Mark S. Berger

Efficacy and Safety of Gemtuzumab Ozogamicin in Patients With CD33-Positive Acute Myeloid Leukemia in First Relapse

PURPOSE Three open-label, multicenter trials were conducted to evaluate the efficacy and safety of single-agent Mylotarg (gemtuzumab ozogamicin; CMA-676; Wyeth Laboratories, Philadelphia, PA), an antibody-targeted chemotherapy agent, in patients with CD33-positive acute myeloid leukemia (AML) in untreated first relapse. PATIENTS AND METHODS The study population comprised 142 patients with AML in first relapse with no history of an antecedent hematologic disorder and a median age of 61 years. All patients received Mylotarg as a 2-hour intravenous infusion, at a dose of 9 mg/m(2), at 2-week intervals for two doses. Patients were evaluated for remission, survival, and treatment-emergent adverse events. RESULTS Thirty percent of patients treated with Mylotarg obtained remission as characterized by 5% or less blasts in the marrow, recovery of neutrophils to at least 1,500/microL, and RBC and platelet transfusion independence. Although patients treated with Mylotarg had relatively high incidences of myelosuppression, grade 3 or 4 hyperbilirubinemia (23%), and elevated hepatic transaminase levels (17%), the incidences of grade 3 or 4 mucositis (4%) and infections (28%) were relatively low. There was a low incidence of severe nausea and vomiting (11%) and no treatment-related cardiotoxicity, cerebellar toxicity, or alopecia. Many patients received Mylotarg on an outpatient basis (38% and 41% of patients for the first and second doses, respectively). Among the 142 patients, the median total duration of hospitalization was 24 days; 16% of patients required 7 days of hospitalization or less. CONCLUSION Administration of the antibody-targeted chemotherapy agent Mylotarg to patients with CD33-positive AML in first relapse induces complete remissions with what appears to be a favorable safety profile.

Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence

In this study, the authors analyzed the efficacy and safety of gemtuzumab ozogamicin (GO) (Mylotarg®), an antibody‐targeted chemotherapy for CD33‐positive acute myeloid leukemia (AML).

A phase i study of the pan bcl-2FamilyInhibitor obatoclax mesylate in patients with advanced hematologic malignancies

Purpose: The outcome of patients with refractory leukemia and myelodysplasia is poor, and new therapies are needed. The antiapoptotic proteins of the Bcl-2 family are overexpressed in these malignancies and are potential therapeutic targets. Therefore, we conducted a phase I clinical trial of the small-molecule pan-Bcl-2 inhibitor, obatoclax mesylate, in patients with refractory leukemia and myelodysplasia to assess its safety and define its optimal dose. Experimental Design: Forty-four patients with refractory leukemia or myelodysplasia were treated with obatoclax mesylate by continuous intravenous infusion at increasing doses and frequencies. Results: A total of 306 infusions of obatoclax mesylate were administered with a median of 5 infusions per patient. The study drug was well tolerated up to the highest dose planned without dose-limiting toxicity. Grade 1/2 central nervous system symptoms were the most common adverse events attributable to the study drug. One patient with acute myeloid leukemia with mixed lineage leukemia t(9;11) rearrangement achieved a complete remission, which lasted 8 months. Three of 14 patients with myelodysplasia showed hematologic improvement with RBC or platelet transfusion independence. Conclusions: Obatoclax mesylate is well tolerated and these results support its further investigation in patients with leukemia and myelodysplasia.

Licensure of Gemtuzumab Ozogamicin for the Treatment of Selected Patients 60 Years of Age or Older with Acute Myeloid Leukemia in First Relapse

This paper discusses background informationand the body of clinical data that has beenaccumulated to demonstrate the efficacy andsafety of gemtuzumab ozogamicin (Mylotarg®Wyeth Pharmaceuticals, Philadelphia, PA).Based on these data, gemtuzumab ozogamicinwas approved by the United States Food andDrug Administration for the treatment ofpatients with CD33-positive acute myeloidleukemia in first relapse who are 60 yearsof age or older and who are not consideredcandidates for other cytotoxicchemotherapy. The recommended dosage ofgemtuzumab ozogamicin is 9 mg/m2,administered as a 2-hour intravenousinfusion for a total of 2 doses with 14days between doses.

A Phase II, Multicenter, Open-Label Study of Obatoclax Mesylate in Patients With Previously Untreated Myelodysplastic Syndromes With Anemia or Thrombocytopenia

BACKGROUND Obatoclax mesylate is a small-molecule Bcl-2 homology domain-3 mimetic that neutralizes antiapoptotic Bcl-2-related proteins. We evaluated obatoclax in untreated MDS patients with anemia/thrombocytopenia. PATIENTS AND METHODS Twenty-four patients with a bone marrow blast count of ≤ 10% and anemia (hemoglobin level < 10 g/dL) or thrombocytopenia (platelet count < 50 × 10(9)/L) were eligible to receive intravenous obatoclax 60 mg over 24 hours every 2 weeks. RESULTS Response rate was 8% (2 patients; hematologic improvement). Disease stabilization/response was maintained ≥ 12 weeks in 50% (12 patients). Because the response rate was below a predetermined threshold, the study was terminated. Adverse events (any grade) included euphoric mood (63%; 15 patients), nausea (38%; 9 patients), and diarrhea (25%; 6 patients); Grade 3/4 adverse events included anemia (21%; 5 patients), thrombocytopenia (13%; 3 patients), and pneumonia (13%; 3 patients). CONCLUSIONS Obatoclax 60 mg every 2 weeks was feasible, but had limited first-line activity in MDS.

Cutting Edge: Selective Oral ROCK2 Inhibitor Reduces Clinical Scores in Patients with Psoriasis Vulgaris and Normalizes Skin Pathology via Concurrent Regulation of IL-17 and IL-10

Targeted inhibition of Rho-associated kinase (ROCK)2 downregulates the proinflammatory T cell response while increasing the regulatory arm of the immune response in animals models of autoimmunity and Th17-skewing human cell culture in vitro. In this study, we report that oral administration of a selective ROCK2 inhibitor, KD025, reduces psoriasis area and severity index scores by 50% from baseline in 46% of patients with psoriasis vulgaris, and it decreases epidermal thickness as well as T cell infiltration in the skin. We observed significant reductions of IL-17 and IL-23, but not IL-6 and TNF-α, whereas IL-10 levels were increased in peripheral blood of clinical responders after 12 wk of treatment with KD025. Collectively, these data demonstrate that an orally available selective ROCK2 inhibitor downregulates the Th17-driven autoimmune response and improved clinical symptoms in psoriatic patients via a defined molecular mechanism that involves concurrent modulation of cytokines without deleterious impact on the rest of the immune system.

Preclinical Assessment of CD171-Directed CAR T Cell Adoptive Therapy For Childhood Neuroblastoma: CE7 Epitope Target Safety and Product Manufacturing Feasibility

Purpose: The identification and vetting of cell surface tumor-restricted epitopes for chimeric antigen receptor (CAR)–redirected T-cell immunotherapy is the subject of intensive investigation. We have focused on CD171 (L1-CAM), an abundant cell surface molecule on neuroblastomas and, specifically, on the glycosylation-dependent tumor-specific epitope recognized by the CE7 monoclonal antibody. Experimental Design: CD171 expression was assessed by IHC using CE7 mAb in tumor microarrays of primary, metastatic, and recurrent neuroblastoma, as well as human and rhesus macaque tissue arrays. The safety of targeting the CE7 epitope of CD171 with CE7-CAR T cells was evaluated in a preclinical rhesus macaque trial on the basis of CD171 homology and CE7 cross reactivity. The feasibility of generating bioactive CAR T cells from heavily pretreated pediatric patients with recurrent/refractory disease was assessed. Results: CD171 is uniformly and abundantly expressed by neuroblastoma tumor specimens obtained at diagnoses and relapse independent of patient clinical risk group. CD171 expression in normal tissues is similar in humans and rhesus macaques. Infusion of up to 1 × 108/kg CE7-CAR+ CTLs in rhesus macaques revealed no signs of specific on-target off-tumor toxicity. Manufacturing of lentivirally transduced CD4+ and CD8+ CE7-CAR T-cell products under GMP was successful in 4 out of 5 consecutively enrolled neuroblastoma patients in a phase I study. All four CE7-CAR T-cell products demonstrated in vitro and in vivo antitumor activity. Conclusions: Our preclinical assessment of the CE7 epitope on CD171 supports its utility and safety as a CAR T-cell target for neuroblastoma immunotherapy. Clin Cancer Res; 23(2); 466–77. ©2016 AACR.

A pain syndrome associated with large adrenal metastases in patients with lung cancer

We report two cases of a pain syndrome caused by large adrenal metastases in patients with lung cancer. A review of the literature identified 23 previously reported patients with primary lung cancers who appear to have had a similar syndrome, although in none of these cases were other likely causes of the pain syndrome carefully excluded. The syndrome characteristically includes unilateral flank pain but may have abdominal components as well, and has only been reported in patients with large metastases (> or = 5 cm in largest diameter). Although the mechanism by which large adrenal metastases cause the pain syndrome is not clear, we suggest that treatment that includes local anesthetic agents or steroids may be effective. The pain syndrome caused by large adrenal metastases is not included in reviews of cancer pain syndromes but needs to be considered in the differential diagnosis of patients with lung cancer and flank or abdominal pain.

Surface marker analysis and karyotype distinguish acute biphenotypic leukemia from acute myelogenous leukemia expressing terminal deoxynucleotidyl transferase

Surface phenotyping by flow cytometry and cytochemical study were used to identify 15 adult patients with acute leukemia displaying ambiguous phenotypes. Differences were found in the blast cell karyotype and immunoglobulin gene rearrangements of terminal deoxynucleotidyl transferase (TdT)‐positive acute myelogenous leukemia (AML) and biphenotypic leukemia expressing B lymphoid and myeloid markers. The karyotypic abnormalities, t(9;22) and t(4;11), were noticed in acute biphenotypic leukemia, and were consistently associated with rearrangement at the immunoglobulin locus. Furthermore, coexpression of CD19/CD20 and either myeloperoxidase or myeloid surface markers were predictive of finding the t(9;22) or t(4;11) karyotype. Patients with TdT‐positive AML, on the other hand, were less likely to show rearrangement at the immunoglobulin locus, and did not have the t(9;22) or t(4;11). Instead, a variety of nonrandom karyotypic abnormalities were seen, including trisomy 13. Unlike common AML, the majority of TdT‐positive cases demonstrated an abnormal karyotype with duplications and/ or deletions present in all cases. In no instance was trisomy 8, t(8;21), t(15;17), or any other isolated translocation identified. The authors therefore suggest that immunophenotyping, when combined with cytochemical analysis of TdT and myeloperoxidase or Sudan black B, may aid in the characterization of subgroups of atypical acute leukemia, such that alternate approaches to therapy can be evaluated. Cancer 68:2161–2168, 1991.

Abstract 2590: KD019: Blood brain barrier penetrant HER2/neu, Src, and EGFR inhibitor

KD019 is an orally bioavailable small molecule inhibitor of molecular drivers of cancer growth and progression, including HER2/neu, Src family nonreceptor tyrosine kinases (Src) and EGFR. This profile of activity underlies the robust activity of KD019 in animal models of cancer. Although alternative agents targeting these tyrosine kinase receptors are available, only KD019 targets all of these pathways without the need for a combination strategy. A more important shortcoming of alternative agents is a lack of blood brain barrier (BBB) penetration (Brain/Plasma concentration ratio In the present work, KD019 is demonstrated to achieve concentrations in the brain equivalent to that in blood utilizing quantitative whole body autoradiography (QWBA). Lister Hooded partially pigmented rats were administered a single dose of 14C labeled KD019 and tissue radioactivity was evaluated utilizing phosphor-storage imaging plates and a Fuji FLA-5100 fluorescent image analyzing system (Quotient Bioresearch, Rushden, UK). Brain/blood radioactivity ratio was approximately 1 at 6-24 hours after dosing indicating significant brain penetration of KD019. BBB penetrance was further supported by a study performed in CD1 mice utilizing LC/MS/MS to determine tissue KD019 concentrations following a single oral dose of 100 mg free base/kg unlabeled drug (Pharmaron, Beijing, China). Brain/plasma KD019 ratios were 2.3-4.4 from 1-24 hours after dosing with brain concentrations of 2137-8253 ng/g tissue, compared to 0.03-0.07 for the EGFR/HER2 inhibitor lapatinib with brain concentrations of 0-286 ng/g tissue. To demonstrate that the penetration of KD019 into the brain parenchyma would translate into anticancer effects, KD019 efficacy was tested in a GL261 orthotopic syngeneic model of glioma (Molecular Imaging, Michigan, USA). GL261-luc2 luciferase expressing cells were implanted intracranially (2 mm right lateral and 1 mm anterior from Bregma, 2-3 mm down from burr hole) into C57BL/6 albino mice. KD019 dosed orally once daily at 75 mg base/kg on Days 8-12 and 15-19 after intracranial implantation significantly reduced the intracranial tumor growth as evaluated by bioluminescence, and extended median survival time by 20%. In conclusion, KD019 is a BBB penetrant TKI with an important and novel profile of kinase activity that, based on the data presented, will be advanced further in nonclinical and clinical experiments aiming at benefiting patients with intracranial tumors, a significant unmet clinical need. KD019 is currently being tested in combination with trastuzumab in patients with HER2-positive breast cancer and brain metastases. Citation Format: James R. Tonra, Masha Poyurovsky, Kevin G. Liu, Jeegar Patel, Nishta Rao, Robert Tilton, John L. Ryan, Mark S. Berger, Larry Witte, Ji-In Kim, Samuel D. Waksal. KD019: Blood brain barrier penetrant HER2/neu, Src, and EGFR inhibitor. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 2590. doi:10.1158/1538-7445.AM2015-2590