302 A phase I trial of intratumoral PVSRIPO in patients with unresectable treatment refractory melanoma

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A329-A329
Author(s):  
Georgia Beasley ◽  
Nellie Farrow ◽  
Karenia Landa ◽  
Maria Angelica Seilm ◽  
Sin-Ho Jung ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Tumor Response ◽  
Clinical Investigation ◽  
Objective Response ◽  
Pathologic Complete Response ◽  
Disease Status ◽  
Primary Objective ◽  
Open Label ◽  
Preclinical Data

BackgroundWhile PD-1/PD-L1 antagonists have improved the prognosis for many patients with melanoma, the majority fail therapy. PVSRIPO is a novel immunotherapy consisting of a non-neurovirulent rhinovirus:poliovirus chimera that activates innate immunity to facilitate a targeted anti-tumor immune response. Preclinical data show that PVSRIPO plus anti-PD-1 therapy leads to a greater anti-tumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (AJCC version 7 stage IIIB, IIIC, or IV) was performed. Eligible patients failed at least prior anti-PD-1 and BRAF/MEK (if BRAF mutant) therapy. The primary objective was to characterize the safety and tolerability of PVSRIPO. 12 patients in 4 cohorts received a total of 1, 2 (into 2 different lesions) or 3 (same lesion 3x or 3 different lesions) injections of PVSRIPO monotherapy, 21 days apart.ResultsPVSRIPO injections were well tolerated with no SAEs or DLTs reported; all TEAEs were grade (G) 1 or 2 (grade 1 pruritus most common at 58%), with all but 2 PVSRIPO-related TEAEs localized to the injected or adjacent lesions ( n=1 G1 hot flash, n=1 G1 fatigue). Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients >5 lesions), 4 of 12 patients (33%) achieved an objective response per irRC, including 4/6 (66%) who received 3 injections (maximum administered). Pathologic complete response (ie, no viable tumor detected in injected and non-injected lesions biopsied) was observed in 2 of 4 (50%) patients with in-transit disease. PVSRIPO response relative to time since prior anti-PD-1 exposure is summarized in table 1. Following study completion/PVSRIPO therapy, 10/12 patients (83%) again received immune checkpoint inhibitor (ICI)-based therapy and 6/12 patients (50%) remained progression free at the data cutoff.Abstract 302 Table 1PVSRIPO anti-tumor response relative to ICI administration and post-study disease statusConclusionsIntratumoral PVSRIPO was well tolerated. When taken together with preclinical data, the anti-tumor responses observed relative to prior or subsequent ICI therapy suggests that PVSRIPO, either alone or in combination with anti-PD-1, may be an effective treatment in anti-PD-1 refractory melanoma. An amendment exploring higher PVSRIPO dose levels is ongoing and a phase 2 study with and without anti-PD-1 in the refractory population is initiating.Ethics ApprovalThis study (NCT03712358) was approved by WIRB; ID 20181772.

scholarly journals Phase I trial of intratumoral PVSRIPO in patients with unresectable, treatment-refractory melanoma

2021 ◽  
Vol 9 (4) ◽  
pp. e002203
Author(s):  
Georgia M Beasley ◽  
Smita K Nair ◽  
Norma E Farrow ◽  
Karenia Landa ◽  
Maria Angelica Selim ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase I ◽  
Phase I Trial ◽  
Clinical Investigation ◽  
Objective Response ◽  
Complete Response ◽  
Primary Objective ◽  
Mitogen Activated Protein Kinase ◽  
Open Label ◽  
Serious Adverse Events

BackgroundWhile programmed cell death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) antagonists have improved the prognosis for many patients with melanoma, around 60% fail therapy. PVSRIPO is a non-neurovirulent rhinovirus:poliovirus chimera that facilitates an antitumor immune response following cell entry via the poliovirus receptor CD155, which is expressed on tumor and antigen-presenting cells. Preclinical studies show that oncolytic virus plus anti-PD-1 therapy leads to a greater antitumor response than either agent alone, warranting clinical investigation.MethodsAn open-label phase I trial of intratumoral PVSRIPO in patients with unresectable melanoma (American Joint Committee on Cancer V.7 stage IIIB, IIIC, or IV) was performed. Eligible patients had disease progression on anti-PD-1 and V-raf murine sarcoma viral oncogene homolog B (BRAF)/mitogen activated protein kinase kinase (MEK) inhibitors (if BRAF mutant). The primary objective was to characterize the safety and tolerability of PVSRIPO. Twelve patients in four cohorts received a total of 1, 2 or 3 injections of PVSRIPO monotherapy, with 21 days between injections.ResultsPVSRIPO injections were well tolerated with no serious adverse events (SAEs) or dose-limiting toxicities (DLTs) reported. All adverse events (AEs) were grade (G) 1 or G2 (G1 pruritus most common at 58%); all but two PVSRIPO-treatment related AEs were localized to the injected or adjacent lesions (n=1 G1 hot flash, n=1 G1 fatigue). Four out of 12 patients (33%) achieved an objective response per immune-related response criteria (two observations, 4 weeks apart), including 4/6 (67%) who received three injections. In the four patients with in-transit disease, a pathological complete response (pCR) was observed in two (50%) patients. Following study completion, 11/12 patients (92%) reinitiated immune checkpoint inhibitor-based therapy, and 6/12 patients (50%) remained without progression at a median follow-up time of 18 months.ConclusionIntratumoral PVSRIPO was well tolerated. Despite the limited number of PVSRIPO treatments relative to the overall lesion burden (67% patients>5 lesions), intratumoral PVSRIPO showed promising antitumor activity, with pCR in injected as well as non-injected lesions in select patients.Trial registration numberNCT03712358

A phase I trial evaluating NBTXR3 activated by radiotherapy in combination with nivolumab or pembrolizumab in patients with advanced cancers.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 2590-2590
Author(s):  
Colette Shen ◽  
Jessica M. Frakes ◽  
Jiaxin Niu ◽  
Ari Rosenberg ◽  
Jared Weiss ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Trial ◽  
Tumor Regression ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Kidney Injury ◽  
Complete Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label

2590 Background: Immune checkpoint inhibitors (ICIs) targeting PD-1 are an effective treatment for a variety of cancers. However, the majority of patients (pts) exhibit resistance to ICIs. Overcoming this resistance represents a major challenge in immuno-oncology. Emerging evidence suggests radiation therapy (RT) produces an immunomodulatory effect that may act synergistically with ICIs. However, RT dose and ultimate efficacy are limited by toxicity to surrounding healthy tissues. NBTXR3, a novel radioenhancer administered by direct intratumoral injection (ITI), is designed at the nanoscale to increase RT dose deposit within tumor cells and subsequent tumor cell killing, without increasing toxicity to surrounding healthy tissue. Preclinical data suggest NBTXR3/RT can trigger a local and systemic anti-tumor immune response and overcome anti-PD-1 resistance. NBTXR3/RT combined with anti-PD-1 may prime the immune system to increase the proportion of ICI responders, or convert ICI non-responders to responders. Methods: This is a multicenter, open-label, phase I trial [NCT03589339] to evaluate NBTXR3/RT/anti-PD-1 in 3 cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to HN re-irradiation, and metastases from any primary cancer eligible for anti-PD-1 (nivolumab or pembrolizumab) treatment specifically localized in the lung (2) or liver (3), respectively. Stereotactic body RT (SBRT) is delivered at tumor-site selective doses per standard practice. The primary objective is NBTXR3/RT/anti-PD-1 recommended phase 2 dose in each cohort. Secondary objectives are anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection. Results: Nine pts have been treated: 3 HNSCC, 4 lung, 2 liver. 7/9 pts were anti-PD-1 non-responders. Overall tumor regression was observed in 8/9 pts. NBTXR3/RT/anti-PD-1 resulted in tumor regression in 6/7 pts who had progressed on prior anti-PD-1. A complete response in the injected lymph node lasting over 1 year was observed in 1 anti-PD-1 naïve pt. 2 SAEs related to anti-PD-1 and possibly related to NBTXR3 (G5 pneumonitis, G4 hyperglycemia) were observed in 1 anti-PD-1 naïve HNSCC pt and considered DLTs. This pt also experienced 2 other SAEs related to anti-PD-1 (G4 diabetic ketoacidosis, G4 acute kidney injury). SBRT-related safety profile was as expected. Updated results will be presented. Conclusions: Data from this first-in-human phase I trial evaluating NBTXR3/RT/anti-PD-1 in pts with advanced cancers, show NBTXR3 ITI is feasible and well-tolerated. NBTXR3/RT/anti-PD-1 demonstrated promising signs of efficacy. Of particular interest, NBTXR3/RT can overcome ICI resistance in pts having progressed on prior anti-PD-1, supporting further development of NBTXR3 in combination with anti-PD-1 as well as other ICIs. Clinical trial information: NCT03589339.

Phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with an anti-PD-1 therapy.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS3173-TPS3173 ◽  
Author(s):  
Colette Shen ◽  
Jessica Frakes ◽  
Jared Weiss ◽  
Jimmy J. Caudell ◽  
Trevor G Hackman ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label ◽  
Open Label Phase

TPS3173 Background: Despite the past decade of transformative advances in immuno-oncology, the response rate to checkpoint inhibitors (ICIs) remains low (~15%). There is significant interest in developing strategies to overcome resistance to these treatments, thus increasing response rate. Emerging evidence suggests that radiation therapy (RT) could potentially augment the antitumor response to ICIs through synergic effect. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. NBTXR3 is a first-in-class radioenhancer administered by direct intratumoral injection, designed at the nanoscale to increase RT dose deposition within tumor cells and RT-dependent tumor cell killing, without increasing surrounding normal tissue toxicity. Preclinical and early clinical data suggest NBTXR3 activated by RT can trigger an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect and produce a systemic response sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: This trial [NCT03589339] is a multicenter, open-label, phase I study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases, or (3) Liver metastases, both from any primary cancer eligible for anti-PD-1 treatment. Approximately two-thirds of patients in each cohort will be anti-PD-1 non-responders. NBTXR3 injected volume is based on a percentage of gross tumor volume (GTV). The primary objective is to determine the R3/RT/PD-1 recommended phase 2 dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, as well as mRNA and cytokine immune marker profiling. To date, three patients have been treated, one in cohort 1, two in cohort 2. Clinical trial information: NCT03589339 .

Preliminary results of a phase I trial of FT516, an off-the-shelf natural killer (NK) cell therapy derived from a clonal master induced pluripotent stem cell (iPSC) line expressing high-affinity, non-cleavable CD16 (hnCD16), in patients (pts) with relapsed/refractory (R/R) B-cell lymphoma (BCL).

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7541-7541
Author(s):  
Paolo Strati ◽  
Veronika Bachanova ◽  
Aaron Goodman ◽  
John M. Pagel ◽  
Januario E. Castro ◽  
...  
Keyword(s):  
Phase I ◽  
Neutrophil Count ◽  
Phase I Trial ◽  
Nk Cell ◽  
Cell Cancer ◽  
Objective Response ◽  
B Cell Lymphoma ◽  
Primary Objective ◽  
Ipsc Line ◽  
Grade 3

7541 Background: FT516 is an investigational, NK cell cancer immunotherapy derived from a clonal master iPSC line. FT516 is engineered with a novel hnCD16 Fc receptor, demonstrated preclinically to maximize antibody-dependent cellular cytotoxicity (Zhu et al. Blood 2020). FT516 can be mass produced and made available off-the-shelf for broad pt access and multi-dose administration. Methods: This is a Phase I trial of FT516 combined with rituximab (R) in pts with R/R BCL. Treatment consists of 2 cycles, each with 3 days lympho-conditioning (fludarabine 30 mg/m2 and cyclophosphamide 500 mg/m2) and 1 dose of R followed by 3 weekly infusions of FT516 (planned doses 30-900 million/dose) with IL-2 (6 MIU after each FT516 dose). The primary objective is to identify the incidence of dose-limiting toxicity (DLT)/dose cohort and the recommended Phase II dose using a standard 3+3 design. Additional objectives include safety, tolerability, preliminary activity, pharmacokinetics, and immunogenicity. Results: Six pts (5 DLBCL, 1 FL, median age 65.5 y) have completed (5) or discontinued (1) study treatment after the DLT period (data cutoff 9 Dec 2020): 2 received 30 million cells/dose, 3 received 90 million cells/dose, and 1 received 300 million cells/dose. All pts received > 1 prior R-containing regimen, and median number of prior therapies was 3 (range 2-6), including CAR-T in 3 pts. FT516 was primarily administered in the outpatient setting. No FT516-related Grade ≥3 adverse events (AEs) or serious AEs, and no events of cytokine release syndrome (CRS), immune effector cell-associated neurotoxicity syndrome (ICANS), or graft-versus-host disease (GvHD) of any grade were reported. DLT (Grade 4 neutrophil count decreased, not recovered to baseline by D29) was reported in the first pt at 30 million cells/dose and R dosing of 375 mg/m2 weekly x 4/cycle, resulting in modification of R dosing to once/cycle; no DLTs were observed with modified R dosing. Most common all grade AEs in ≥3 pts: fatigue (4 pts) and decreased appetite, nausea, neutrophil count decreased, and headache (3 pts each). Grade ≥3 AEs in ≥2 pts: neutrophil count decreased (3 pts) and febrile neutropenia and platelet count decreased (2 pts each); none considered related to FT516. Host anti-product B- or T-cell immunogenicity was not observed. Three of 4 pts treated at ≥90 million cells/dose achieved objective response (2 complete responses [CRs] and 1 partial response). Conclusions: Administration of up to 6 doses of FT516 cells, including up to 300 million cells/dose, appears to be safe and tolerable, without CRS, ICANS, or GvHD. Activity was observed, including CRs, in heavily pretreated pts. Dose escalation is ongoing. Updated clinical and translational data will be presented. Clinical trial information: NCT04023071.

Oral DNA vaccination targeting VEGFR-2 combined with anti-PD-L1 avelumab in patients with progressive glioblastoma, a phase I/II study: NCT03750071.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2076-TPS2076
Author(s):  
Wolfgang Wick ◽  
Antje Wick ◽  
Michael Platten ◽  
Olivier L. Chinot ◽  
Martin J. Van Den Bent ◽  
...  
Keyword(s):  
Phase I ◽  
Clinical Response ◽  
Oral Vaccine ◽  
Objective Response ◽  
Safety Evaluation ◽  
Data Safety Monitoring Board ◽  
Primary Objective ◽  
Open Label ◽  
Before And After ◽  
Open Label Phase

TPS2076 Background: The vaccine (VXM01) is a VEGFR-2 coding DNA vaccine, using a Salmonella Ty21a carrier for oral application. VEGFR-2 is over-expressed in glioblastoma and serves as a promising target for VEGFR-2 primed T cells with the potential to alter tumor angiogenesis and/or eliminate VEGFR-2 expressing tumor cells. VXM01 was well tolerated in a previous phase I/II study involving 14 patients with progressive glioblastoma multiforme. Immunological correlates of vaccination and anti-tumor immunity in the blood and in the tumor were detected. At least one objective clinical response was attributed to vaccine monotherapy, with one more PR achieved in combination with nivolumab. Prolonged overall survival was associated with peripheral immune responses against VEGFR-2, J Clin Oncol 36, 2018 (suppl; abstr 2017). A combination study with the anti PD-L1 checkpoint inhibitor monoclonal antibody avelumab is currently underway. Methods: A multicentre, open-label phase I/II study ( EudraCT.gov no. 2017-003076-31), will enrol 30 patients with progressive glioblastoma, previously treated with temozolomide/radiotherapy. The primary objective is to evaluate safety and tolerability of the vaccine in combination with avelumab. In a 1+2 safety run in, two cohorts of non-reoperable patients will be vaccinated with one of 2 doses of the oral vaccine (106 or 107 CFU) with concurrent intravenous avelumab. After safety evaluation and recommendation of study continuation by the Data Safety Monitoring Board, 18 non-re-operable and 6 re-operable patients will be treated with 107 CFU of the vaccine + avelumab. Vaccinations for all patients will be on day 1, 3, 5, and 7, followed by 4-weekly boosts until progression. Avelumab 800 mg will be administered every two weeks until progression. The enrolment of cohort 1 started with inclusion of the 1st patient in November 2018. The end of study is week 60. Follow up visits will be on months 1, 3, 6, 12 and 24. Objective response rate (ORR), clinical response using iRano criteria, immunological correlates before and after treatment using ELISpot, FACS, TCR-sequencing, IF, and IHC laboratory methods. Clinical trial information: NCT03750071.

An open-label, phase I trial of BI 754091 alone and in combination with BI 754111 in Asian patients (pts) with advanced solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3054-3054
Author(s):  
Yoon-Koo Kang ◽  
Kensei Yamaguchi ◽  
Do-Youn Oh ◽  
Shunsuke Kondo ◽  
Yasutoshi Kuboki ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Primary Endpoint ◽  
Dose Escalation ◽  
Phase I Trial ◽  
Objective Response ◽  
Hepatocellular Cancer ◽  
Maximum Tolerated Dose ◽  
Advanced Solid Tumors ◽  
Open Label

3054 Background: Dual blockade of immune checkpoint molecules, PD-1 and LAG-3, may enhance the anti-tumor response versus PD-1 blockade alone. This Phase I trial investigated BI 754091, an anti-PD-1 antibody, as monotherapy and in combination with BI 754111, an anti-LAG-3 antibody, in Asian pts with advanced solid tumors. Methods: This trial comprised 3 parts. Parts 1 and 2 (dose escalation) were in pts with unresectable/metastatic solid tumors. In Part 1, pts received BI 754091 240 mg intravenously (iv), every 3 weeks (q3w); in Part 2, pts received BI 754091 240 mg in combination with BI 754111 (400 mg, 600 mg or 800 mg iv, q3w). Dose escalation was guided by a Bayesian logistic regression model, with overdose control. The primary endpoint in Parts 1 and 2 was maximum tolerated dose (MTD) of BI 754091 alone or in combination with BI 754111, based on dose-limiting toxicities (DLTs) in Cycle 1. In Part 3, BI 754091 240 mg plus BI 754111 600 mg q3w was assessed in 4 expansion cohorts. Cohorts A–C included pts with: A) gastric/esophagogastric junction cancer; B) esophageal cancer; C) hepatocellular cancer; all had received ≥1 line of prior systemic therapy and no prior anti-PD-(L)1 therapy. Cohort D included pts who had received prior anti-PD-(L)1 therapy for the tumor types in Cohorts A–C. The primary endpoint in Part 3 was objective response (confirmed complete response or partial response [PR] per RECIST 1.1). Results: In Part 1, 6 pts received BI 754091 240 mg. In Part 2, 9 pts received BI 754091 240 mg plus BI 754111 (400 mg/600 mg/800 mg; n = 3 per cohort). No DLTs were reported in Parts 1 and 2. In Part 3, 121 pts were treated (97 [80%] male, median age 61 years [range 23–80]); Cohorts A/B/C/D included 33/33/20/35 pts. All-grade adverse events (AEs) and treatment-related AEs (TRAEs) were experienced by 96 (79%) and 47 (39%) pts, respectively. The most commonly reported AEs (all/≥G3) were pyrexia (21%/0%), decreased appetite (17%/2%), anemia (11%/6%), and nausea (9%/0%). 36 (30%) pts reported immune-related AEs, most commonly hypothyroidism, in 7 (6%) pts. Confirmed PR was observed in 6 pts (5%; Cohort A/B, n = 4/2) and 35 (29%) pts had stable disease (Cohort A/B/C/D, n = 9/11/10/5). Conclusions: MTD was not reached for BI 754091 monotherapy or for BI 754091 in combination with BI 754111. The recommended dose for the combination was determined as BI 754091 240 mg plus BI 754111 600 mg q3w. Treatment was well tolerated and consistent with that observed in the global trial. Preliminary anti-tumor activity was seen. Clinical trial information: NCT03433898 .

NANORAY-1100: A phase I study of NBTXR3 activated by radiotherapy in patients with advanced cancers treated with anti-PD-1 therapy.

2020 ◽  
Vol 38 (5_suppl) ◽  
pp. TPS86-TPS86 ◽  
Author(s):  
Colette J. Shen ◽  
Katherine LaRoque Jameson ◽  
Jared Weiss ◽  
Trevor Hackman ◽  
Robert Dixon ◽  
...  
Keyword(s):  
Tumor Response ◽  
Checkpoint Inhibitors ◽  
Lung Metastases ◽  
Phase 1 ◽  
Immune Therapy ◽  
Objective Response ◽  
Systemic Effect ◽  
Primary Objective ◽  
Primary Cancer ◽  
Open Label

TPS86 Background: Most cancer patients present resistance to immune therapy; only approximately 15% of patients respond to immune checkpoint inhibitors (ICI). Strategies able to increase ICI response are thus of great interest. Radiotherapy (RT), by acting as an immunomodulator is a good candidate to increase the proportion of ICI responders. However, RT dose and ultimate efficacy are limited by potential toxicity to healthy tissues. NBTXR3, a first in class radioenhancer administered by intratumoral injection, has been designed at the nanoscale to increase RT energy dose deposition within the tumor. The result is increased radiation-dependent tumor cell killing, without increasing radiation exposure of healthy tissues. Preclinical and early clinical data suggest NBTXR3 activated by RT can increase the anti-tumor response yielding both local and systemic (abscopal) effects. We hypothesize that NBTXR3 activated by RT, in combination with anti-PD-1 therapy (R3/RT/PD-1), will act synergistically to maximize the local RT effect while also producing a systemic effect sufficient to increase the proportion of ICI responders or convert ICI non-responders to responders. Methods: NANORAY-1100 [NCT03589339] is a multicenter, open-label, phase 1 study to evaluate safety and tolerability of R3/RT/PD-1 in three cohorts: (1) Locoregionally recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2) Lung metastases from any primary cancer eligible for anti-PD-1, or (3) Liver metastases from any primary cancer eligible for anti-PD-1. Approximately two-thirds of each cohort will be composed of anti-PD-1 non-responders. NBTXR3 injection volume is based on a percentage of gross tumor volume (GTV) determined by central review. The primary objective is to determine R3/RT/PD-1 RP2D. Secondary objectives are to evaluate anti-tumor response (objective response rate; ORR) of R3/RT/PD-1, safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile. Exploratory objectives will assess biomarkers of R3/RT/PD-1 response, including PD-L1 status by IHC, mRNA and cytokine immune marker profiling. Clinical trial information: NCT03589339.

A phase I evaluation of vandetanib plus paclitaxel, carboplatin, 5-fluorouracil, and XRT induction therapy followed by surgery for previously untreated locally advanced cancer of the esophagus and GE junction.

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 74-74 ◽  
Author(s):  
Igor A. Astsaturov ◽  
Joshua E. Meyer ◽  
Jonathan D. Cheng ◽  
Anthony J. Olszanski ◽  
Holly Dushkin ◽  
...  
Keyword(s):  
Phase I ◽  
Locally Advanced ◽  
Pathologic Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Cancer Center ◽  
Clinical Activity ◽  
Open Label ◽  
Curative Intent ◽  
Carcinoma Of The Esophagus

74 Background: Vandetanib (Vb) is an oral inhibitor that selectively targets VEGFR2, VEGFR3, RET and EGFR. Preclinical models indicate synergy with radiation and chemotherapy. We report the final results from an open-label phase I study of pre-operative Vb with carboplatin, paclitaxel, 5FU and radiation in pts with operable esophageal and GE junction (GEJ) carcinomas. Methods: Pts with operable PET/CT and EUS-staged carcinoma of the esophagus and GEJ received once daily Vb with concomitant RT (1.8 Gy/d, total 45 Gy) plus carboplatin AUC5 (d1 and 29), paclitaxel (50 mg/m2, d1,8,15,22,29), and 5-FU (CI 225 mg/m2, M-F, 5 wks). The primary objective was the safety, tolerability and the maximum tolerated dose of Vb in this combination. Planned dose escalations of Vb: 100, 200 and 300 mg daily with a “3+3” design. Results: Nine male pts (median age 58 (35-77), stage II, T2-3N0 (2 pts), III, T2-3N+ (7 pts)) were accrued between 03/2009 and 08/2010 at Fox Chase Cancer Center: 2/9 pts had esophageal squamous carcinoma (SCC) and 7/9 pts had adenocarcinoma including GEJ (2 pts). All patients completed the planned induction chemoradiation and underwent esophagectomy with curative intent. Of 3 initial pts at Vb 100 mg, one with SCC died on day 99 from GI hemorrhage which was considered treatment-related. Three more pts received Vb 100 mg and 3 pts received Vb 200 mg daily. Dose limiting toxicities (DLT) occurred in 2/3 pts receiving Vb 200 mg (esophago-gastric anastomotic leak, and diarrhea requiring Vb dose reduction). Grade 3 non-hematological toxicities included diarrhea (2), anorexia (1), abdominal pain (1), hyponatremia (1), AST/ALT (1), depression (1). Dose escalation to 300 mg Vb was not attempted. 5/9 pts had a pathologic complete response (no tumor seen, 56%), 5/9 remain disease free with median followup of 23 months (13-31). 3 pts had distant recurrences at 322, 334 and 561 days. Conclusions: Targeting VEGFR/RET/EGFR with Vb at 100 mg daily in combination with induction chemoradiotherapy for operable esophageal and GEJ cancer is well tolerated and with promising clinical activity warranting further phase II evaluation.

410 Phase I study of intratumoral NBTXR3 in combination with anti-PD-1 in patients with advanced cancers

2020 ◽  
Vol 8 (Suppl 3) ◽  
pp. A435-A435
Author(s):  
Colette Shen ◽  
Jessica Frakes ◽  
Jiaxin Niu ◽  
Jared Weiss ◽  
Jimmy Caudell ◽  
...  
Keyword(s):  
Immune Response ◽  
Phase I ◽  
Response Rate ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Intratumoral Injection ◽  
Primary Objective ◽  
Open Label ◽  
Subsequent Increase ◽  
Open Label Phase

BackgroundCancer immunotherapies have shown promising clinical outcomes; however, the majority of patients are non-responders or will develop resistance during the course of treatment. One of the current challenges is to increase the response rate to immune checkpoint inhibitors (ICIs). Combining immunotherapy with radiation therapy (RT) is emerging as a valuable strategy to prime the immune response. However, RT dose and ultimate efficacy are limited by toxicity related to exposure of healthy tissues. First-in-class radioenhancer NBTXR3, administered by one-time direct intratumoral injection, is designed at the nanoscale to increase RT dose deposit with subsequent increase in tumor cell killing, without increasing toxicity to normal tissue. Preclinical and early clinical data suggest NBTXR3/RT can prime the immune system and act as an in situ vaccine leading to an anti-tumor immune response, producing both local and systemic (abscopal) effects. We hypothesize NBTXR3/RT in combination with anti-PD-1 (NBTXR3/RT/PD-1), will act synergistically to increase the proportion of ICI responders or convert ICI non-responders to responders.MethodsA multicenter, open-label, phase I trial [NCT03589339] evaluating safety and tolerability of NBTXR3/RT/PD-1 in three cohorts: (1; H&N) Locoregional recurrent or recurrent and metastatic head and neck squamous cell carcinoma (HNSCC) amenable to re-irradiation of the HN field, (2; lung) lung or (3; liver) liver metastases from any primary cancer eligible for approved anti-PD-1 treatment. NBTXR3 injected volume is based on a percentage of baseline tumor volume. Stereotactic body RT (SBRT) is delivered as per standard practice. The primary objective is to determine NBTXR3/RT/PD-1 recommended phase II dose in each cohort. Secondary objectives are to evaluate anti-tumor response (objective response rate), safety and feasibility of NBTXR3 injection, and NBTXR3 body kinetic profile.ResultsTo date 6 patients have been treated: 3 in H&N (2 anti-PD-1 naïve) and 3 in lung (all anti-PD-1 non-responders. No DLT or SAE has been observed. Grade 2 nausea related to NBTXR3 or injection procedure was observed in H&N. 2 H&N patients and 3 lung patients have completed RT and initiated anti-PD-1 treatment. RT-related safety profile was as expected. Tumor shrinkage was observed in 1 anti-PD-1 naive and 2 anti-PD-1 non-responders and additional preliminary efficacy and updated safety results will be presented.ConclusionsTo date, NBTXR3 administration activated by SBRT in combination with anti-PD-1 treatment has been safe and well tolerated in patients with advanced cancers. Promising early signs of efficacy in anti-PD-1 naïve, as well as in patients having progressed on previous anti-PD-1 therapy will be presented.Trial RegistrationNCT03589339Ethics ApprovalThis study was approved by local institution’s review board

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