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.

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 .

scholarly journals 413 Toripalimab in combination with concurrent chemoradiation in patients with advanced/metastatic esophageal carcinoma: protocol for a single-arm, prospective, open-label, phase II clinical trial

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A444-A444
Author(s):  
Lei Wu ◽  
Yi Wang ◽  
Gang Wan ◽  
Jiahua Lv ◽  
Qifeng Wang ◽  
...  
Keyword(s):  
Esophageal Carcinoma ◽  
Checkpoint Inhibitors ◽  
Objective Response ◽  
Stage Iv ◽  
Predictive Biomarkers ◽  
Primary Objective ◽  
High Morbidity ◽  
Efficacy And Safety ◽  
Open Label ◽  
Carboplatin Auc

BackgroundEsophageal carcinoma is a disease with high morbidity and mortality in China and, recently, Immune checkpoint inhibitors(ICIs) combined with chemotherapy have shown good efficacy and safety for treatment; however, some patients still suffer from tumor progression or metastasis after treatment. Clinical studies have confirmed that immunotherapy combined with chemoradiotherapy can significantly improve the prognosis of patients with advanced esophageal cancer, but the efficacy and safety of adding radiotherapy to immunotherapy and chemotherapy have been less reported.MethodsThis is an open-label, single-arm, and single-center phase ll trial.Patients with unresectable stage IV esophageal squamous cell carcinoma(ESCC) who had not received prior systemic therapy were enrolled. The patients were treated with two cycles of toripalimab (240 mg d1, Q3W) combined with induction chemotherapy (paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6, d1, Q3W), sequentially combined with concurrent chemoradiotherapy (30–50 Gy in 15–25 fractions, paclitaxel 135–175 mg/m2, d1+carboplatin AUC=4–6 d1, Q3W), followed by maintenance treatment with toripalimab (240 mg d1, Q3W) for 1 year. The primary objective of this trial is to evaluate the progression-free survival (PFS) of this combination therapy;and the secondary objective is related to the assessment of objective response rate (ORR), the disease control rate (DCR), the duration of remission (DOR), the 1- and 2-year overall survival(OS) rates, the safety and tolerability of patients to treatment, and the identification of the changes in the health-related quality of life (HRQoL) of patients. Furthermore, we aimed to identify predictive biomarkers (such as the expression of PD-L1 ctDNA and cytokines) and to explore the relationship between these biomarkers and tumor response to the study treatment.AcknowledgementsWe thank all the participants and their advisors involving in this study. We owe thanks to the patients in our study and their family members.Trial RegistrationChiCTR(ChiCTR2100046715). Registered on the 27th of May 2021.Ethics ApprovalThe study protocol is approved by Ethics Committee of Sichuan Cancer Hospital (SCCHEC-02-2021-021).Changes to the protocol will be communicated via protocol amendment by the study principal investigators. Written informed consent will be obtained from all participants.

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 II study of cabozantinib (cabo) combined with pembrolizumab (pembro) in metastatic or recurrent gastric and gastroesophageal adenocarcinoma (GEC) to overcome resistance to checkpoint inhibitors.

2021 ◽  
Vol 39 (3_suppl) ◽  
pp. TPS253-TPS253
Author(s):  
Farshid Dayyani ◽  
Chloe Thomas ◽  
Gwendolyn Ung ◽  
Thomas H Taylor
Keyword(s):  
Checkpoint Inhibitors ◽  
Treatment Options ◽  
Objective Response ◽  
Unmet Need ◽  
Primary Objective ◽  
Phase 2 ◽  
Open Label ◽  
Secondary Resistance ◽  
Phase 2 Trial ◽  
Number Of Patients

TPS253 Background: GEC is the third leading cause of cancer mortality and the fifth most common malignancy worldwide. Fluoropyrimidine and platinum-based combinations are the most commonly used 1L treatment regimens. There are few standard treatment options after 1st line regimens. In the 3L+ GEC Keynote-059 trial, objective response rate (ORR) with Pembro was 15.5% in PD-L1(+) vs. 6.4% in PD-L1(-) tumors. While the responses were durable, the 6-months PFS (6-PFS) was only 14.1% and the median PFS was 2.0 mo. This highlights the remaining unmet need for the majority of patients who either are refractory or develop disease progression following treatment with PD-1 inhibitors in GEC. Cabo plus checkpoint inhibitors have shown clinical benefit in various cancers including hepatocellular, renal cell (RCC), urothelial and castration-resistant prostate cancers. In the CheckMate-9ER trial, Cabo+Nivolumab improved both OS and PFS vs sunitinib in 1L RCC. In patients with RCC who had progression on anti-PD1 inhibitor treatment, Cabo showed promising activity with an ORR of 33% and DCR of 79% (ESMO 2018, abstract 3793). Hypothesis: Based on preclinical and clinical observations, Cabo might contribute to overcoming primary or secondary resistance to PD-1 blockade in GEC. Methods: Prospective, open label, non-randomized phase 2 trial. Eligibility: Diagnosis of GEC, 2+ line of treatment including previous fluoropyrimidine/platinum, ECOG 0-2, adequate organ function, prior checkpoint inhibitor if tumor PD-L1 CPS≥10%. Treatment: Cabozantinib 40mg PO daily, Pembrolizumab 200 mg IV on day 1 of 21d cycle. Primary objective: Feasibility of the combination and estimate of efficacy. Primary endpoint:PFS-6. Secondary objectives: OS, ORR, adverse events. Total number of patients to be enrolled N = 27. Current enrollment (Sep 2020) N = 10. Statistics: If the PFS-6 is > 25%, the study would be regarded as positive, in which case it is planned to expand patient enrollment into a larger single arm phase 2 trial with additional sites to establish the efficacy of the regimen. Clinical trial information: NCT04164979.

Phase I study of AMG 160, a half-life extended bispecific T-cell engager (HLE BiTE) immune therapy targeting prostate-specific membrane antigen (PSMA), in patients with metastatic castration-resistant prostate cancer (mCRPC).

2020 ◽  
Vol 38 (6_suppl) ◽  
pp. TPS261-TPS261 ◽  
Author(s):  
Ben Tran ◽  
Lisa Horvath ◽  
Tanya B. Dorff ◽  
Richard Greil ◽  
Jean-Pascal H. Machiels ◽  
...  
Keyword(s):  
T Cells ◽  
Tumor Cells ◽  
Phase 1 ◽  
Immune Therapy ◽  
Objective Response ◽  
Total Serum ◽  
Leptomeningeal Disease ◽  
Castration Resistant Prostate Cancer ◽  
Open Label ◽  
Pet Ct

TPS261 Background: AMG 160 is a novel HLE BiTE immune therapy that redirects T cells to kill tumor cells by binding to PSMA on tumor cells and CD3 on T cells. Methods: Primary objectives of this open-label, ascending, multiple-dose, phase 1 study (NCT03792841) are to evaluate safety and tolerability and determine the maximum tolerated dose (MTD) or recommended phase 2 dose (RP2D) of AMG 160 in men with mCRPC; secondary objectives are to characterize pharmacokinetics (PK) and evaluate preliminary efficacy. The dose exploration will estimate the MTD or RP2D by Bayesian logistic regression modeling. The dose expansion will assess safety, efficacy, PK, and pharmacodynamics (PD) of the selected dose and provide further safety and efficacy data. PD biomarkers and potential patient selection biomarkers will be explored. Preliminary antitumor activity will be assessed by objective response per RECIST 1.1 with PCWG3 modifications, PSA response, duration of response, time to progression, PFS (radiographic and PSA)/OS, and circulating tumor cell (CTC) response (CTC0 and CTC conversion). Imaging will include CT/MRI, bone scan, 68Ga-PSMA-11 PET/CT, and 18F-FDG PET/CT. In cycle 1, patients will be pretreated with dexamethasone before short-term IV infusion of AMG 160 and will be hospitalized for 72 h after each AMG 160 dose. Key inclusion criteria: age ≥18 y; histologically/cytologically confirmed mCRPC that progressed after novel hormone therapy; failure of 1–2 taxane-based regimens or have refused a taxane regimen; bilateral orchiectomy or continuous androgen-deprivation therapy; evidence of progressive disease; total serum testosterone ≤50 ng/dL. Key exclusion criteria: active autoimmune disease or diseases requiring immunosuppressive therapy (low-dose prednisone permitted); CNS metastases, leptomeningeal disease, or spinal cord compression; prior PSMA-targeted therapy (177Lu-PSMA-617 may be allowed). The study will enroll 30–50 patients in the dose exploration and 50 patients in the dose expansion globally. The study opened in January 2019; dose exploration is ongoing. Clinical trial information: NCT03792841.

CA045-001: A phase III, randomized, open label study of bempegaldesleukin (NKTR-214) plus nivolumab (NIVO) versus NIVO monotherapy in patients (pts) with previously untreated, unresectable or metastatic melanoma (MEL).

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS9601-TPS9601 ◽  
Author(s):  
Nikhil I. Khushalani ◽  
Adi Diab ◽  
Paolo Antonio Ascierto ◽  
James M.G. Larkin ◽  
Shahneen Kaur Sandhu ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Objective Response ◽  
Development Program ◽  
Life Assessment ◽  
Phase Iii ◽  
Open Label ◽  
Phase 3 ◽  
Open Label Study ◽  
Label Study

TPS9601 Background: Standard of care for pts with previously untreated, unresectable or metastatic MEL includes checkpoint inhibitors. Bempegaldesleukin is a CD122-preferential IL-2 pathway agonist designed to provide sustained signaling through the IL-2 βγ receptor to activate and proliferate effector CD8+ T and NK cells over T-regulatory cells in the tumor (Hurwitz ME et al. ASCO GU 2017). In the dose-expansion phase of the phase 1/2 PIVOT-02 trial, bempegaldesleukin + NIVO was well tolerated at the recommended phase 2 dose (RP2D; bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W), and previously untreated pts with MEL receiving the RP2D achieved an objective response rate (ORR) of 20/38 (53%) and a complete response of 9/38 (24%) by independent radiology review (Diab A et al. SITC 2018). Presented is the design of the first phase 3 trial in the bempegaldesleukin + NIVO development program in pts with previously untreated, unresectable or metastatic MEL. Methods: This phase 3, randomized, open-label study aims to evaluate the effectiveness, safety, and tolerability of bempegaldesleukin + NIVO (NCT03635983). Eligible pts are ≥12 y with histologically confirmed stage III (unresectable) or stage IV MEL and ECOG PS ≤1 or Lansky PS ≥80% (minors 12-17 y). Pts are ineligible if they have active brain or leptomeningeal metastases, uveal MEL, or a recurrence within 6 mo of completing adjuvant treatment with any approved agent. Pts will be stratified by PD-L1 status (measured using PD-L1 IHC 28-8 pharmDx), BRAF mutation status, and lactate dehydrogenase level, and will be randomized to receive bempegaldesleukin 0.006 mg/kg IV Q3W + NIVO 360 mg IV Q3W or NIVO 360 mg IV Q3W up to 24 mo, or until progression or unacceptable toxicity (N ~ 764). Primary endpoints are ORR and progression-free survival (PFS) by blinded independent central review (BICR) and overall survival (OS). Secondary endpoints include ORR and PFS by investigator, ORR and PFS by BICR in biomarker population, OS in biomarker population, and safety. Additional endpoints include pharmacokinetics and quality-of-life assessment. Clinical trial information: NCT03635983.

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.

A phase 2 trial of CRS-207 and pembrolizumab in adults with recurrence of metastatic gastric, gastroesophageal junction (GEJ), or esophageal adenocarcinomas.

2018 ◽  
Vol 36 (4_suppl) ◽  
pp. TPS200-TPS200
Author(s):  
Ronan Joseph Kelly ◽  
Thomas Adam Abrams ◽  
Daniel V.T. Catenacci ◽  
Zev A. Wainberg ◽  
Bruce Shih-Li Lin ◽  
...  
Keyword(s):  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Gastroesophageal Junction ◽  
Objective Response ◽  
Clinical Activity ◽  
Cell Mediated Immunity ◽  
Specific Cell ◽  
Phase 2 ◽  
Open Label ◽  
Mesothelin Expression

TPS200 Background: CRS-207 is a live, attenuated, double-deleted Listeria monocytogenes (LADD) strain with a mesothelin expression cassette inserted. CRS-207 has a well-established, manageable toxicity profile and can elicit mesothelin-specific cell-mediated immunity. Clinical activity of CRS-207 has been shown in a separate Phase 1 trial of mesothelioma. In gastroesophageal (GE) cancers, mesothelin expression is estimated between 30% – 50% and has been correlated with poor prognosis. Preclinical models suggest the combination of LADD-based immunotherapeutics and a PD1 inhibitor may induce more sustained anti-tumor responses than either LADD or PD1 inhibitor monotherapy. GE cancers are responsive to PD1 inhibitors in a subset of patients; this trial proposes to evaluate the efficacy of CRS-207 combined with pembrolizumab in patients with relapsed GE cancer, and to correlate clinical activity with mesothelin expression level. Methods: This Phase 2, open-label, single-arm, multicenter clinical study (NCT 03122548) will enroll approximately 79 subjects at 20 sites. Adults with histologically-confirmed, advanced gastric, GEJ, or esophageal adenocarcinomas are eligible. Subjects must have received 1 or 2 prior treatment regimens, which must have included a platinum and a fluoropyrimidine. Subjects must have disease progression with measurable tumors. A pre-treatment biopsy of either the primary tumor or metastatic site is required prior to dosing. Subjects with prior exposure to checkpoint inhibitors or other immunotherapies are excluded. From cycle 1 to 4 during the treatment and evaluation period, pembrolizumab (IV 200 mg) and CRS-207 (IV 1 x 109 CFU) are both administered in 3-week cycles. Afterward, pembrolizumab will be administered once every 3 weeks; CRS-207 will be given once every 6 weeks. CT scans will be performed every 6 weeks to monitor disease status. The primary endpoint is objective response rate defined by RECIST 1.1. Clinical trial information: NCT03122548.

A phase Ib trial of cabozantinib in combination with durvalumab (MEDI4736) in previously treated patients with advanced gastroesophageal cancer and other gastrointestinal (GI) malignancies (CAMILLA).

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. TPS56-TPS56 ◽  
Author(s):  
Anwaar Saeed ◽  
Devin Koestler ◽  
Stephen K. Williamson ◽  
Joaquina Celebre Baranda ◽  
Weijing Sun ◽  
...  
Keyword(s):  
Tumor Microenvironment ◽  
Dose Escalation ◽  
Tyrosine Kinases ◽  
Checkpoint Inhibitors ◽  
Standard Dose ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Current Standard ◽  
Open Label

TPS56 Background: GI malignancies including Gastric (GC), esophageal (EAC), colon (CRC), and hepatocellular carcinoma (HCC) remain a significant health problem in the US & globally. The current standard upfront therapy has < 12 month median survival. Hypoxia mimetic agents such as VEGFR targeted therapy down regulate the angiogenesis pathway and sensitize tumors to chemotherapy. Cabozantinib targets multiple tyrosine kinases, including VEGFR, MET, and AXL, and has been reported to show immunomodulatory properties that may counteract tumor-induced immunosuppression, providing a rationale for combining it with PD-1 or PD-L1 inhibitors. We believe that modulating the tumor microenvironment with small molecule inhibitors like cabozantinib will have synergistic effect when combined with checkpoint based immunotherapy like durvaluamb in patients with chemo refractory GC, EAC, CRC and HCC. Methods: The study is funded by research grants from both Exelixis and AstraZeneca. A phase 1 dose escalation is followed by an open-label single arm expansion. Dose escalation will be conducted using a 3+3 design. Starting dose for cabozantinib is 20mg daily. Single agent durvalumab MTD has been used, given that a regimen with full dose durvalumab may be better accepted as a backbone for comparison in future studies. MTD of cabozantinib in combination with standard dose durvalumab will be defined as the highest safely tolerated dose where 0/6 or 1/6 patients experience a DLT and ≥ 2 patients have experienced a DLT at the next higher dose level. Primary objective is to determine the Recommended Phase 2 Dose (RP2D). Secondary objectives include safety, ORR, PFS and OS. Eligible patients received > 1 line of therapy, no prior checkpoint inhibitors, have measurable disease, & ECOG PS 0-1. Phase 1 dose escalation will enroll 9-18 patients and the expansion phase will enroll 12-21 patients. Correlative studies include assessment of tumor microenvironment, angiogenesis & immune molecular markers. The dose escalation phase is currently enrolling. Clinical trial information: NCT03539822.

A multicenter, open-label, phase I study of nivolumab alone or in combination with gemcitabine plus cisplatin in patients with unresectable or recurrent biliary tract cancer.

2019 ◽  
Vol 37 (4_suppl) ◽  
pp. 306-306 ◽  
Author(s):  
Masafumi Ikeda ◽  
Makoto Ueno ◽  
Chigusa Morizane ◽  
Satoshi Kobayashi ◽  
Izumi Ohno ◽  
...  
Keyword(s):  
Biliary Tract ◽  
Biliary Tract Cancer ◽  
Combined Therapy ◽  
Phase 1 ◽  
Objective Response ◽  
Primary Objective ◽  
Clinical Activity ◽  
Open Label ◽  
Phase 1 Study ◽  
Tract Cancer

306 Background: This phase 1 study evaluated the safety and efficacy of the immune checkpoint inhibitor nivolumab (monotherapy or combined with chemotherapy) in Japanese patients with biliary tract cancer (BTC). Methods: In the monotherapy cohort (N = 30), patients with unresectable/recurrent BTC refractory or intolerant to gemcitabine-based treatment regimens received nivolumab monotherapy (240 mg, 2-week intervals). In the combined therapy cohort (N = 30), chemonaïve patients with unresectable/recurrent BTC received nivolumab (240 mg, 2-week intervals) plus cisplatin-gemcitabine chemotherapy. The primary objective was tolerability and safety. Secondary efficacy endpoints included overall survival (OS), progression-free survival (PFS) and objective response rate (ORR) (central assessment). Results: The most frequently reported nivolumab-related adverse events were decreased appetite (5/30, 17%), malaise (4/30, 13%), and pruritus (4/30, 13%) in the monotherapy cohort, and malaise (8/30, 27%) and decreased appetite (7/30, 23%) in the combined therapy cohort. Median duration of follow-up for efficacy (Table) was 5.1 months (mo; monotherapy cohort) and 8.2 mo (combined therapy cohort). In the monotherapy cohort, median OS and median PFS were longer in patients with programmed death-ligand 1 (PD-L1) ≥ 1% (including the patient who responded) than in those with PD-L1 < 1% (Table). In the combined therapy cohort, the ORR was higher, but median OS and median PFS were lower, in patients with PD-L1 ≥ 1% than in those with PD-L1 < 1% (Table). Conclusions: Nivolumab was well tolerated, with a manageable safety profile and signs of clinical activity, in this phase 1 study in patients with unresectable/recurrent BTC. PD-L1 expression status may predict clinical activity of nivolumab in advanced BTC. Clinical trial information: JapicCTI-153098. [Table: see text]

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