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Open Access Publications from the University of California

Scholarly Works (8 results)

  • Thesis
  • Peer Reviewed
UCLA Electronic Theses and Dissertations (2015)

Purpose:

Preclinical models suggest bidirectional signaling between estrogen receptor

(ER) and epidermal growth factor receptor (EGFR) pathways in lung cancer. This phase II randomized clinical trial of erlotinib, an EGFR inhibitor, and fulvestrant, an ER antagonist, versus erlotinib alone, evaluated efficacy in advanced stage non-small cell lung cancer (NSCLC) patients. The purpose of this investigation is to evaluate the influence of various clinical, biochemical, and histopathological features as predictive or prognostic markers.

Methods:

Patients who met eligibility criteria for the study were enrolled in a 2:1 ratio to

combination erlotinib and fulvestrant or erlotinib alone. Primary endpoint was objective tumor response rate, while secondary analysis included overall survival (OS) and progression free survival (PFS). Analysis included blood estrogen (estradiol and estrone) run in duplicate, and a panel of relevant biomarkers obtained at the beginning of the first three 28-day cycles. Pre-treatment tumor tissue was obtained and evaluated using immunohistochemistry (IHC) for estrogen receptor (ER)-α, ER-β, and progesterone receptor.

Results:

106 patients were randomized to a treatment arm between March 2006 and June

2011 with 100 patients receiving at least one dose of therapy. Clinical response data were available for 82 patients. Median PFS was 4.3 and 1.9 months for the erlotinib plus fulvestrant arm versus the erlotinib alone arm (HR 0.64, 95% CI 0.34-1.08). Median OS was 11.6 and 8.6 months for the erlotinib plus fulvestrant versus the erlotinib alone arm (HR 0.9876 95% CI 0.60-1.6). Blood analysis showed that after 1 cycle of treatment, placental growth factor (PlGF) and transforming growth factor-α (TGF-α) were higher in patients that had progressive disease (PD) compared to partial response (PR) plus stable disease (SD),

p=0.02 and p=0.02, respectively. In the tissue, ER-α or progesterone receptor positivity did not demonstrate a significant difference in response for patients treated with the combination erlotinib and fulvestrant, Chi-squared test, p=0.96. Moreover, cytoplasmic ER-β H score was higher in patients with PD versus PR + SD (median 90 versus 20 respectively, p=0.01). The dataset did not demonstrate statistical significance by treatment arm (median 60 versus 65 in the erlotinib versus erlotinib plus fulvestrant, p=0.59).

Conclusion:

Combination erlotinib and fulvestrant in this study did not show superiority over

erlotinib alone with respect to OS and PFS. Blood estrogen and estrone levels did not correlate with response or treatment arm. Biomarkers that may be prognostic include cytoplasmic ER-β H score, while higher Cycle 2 Day 1 PlGF and TGF-α levels may suggest a poor response.

    Cover page: Blood and Tissue Biomarkers in Advanced Non-Small Cell Lung Cancer (NSCLC) Patients Treated with Erlotinib (Tarceva?) Alone or Erlotinib and Fulvestrant (Faslodex?): A Phase II Clinical Trial Analysis
    • Article
    • Peer Reviewed
    UCLA Previously Published Works (2014)
    The true potential of cytokine therapies in cancer treatment is limited by the inability to deliver optimal concentrations into tumor sites due to dose-limiting systemic toxicities. To maximize the efficacy of cytokine therapy, recombinant antibody-cytokine fusion proteins have been constructed by a number of groups to harness the tumor-targeting ability of monoclonal antibodies. The aim is to guide cytokines specifically to tumor sites where they might stimulate more optimal anti-tumor immune responses while avoiding the systemic toxicities of free cytokine therapy. Antibody-cytokine fusion proteins containing interleukin (IL)-2, IL-12, IL-21, tumor necrosis factor (TNF)α, and interferons (IFNs) α, β, and γ have been constructed and have shown anti-tumor activity in preclinical and early-phase clinical studies. Future priorities for development of this technology include optimization of tumor targeting, bioactivity of the fused cytokine, and choice of appropriate agents for combination therapies. This review is intended to serve as a framework for engineering an ideal antibody-cytokine fusion protein, focusing on previously developed constructs and their clinical trial results.
      Cover page: Antibody-cytokine fusion proteins for treatment of cancer: engineering cytokines for improved efficacy and safety.
      • Article
      • Peer Reviewed
      UCLA Previously Published Works (2019)
        Cover page: Cardiac Complications in the Adult Bone Marrow Transplant Patient
        • Article
        • Peer Reviewed
        UCLA Previously Published Works (2020)

        Background

        High-dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) has been investigated in patients with primary central nervous system lymphoma (PCNSL) and non-Hodgkin lymphoma (NHL) with CNS involvement and has shown promising results.

        Patients and methods

        A retrospective analysis was performed of 48 consecutive patients who had undergone HDC/ASCT with TBC (thiotepa, busulfan, cyclophosphamide) conditioning for PCNSL (27 patients), secondary CNS lymphoma (SCNSL) (8 patients), or relapsed disease with CNS involvement (13 patients) from July 2006 to December 2017. Of the 27 patients with PCNSL, 21 had undergone ASCT at first complete remission (CR1).

        Results

        The 2-year progression-free survival (PFS) rate was 80.5% (95% confidence interval [CI], 69.9-92.9) and the 2-year overall survival (OS) rate was 80.1% (95% CI, 69.2%-92.7%) among all patients. The 2-year PFS and OS rate for patients with PCNSL in CR1 was 95.2% (95% CI, 86.6%-100%) and 95.2% (95% CI, 86.6%-100%), respectively. On univariate analysis of the patients with PCNSL, ASCT in CR1 was the only variable statistically significant for outcome (P = .007 for PFS; P = .008 for OS). Among patients with SCNSL or CNS relapse, the 2-year PFS and OS rate were comparable at 75.9% (95% CI, 59.5%-96.8%) and 75.3% (95% CI, 58.6%-98.6%), respectively. The most common side effects were febrile neutropenia (89.6%; of which 66.7% had an infectious etiology identified), nausea/vomiting (85.4%), diarrhea (93.8%), mucositis (89.6%), and electrolyte abnormalities (89.6%). Four patients (8.3%) died of treatment-related overwhelming infection; of these patients, 3 had SCNSL.

        Conclusion

        HDC and ASCT using TBC conditioning for both PCNSL and secondary CNS NHL appears to have encouraging long-term efficacy with manageable side effects.
          Cover page: Durable Survival Outcomes in Primary and Secondary Central Nervous System Lymphoma After High-dose Chemotherapy and Autologous Stem Cell Transplantation Using a Thiotepa, Busulfan, and Cyclophosphamide Conditioning Regimen
          • Article
          • Peer Reviewed
          UCLA Previously Published Works (2018)
          An important emerging form of immunotherapy targeting B cell malignancies is chimeric antigen receptor (CAR) T cell therapy. Despite encouraging response rates of anti-CD19 CAR T cell therapy in B cell lymphomas, limited durability of response necessitates further study to potentiate CAR T cell efficacy. Antibody-targeted interferon (IFN) therapy is a novel approach in immunotherapy. Given the ability of IFNs to promote T cell activation and survival, target cell recognition, and cytotoxicity, we asked whether antibody-targeted IFN could enhance the antitumor effects of anti-CD19 CAR T cells. We produced an anti-CD20-IFN fusion protein containing the potent type 1 IFN isoform alpha14 (α14), and demonstrated its ability to suppress proliferation and induce apoptosis of human B cell lymphomas. Indeed, with the combination of anti-CD20-hIFNα14 and CAR T cells, we found enhanced cell killing among B cell lymphoma lines. Importantly, for all cell lines pretreated with anti-CD20-hIFNα14, the subsequent cytokine production by CAR T cells was markedly increased regardless of the degree of cell killing. Thus, several activities of CD19 CAR T cells were enhanced in the presence of anti-CD20-hIFNα14. These data suggest that antibody-targeted IFN may be an important novel approach to improving the efficacy of CAR T cell therapy.
            Cover page: Activity of Anti-CD19 Chimeric Antigen Receptor T Cells Against B Cell Lymphoma Is Enhanced by Antibody-Targeted Interferon-Alpha
            • Article
            • Peer Reviewed
            UC Irvine Previously Published Works (2023)
            Lymphomas are not infrequently associated with the Epstein-Barr virus (EBV), and EBV positivity is linked to worse outcomes in several subtypes. Nanatinostat is a class-I selective oral histone deacetylase inhibitor that induces the expression of lytic EBV BGLF4 protein kinase in EBV+ tumor cells, activating ganciclovir via phosphorylation, resulting in tumor cell apoptosis. This phase 1b/2 study investigated the combination of nanatinostat with valganciclovir in patients aged ≥18 years with EBV+ lymphomas relapsed/refractory to ≥1 prior systemic therapy with no viable curative treatment options. In the phase 1b part, 25 patients were enrolled into 5 dose escalation cohorts to determine the recommended phase 2 dose (RP2D) for phase 2 expansion. Phase 2 patients (n = 30) received RP2D (nanatinostat 20 mg daily, 4 days per week with valganciclovir 900 mg orally daily) for 28-day cycles. The primary end points were safety, RP2D determination (phase 1b), and overall response rate (ORR; phase 2). Overall, 55 patients were enrolled (B-non-Hodgkin lymphoma [B-NHL], [n = 10]; angioimmunoblastic T-cell lymphoma-NHL, [n = 21]; classical Hodgkin lymphoma, [n = 11]; and immunodeficiency-associated lymphoproliferative disorders, [n = 13]). The ORR was 40% in 43 evaluable patients (complete response rate [CRR], 19% [n = 8]) with a median duration of response of 10.4 months. For angioimmunoblastic T-cell lymphoma-NHL (n = 15; all refractory to the last prior therapy), the ORR/CRR ratio was 60%/27%. The most common adverse events were nausea (38% any grade) and cytopenia (grade 3/4 neutropenia [29%], thrombocytopenia [20%], and anemia [20%]). This novel oral regimen provided encouraging efficacy across several EBV+ lymphoma subtypes and warrants further evaluation; a confirmatory phase 2 study (NCT05011058) is underway. This phase 1b/2 study is registered at www.clinicaltrials.gov as #NCT03397706.
              Cover page: Targeted therapy with nanatinostat and valganciclovir in recurrent EBV-positive lymphoid malignancies: a phase 1b/2 study.
              • Article
              • Peer Reviewed
              UCLA Previously Published Works (2021)

              Introduction

              Estrogen receptors (ER) (ERα, ERβ) and aromatase (key enzyme for estrogen synthesis) are expressed in most human NSCLCs. High intratumoral estrogen levels and elevated aromatase expression in NSCLC predict poor outcome. This open-label, phase 1b, single-center study evaluated the safety and tolerability of escalating doses of the aromatase inhibitor, exemestane, in combination with carboplatin and pemetrexed in postmenopausal women with stage IV nonsquamous NSCLC.

              Methods

              Patients received exemestane (starting 1-wk before chemotherapy) at 25 mg orally (PO) daily (cohort 1) or 50 mg PO daily (cohort 2) combined with carboplatin (area under the curve 6 mg × min/mL) and pemetrexed (500 mg/m2) intravenously every 3 weeks for four cycles. Thereafter, patients were eligible for continued therapy with exemestane and pemetrexed or pemetrexed alone.

              Results

              A total of 10 patients consented for therapy, and two patients failed in the screening. Four patients completed the therapy in cohort 1 and four patients in cohort 2. The median number of cycles administered was 15 (range: 1-54). Maximum tolerated dose was exemestane 50 mg PO daily with combination chemotherapy. Intention-to-treat analysis revealed an objective response rate (ORR) of 62.5% (five of eight patients with partial response) and a clinical benefit rate of 87.5% (seven of eight patients with either stable disease or partial response). ORR was associated with aromatase expression (p = 0.02). Circulating estrogen levels decreased with exemestane use, and quality of life measurements did not significantly change during the treatment. There were no adverse events.

              Conclusions

              The combination of carboplatin, pemetrexed, and exemestane in postmenopausal women with metastatic NSCLC is safe and well tolerated. Biomarker studies revealed that ORR correlates with tumor aromatase expression. These findings support future clinical trials to confirm the antitumor efficacy with this combination therapy.
                Cover page: Investigation of Combination Treatment With an Aromatase Inhibitor Exemestane and Carboplatin-Based Therapy for Postmenopausal Women With Advanced NSCLC
                • Article
                • Peer Reviewed
                UCLA Previously Published Works (2018)

                Objectives

                This open-label, randomized phase II trial evaluated antitumor efficacy of an antiestrogen, fulvestrant, in combination with human epidermal growth factor receptor (EGFR) inhibitor, erlotinib, in advanced non-small cell lung cancer (NSCLC) patients.

                Materials and methods

                Patients with advanced or metastatic NSCLC, ECOG 0-2, previous chemotherapy unless patient refusal, and no prior EGFR-directed therapy were randomized 2:1 to erlotinib 150 mg oral daily plus 500 mg intramuscular fulvestrant on day 1, 15, 29 and every 28 days thereafter or erlotinib alone 150 mg oral daily. The primary end point was objective response rate (ORR); secondary endpoints included progression free survival (PFS) and overall survival (OS).

                Results

                Among 106 randomized patients, 100 received at least one dose of study drug. ORR was 16.4% (11 of 67 patients) for the combination versus 12.1% (4 of 33 patients) for erlotinib (p = 0.77). PFS median 3.5 versus 1.9 months [HR = 0.86, 95% CI (0.52-1.43), p = 0.29] and OS median 9.5 versus 5.8 months [HR = 0.92, 95% CI (0.57-1.48), p = 0.74] numerically favored the combination. In an unplanned subset analysis, among EGFR wild type patients (n = 51), but not EGFR mutant patients (n = 17), median PFS was 3.5 versus 1.7 months [HR = 0.35, 95% CI (0.14-0.86), p = 0.02] and OS was 6.2 versus 5.2 months [HR = 0.72, 95% CI (0.35-1.48), p = 0.37] for combined therapy versus erlotinib, respectively. Notably, EGFR WT patients were more likely to be hormone receptor-positive (either estrogen receptor α- and/or progesterone receptor-positive) compared to EGFR mutant patients (50% versus 9.1%, respectively) (p = 0.03). Treatment was well tolerated with predominant grade 1-2 dermatologic and gastrointestinal adverse effects.

                Conclusion

                Addition of fulvestrant to erlotinib was well tolerated, with increased activity noted among EGFR wild type patients compared to erlotinib alone, albeit in an unplanned subset analysis.
                  Cover page: Randomized phase II study of fulvestrant and erlotinib compared with erlotinib alone in patients with advanced or metastatic non-small cell lung cancer
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