A phase I dose-escalation trial of alpha-tocopheryloxyacetic acid and concurrent trastuzumab in patients with treatment refractory HER2+ metastatic breast cancer.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS1103-TPS1103
Author(s):  
William R Gwin ◽  
Jennifer Childs ◽  
Doreen Higgins ◽  
Kellie Ann Burton ◽  
Kristin Kuano ◽  
...  
Keyword(s):  
Breast Cancer ◽  
T Cells ◽  
Phase I ◽  
Clinical Response ◽  
Cd8 T Cells ◽  
Dose Escalation ◽  
Effector Memory ◽  
Practical Consideration ◽  
Her2 Breast Cancer

TPS1103 Background: Metastatic HER2+ breast cancer, while initially responsive to trastuzumab, pertuzumab, and TDM-1, eventually progresses. The FDA recently approved trastuzumab deruxtecan, showing benefit in progression free survival but not in overall survival to date. Thus, additional therapies are needed for patients who progress on these HER2 directed agents. In metastatic HER2+ breast cancer, HER2-specific Th1 immune responses and higher CD4+ Th1 and CD8+ TIL levels are associated with a survival benefit. As this Type 1 immunity occurs in a minority of patients, additional immune modulation is needed. Alpha-tocopheryloxyacetic acid (α-TEA) has been reported to augment Type 1 immunity through increasing activated effector memory CD4+ and CD8+ T cells and decreasing immune suppressive CD4+CD25+ regulatory T cells in the tumor microenvironment. When given concurrently with an anti-HER2 antibody (7.16.4) in a pre-clinical tumor model, α-TEA synergized with 7.16.4 to induce tumor regression. We hypothesize that α-TEA and trastuzumab combination therapy in metastatic HER2+ breast cancer will be well tolerated, induce a clinical response, and augment anti-tumor Th1 immunity. Methods: Trial Design: Phase I dose escalation trial of α-TEA in combination with trastuzumab. Patients with metastatic HER2+ breast cancer will receive one of four doses sequentially of α-TEA: 0.6 mg/kg, 1.2 mg/kg, 2.4 mg/kg, and 4.8 mg/kg. Toxicity is assessed at baseline and through end of study. Blood and tumor tissue will be collected for immunologic monitoring and evaluation. Clinical response will be evaluated according to RECIST 1.1. Eligibility : Patients with progressive metastatic HER2+ breast cancer who have previously progressed on trastuzumab/pertuzumab and TDM-1. Specific Aims: Determine: (1) safety of four escalating doses of α-TEA with concurrent trastuzumab, (2) clinical response rate of α-TEA with concurrent trastuzumab (3) if concurrent α-TEA and trastuzumab increases activated effector memory CD4+ and CD8+ T cells, and (4) if concurrent α-TEA and trastuzumab increase the number of HER2-specific T cells. Statistical Methods: (1) The sample size of 24 and cohort size of 6 are determined by simulation experiments and practical consideration, (2) clinical response will be evaluated; overall PFS and OS will be calculated, (3) activated effector memory CD4+ and CD8+ T-cells will be analyzed (4) HER2-specific IFN-g/IL-10 ratios will be evaluated. Targeted Accrual : Twenty-four (24) patients. Clinical trial information: NCT04120246 .

Phase I dose-escalation trial of ONT-380 in combination with trastuzumab in participants with brain metastases from HER2+ breast cancer.

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. TPS660-TPS660 ◽  
Author(s):  
Otto Metzger-Filho ◽  
William Thomas Barry ◽  
Ian E. Krop ◽  
W. Jerry Younger ◽  
Elizabeth S Lawler ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Brain Metastases ◽  
Phase I ◽  
Dose Escalation ◽  
Her2 Breast Cancer

scholarly journals CTIM-07. IDENTIFICATION OF A BASELINE BIOMARKER ASSOCIATED WITH TUMOR RESPONSES IN A PHASE I/IIa TRIAL OF A THERAPEUTIC CMV VACCINE AGAINST RECURRENT GLIOBLASTOMA (GBM)

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii34-ii34
Author(s):  
Patrick Wen ◽  
David Reardon ◽  
Deborah Forst ◽  
Eudocia Lee ◽  
Fabio Iwamoto ◽  
...  
Keyword(s):  
T Cells ◽  
Phase I ◽  
Cd8 T Cells ◽  
Peripheral Blood ◽  
Brain Mri ◽  
Absolute Lymphocyte Count ◽  
Immune Monitoring ◽  
Recurrent Glioblastoma ◽  
Effector Memory ◽  
Intradermal Vaccination

Abstract Cytomegalovirus (CMV) antigens have been reported in over 90% of GBM tumors. CD4+ and CD8+ T cells are most frequently directed against the gB and pp65 antigens, respectively, and are immunogenic targets in a CMV-based GBM vaccine. We enrolled 10 patients (6 women, 4 men) with KPS at least 70 and first recurrence of GBM to a trial (Phase IIa extension) of gB/pp65 enveloped virus-like particles (eVLPs) with GM-CSF. Intradermal vaccination was administered every 4 weeks, with serologic immune-monitoring 2 weeks after each vaccination and surveillance brain MRI scans every 6 weeks. Median age was 59 years (range 33–67). Among 8 response-evaluable patients, we observed 1 SD and 1 PR. Among all patients treated on phase I and II (n=26), a normal baseline ratio of CD4/CD8 T cells in peripheral blood predicted response (n=6). Other baseline peripheral blood markers did not correlate with efficacy, including total white blood cell, lymphocyte percentage, and absolute lymphocyte count. During treatment, the peripheral blood of responders demonstrated dynamic losses followed by subsequent reappearance and expansion of CMV-specific CD4+ effector memory T cells. Based on these encouraging results, a new arm is enrolling subjects combining gB/pp65 eVLPs (at the same dose) formulated with adjuvant intramuscular AS01B and results will be presented.

scholarly journals Partial exhaustion of CD8 T cells and clinical response to teplizumab in new-onset type 1 diabetes

2016 ◽  
Vol 1 (5) ◽  
pp. eaai7793-eaai7793 ◽  
Author(s):  
S. A. Long ◽  
J. Thorpe ◽  
H. A. DeBerg ◽  
V. Gersuk ◽  
J. A. Eddy ◽  
...  
Keyword(s):  
T Cells ◽  
Type 1 Diabetes ◽  
Clinical Response ◽  
Cd8 T Cells ◽  
Onset Type ◽  
New Onset

Phase I dose-escalation trial of a recombinant HER2 vaccine in patients with Stage II/III HER2+ breast cancer

2005 ◽  
Vol 23 (16_suppl) ◽  
pp. 2520-2520 ◽  
Author(s):  
S. Limentani ◽  
T. Dorval ◽  
S. White ◽  
G. Curigliano ◽  
M. Campone ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Stage Ii ◽  
Her2 Breast Cancer

A phase I/IB dose-escalation study of BEZ235 in combination with trastuzumab in patients with PI3-kinase or PTEN altered HER2+ metastatic breast cancer.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 508-508 ◽  
Author(s):  
Ian E. Krop ◽  
Cristina Saura ◽  
Jordi Rodon Ahnert ◽  
Carlos Becerra ◽  
Carolyn D. Britten ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Metastatic Breast Cancer ◽  
Phase I ◽  
Dose Escalation ◽  
Single Agent ◽  
Metastatic Breast ◽  
Pi3k Pathway ◽  
Dose Escalation Study ◽  
Her2 Breast Cancer ◽  
Disease Stabilization

508 Background: Alterations in the PI3K/AKT/mTOR pathway have been implicated in resistance to trastuzumab (T) in HER2+ breast cancer. BEZ235, a potent oral dual PI3K/mTORC1/2 inhibitor, has demonstrated growth inhibition and apoptosis in HER2+ breast cancer models, including those harboring PI3K pathway alterations, and with T resistance. In a Phase I study, BEZ235 was well tolerated as a single agent in pts with advanced solid tumors. The aim of this study was to determine the MTD of BEZ235 in combination with T in pts with T-resistant HER2+ metastatic breast cancer (mBC) with alterations of the PI3K pathway. Methods: Pts with T-resistant HER2+ mBC (i.e. disease progression during adjuvant therapy or metastatic disease on therapy with T) received oral BEZ235 daily, with weekly T (2 mg/kg). Pts were eligible for enrollment if a tumor sample was demonstrated to contain a molecular alteration of PIK3CA and/or PTEN. Dose escalation was guided by a Bayesian logistic regression model with overdose control. Results: As of 23 Sep 2011, 15 of the 19 enrolled pts were evaluable for dose escalation analysis. BEZ235 was evaluated at 3 dose levels: (1) 400 mg/day (3 pts); (2) 600 mg/day (6 pts); (3) 800 mg/day (10 pts), administered either in capsule form (400 mg) or in sachet form (600 mg and 800 mg). The MTD of BEZ235 in combination with T was estimated to be 600 mg/day. Observed DLTs were G3 nausea at 600 mg/day (1 pt), and G3 nausea, G3 fatigue and G3 skin rash (1 pt each) at 800 mg/day. The most frequent G3/4 adverse events (CTCAE v3.0) suspected to be related to study treatment were diarrhea (4 pts) and nausea (2 pts). No deaths related to study treatment occurred. 1 pt with lung and brain metastases had a partial response. 4 pts had disease stabilization for ≥4 cycles (16 weeks), including 1 pt with liver metastases, in whom BEZ235/T treatment resulted in disease stabilization for more than 21 cycles (84 weeks). Conclusions: BEZ235in combination with T demonstrated an acceptable safety profile in pts with HER2+ mBC and PI3K pathway alterations. Following the Bayesian model recommendation, the MTD for BEZ235 in combination with T was estimated to be 600 mg/day. The safety expansion arm is ongoing at the MTD.

Phase I/II Study of Marrow Infiltrating Lymphocytes (MILs) Generates Measurable Myeloma-Specific Immunity in the Autologous Stem Cell Transplant (SCT) Setting

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 997-997
Author(s):  
Kimberly Noonan ◽  
Carol A. Huff ◽  
Janice M Davis Sproul ◽  
Mario Victor M Lemas ◽  
Lakshmi Rudraraju ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Clinical Response ◽  
Peripheral Blood ◽  
Immune Monitoring ◽  
Adoptive T Cell Therapy ◽  
Effector Memory ◽  
Cell Transplant ◽  
T Cell Therapy

Abstract Abstract 997 Adoptive T cell therapy requires the infusion of highly tumor specific T cells capable of trafficking to the tumor site, killing the tumor and persisting over time. MILs (as compared to peripheral blood T cells) possess many of these features (Noonan, Ca, Res. 2006). We here report the initial results from our Phase I/II trial. 22 patients were transplanted with a Melphalan-200. 19 with a CD34-selected product, 1 unselected autologous stem cells and 2 auto-BMT. 12 underwent SCT as initial consolidation and 10 patients with relapsed disease that were heavily pre-treated with an average of 3.2 prior therapies. Mean ISS score was 2.0. Average age was 56 (29–71). MILs were expanded with anti-CD3/CD28 beads for 7 days (avg. fold expansion 48.5 and avg. cell dose 2.8×10e7 CD3/kg). MILs were infused on day +3. Patients in a CR were ineligible for this study. The best clinical response included 6CRs (27%), 10PRs (45%). Autologous GVHD which was observed in 32% of patients, was limited to the skin and required no treatment. Development of this syndome did not correlate with improved clinical outcomes. Lymphoid recovery was rapid with a mean absolute lymphocyte count (ALC) on day 15 of 886 cells/ul. The laboratory immune monitoring studies were only performed in the bone marrow – the disease site and not in the peripheral blood. The percent CD3+ T cells in the BM was 13% at baseline with a CD4:CD8 ratio of 1:3. By day 60, BM T cell reconstitution was complete and showed an inversion of the CD4:8 ratio of 0.39 that persisted through day 360. At baseline, there were more CD4 effector memory (CD4EM) (CD62L−/CD45RO+) than CD4 central memory (CD4CM) (CD62L+/CD45RO+) (43% vs 27%). The CD4CM population peaked on day 60 at 43% and persisted through 1 year, CD4EM remained unchanged, and the CD4Effector decreased from 19.8% to 5.6%. The CD8 subpopulations remained unchanged from pre-SCT to 1 year post-SCT. Treg numbers doubled from harvest to post-SCT consistent with previous studies showing a greater number of Tregs in healthy BM compared to MM-BM. Activated T cells (CD69+) doubled from pre- to post-SCT. IFNγ production in both CD4 and CD8 cells more than doubled compared to pre-SCT and was maintained at 1 year suggesting the persistence of the infused MILs. The immune monitoring in the BM based on clinical responses revealed that patients achieving a CR/PR showed greater CD8 numbers at day +60 compared to stable disease (SD) or progressive disease (PD)(14.5% vs. 7.6%, respectively) and inversion of the CD4/CD8 ratio at 1 year (0.55 vs 1.26). In patients with SD or PD, the immune infiltrate in the BM was characterized by a large numbers of effector and effector-memory T cells and few CD8CM at baseline. CR patients possessed the fewest CD8Effector and the most CD8CM with persistence of CD8CM out to one year. These patients also showed a greater expansion in IFNγ cells as well as a greater amount of IFNγ production at each time point. Importantly, tumor-specific IFNγ production of CD3 cells in the BM was predictive of a clinical response. Patients achieving a CR showed twice the antigen-specific IFNγ production compared to all other groups at day 180 which persisted through 1 year. Analyses of additional immune subsets will be discussed in greater detail. This is the first reported trial utilizing activated MILs as a source of tumor specific T cells. We have demonstrated the ability to effectively expand MILs ex vivo and provide an analysis of the parameters of immune reconstitution demonstrating that the clinical outcome correlated with the robustness of the immune response in the BM. Disclosures: Luznik: Otsuka Pharmaceuticals: Research Funding.

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