS at 18 months after randomization. Key secondary objectives are 3-year OS and DFS, progression during neoadjuvant therapy and QoL. In the perioperative group tumor tissue will be collected prior to and post-surgery and subjected to microdissection and exome sequencing of tumor tissue. Tumor regression will be assessed both in the perioperative and the adjuvant group, respectively. In addition, circulating tumor-DNA will be analyzed in patients with the best and the worst responses to the neoadjuvant treatment. Start of trial will be in IV/2014 in 20 high-volume centers for pancreatic surgery in Germany. Clinical trial information: NCT02047513. Clinical trial information: NCT02047513.

A phase I multicenter study of the combination of temozolomide and pazopanib in advanced pancreatic neuroendocrine tumors (PNET).

2015 ◽  
Vol 33 (3_suppl) ◽  
pp. TPS492-TPS492
Author(s):  
Aparna Kalyan ◽  
Sheetal Kircher ◽  
Crystal Shereen Denlinger ◽  
Jordan Berlin ◽  
Mary F Mulcahy ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Once Daily ◽  
Oncology Research ◽  
Flow Perfusion ◽  
Proven Efficacy ◽  
Cancer Network ◽  
Clinical Trial Information

TPS492 Background: Everolimus and sunitinib targeted therapy have proven efficacy in advanced PNET, with ORR 5-9% and PFS HR < 0.5 compared to placebo.Additionally, a single arm phase II study showed promising activity with temozolomide and capecitabine combination with an ORR of 70%. Rationale:PNETs are distinguished by their vascularlity and up-regulation of VEGF factors. In the preclinical setting, the combination of temozolomide and sunitinib appears to act synergistically by altering the tumor microenvironment enhancing activity of temozolomide. Pazopanib has shown activity in a single arm phase II study in advanced PNETs with a 6-month PFS rate of 80% and ORR of 17%. There is sufficient preclinical and clinical evidence suggesting that the combination of an anti-angiogenic agent with temozolomide is more efficacious, hence, our rationale for the current study. Methods: Objectives: (1) Determine the MTD and toxicity profile of temozolomide + pazopanib. (2) Describe the PK profile of this combination. (3) Observe the ORR. Trial Design:Open label Phase I study to determine the MTD and safety profile employing a 3+3 dose-escalation model of the combination of temozolomide and pazopanib in patients with advanced PNET who have received between 1-4 prior therapies. Cohort 1: temozolomide at 150 mg/m2 on Days 1-7 and 15-21, and pazopanib 400 mg orally once daily continuously throughout cycle of 28 days. Once MTD is determined, PK sampling will be performed in 6 additional patients enrolled at the MTD. To date, eleven patients have been enrolled in cohort 1 and cohort -1. Cohort -1 is currently accruing at the reduced dose level of temozolomide 100mg/m2 and pazopanib 400mg daily for the duration of the cycle. The trial is funded to proceed to a single arm phase II with exploratory end points: (1) Correlation of MGMT expression by IHC to ORR and PFS (2) tumor blood flow (perfusion CT imaging) relationship with ORR. (This study was approved and funded by the National Comprehensive Cancer Network (NCCN) Oncology Research Program from general research support provided by GlaxoSmithKline.) Clinical Trial information: NCT01465659. Clinical trial information: NCT01465659.

Open-label phase II study evaluating the efficacy of concurrent administration of radium Ra 223 dichloride (Ra-223) and abiraterone acetate (AA) in men with castration-resistant prostate cancer (CRPC) patients with symptomatic bone metastases.

2016 ◽  
Vol 34 (2_suppl) ◽  
pp. 177-177 ◽  
Author(s):  
Neal D. Shore
Keyword(s):  
Prostate Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Abiraterone Acetate ◽  
Time To Event ◽  
Open Label ◽  
Kaplan Meier ◽  
Open Label Phase ◽  
Clinical Trial Information

177 Background: Abiraterone Acetate (AA), a CYP17 inhibitor, further decreases serum testosterone for castrate resistant prostate cancer patients. Radium Ra 223 dichloride (Ra-223), an alpha-emitting radioisotope is a calcium mimetic, forming complexes with hydroxyapatite at sites of bone metastasis (mets). This study evaluates the combinatorial use of concurrent AA + Ra-223 in CRPC patients with symptomatic bone mets. Methods: In this open-label, phase II study (NCT02097303), 30 patients with symptomatic bone mCRPC with no visceral mets were enrolled. All evaluable patients are treated with Rad-223 every 4 weeks x 6 doses, and concomitant AA 1000 mg + prednisone 5 mg BID. The primary endpoint is efficacy. Secondary endpoints include safety, time to measurable disease progression and SRE's, PSA and ALP progression, progression to further antineoplastic therapy and performance status changes. Patients are assessed at screening, weeks 1, 5, 9, 13, 17, 21 and 25. Data will be presented according to all metrics detailed, and by subject and visit. Time to event variables will be summarized using the Kaplan-Meier method to estimate the median, 25th and 75th percentiles, minimum and maximum and the 95% confidence interval for the median time to event. Kaplan-Meier plots will also be generated. This trial is ongoing and closed to enrollment. Clinical trial information: NCT02097303. Results: Pending. Last patient last visit scheduled to occur in December, 2015. Conclusions: Pending. Clinical trial information: NCT02097303.

A phase II study investigating biological effects of maintenance usage of hydroxychloroquine on Par-4 levels in patients with resected tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3085-3085
Author(s):  
Peng Wang ◽  
Ravshan Burikhanov ◽  
Heidi Weiss ◽  
Rani Jayswal ◽  
Susanne M. Arnold ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Disease Progression ◽  
Phase Ii ◽  
Interim Analysis ◽  
Phase Ii Study ◽  
Biological Effects ◽  
Fold Increase ◽  
Two Stage ◽  
Stage Design

3085 Background: Hydroxychloroquine (HCQ) is an inducer of the tumor suppressor Par-4 (prostate apoptosis response-4) secretion from normal cells. Secreted Par-4 causes paracrine apoptosis of tumor cells in mice. Established dosing of HCQ 200 mg bid induces Par-4 secretion but not the autophagy-inhibition marker p62 and correlates with apoptosis induction in patients' tumors. Methods: This is a single-arm, single institute phase II study to characterize the biological effects of 3-months of HCQ at fixed-dose (200 mg p.o. twice a day) on plasma Par-4 levels in adults with resected solid tumors. The primary endpoint is proportion of patients who will exhibit a two-fold increase in Par-4 levels from baseline compared to 3 months of follow-up. 12-month progression free survival (PFS) is one of the secondary endpoints. A Simon's two-stage design was used to test the null hypothesis that the proportion of patients exhibiting a two-fold increase in Par-4 is equal to 50% compared to 70% using a one-sided alternative. These hypothesized assumptions are based on a small pilot human data and from a phase I clinical trial on a small number of patients (n = 9). The first stage of interim analysis will be performed after a total of 15 patients have been accrued. If there are eight or fewer responses occurred, the study will be stopped. Otherwise, 28 additional patients will be accrued for a total of 43 subjects. Results: A total of 19 patients were enrolled in the trial. Per protocol, the interim analysis and stopping boundary is based on the first 15 patients. A total of 4 out of 15 patients (26.7%) 95% CI: 8% - 55% exhibited a >2-fold increase in Par-4 levels at 3 months. This did not surpass the stopping bound for futility and thus indicates stopping of patient accrual based on the assumptions used for the Simon's two-stage design. 7 out of 19 patients (36.8%) 95% CI: 16% - 62% who exhibited at least a 2-fold increase at either 2 or 3 months of follow-up, 50% (95% CI: 26% - 74%) and 56% (95% CI: 31% -79%) exhibited a 1.5-fold and 1.25-fold increase respectively. To date, 10/19 patients finished 12-month follow-up, 4/19 and 5/19 finished 6-month and 3-month follow up respectively. 2 of 12 patients with less than 2-fold increase of Par-4 developed disease progression. None of 7 patients with 2-fold increase of Par-4 showed disease progression. Conclusions: Despite that the study was terminated prematurely, to our knowledge this is the first study in human to identify dynamic changes of serum Par-4 while on long-term of usage of HCQ. We also demonstrate trend of PFS benefit especially for subjects having 2-fold increase of Par-4 induction. Identification of tumors more Par-4 sensitive and predictive biomarkers of Par-4 induction are necessary to continue our investigation. Clinical trial information: NCT02232243.

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