Megan M. O'Meara

Brentuximab vedotin combined with ABVD or AVD for patients with newly diagnosed Hodgkin's lymphoma: a phase 1, open-label, dose-escalation study

BACKGROUND Roughly 70-80% of patients with advanced stage Hodgkins lymphoma are cured with various first-line and second-line treatments, including ABVD, BEACOPP, and stem-cell transplantation. Brentuximab vedotin has shown significant clinical activity, with a manageable safety profile, in patients with relapsed or refractory Hodgkins lymphoma. We aimed to assess the safety and early clinical efficacy of this drug as first-line treatment in combination with standard or modified-standard treatment in patients with previously untreated Hodgkins lymphoma. METHODS We did a phase 1, open-label, dose-escalation safety study comparing brentuximab vedotin in combination with standard (ABVD) or a modified-standard (AVD) treatment. Patients were enrolled into the groups sequentially. Main entry criteria were newly diagnosed, treatment-naive, CD30-positive patients with Hodgkins lymphoma who had histologically confirmed stage IIA bulky disease or stage IIB-IV disease and an Eastern Cooperative Oncology Group performance status of two or less. Patients received doses of 0·6, 0·9, or 1·2 mg/kg brentuximab vedotin by intravenous infusion every 2 weeks with either ABVD (25 mg/m(2) doxorubicin, 10 units/m(2) bleomycin, 6 mg/m(2) vinblastine, and 375 mg/m(2) dacarbazine) or AVD (ABVD modified regimen without the inclusion of bleomycin) for up to six cycles. Our primary objectives were to assess the safety profile and establish the maximum tolerated dose (MTD) of brentuximab vedotin in combination with ABVD and AVD. The safety profile and MTD was assessed for the safety population. The study has completed and the final analysis is presented. This study was registered with ClinicalTrials.gov, number NCT01060904. FINDINGS Between Jan 29, 2010, and Sept 17, 2012, 51 patients were enrolled and received at least one dose of brentuximab vedotin. The maximum tolerated dose of brentuximab vedotin when combined with ABVD or AVD was not exceeded at 1·2 mg/kg. 21 (95%) of 22 patients given brentuximab vedotin and ABVD achieved complete remission, as did 24 (96%) of 25 patients given brentuximab vedotin and AVD. Adverse events were generally grade 1 or 2; however, an unacceptable number of patients in the brentuximab vedotin and ABVD groups had pulmonary toxic effects (11 [44%] of 25), which exceeded the historical incidence for ABVD alone. No patients experienced pulmonary toxic effects when treated with brentuximab vedotin plus AVD. The most common grade 3 or worse events were neutropenia (20 [80%] of 25 patients in the brentuximab vedotin and ABVD group vs 20 [77%] of 26 patients in the brentuximab vedotin and AVD group), anaemia (five [20%] vs three [12%]), febrile neutropenia (five [20%] vs two [8%]), pulmonary toxic effects (six [24%] vs 0), syncope (three [12%] vs two [8%]), dyspnoea (three [12%] vs one [4%]), pulmonary embolism (three [12%] vs 0), fatigue (one [4%] each), and leucopenia (one [4%] each). Serious events occured in 41% of all patients (14 [56%] in the brentuximab vedotin and ABVD group and seven [27%] in the brentuximab vedotin and AVD group). Serious events occurring in 10% of patients or more overall were febrile neutropenia (four [16%] in the brentuximab vedotin and ABVD group vs two [8%] in the brentuximab vedotin and AVD group), and, in the brentuximab vedotin and ABVD group only, pulmonary toxic effects (six [24%]). INTERPRETATION Brentuximab vedotin should not be given with bleomycin in general or specifically as first-line therapy for patients with treatment naive, advanced stage Hodgkins lymphoma. 1·2 mg/kg brentuximab vedotin combined with AVD given every 2 weeks was generally well tolerated by patients. At present, a phase 3 trial comparing brentuximab vedotin plus AVD to ABVD alone is ongoing (ClinicalTrials.gov, number NCT01712490) and will formally assess whether brentuximab vedotin plus AVD might redefine therapy in treatment-naive patients with Hodgkins lymphoma. FUNDING Seattle Genetics Inc and Takeda Pharmaceuticals International Co.

A Multiantigen Vaccine Targeting Neu, IGFBP-2, and IGF-IR Prevents Tumor Progression in Mice with Preinvasive Breast Disease

A multiantigen multipeptide vaccine, targeting proteins expressed in preinvasive breast lesions, can stimulate type I CD4+ T cells which have been shown to be deficient in both patients with breast cancer and mice that develop mammary tumors. Transgenic mice (TgMMTV-neu) were immunized with a multiantigen peptide vaccine specific for neu, insulin—like growth factor-binding protein 2 and insulin-like growth factor receptor-I at a time when some of the animals already had preinvasive lesions (18 weeks of age). Although immunization with each individual antigen was partially effective in inhibiting tumor growth, immunization with the multiantigen vaccine was highly effective, blocking development of palpable lesions in 65% of mice and slowing tumor growth in the infrequent palpable tumors, which did arise. Protection was mediated by CD4+ T cells, and the few slow-growing tumors that did develop demonstrated a significant increase in intratumoral CD8+ T cells as compared with controls (P = 0.0007). We also combined the vaccine with agents that were, by themselves, partially effective inhibitors of tumor progression in this model; lapatinib and the RXR agonist bexarotene. Although the combination of lapatinib and vaccination performed similarly to vaccination alone (P = 0.735), bexarotene and vaccination significantly enhanced disease-free survival (P < 0.0001), and approximately 90% of the mice showed no pathologic evidence of carcinomas at one year. The vaccine also demonstrated significant clinical efficacy in an additional transgenic model of breast cancer (TgC3(I)-Tag). Chemoimmunoprevention combinations may be an effective approach to breast cancer prevention even when the vaccine is administered in the presence of subclinical disease. Cancer Prev Res; 6(12); 1273–82. ©2013 AACR.

Brentuximab vedotin in patients aged 60 years or older with relapsed or refractory CD30-positive lymphomas: a retrospective evaluation of safety and efficacy

Abstract Older adults constitute a significant proportion of the cancer population, but are underrepresented in clinical trials. We conducted a retrospective analysis of the safety and efficacy of brentuximab vedotin in adults ≥ 60 years with relapsed CD30-positive lymphomas. Baseline characteristics and safety data were compared for older (median age 66) and younger patients (< 60 years, median age 32). Exposure to brentuximab vedotin was comparable. Older patients had more preexisting conditions (median 11 vs. 6) and were receiving more concomitant medications (median 7.5 vs. 4). Higher rates of anemia (30% vs. 10%), peripheral sensory neuropathy (60% vs. 46%), fatigue (58% vs. 43%) and adverse events ≥ grade 3 (70% vs. 56%) occurred in older patients. Objective response rates were 56% and 100% in older patients with Hodgkin lymphoma and systemic anaplastic large cell lymphoma, respectively. With appropriate monitoring, brentuximab vedotin may represent a meaningful clinical option for older patients with relapsed CD30-positive lymphomas.

A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia

Vadastuximab talirine (SGN-CD33A, 33A) is an antibody-drug conjugate consisting of pyrrolobenzodiazepine dimers linked to a monoclonal antibody targeting CD33, which is expressed in the majority of acute myeloid leukemia (AML) patients. This phase 1 study evaluated the safety, pharmacokinetics, and preliminary activity of vadastuximab talirine and determined the recommended monotherapy dose in patients with relapsed or refractory AML. Additional expansion cohorts tested vadastuximab talirine in specific subpopulations of relapsed AML, and in a cohort of older, treatment-naive patients. Patients received vadastuximab talirine IV on day 1 (5-60 µg/kg) or on days 1 and 4 (20 µg/kg) of 21-day cycles. A total of 131 patients (median age, 73 years [range, 26-89 years]) had intermediate I-II (48%) or adverse (34%) risk by European LeukemiaNet classification; 50% of patients had underlying myelodysplasia. Two dose-limiting toxicities (grade 2 pulmonary embolism and grade 4 hypocellular marrow) occurred during dose finding. Most adverse events (AEs) were consistent with myelosuppression; nonhematologic AEs included fatigue, nausea, and diarrhea. The 30-day mortality was 8%. At the recommended monotherapy dose of 40 µg/kg, the complete remission + CRi rate was 28% (5 of 18 patients); 50% of patients who responded achieved minimal residual disease negativity. In patients across dose levels who achieved CR or CRi, the median time to full count recovery was 6.4 weeks for neutrophils (≥1000/µL) and 10.6 weeks for platelets (≥100 × 109/L). Vadastuximab talirine demonstrates activity and a tolerable safety profile as a single agent in patients with AML. The recommended monotherapy dose of vadastuximab talirine is 40 µg/kg. This trial was registered at www.clinicaltrials.gov as # NCT01902329.

Immunization against HIF-1α Inhibits the Growth of Basal Mammary Tumors and Targets Mammary Stem Cells In Vivo

Purpose: Triple-negative breast cancer (TNBC) represents a cancer stem cell–enriched phenotype. Hypoxia-inducible factor-1α (HIF-1α) induces the expression of proteins associated with stemness and is highly upregulated in TNBC. We questioned whether HIF-1α was immunogenic and whether vaccination targeting HIF-1α would impact the growth of basal-like mammary tumors in transgenic mice. Experimental Design: We evaluated HIF-1α–specific IgG in sera from controls and patients with breast cancer. Class II epitopes derived from the HIF-1α protein sequence were validated by ELISPOT. To assess therapeutic efficacy, we immunized Tg-MMTVneu and C3(1)Tag mice with HIF-1α Th1-inducing peptides. Stem cells were isolated via magnetic bead separation. Levels of HIF-1α and stem cells in the tumor were quantitated by Western blotting and flow cytometry. Results: The magnitude (P < 0.001) and incidence (P < 0.001) of HIF-1α–specific IgG were elevated in TNBC patients compared with controls. Both breast cancer patients and donors showed evidence of HIF-1α–specific Th1 and Th2 immunity. Three HIF-1α–specific Th1 class II restricted epitopes that were highly homologous between species elicited type I immunity in mice. After HIF-1α vaccination, mammary tumor growth was significantly inhibited in only C3(1)Tag (basal-like/stem cellhigh; P < 0.001) not TgMMTV-neu (luminal/neu/stem celllow; P = 0.859) murine models. Vaccination increased type I T cells in the tumor (P = 0.001) and decreased cells expressing the stem cell marker, Sca-1, compared with controls (P = 0.004). Conclusions: An HIF-1α vaccine may be uniquely effective in limiting tumor growth in TNBC. Inhibiting outgrowth of breast cancer stem cells via active immunization in the adjuvant setting may impact disease recurrence. Clin Cancer Res; 23(13); 3396–404. ©2016 AACR.

Abstract DDT02-02: SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms

Increased fucosylation is associated with tumor progression and metastasis, and targeting fucosylation is a novel strategy in cancer therapy. 2-Fluorofucose (SGN-2FF) has been shown to inhibit cellular fucosylation by depletion of the fucosylation substrate GDP-fucose, as well as by direct inhibition of fucosyltransferases, leading to the production of afucosylated glycoproteins including antibodies. SGN-2FF has antitumor activity in multiple mouse tumor models, showing substantial tumor growth delay. SGN-2FF also enhanced the protective effect of a lymphoma vaccine in a syngeneic mouse model (1). This protection was determined to be immune dependent since depletion of CD4 and CD8 T cells reduced the SGN-2FF/vaccine activity. In vitro, SGN-2FF has been shown to activate human T cells in an antigen-dependent manner. Therefore, by inhibiting fucosylation SGN-2FF can potentially work through multiple mechanisms, including but not limited to effects on immune cells, tumor cells, and the tumor microenvironment. A first-in-human, phase 1, multicenter dose-escalation study of SGN-2FF is ongoing to investigate the safety, pharmacokinetics, and antitumor activity of SGN-2FF given orally to patients with advanced solid tumors (NCT# 02952989). Pharmacodynamic effects, including markers of fucosylation status, will also be evaluated to help determine the optimal biologic dose. This presentation reviews the preclinical activity data of SGN-2FF and describes the design of the phase 1 study, showing how demonstrated preclinical pharmacodynamic effects on fucosylation status informed how activity and pharmacodynamics will be monitored and evaluated in the phase 1 study. Reference 1. Okeley NM, Alley SC, Anderson ME, Boursalian TE, Burke PJ, Emmerton KM, et al. Development of orally active inhibitors of protein and cellular fucosylation. Proc Natl Acad Sci U S A 2013;110:5404-9. Citation Format: Stephen C. Alley, Megan O9Meara, Shyra J. Gardai, Nicole M. Okeley. SGN-2FF: A novel small molecule inhibitor of fucosylation with preclinical antitumor activity through multiple immune mechanisms [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr DDT02-02. doi:10.1158/1538-7445.AM2017-DDT02-02

A phase 1 trial of vadastuximab talirine combined with hypomethylating agents in patients with CD33 positive AML

Treatment of acute myeloid leukemia (AML) among the elderly is challenging because of intolerance of intensive therapy and therapy-resistant biology. Hypomethylating agents (HMAs) are commonly used, with suboptimal outcomes. Vadastuximab talirine is a CD33-directed antibody conjugated to pyrrolobenzodiazepine (PBD) dimers. Preclinically, HMAs followed by vadastuximab talirine produced upregulated CD33 expression, increased DNA incorporation by PBD, and enhanced cytotoxicity. A combination cohort in a phase 1 study (NCT01902329) assessed safety, tolerability, and activity of vadastuximab talirine with HMAs. Those eligible had Eastern Cooperative Oncology Group status 0 to 1 and previously untreated CD33-positive AML, and declined intensive therapy. Vadastuximab talirine was administered intravenously at 10 μg/kg on last day of HMA (azacitidine or decitabine) infusion in 4-week cycles. Among 53 patients treated, the median age was 75 years. Patients had adverse (38%) or intermediate (62%) cytogenetic risk. Median treatment duration was 19.3 weeks. No dose-limiting toxicities were reported. The majority of adverse events were a result of myelosuppression, with some causing therapy delays. Thirty- and 60-day mortality rates were 2% and 8%, respectively. The composite remission rate (complete remission [CR] and CR with incomplete blood count recovery) was 70%. Fifty-one percent of remissions were minimal residual disease-negative by flow cytometry. Similarly high remission rates were observed in patients with secondary AML, aged at least 75 years, and with adverse cytogenetic risk. Median relapse-free survival and overall survival were 7.7 and 11.3 months, respectively. Compared with historical data for HMA monotherapy, the combination of vadastuximab talirine with HMAs produced a high remission rate, but was accompanied by increased hematologic toxicity.

Vaccine targeting HIF1A in triple negative breast cancer

The high rates of relapse in triple negative breast cancer (TNBC) are thought to be due to the presence of increased levels of cancer stem cells (CSC), which have been shown to be resistant to standard therapies. It has been demonstrated that hypoxia-inducible factor 1 (HIF1A) can induce the expression of numerous gene products associated with stem-ness and epithelial-mesenchymal transition in breast cancer cells and has been shown to be hyperactivated in TNBC. In this study, we aimed to target HIF1A with a therapeutic immune response through active immunization. HIF1A is a tumor-associated antigen. We have determined that both the magnitude and incidence of HIF1A-specific IgG is significantly elevated in TNBC compared to volunteer donors. We identified epitopes derived from HIF1A that selectively elicited IFN-gamma secretion with little to no IL-10 secretion in human peripheral blood mononuclear cells and T cell lines generated with these epitopes responded to recombinant HIF1A protein. Furthermore, these epitopes are highly homologous between mouse and man. To evaluate therapeutic efficacy, we immunized MMTV-neu (HER2+ model) and C3(1)Tag (TNBC model) mice with a plasmid-based vaccine containing an extended sequence of the identified epitopes. Tumor growth was inhibited over 80% (p < 0.0001) in the TNBC model; however, growth was inhibited only by 40% (p < 0.01) in the HER2+ model. We determined the majority of the tumor cells from the TNBC model expressed the mouse stem cell marker, Sca-1, whereas only a minority of the cells derived from the HER2+ model expressed the marker. Finally, we detected a 52% decrease in tumor Sca-1 expression after HIF1A-specific vaccination in the TNBC model (p = 0.004). Targeting HIF1A via active immunization may be an effective way to prevent disease relapse in patients with TNBC.

Abstract SY24-03: Vaccines for the prevention of cancer

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Active immunization against infectious disease pathogens has been one of the most successful primary disease prevention modalities to impact human health. In developed countries, common childhood infections such as polio and diphtheria have been nearly eradicated due to standardized childhood vaccination regimens. Stimulating an effective immune response via antigen-targeted immunization will result in the development of immunologic memory allowing neutralizing antibodies or cytotoxic T cells to become mobilized when exposed to the pathogen at a later date. The development of effective vaccines against viruses that are associated with cancer initiation, such hepatitis B/hepatoma and human papilloma virus/cervical cancer, have resulted in a decrease in the incidence of these malignancies. For the majority of common human cancers, however, there are few infectious pathogens identified as direct etiologic agents instrumental in the induction of malignancy. Tumor-associated proteins that can serve as immunologic targets for active immunization have been identified. The majority of identified tumor antigens are not mutated, but rather, are self proteins. Over the last decade a variety of vaccination strategies have been developed to allow the generation of immunity to these cancer-related proteins and vaccines targeting such antigens have been used for the treatment of a wide variety of human malignancy. Although the clinical success of cancer vaccines has been variable, several observations can be made: (1) functional tumor-specific T cell and antibody immunity can be generated after vaccination in patients with cancer targeting such ubiquitous antigens as hTERT, HER-2/neu, and EGFR, (2) in clinical trials that have enrolled hundreds of patients, immunization against nonmutated self tumor antigens has not resulted in excessive toxicity. Indeed, in most reported studies of vaccination with antigen and standard adjuvants, toxicity is limited to grade 1 and 2 events, and (3) vaccines are most likely to be clinically effective when administered in a minimal disease state. The safety profile of cancer vaccines in the therapeutic setting has allowed the exploration of multiantigen immunization for cancer prevention. Mice that have been genetically engineered to develop specific malignancies offer a model to evaluate cancer prevention approaches, in particular active immunization. Investigations have shown that such murine models often have similar genetic alterations and histology as the human malignancy being modeled. Moreover, the antigenic repertoire in mice is similar to that observed in humans as well. We have developed a multiantigen polyepitope vaccine targeting immunogenic proteins associated with oncogenesis and assessed whether we could prevent the development of breast cancer in middle-aged TgMMTV-neu mice. The multiantigen vaccine inhibited tumor growth in 50-80% of mice and was superior to individual antigen immunizations in protecting mice against breast cancer (p<0.05). Studies demonstrated that vaccine induced tumor protection was mediated by T cells and even vaccinated mice that were unprotected by immunization and eventually developed tumors demonstrated evidence of high levels of type I immunity, evidence of T cells with potent antitumor activity, and tumor trafficking CD8+ T cells. To determine the cause of vaccine failure, we evaluated the mammary tissue of 18 week old animals at the time of immunization which revealed a significant incidence of subclinical breast tumors, both premalignant and malignant. The addition of bexarotene, a retinoid X receptor (RXR) agonist, to multiantigen vaccination significantly increased the proportion of protected animals and was superior to both bexarotene and vaccine alone in inhibiting the development of breast cancer (p<0.01). There was no evidence of autoimmune toxicity in immunized mice. These data suggest breast cancer vaccines targeting biologically relevant proteins may be an effective approach to the prevention of breast cancer even when administered in the presence of subclinical disease if combined with an antiproliferative agent. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr SY24-03. doi:10.1158/1538-7445.AM2011-SY24-03