A phase I multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2523-2523 ◽  
Author(s):  
Howard A. Burris ◽  
Manish R. Patel ◽  
Daniel C. Cho ◽  
Jeffrey Melson Clarke ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Metastatic Cancer ◽  
Low Grade ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Phase 2 Clinical Trial ◽  
Personalized Approach

2523 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: A phase I dose escalation study of mRNA-4157 as adjuvant monotherapy in patients with resected solid tumors (melanoma, bladder carcinoma, HPV negative HNSCC, NSCLC, SCLC, MSI-High, or TMB High cancers) and in combination with pembrolizumab in patients with advanced or metastatic cancer is being conducted to evaluate safety. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients may receive up to 9 cycles (Q3W) of mRNA-4157 by intramuscular injection (0.04 – 1 mg). In the combination arm, pembrolizumab (200 mg) is administered for two cycles prior to combination with mRNA-4157; patients may continue pembrolizumab after completion of 9 cycles of combination therapy. Primary end points include safety, tolerability, and recommended phase 2 dose. Results: 33 patients received mRNA-4157; 13 as monotherapy and 20 in combination with pembrolizumab. No DLTs were reported, and treatment related AEs have generally been of low grade and reversible, and no drug related SAEs or AEs ≥ grade 3 have been observed. Of the 13 patients on adjuvant monotherapy (3 melanoma, 8 NSCLC, 2 MSI-High), 12 patients remain disease free on study, median follow-up of 8 months. 20 patients have been treated in combination (1 TMB-high, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high), 12 had progressed on prior CPI, 16 have been restaged and there are 1 CR (on pembrolizumab prior to vaccination), 2 PR, 5 SD for at least 5 combination cycles, 5 PD, 2 iuPD, and 1 patient is non-evaluable for response but remains on study. Neoantigen specific T cell responses have been detected by IFN-γ ELISpot from PBMCs. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT03313778.

scholarly journals A phase 1, open-label, multicenter study to assess the safety, tolerability, and immunogenicity of mRNA-4157 alone in subjects with resected solid tumors and in combination with pembrolizumab in subjects with unresectable solid tumors (Keynote-603).

2019 ◽  
Vol 5 (suppl) ◽  
pp. 93-93
Author(s):  
Howard A. Burris III ◽  
Manish R. Patel ◽  
Daniel C. Cho ◽  
Jeffrey Melson Clarke ◽  
Martin Gutierrez ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Solid Tumors ◽  
Phase 1 ◽  
Open Label ◽  
Dose Escalation Study ◽  
Phase 2 Clinical Trial ◽  
Clinical Responses ◽  
Grade 3 ◽  
Personalized Approach

93 Background: T-cell targeting of mutation-derived epitopes (neoantigens) has been demonstrated to drive anti-tumor responses. Immunizing patients against such neoantigens in combination with a checkpoint inhibitor (CPI) may elicit greater anti-tumor responses than CPI alone. Mutations are rarely shared between patients, thus requiring a personalized approach to vaccine design. Methods: This is an interim report of a phase I dose escalation study of mRNA-4157 given as monotherapy in patients with resected solid tumors and in combination with pembrolizumab in patients with unresectable solid tumors. mRNA-4157 is a lipid encapsulated personalized vaccine encoding multiple neoantigens selected using a proprietary algorithm designed to induce neoantigen specific T cells and associated anti-tumor responses. Patients received up to 9 cycles (Q3W) of mRNA-4157 by IM injection (0.04 – 1 mg). In combination arm, pembrolizumab (200 mg) was administered for two cycles prior to combination with mRNA-4157 for up to 9 cycles and may continue on pembrolizumab monotherapy for up to 2 years. Results: As of 10-May-2019, 33 patients received mRNA-4157 alone or in combination. No DLTs or related SAEs or AEs ≥ grade 3 were reported. Of the 13 patients treated with monotherapy (3 melanoma, 8 NSCLC, 2 MSI-high CRC), 11 patients remain disease free on study, median follow-up of 10 months. Of the 20 patients treated in combination (1 TMB-high metastatic cutaneous squamous cell, 4 bladder, 2 HNSCC, 1 melanoma, 7 NSCLC, 2 SCLC, 3 MSI-high (CRC, prostate, endometrial), 13 had received prior CPI, 5 PRs (2 in patients previously treated with PD-1/L1 inhibitors), 6 SD, and 8 PD were reported. Neoantigen specific CD8+ T-cell responses have been detected. Conclusions: mRNA-4157 is safe and well tolerated at all dose levels tested. Clinical responses have been observed in combination with pembrolizumab and neoantigen-specific T cells have been induced, supporting the advancement of mRNA-4157 to phase 2. Clinical trial information: NCT 03739931.

Phase I trial of Seneca Valley Virus (NTX-010), a newly discovered systemically deliverable oncolytic picornavirus, in patients with solid tumors with neuroendocrine features

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 18014-18014
Author(s):  
C. M. Rudin ◽  
D. Lansey ◽  
K. D. Burroughs ◽  
L. M. Hales ◽  
J. R. Neefe ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Metastatic Cancer ◽  
Cell Cancer ◽  
Safety Data ◽  
Small Cell ◽  
Low Grade ◽  
Viral Kinetics ◽  
Xenograft Models

18014 Background: NTX-010 is a replication-competent cytolytic picornavirus with selective tropism for cancers with neuroendocrine features. NTX-010 mediates high selective cytotoxicity for tumor cells with neuroendocrine properties and has no cytotoxicity on any human adult cell type tested. Antitumor efficacy has been demonstrated in 11/11 xenograft models, including metastatic, orthotopic, and syngeneic models. Intravenous (IV) administration of doses as low as 107 vp/kg are effective in xenograft models of small cell lung cancer. No significant toxicity in animals is seen at doses up to 1013 vp/kg. Methods: We initiated a single dose administration phase I dose-escalation study in patients with advanced solid tumors with neuroendocrine markers (CD56+, synaptophysin+, or chromogranin A+), starting at 107 vp/kg IV over 1h. Planned dose escalation is in log increments. Results: The first dose cohort has been completed, with no dose-limiting toxicities observed. Low grade fever, chills, arthralgias and myalgias starting 3 - 4 days after virus administration and lasting less than a week have been noted. The first study subject, with a widely metastatic small cell cancer with bladder invasion, demonstrated viral replication in vivo peaking d4 with >10,000-fold amplification of the input dose. This subject had complete clearance of infectious virus by day 17, but persistence of viral RNA detectable by RT-PCR in blood and urine until the time of her death from metastatic cancer on day 28. Autopsy demonstrated extensive intratumoral necrosis, and immunohistochemistry confirmed the presence of NTX-010 capsid protein in liver metastases but not adjacent normal liver. Conclusions: NTX-010 is a novel first-in-class anticancer virus with selective tropism for tumors with neuroendocrine features. This is the first anticancer virus given intravenously with documented selective intratumoral infection and replication. Administration was well tolerated. Safety data and viral kinetics will be presented. No significant financial relationships to disclose.

Phase I experience with first in class TnMUC1 targeted chimeric antigen receptor T-cells in patients with advanced TnMUC1 positive solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. e14513-e14513
Author(s):  
Rodolfo Gutierrez ◽  
Payal D Shah ◽  
Omid Hamid ◽  
Alfred L. Garfall ◽  
Avery Posey ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
Chimeric Antigen Receptor ◽  
Dose Escalation ◽  
Intracellular Signaling ◽  
Antigen Receptor ◽  
Low Grade ◽  
Gi Symptoms ◽  
Dose Levels

e14513 Background: MUC1 is a glycoprotein that is expressed in healthy tissues on the luminal surface of simple and glandular epithelium. In tumors that arise from these cells, an alternate form with aberrant glycosylation is frequently over expressed and distinguishes tumor associated TnMUC1 from normal MUC1. We have generated a novel chimeric antigen receptor (CAR) targeting the TnMUC antigen comprised of a mouse anti-human scFv derived from the monoclonal antibody 5E5 which recognizes the epitope comprising Tn glycan of MUC1, a CD8a transmembrane region and dual CD2 and CD3z intracellular signaling domains. CD2 signaling in T-cells has been demonstrated to result in delayed exhaustion. The novel incorporation of this co-stimulatory domain may lead to enhanced persistence of the CART cells which is believed to be critical for efficacy in solid-tumors. Methods: This is a multi-center first in human Phase I study to evaluate the safety and preliminary efficacy of CART-TnMUC1-Cells for the treatment of solid-tumors. Solid-tumors included in the dose-escalation phase include metastatic treatment-resistant ovarian cancer (OC), pancreatic adenocarcinoma (PC), triple-negative breast cancer (TNBC) or non-small lung cancer (NSCLC). All patients must have TnMUC1 expression as determined by immunohistochemistry. Results: As of January 2021, a total of six patients were treated. Three in Cohort 1 (no lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 OC, 1 TNBC and 1 PC) and 3 in Cohort 2 (flu/cy lymphodepletion; dose = 1-2 x 107 TDN CART cells; tumors = 1 NSCLC and 2 OC). None of the patients treated experienced DLT’s. The trial is currently enrolling to Cohort 3 (flu/cy lymphodepletion, 5-6 x 107 TDN). No CRS, neurotoxicity, serious adverse reactions and no on-target/off-tumor toxicity was observed at these dose levels. The most common AE’s were low-grade GI symptoms (e.g., nausea, abdominal pain) in 5/6 patients (83.3%), generalized disorders (e.g., chills, fatigue) in 5/6 (83.3%) and hematologic disorders (e.g., anemia, neutropenia) in 3/6 (50%) of patients. CAR expansion was demonstrated in all patients and was improved in Cohort 2 following LD chemotherapy. Preliminary efficacy assessed by RECIST v1.1 at Day +28 demonstrate SD in all patients in Cohort 2. Conclusions: This is the first report of a novel CART-TnMUC1 construct containing a CD2 co-stimulatory domain that has been used in clinical trials for the treatment of refractory solid-tumor malignancies. While the study is still early in dose-escalation having completed only 2 of 6 planned dose levels there is no evidence of safety concerns or on-target/off-tumor toxicity. Additional safety, efficacy and biomarker data is currently being reviewed and will be presented. Clinical trial information: NCT04025216.

A phase I dose-escalation study of the MDM2-p53 antagonist BI 907828 in patients (pts) with advanced solid tumors.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 3016-3016
Author(s):  
Patricia LoRusso ◽  
Mrinal M. Gounder ◽  
Manish R. Patel ◽  
Noboru Yamamoto ◽  
Todd Michael Bauer ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Dose Escalation ◽  
Geometric Mean ◽  
Dose Range ◽  
Low Grade ◽  
Advanced Solid Tumors ◽  
Dose Escalation Study

3016 Background: BI 907828, a highly potent and orally administered MDM2-p53 antagonist, showed antitumor efficacy in vivo, especially in TP53 wild-type MDM2-amplified de-differentiated liposarcoma (DDLPS) patient-derived xenografts and syngeneic models. Methods: NCT03449381 is a phase I study of BI 907828 in pts with solid tumors. The objectives of the dose-escalation part were to determine the maximum tolerated dose (MTD) based on the frequency of pts with dose-limiting toxicities (DLTs) during cycle 1, determine the recommended dose for expansion, and evaluate the safety and tolerability of two dosing schedules: BI 907828 given on day 1 of 21-day cycles (Arm A) or days 1 and 8 of 28-day cycles (Arm B). Dose escalation was guided by a Bayesian logistic regression model. The secondary objectives include pharmacokinetics (PK), pharmacodynamics and antitumor activity. Results: At January 15, 2021, 54 pts with advanced solid tumors (median of 2 lines of prior systemic therapies; range 0–11) were treated with BI 907828 (Arm A, 29 pts, dose range 10–80 mg; Arm B, 25 pts, dose range 5–60 mg). In Arm A, 5 pts experienced DLTs in cycle 1, including one Grade (Gr) 3 Nausea and one Gr 3 Thrombocytopenia at 45 mg, one Gr 3 Enterocolitis at 60 mg, and one Gr 4 Neutropenia and one Gr 4 Thrombocytopenia at 80 mg. In Arm B, 3 DLTs were reported: one Gr 4 Thrombocytopenia at 45 mg, one Gr 4 Neutropenia associated with Gr 4 Thrombocytopenia, and one Gr 3 Neutropenia at 60 mg. The most common Gr 3/4 treatment-related adverse events (AEs) were Thrombocytopenia (28.6%), Neutropenia (10.7%) and Nausea (10.7%) in Arm A, and Thrombocytopenia (16.6%) and Neutropenia (12.5%) in Arm B. Preliminary PK data indicate that BI 907828 reaches Tmax at 4–6 h. Mean plasma exposures (Cmax and AUC0-inf) increased with dose. The geometric mean (gMean) Clearance/F was 5–19 mL/min and the gMean apparent volume of distribution was 23–57 L. The gMean half-lives estimated after the 1st dose were 26–55 h. Inter-patient variability in exposure was moderate. An increase in the target engagement biomarker GDF-15 in plasma was observed. The mean fold-change from baseline ranged from 8 to 49. Antitumor activity was seen in both schedules. In Arm A, a confirmed PR was seen in 2 pts with MDM2-amplified LPS (one PR lasted > 2 years) and SD in 17 pts. In Arm B, 2 pts had PR (one confirmed in MDM2-amplified LPS and one not yet confirmed in MDM2-amplified pancreatic adenocarcinoma) and 14 had SD. Of note, 5 of 10 pts with DDLPS were progression-free for ≥9 months. Conclusions: BI 907828 showed a manageable safety profile, favorable PK properties and early signs of efficacy, especially in MDM2-amplified tumors. With both dosing regimens, DLTs were Neutropenia and Thrombocytopenia. Non-hematologic AEs, mainly gastrointestinal, were mostly low-grade and not dose-limiting. The MTD of 60 mg in Arm A (day 1 of 21-day cycles) and 45 mg in Arm B (days 1 and 8 of 28-day cycles) are awaiting confirmation. Clinical trial information: NCT03449381.

Phase I Study of Adoptive T-Cell Therapy Using Antigen-Specific CD8+ T Cells for the Treatment of Patients With Metastatic Melanoma

2006 ◽  
Vol 24 (31) ◽  
pp. 5060-5069 ◽  
Author(s):  
Andreas Mackensen ◽  
Norbert Meidenbauer ◽  
Sandra Vogl ◽  
Monika Laumer ◽  
Jana Berger ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Adverse Effects ◽  
Phase I ◽  
Metastatic Melanoma ◽  
Adoptive Transfer ◽  
Phase I Study ◽  
Low Grade ◽  
Melanoma Patients

Purpose The adoptive transfer of in vitro generated tumor antigen-specific cytotoxic T lymphocytes (CTL) provides a promising approach to the immunotherapy of cancer. A phase I study was conducted to test the feasibility, safety, and survival of adoptively transferred Melan-A–specific CTL lines in melanoma patients. Patients and Methods Eleven HLA-A2+ patients with metastatic melanoma received at least three intravenous infusions of Melan-A–specific CTL at 2-week intervals. CTL were generated by four rounds of in vitro stimulation of purified CD8+ peripheral blood lymphocytes with autologous dendritic cells pulsed with an HLA-A2 binding Melan-A peptide. Each T-cell infusion was accompanied by a 6-day course of low-dose interleukin-2. Results A total of 52 T-cell infusions were administered, averaging 2.1 × 108 Melan-A–specific CTL per infusion. Clinical adverse effects were mild and consisted of chills and low-grade fever in seven of 11 patients. Clinical and immunologic responses revealed an antitumor response in three of 11 patients (one complete regression, one partial regression, one mixed response), an elevated frequency of circulating Melan-A tetramer+ T cells up to 2 weeks in all the patients with a maximal frequency of 2% of total CD8+ T cells, an increase in eosinophils to up to 50% in seven of 11 patients, and a selective loss of Melan-A expression in lymph node metastases in two evaluated patients after T-cell transfer. Conclusion Our data indicate that the adoptive transfer of antigen-specific T cells in melanoma patients can induce clinical tumor-specific immune responses without major adverse effects.

Phase I study of CRISPR-engineered CAR-T cells with PD-1 inactivation in treating mesothelin-positive solid tumors.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 3038-3038
Author(s):  
Zhenguang Wang ◽  
Meixia Chen ◽  
Yan Zhang ◽  
Yang Liu ◽  
Qingming Yang ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Surface Expression ◽  
Dose Escalation Study ◽  
Car T Cells ◽  
Car T ◽  
The Mean

3038 Background: Our previous phase I study with MPTK-CAR-T (mesothelin-directed 28ζ CAR-T cells with PD-1 and TCR disruption by CRISPR-Cas9 system) demonstrated feasibility and safety of CRISPR-mediated PD-1 inactivation in CAR-T cells, and suggested the natural TCR is beneficial for the proliferation of CAR-T cells in solid tumors. Based on these observations, we initiated a pilot dose escalation study to investigate mesothelin-directed CAR-T cells with only PD-1 disruption by CRISPR (termed as GC008t) in patients with mesothelin-positive advanced solid tumors (NCT03747965). Methods: On the data cut-off date (Jan 20, 2020), nine patients (6 pancreatic cancers, 2 ovarian cancers, 1 colorectal cancer) were treated (5 received ≥12 numbers of therapy), three in cohort 1 (0.1-0.2×107/kg), four in cohort 2 (0.5-1.0×107/kg), two in cohort 3 (2.5-5×107/kg). Eight of the 9 patients received lymphodepletion regimen of cyclophosphamide and nab-paclitaxel with or without gemcitabine. Four of the 9 patients received repeat infusions of GC008t per protocol. Results: Comparable proliferation capacity was observed in vitro between the MPTK-CAR-T and the GC008t products. The mean PD-1 surface expression in cell products was 0.5% (range, 0.2%-0.9%). GC008t infusions were well tolerated with no observed on-target/off-tumor toxicity, autoimmune activity. Only two patients in cohort 3 developed grade 1 CRS with fever and rash. Circulating GC008t expanded with a peak at day 7-14 and became undetectable by qPCR beyond 1 month. The mean peak levels of circulating CAR-T cells between GC008t and MPTK-CAR-T at similar dose level were not statistically significant. Failure of GC008t engraftment after repeat infusion was observed in 2 out of 4 patients. The best response of the 7 evaluable patients was stable disease in 4 and partial response in 2 patients (dosed ≥ 1×107/kg) with PFS of 80 and 160 days. Conclusions: Phase I trial of GC008t further establishes that genetic inactivation of PD-1 in CAR-T cells by CRISPR is feasible and safe. The expansion and persistence of CAR-T cells with PD-1 disruption is not improved significantly even in the setting of natural TCR and lymphodepletion. Future endeavors are needed to improve the clinical efficacy of CAR-T therapy in the treatment of solid tumor. Clinical trial information: NCT03747965 .

scholarly journals 535 A phase I/II study of REGN7075 (EGFRxCD28 costimulatory bispecific antibody) in combination with cemiplimab (anti–PD-1) in patients with advanced solid tumors

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A565-A565
Author(s):  
Nehal Lakhani ◽  
Melissa Johnson ◽  
Roman Groisberg ◽  
Hyunsil Han ◽  
Kerry Casey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Solid Tumors ◽  
Tumor Cells ◽  
Group Performance ◽  
Bispecific Antibodies ◽  
Advanced Solid Tumors ◽  
Link Type ◽  
Anti Tumor Activity

BackgroundT-cell redirecting bispecific antibodies (bsAbs) are therapeutics that recognize two distinct antigens: a tumor-associated antigen on tumor cells to promote recruitment of T-cells to the tumor, and a receptor on T-cells to potentiate anti-tumor activity. REGN7075 is a human immunoglobulin G4-based costimulatory bsAb designed to bridge epidermal growth factor receptor (EGFR) positive tumor cells with CD28 positive T-cells and to provide amplified T-cell receptor-CD3 complex-mediated T-cell activation within the tumor, through the activation of CD28 co-stimulation. In genetically humanized immunocompetent mouse models, REGN7075 in combination with anti–PD-1 (antibody directed against programmed cell death-1 receptor) improved anti-tumor activity compared with either single agent alone.1MethodsThis is an open label, Phase I/II, first-in-human study evaluating the safety, tolerability, pharmacokinetics, and preliminary anti-tumor activity of REGN7075 (EGFRxCD28) alone and in combination with cemiplimab in patients with advanced solid tumors (NCT04626635). Patients must have a protocol-defined advanced solid tumor, be ≥18 years of age (≥20 years in Japan), have an Eastern Cooperative Oncology Group performance status of 0 or 1, and be naïve to anti–PD-1/anti–PD-ligand(L)1.This study includes dose escalation (a 4+3 design modified from 3+3; Part 1) and expansion phases (Part 2). In Part 1, patients will receive a lead-in of REGN7075 monotherapy for 3 weeks followed by combination therapy with cemiplimab 350 mg every 3 weeks. Study therapies are administered until disease progression, intolerable adverse events, withdrawal of consent, or other stopping criterion is met. Once a recommended Phase 2 dose is determined in Part 1, four tumor-specific expansion cohorts will be opened: non-small cell lung cancer (PD-L1 ≥50%), triple-negative breast cancer, colorectal cancer (microsatellite stable), and cutaneous squamous cell carcinoma. Primary endpoints are safety and tolerability of REGN7075 alone or in combination with cemiplimab for Part 1, and objective response rate per Response Evaluation Criteria in Solid Tumors version 1.1 for Part 2. This study is currently open to enrollment.Trial RegistrationClinicalTrials.gov identifier NCT04626635.ReferencesWaite JC, Wang B, Haber L, et al. Tumor-targeted CD28 bispecific antibodies enhance the antitumor efficacy of PD-1 immunotherapy. Sci Transl Med 2020;12:2325.Ethics ApprovalThis study was conducted in accordance with the principles of the Declaration of Helsinki and the International Conference on Harmonization Good Clinical Practice guidelines. The study protocol and all amendments were approved by the institutional review board/ethics committee at each participating study site.ConsentAll patients provided written informed consent.

A pediatric phase I trial and pharmacokinetic (PK) study of erlotinib (ERL) followed by the combination of ERL with temozolomide (TMZ): A Children’s Oncology Group Study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 9015-9015 ◽  
Author(s):  
R. I. Jakacki ◽  
J. Tersak ◽  
S. Blaney ◽  
M. Krailo ◽  
M. Hamilton ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Single Agent ◽  
Phase 2 ◽  
Dose Escalation Study ◽  
Minor Response ◽  
Pediatric Solid Tumors ◽  
Phase 2 Trial ◽  
Egfr Family ◽  
A Minor

9015 Background: EGFR is potently inhibited by ERL. Aberrant cell signaling via the EGFR family has been implicated in the development of several human cancers, including certain pediatric solid tumors. Methods: A phase I dose escalation study in children with refractory solid tumors was conducted to define the maximal tolerated dose (MTD) and dose limiting toxicities (DLTs) of single agent ERL, determine the tolerability of the combination of ERL and TMZ, and to determine the PK of ERL. Pts received single agent ERL qd × 28 d followed by ERL qd continuously in combination with TMZ 180 mg/m2/day × 5d. Cycles were repeated q 28 d. ERL was initially administered using the IV formulation given orally. The tablet form was subsequently studied at the MTD to further evaluate PK. Results: 46 pts (36 fully evaluable for toxicity) median age 11.5 yrs (range 3–20 yrs), were enrolled in cohorts of 3–6 pts at ERL doses of 35, 50, 65, 85 and 110 mg/m2/d. At the 110 mg/m2/day dose level, 2/4 pts had DLT (1 rash, 1 hyperbilirubinemia). In the expanded cohort at the MTD of 85 mg/m2/d, (n=21), 3 pts had DLT (2 rash, 1 diarrhea). Non-DLTs observed during the single agent cycle included diarrhea (n=14), rash (n=9), hyperbilirubinemia (n=7), neutropenia and/or thrombocytopenia (n=5). 1 pt with a soft tissue sarcoma had a minor response after 28d of single agent ERL, continuing to a PR by cycle 4. 3 pts (2 neuroblastoma, 1 neurocytoma) had prolonged responses (13–20+ months) to the combination. Oral administration of the IV formulation resulted in a higher Cmax and a lower Cmin compared to the adult data using tablets. Median apparent clearance was 2.85 (range 1.61–6.37) L/hr/m2 with a terminal half of 8.45 (5.1–27.1) hr. No PK interaction was observed between ERL and TMZ and the combination was well tolerated. Conclusions: The pediatric recommended phase 2 dose of ERL of 85 mg/m2/day, either alone or in combination with TMZ, is well tolerated in children. A COG phase 2 trial is planned. [Table: see text]

Phase I study of anti-PD1 in combination with low-dose decitabine in patients with advanced and untreated malignancies.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e14555-e14555
Author(s):  
Chunmeng Wang ◽  
Yang Liu ◽  
Wenying Zhang ◽  
Meixia Chen ◽  
Lu Shi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cells ◽  
T Cell ◽  
Antitumor Activity ◽  
Phase I ◽  
Solid Tumors ◽  
Phase I Study ◽  
Low Dose ◽  
Severe Toxicity ◽  
Clinical Trial Information

e14555 Background: Anti-PD1 have produced significant antitumor activity in multiply malignancies, however, resistance to anti-PD1 is becoming increasingly apparent in recent years. Low-dose decitabine, a classical DNA hypomethylating agent, was shown to boost effector T cell function and trigger a T cell-mediated response. This phase I study was designed to assess the safety, immunological effects and antitumor activity of this novel combination in patients with advancedanduntreated lymphomas and solid tumors. Methods: Patients were treated with decitabine (10mg/d on day 1-5) and anti-PD1 (2-3mg/kg, day 8) per 3 weeks. Modified salvage regimens (lymphoma: COP; solid tumors: platinum-based chemotherapy) were allowed to be intermittently inserted for patients with aggressive progression. Treatment continued unless disease progression or severe toxicity. Safety was assessed by CTCAEv4.0, and response by standard international criteria. The phenotype and activity of T cells were periodically measured in peripheral blood by flow cytometry. Results: Todate, 11 patients with heavily treated history and refractory bulky lesions have been enrolled, including 8 with lymphomas (7 NHL, 1 HL resistant to anti-PD1) and 3 with metastatic solid tumors (2 gastric cancers, 1 esophageal cancer) failure to anti-PD1. 5 patients (45%) experienced Grade ≥ 3 toxicities, with 1 taken off due to toxicity, and 1 died of asystole during the term of severe cytokine release syndrome (CRS). The common events of leukocytopenia and CRS were prominent features of anti-PD1 plus decitabine. 9 patients were evaluable for response, 1 HL obtained complete response, 3 NHL and 3 solid tumors achieved partial response, and 2 NHL had stable disease with nearly 20% shrinkage. The frequency of interferon-γ-producing CD8+ T cells in the total CD3+ population was largely increased after anti-PD1 plus decitabine infusion. Conclusions: Decitabine augmented the pro-inflammatory effects of anti-PD1 characterized by systemic inflammation response, and further improved antitumor activity of anti-PD1. Clinical trial information: NCT02961101. Clinical trial information: NCT02961101.

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