Interim results of a randomized phase II study of PEGPH20 added to nab-paclitaxel/gemcitabine in patients with stage IV previously untreated pancreatic cancer.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 439-439 ◽  
Author(s):  
Sunil R. Hingorani ◽  
William Proctor Harris ◽  
Tara Elisabeth Seery ◽  
Lei Zheng ◽  
Darren Sigal ◽  
...  
Keyword(s):  
Pancreatic Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Randomized Study ◽  
Safety Data ◽  
Stage Iv ◽  
Phase Iii ◽  
Clinical Hold ◽  
Stage 1 ◽  
Clinical Trial Information

439 Background: Poor outcome in pancreatic cancer (PDA) is associated partly with stromal hyaluronan (HA) accumulation, which compromises chemotherapy perfusion. PEGPH20, PEGylated recombinant human hyaluronidase, potentiates chemotherapy by depleting HA in tumors. Methods: In an ongoing, phase II, open-label, randomized study of PEGPH20+nab-paclitaxel (Nab)+Gemcitabine (Gem) (PAG) vs Nab+Gem (AG) in previously untreated stage IV PDA, pts receive PEGPH20 3 µg/kg twice weekly (C1), then weekly (C2+) with standard AG dosing. HA status was tested retrospectively. After a temporary clinical hold (Apr-Jul 2014) for an imbalance in thromboembolic (TE) events (29% PAG vs 15% AG), the protocol was amended to exclude high-TE-risk pts and add enoxaparin (LMWH) prophylaxis. Endpoints are PFS and TE events (primary); PFS and ORR by HA level and OS (secondary). Efficacy and safety data through Dec 2014 are for pts enrolled up to clinical hold (Stage 1); TE data are through Sep 2015 (Stage 2). Results: 135 pts were treated (74 PAG, 61 AG). PFS results are shown below (median follow-up 7 mo). In HA-high pts receiving PAG vs AG, ORR was 52% (1 CR) vs 24% (P=.038); ORR was 37% vs 38% in HA-low pts. OS was 12 mo vs 9 mo (HR=0.62) despite 12/23 PAG pts discontinuing PEGPH20 at clinical hold. Common ADRs (PAG vs AG) included peripheral edema (58% vs 31%), muscle spasms (55% vs 1.6%), and neutropenia (32% vs 18%). TE events were: Stage 1 42% vs 25% (no LMWH); Stage 2 (with LMWH; 40 mg/d or 40 mg/d increased to 1 mg/kg/d) 28% vs 29%; (1 mg/kg/d) 5% vs 6%; overall (40 mg/d or 1 mg/kg/d) 13% each arm (to be updated). Conclusions: Pts with HA-high tumors receiving PAG, vs AG, showed significant improvements in PFS and ORR and a trend toward improved OS. PAG was well tolerated, with TE events reduced with LMWH prophylaxis. A global phase III trial of PAG will initiate Q1 2016. Clinical Trial Information: NCT01839487. Clinical trial information: NCT01839487. [Table: see text]

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 randomized, double-blinded, placebo-controlled multicenter phase II trial of adjuvant immunotherapy with tecemotide (L-BLP25) after R0/R1 hepatic colorectal cancer metastasectomy (LICC): Final results.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 480-480
Author(s):  
Carl Christoph Schimanski ◽  
Stefan Kasper ◽  
Susanna Hegewisch-Becker ◽  
Jan Schroeder ◽  
Friedrich Overkamp ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Clinical Trial ◽  
Phase Ii ◽  
Cox Regression ◽  
Phase Ii Trial ◽  
Stage Iv ◽  
High Recurrence Rate ◽  
Muc1 Expression ◽  
Double Blinded ◽  
Clinical Trial Information

480 Background: Hepatic metastasectomy is the only potential curative treatment option for stage IV colorectal cancer (CRC) limited to liver metastases (LM). After R0 resection of LM the high recurrence rate remains a major challenge. L-BLP25 is an antigen-specific cancer vaccine targeting mucin 1 (MUC1). The LICC trial aimed to improve survival outcome in mCRC patients (pts) after R0/R1 LM resection. Methods: This LICC trial, a binational, multicenter, double-blinded, placebo controlled phase II trial, included pts with stage IV LM limited CRC after resection of primary tumor and LM (R0/R1) within the last 8 weeks, ECOG 0/1 and adequate organ function. Pts were 2:1 randomized to receive L-BLP25 or placebo. L-BLP25 930 µg was administered as 8 weekly subcutaneous doses followed by 6 week maintenance intervals until recurrence or a maximum of 2 years. Cyclophosphamide 300 mg/m2 (CP) or matching saline (NS) was given intravenously 3 days prior to first L-BLP25/placebo. Co-primary endpoints were recurrence-free survival (RFS) and 3-year overall survival (OS), secondary endpoints were RFS and OS in subgroups with different MUC1 expression and safety. Differences in RFS and OS were analyzed with exploratory log-rank tests on the intention-to-treat population. Results: Of 121 pts enrolled between Oct 2011 and Dec 2014, 79 pts received L-BLP25+CP, 42 placebo+NS. Baseline characteristics were well balanced. Median age was 60 years. Median RFS was 6.1 (90% CI: 5.8-8.8) vs. 11.4 months (90% CI: 5.0-20.3) and estimated 3-year OS rate 69.1% vs. 79.1% for L-BLP25 and placebo, respectively. Two-factorial Cox regression models showed no impact of MUC1 expression or treatment on RFS or OS. The most common L-BLP25-related grade 3/4 adverse events were diarrhea, anemia and back pain. There was one death in the L-BLP25 arm due to Merkel cell carcinoma assessed by the investigator as being potentially related to vaccination. Conclusions: The LICC trial failed to meet its primary endpoint of significantly improving RFS and OS with L-BLP25. MUC1 expression was not associated with outcome. Clinical trial information: NCT01462513 . Clinical trial information: NCT01462513.

A phase II pilot trial with RP101 in advanced pancreatic carcinoma

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14000-14000
Author(s):  
R. Fahrig ◽  
D. Quietzsch ◽  
V. Heinemann ◽  
A. Liebert ◽  
M. Haenel
Keyword(s):  
Pancreatic Cancer ◽  
Treatment Group ◽  
Pancreatic Carcinoma ◽  
Phase Ii ◽  
Pilot Trial ◽  
Stage Iv ◽  
Historical Control ◽  
Phase Iii ◽  
Stage Iii ◽  
Similar Proportion

14000 Background: (E)-5-(2-bromovinyl)-2’-deoxyuridine (BVDU, RP101), which supports apoptosis and prevents the acquisition of chemoresistance, was tested in cultured human pancreatic tumor cells. RP101 down-regulated uridine phosphorylase, a marker of poor prognosis, and APEX1, which is involved in DNA repair, and repressed Stat-3 and its target VEGF. Furthermore, RP101 activated antitumor immunity. These results encouraged us to investigate the effect of RP101 in combination with gemcitabine (GEM) and cisplatin (CIS) in patients with advanced pancreatic cancer. Methods: A phase II pilot trial was designed to compare the GEM/CIS/RP101 combination to historical GEM/CIS combination. The primary endpoint was survival. 13 pts with histological documented pancreatic carcinoma received GEM 1.000 mg/m2 plus CIS 50 mg/m2 on days 1 and 15 of a 28-day schedule. RP101 treatment was on the same day and for four days after chemotherapy (500 mg/day). Results: All patients showed at least a stable disease, and 33% of them a PR. As a historical control, 22 pts were selected by random generator from 98 patients enrolled in a previous Phase III study performed in the same centers, 15 with stage IV and 7 with stage III disease, resulting in a similar proportion of stage III to IV patients as in the RP101 co-treatment group (nine stage IV and four stage III). In the RP101-co-treatment group the median survival was significantly longer than that of the historical control group (447 days vs. 186 days, p=0.007). Time to progression (TTP) was also prolonged (280 days vs. 104 days, p=0.004). Ten of the 13 pts lived longer than one year, 4 nearly two years after first treatment. Conclusions: The combined use of GEM/CIS/RP101 prolonged progression-free and overall survival in locally advanced and metastatic pancreatic cancer when compared to all published studies with all combinations of drugs. A repeat study with GEM/RP101 shows similar promising results indicating that the combination of RP101 with GEM should be explored in larger studies in patients with advance pancreatic cancer. [Table: see text]

Sunitinib (SU) in patients with advanced, progressive pancreatic neuroendocrine tumors (pNET): Final overall survival (OS) results from a phase III randomized study including adjustment for crossover.

2016 ◽  
Vol 34 (4_suppl) ◽  
pp. 309-309 ◽  
Author(s):  
Eric Raymond ◽  
Patricia Niccoli ◽  
Daniel Castellano ◽  
Juan W. Valle ◽  
Pascal Hammel ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Proportional Hazards Model ◽  
Failure Time ◽  
Randomized Study ◽  
Cox Proportional Hazards ◽  
Cox Proportional Hazards Model ◽  
Phase Iii ◽  
Double Blind ◽  
Clinical Trial Information

309 Background: In 2010, the pivotal double blind Phase III study met its primary endpoint with a median progression-free survival (PFS) of 11.4 months (mo) for sunitinib vs. 5.5 mo for placebo (PBO) (HR=0.42; 95% CI 0.26-0.66; P <0.001) in patients (pts) with advanced, progressive pNET. This trial showed an OS difference favouring sunitinib (HR=0.41; 95% CI 0.19-0.89; P = 0.02). At 2 years since study closure, median OS was 33.0 mo for SU and 26.7 mo for PBO (HR=0.71; 95% CI 0.47-1.09; P = 0.115). Methods: A total of 171 pts were randomly assigned 1:1 to SU 37.5 mg continuous daily dose (n = 86) or PBO (n = 85). The primary end-point was investigator assessed PFS. Pts receiving PBO could crossover to SU at disease progression. Final OS at 5 years follow-up since study closure was analyzed using the Kaplan-Meier method and Cox proportional hazards model in the intent-to-treat (ITT) population. In addition, a series of methods were used to adjust for cross-over including rank-preserving structural failure time (RPSFT). Clinical trial information: NCT00428597 . Results: At 5 years follow-up since study closure, the median OS was 38.6 mo for those randomized to SU and 29.1 mo for those randomized to PBO (HR=0.73, 95% CI 0.50-1.06; P = 0.094). In total, 59 pts randomized to PBO (69%) crossed over to SU. OS results obtained applying methods to adjust for cross-over are shown in Table 1. Conclusions: The 5-year OS difference (9.5 mo) between SU and PBO is confirmed. Correction for crossover yielded a stronger OS advantage with SU, confirming that crossover likely confounded the OS results. Clinical trial information: NCT00428597. [Table: see text]

Phase Ib study of concurrent durvalumab and radiation therapy (DUART) followed by adjuvant durvalumab in patients with urothelial cancer of the bladder: BTCRC-GU15-023 study.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 455-455 ◽  
Author(s):  
Monika Joshi ◽  
Leonard Tuanquin ◽  
Matthew Kaag ◽  
Yousef Zakharia ◽  
Jason Liao ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Human Monoclonal Antibody ◽  
Locally Advanced ◽  
Safety Data ◽  
Stage Iv ◽  
Phase Ib ◽  
Cancer Of The Bladder ◽  
Platinum Refractory ◽  
Grade 3 ◽  
Clinical Trial Information

455 Background: There is a significant variation in the treatment of locally advanced unresectable (T2-4 N0-2 M0) or cisplatin-ineligible (non-cis) bladder cancer (BC) patients (pts). The advent of immunotherapy (IO) in non-cis stage IV BC has been promising (response rate [RR] 23%; median survival 16 mo) but we are still in need of novel combinations for locally advanced unresectable BC. Durvalumab (Durva) is a human monoclonal antibody that inhibits the binding of PD-L1 to PD-1 on T-cell receptors. It has shown efficacy in platinum refractory BC with RR of 17%. Radiation (RT) is also effective in BC and can upregulate pro-inflammatory signals allowing for improved antitumor activity of IO. We report the safety data from phase Ib trial of combining RT with Durva (DurvaRT) in locally advanced BC. Methods: Treatment (Rx) naïve or post neoadjuvant chemotherapy pts with T3-4, N0-2, M0 who were either unresectable or unfit for surgery were treated with DurvaRT followed by Durva. Rx naïve locally advanced non-cis pts were also included in the study. DurvaRT: Durva 1500mg D1, D28 plus concurrent RT, 64.8Gy given in 36 fractions over 7weeks starting D1. These patients then started adjuvant Q4 weekly Durva after 4 weeks for 12 months. Primary end point for Ph Ib was safety of combining Durva with RT during 7-weeks period. Results: We enrolled 6 pts on phase Ib. 5/6 pts had completed the DurvaRT phase and none of them had any dose limiting toxicity. The table below summarizes the treatment related adverse events (TRAE). Post DurvaRT 3/4 pts have ongoing ORR; 1 pt. had progression; Rx response evaluation in 2 pts is ongoing. Clinical trial information: NCT02891161. Conclusions: DurvaRT was tolerable in pts with locally advanced unresectable BC, where there is a dearth for good Rx options. No grade 3 immune related AEs were observed during DurvaRT. Further investigation with DurvaRT is ongoing to evaluate the efficacy in this subset of pts (Clinical trial # NCT02891161).[Table: see text]

Phase II clinical trial with a second generation, GM-CSF encoding, oncolytic herpesvirus in unresectable metastatic melanoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 9035-9035 ◽  
Author(s):  
N. N. Senzer ◽  
H. Kaufman ◽  
T. Amatruda ◽  
M. Nemunaitis ◽  
G. Daniels ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Metastatic Melanoma ◽  
Phase Ii ◽  
Response Rate ◽  
Objective Response ◽  
Stage Iv ◽  
Complete Response ◽  
Phase Iii ◽  
Stage Iiic ◽  
Gm Csf

9035 Background: OncoVEXGM-CSF is a an oncolytic HSV, encoding GM-CSF . We recently completed a phase II trial involving 50 advanced melanoma patients (stage IIIc and IV) with at least one injection accessible lesion, including by ultrasound. Methods: Patients received a single IT injection of 106 pfu/ml apportioned between 10 or less injectable tumors, followed 3 wks later by 24 or less sequential injections of 108 pfu/ml every 2 wks until clinically significant disease progression, or overall or injectable lesion complete response. Response (RECIST modified to allow progression before response and biopsy of residual masses) and survival were monitored. Results: All 50 pts have been enrolled and are evaluable (Stage IIIc, n=10; IV M1a, n=16; IV M1b, n=4; IV M1c, n=20). A median of 6 injections were administered. Adverse effects were limited and generally involved transient flu-like symptoms. Both injected and uninjected regional and distant disease demonstrated response including clearly documented responses at uninjected visceral sites. The overall response rate was 26% (8 CR, 5 PR); 10 responses have been maintained for >6 months and 2 are ongoing at <6months, the longest currently being at 35 months from first dose. 93% of patients (14 of 15) with PR, CR or surgical CR remain alive. Ten additional patients had SD for >3 months. Kaplan Meier one year survival is 61% overall, 58% stage IV only, 48% for Stage IV M1c. The median OS is 16+ months. Conclusions: The 1-year survival and durable objective response rate are encouraging. Responses of distant and visceral disease provide further compelling evidence of systemic effectiveness. This, combined with a limited toxicity profile, suggests OncoVEXGM-CSF is a promising treatment for metastatic melanoma. A phase III clinical trial is planned. [Table: see text]

Overall survival (OS) analysis from an expanded access program (EAP) of nivolumab (NIVO) in combination with ipilimumab (IPI) in patients with advanced melanoma (MEL).

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 9522-9522 ◽  
Author(s):  
David Hogg ◽  
Paul B. Chapman ◽  
Mario Sznol ◽  
Christopher D. Lao ◽  
Rene Gonzalez ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Phase Ii ◽  
Safety Data ◽  
Stage Iv ◽  
Clinical Trial Data ◽  
Induction Phase ◽  
Drug Induced ◽  
Metastatic Setting ◽  
Treatment Naïve ◽  
Grade 3

9522 Background: NIVO (anti-PD-1) and IPI (anti-CTLA-4), alone and in combination, are approved for the treatment of MEL. Phase II and III trials showed improved efficacy for NIVO+IPI versus IPI alone, but with a higher frequency of adverse events (AEs). In the phase II CheckMate 069 trial, the 2-year OS rate was 63.8% for all patients (pts) in the NIVO+IPI group. We report the first OS analysis, as well as updated safety data, from a North American EAP of NIVO+IPI in pts with MEL (CheckMate 218; NCT02186249). Methods: CheckMate 218 included pts with MEL who could have progressed on other therapies, but were anti-CTLA-4 and anti-PD-1 treatment-naive. Pts received NIVO 1 mg/kg + IPI 3 mg/kg Q3W x 4, followed by NIVO 3 mg/kg Q2W until disease progression or a maximum of 48 weeks from the first monotherapy dose. We assessed OS in the US cohort (n = 580) and safety in all pts (n = 732). Pts were followed for a minimum of 1 year in the USA and 6 months in Canada. Results: Of 732 pts, 43% had a BRAFmutation, 84% stage IV MEL, 51% M1c disease, 31% LDH > ULN (9% LDH > 2x ULN), and 13% received ≥1 prior systemic therapy in the metastatic setting. All pts received a median of 3 doses each for NIVO (range: 1–4) and IPI (range: 0–4) in the induction phase; 34% of pts received at least 1 dose of NIVO maintenance. The 1- and 2-year OS rates were 78.6% (95% CI: 74.2–82.4) and 65.3% (95% CI: 56.1–73.0), respectively. AEs of any grade occurred in 717 pts (98%), with grade 3/4 AEs in 470 pts (64%). Immune-modulating medications were used to manage any grade AEs, including grade 1/2 skin and gastrointestinal AEs, in 538 of 717 pts (75%), and to manage grade 3/4 AEs in 279 of 470 pts (59%). The most common treatment-related AEs of any grade were diarrhea (39%), pruritus (26%), and an increase in aspartate aminotransferase level (23%). Treatment-related deaths in 2 pts were reported as drug-induced liver injury and myocardial infarction. Conclusions: In this EAP, which included pts who had received prior systemic therapies for MEL and pts with poor prognostic factors generally not included in clinical trials, NIVO+IPI treatment demonstrated survival outcomes and a safety profile consistent with clinical trial data. Clinical trial information: NCT02186249.

scholarly journals A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique.

1987 ◽  
Vol 5 (6) ◽  
pp. 941-950 ◽  
Author(s):  
T Philip ◽  
R Ghalie ◽  
R Pinkerton ◽  
J M Zucker ◽  
J L Bernard ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Bone Marrow Involvement ◽  
Stage Iv ◽  
Observation Time ◽  
Phase Iii ◽  
High Dose ◽  
Initial Stage ◽  
Duration Of Response

Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.

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.

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