Phase I Study of KW-0761, a Humanized Anti-CCR4 Antibody, in Patients (Pts) with Relapsed or Refractory Adult T-Cell Leukemia-Lymphoma (ATLL) and Peripheral T-Cell Lymphoma (PTCL): Preliminary Results.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4492-4492 ◽  
Author(s):  
Naokuni Uike ◽  
Kunihiro Tsukasaki ◽  
Atae Utsunomiya ◽  
Kensei Tobinai ◽  
Yasuo Morishima ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Tumor Cells ◽  
Single Agent ◽  
Atll Patient ◽  
Intravenous Injections ◽  
Adult T Cell Leukemia ◽  
Atll Cell ◽  
Igg1 Monoclonal Antibody ◽  
Anti Tumor Activity

Abstract Introduction: KW-0761 is a defucosylated humanized IgG1 monoclonal antibody against CC chemokine receptor 4 (CCR4). Previous studies revealed that CCR4 was over-expressed on tumor cells from 88% of pts with ATLL and 38% of pts with PTCL. CCR4 expression was associated with unfavorable prognosis in both diseases. These evidences suggest that CCR4 could be a reasonable molecular target for treatment of CCR4-positive ATLL and PTCL. KW-0761 exerted very potent ADCC but not CDC against cultured ATLL cell lines using normal effecter cells. KW-0761 also exhibited potent ADCC against freshly isolated ATLL cells using the auto-effecter cells. Methods: KW-0761 is being investigated in a Phase I, single-agent, dose-escalation, multicenter study for relapsed or refractory pts with ATLL or PTCL after undergoing the initial chemotherapy. Eligible pts were required to express CCR4 on their tumor cells by FCM and/or IHC. This phase I trial was designed to evaluate toxicity, pharmacokinetics (PK), immunogenicity and anti-tumor activity. Toxicity was evaluated by NCI CTCAE (v3.0). Pts were planned to receive four weekly intravenous injections of KW-0761 at the doses of 0.01, 0.1, 0.5 and 1.0 mg/kg. Results: As of August 10, 2007, 6 pts (1 PTCL and 5 ATLL) have been treated with KW-0761 at the dose of 0.01 (N=3) and 0.1 mg/kg (N=3). Three pts were evaluable for toxicity, PK, immunogenicity and 4 pts were evaluable for anti-tumor activity. KW-0761 was well tolerated with no dose-limiting toxicities. Reversible grade (G) 3 toxicities were lymphocytopenia and herpes zoster. G1-2 adverse events were; rash, constipation, nausea, EF decrease, neutropenia, thrombocytopenia, eosinophilia, lymphocytopenia, ALP increase and QT prolongation. In one leukemic ATLL pt with swollen lymph nodes (LNs) treated at 0.01 mg/kg, peripheral ATLL cells disappeared and the LNs were decreased in size, attaining PR. In another leukemic ATLL pt with skin involvement treated at 0.1 mg/kg, peripheral ATLL cells disappeared and the skin achieved PR by Physicians Global Assessment of Clinical Conditions (PGA). One ATLL pt with skin and bone involvement at 0.01 mg/kg showed SD. Preliminary PK analysis at 0.01 mg/kg showed that Cmax and T1/2 after the 4th dosing was 323.7 56.7 ng/ml and 244 117 hrs, respectively. KW-0761 did not exhibit immunogenicity at 0.01 mg/kg. Conclusions: Preliminary phase I data warrant further investigations of KW-0761, a first-in-class humanized anti-CCR4 antibody, against CCR4-positive peripheral T-cell malignancies including ATLL. Patient accrual is ongoing and the updated results will be presented at the meeting.

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.

scholarly journals 121 ICAM-1-specific affinity tuned CAR T cells expressing SSTR2 for real-time imaging

2021 ◽  
Vol 9 (Suppl 3) ◽  
pp. A130-A130
Author(s):  
Jingmei Hsu ◽  
Eric von Hofe ◽  
Michael Hsu ◽  
Koen Van Besien ◽  
Thomas Fahey ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
Phase I ◽  
Tumor Cells ◽  
Somatostatin Receptor ◽  
Laboratory Animals ◽  
Therapeutic Window ◽  
Car T Cells ◽  
Car T

BackgroundThe use of CAR T cells for solid tumors has a number of challenges, such as lack of tumor-specific targets, CAR T cell exhaustion, and the immunosuppressive tumor microenvironment. To address these challenges, AffyImmune has developed technologies to affinity tune and track CAR T cells in patients. The targeting moiety is affinity tuned to preferentially bind to tumor cells overexpressing the target while leaving normal cells with low basal levels untouched, thereby increasing the therapeutic window and allowing for more physiological T cell killing. The CAR T cells are designed to express SSTR2 (somatostatin receptor 2), which allows for the tracking of CAR T cells in vivo via PET/CT scan using FDA-approved DOTATATE.MethodsAIC100 was generated by affinity tuning the I-domain of LFA-1, the physiological ligand to ICAM-1. Various mutants with 106-fold difference in affinity were evaluated for affinity. This allowed structure activity relationships to be conducted using CAR T cells expressing the various affinity mutants against targets with varying antigen densities. The variant with micromolar affinity was clearly the most effective in non-clinical animal models. AIC100 is currently being evaluated to assess safety, CAR T expansion, tumor localization, and preliminary activity in patients with advanced thyroid cancer in a phase I study (NCT04420754). Our study uses a modified toxicity probability interval design with three dosage groups of 10 x 106, 100 x 106, and 500 x 106 cells.ResultsPreclinical studies demonstrated greater in vivo anti-tumor activity and safety with lower affinity CAR T cells. A single dose of AIC100 resulted in tumor elimination and significantly improved survival of animals. AIC100 activity was confirmed in other high ICAM-1 tumor models including breast, gastric, and multiple myeloma. In a Phase I patient given 10-million CAR T cells, near synchronous imaging of FDG and DOTATATE revealed preliminary evidence of transient CAR T expansion and tumor reduction at multiple tumor lesions, with the peak of CAR T density coinciding with the spike in CAR T numbers in blood.ConclusionsWe have developed affinity tuned CAR T cells designed to selectively target ICAM-1 overexpressing tumor cells and to spatiotemporally image CAR T cells. Near-synchronous FDG and DOTATATE scans will enhance patient safety by early detection of off-tumor CAR T activity and validation of tumor response. We anticipate that our ‘tune and track’ technology will be widely applicable to developing potent yet safe CAR T cells against hard-to-treat solid cancers.Trial RegistrationNCT04420754Ethics ApprovalIRB number19-12021154IACUC (animal welfare): All animal experiments were performed in accordance with the National Institute of Health’s Guide for the Care and Use of Laboratory Animals. Animal handling protocols were approved by the Institutional Laboratory Animal Use and Care Committee of Weill Cornell Medicine (Permit Number: 2012–0063).

scholarly journals Updates in Clinical Data on FDA Fast Track Drugs for Relapsed Refractory Multiple Myeloma: A Systematic Review of Literature

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5579-5579
Author(s):  
Muhammad Abdullah Yousaf ◽  
Muhaddis Ejaz Ahmad ◽  
Maaz Ahmed Yusufi ◽  
Asim Tameez ud din ◽  
Muhammad Qudrat Ullah ◽  
...  
Keyword(s):  
T Cell ◽  
Partial Response ◽  
Phase I ◽  
Phase I Study ◽  
Fast Track ◽  
Single Agent ◽  
Phase Ib ◽  
D 20 ◽  
Combination Regimens ◽  
Good Partial Response

Introduction FDA (Food and Drug Administration) fast track program facilitates the development and accelerated review of new drugs aimed at treating life-threatening conditions and having the potential to address unmet medical needs. FDA fast track drugs (2019) for relapsed refractory MM include selective exportin-1 (XPO-1) inhibitors, first generation Selinexor / KPT-330 (S) and second generation KPT-8602, and an anti-B-cell maturation antigen (BCMA) bispecific T-cell engager (BiTE), AMG-420. The aim of our study is to analyze published literature for updates in clinical data viz efficacy and toxicity of these new agents in pts with RRMM. Methods Following PRISMA guidelines, we performed a comprehensive literature search on articles published after 2014 using Pubmed, Embase, Cochrane and Web of Science. Fifty-eight articles were identified initially and after a detailed scrutiny, we finalized 8 studies involving 299 RRMM patients and summarized the data using absolute values and percentages. Chimeric antigen receptor (CAR) T-cell therapy was excluded from our manuscript. Results Selinexor / KPT-330: A total of 6 studies (Table 1) involving 258 RRMM pts were included. In a phase Ib/II study by Bahlis et al., S was given in combination with bortezomib (V) and dexamethasone (d) to 22 pts with 4 median prior lines of therapy. The overall response rate (ORR) was 77% with complete response (CR) in 5%, partial response (PR) in 50% and very good partial response (VGPR) in 23% pts. In another phase Ib/II study by the same author, SVd was given to 42 pts with 3 median prior therapies. In 40 evaluable pts, ORR was 63% with CR in 8%, PR in 33%, and VGPR in 23%. The progression free survival (PFS) was 9 months. In a phase I/II study by Broijl et al., S (45 or 30 mg/m2) was given in combination with Vd to pts with median 3 prior treatments. Among 5 evaluable pts who received 45 mg/m2 of S, PR was observed in 80% and VGPR was observed in 40% pts. OS was 100% and 75% at 12 and 24 months respectively and PFS was 17 months. In pts who received S (30 mg/m2) with Vd, PR was observed in 67% and VGPR was observed in 17% pts. OS was 75% at 12 months and PFS was 10 months. In a phase II study by Vogl et al, 79 pts received S (80 mg) in combination with d (20 mg), both orally and twice weekly. Median prior therapies received were 7. In 78 evaluable patients, the ORR was 21% with PR in 15% and VGPR in 5%. OS and PFS were 9.3 and 2.3 months respectively. In a phase I study by Chen et al., 84 pts having received 6 median prior therapies were included. S was given either alone or in combination with d. Fourteen pts were rendered ineligible for response. ORR was 4% for pts who received single-agent S and 22% for those who received S+d. PR was observed in 4% of single-agent S pts. Among S+d pts, all responses were observed in S (45 mg/m2) plus d (20 mg) group (ORR 50%) with CR in 8% and PR in 42% pts. In a phase I study by Jakobowiak et al., 18 pts with median 3 prior therapies were included. S in combination with carfilzomib (CFZ) and d were given. Among 16 evaluable patients, PR was observed in 63% and VGPR was observed in 25% pts. On July 3, 2019, FDA granted accelerated approval to selinexor. KP-8602: In a phase I/II trial by Cornell et al., involving 6 pts, KP-8602 (5 mg PO QDx5) in combination with dexamethasone (20 mg 2QWK) was given for 28 days. they had received 6 median prior lines of therapy. PR was observed in 16% of the pts. AMG-420: In a phase I study by Topp et al., 35 pts with median 4 prior lines of therapy were included. Single-agent AMG-420 (0.2-800 µg/day) was given. CR was observed in 17% pts. The highest dose at which a CR was observed was 400 µg/day. It was also the dose at which maximum number of pts showed a CR (n=3, 9%). A partial response (PR) and a very good partial response (VGPR) was also observed in 1 patient each i.e. 3%. Conclusion Combination regimens of SVd has superior efficacy as compared to S monotherapy. Major adverse events reported with both single-agent and combination regimens are hematological i.e. thrombocytopenia, neutropenia and anemia. KP-8602 has promising efficacy in limited pts and appear to have better adverse effect profile. AMG-420 has shown promising activity and tolerability in RRMM pts at a dose of 400 µg/day with no major toxicities at this dose. The published data on these drugs is scarce, still emerging and warrants further investigation. Disclosures Anwer: In-Cyte: Speakers Bureau; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees.

scholarly journals High expression of NAMPT in adult T-cell leukemia/lymphoma and anti-tumor activity of a NAMPT inhibitor

2019 ◽  
Vol 865 ◽  
pp. 172738 ◽  
Author(s):  
Tomohiro Kozako ◽  
Akiyoshi Aikawa ◽  
Takeo Ohsugi ◽  
Yu-ichiro Uchida ◽  
Naho Kato ◽  
...  
Keyword(s):  
T Cell ◽  
High Expression ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia ◽  
Anti Tumor Activity

scholarly journals Autologous tumor cell vaccine induces antitumor T cell immune responses in patients with mantle cell lymphoma: A phase I/II trial

2020 ◽  
Vol 217 (9) ◽  
Author(s):  
Matthew J. Frank ◽  
Michael S. Khodadoust ◽  
Debra K. Czerwinski ◽  
Ole A.W. Haabeth ◽  
Michael P. Chu ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Phase I ◽  
Mantle Cell Lymphoma ◽  
Tumor Cells ◽  
Cell Lymphoma ◽  
Cell Vaccine ◽  
Autologous Tumor ◽  
Mantle Cell ◽  
T Cell Immune Responses

Here, we report on the results of a phase I/II trial (NCT00490529) for patients with mantle cell lymphoma who, having achieved remission after immunochemotherapy, were vaccinated with irradiated, CpG-activated tumor cells. Subsequently, vaccine-primed lymphocytes were collected and reinfused after a standard autologous stem cell transplantation (ASCT). The primary endpoint was detection of minimal residual disease (MRD) within 1 yr after ASCT at the previously validated threshold of ≥1 malignant cell per 10,000 leukocyte equivalents. Of 45 evaluable patients, 40 (89%) were found to be MRD negative, and the MRD-positive patients experienced early subsequent relapse. The vaccination induced antitumor CD8 T cell immune responses in 40% of patients, and these were associated with favorable clinical outcomes. Patients with high tumor PD-L1 expression after in vitro exposure to CpG had inferior outcomes. Vaccination with CpG-stimulated autologous tumor cells followed by the adoptive transfer of vaccine-primed lymphocytes after ASCT is feasible and safe.

Interleukin-2 production by primary adult T cell leukemia tumor cells is macrophage dependent

1992 ◽  
Vol 41 (4) ◽  
pp. 258-263 ◽  
Author(s):  
Naomichi Arima ◽  
Yasuhisa Daitoku ◽  
Shiroh Hidakia ◽  
Kakushi Matsushita ◽  
Hideo Ohtsubo ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Interleukin 2 ◽  
T Cell Leukemia ◽  
Cell Leukemia ◽  
Adult T Cell Leukemia

Interim Analysis of a Phase II Study of Denileukin Diftitox (Ontak) for Relapsed/Refractory T-Cell Non-Hodgkin’s Lymphoma.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2641-2641 ◽  
Author(s):  
Nam H. Dang ◽  
Barbara Pro ◽  
Fredrick B. Hagemeister ◽  
Dan Jones ◽  
Barry Samuels ◽  
...  
Keyword(s):  
T Cell ◽  
Tumor Cells ◽  
Phase Ii ◽  
Hodgkin’S Lymphoma ◽  
Phase Ii Study ◽  
Single Agent ◽  
Hodgkin's Lymphoma ◽  
Denileukin Diftitox ◽  
Non Hodgkin’S Lymphoma ◽  
Non Hodgkin's Lymphoma

Abstract Denileukin diftitox (Ontak) is a fusion protein combining the enzymatically active domain of diphtheria toxin and the full-length sequence of interleukin-2 (IL-2) that targets tumor cells expressing the IL-2 receptor (IL-2R). The drug has established efficacy in cutaneous T-cell lymphoma (CTCL), and we have recently demonstrated its single-agent activity in B-cell non Hodgkin’s lymphoma (NHL) (Dang et al. Journal of Clinical Oncology. In Press). We initiated a phase II study to evaluate its efficacy in relapsed/refractory T-cell NHL, excluding CTCL. Denileukin diftitox was administered at a dose schedule of 18 μg/kg/day by IV infusion once daily for 5 days every three weeks, for up to 8 cycles. Premedications in the form of corticosteroids, antihistamines and fluids were given prior to each drug infusion to reduce the incidence and severity of acute hypersensitivity. 14 patients are currently evaluable for response. Median age was 57 (range 26–80), and mean number of previous treatments was 2.2 (range 1–4). Tumor CD25 status was determined by immunohistochemistry and/or flow cytometry, with CD25-positivity being defined as 10% or more of tumor cells expressing detectable CD25. Of the 7 patients with CD25+ T-NHL, there were 2 CR (1 case of Alk-1 negative ALCL and 1 case of PTCL), 3 PR (1 case of PTCL and 2 cases of angioimmunoblastic lymphoma), 1 SD (1 case of PTCL) and 1 PD (1 case of PTCL). Of the 7 patients with CD25− T-NHL, there were 2 PR (1 case of PTCL and 1 case of T/NK-lymphoma), 4 SD (3 cases of PTCL and 1 case of Sezary syndrome), and 1 PD (1 case of angioimmunoblastic lymphoma). Overall response rate (CR+ PR) was 50%, with 2 of 14 patients having CR (14%) and 5 of 14 patients having PR (36%). One patient with Alk-1negative ALCL still has an ongoing CR at 15+ months. Treatment was well-tolerated, with the majority of toxicity being grade 1 or 2 and transient. Denileukin diftitox appears to have activity in relapsed/refractory T-cell NHL, and is well-tolerated at the dosing schedule tested. Additional patients are being studied to further evaluate the relationship between detectable CD25 expression and tumor response to denileukin diftitox.

A Phase I Study of Immunization of Indolent Non Hodgkin’s Lymphoma Patients with Autologous Monocyte-Derived Dendritic Cells Loaded with Heat Shocked and Killed Autologous Tumor Cells.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2437-2437
Author(s):  
Massimo Di Nicola ◽  
Carmelo Carlo-Stella ◽  
Maddalena Marchesi ◽  
Gianluca Del Conte ◽  
Liliana Devizzi ◽  
...  
Keyword(s):  
T Cells ◽  
Lymph Node ◽  
T Cell ◽  
Lymph Nodes ◽  
Phase I ◽  
Tumor Cells ◽  
Phase I Study ◽  
The Other ◽  
High Dose ◽  
Autologous Tumor

Abstract B-cell malignancies represent a potential target for anti-cancer vaccination programs due to the expression of tumor-specific antigens. Although immunization with tumor-derived idiotype protein is a frequently used procedure, vaccination with DCs loaded with killed tumor cells may activate response to a much wider range of antigens, without requiring prior molecular identification of such determinants. Furthermore, such DC-based vaccines could be available to all patients, irrespective of the HLA type. To evaluate the safety and tolerability of this approach, 18 patients with measurable relapse/refractory follicular (FCL; n= 12) and lymphoplasmocytoid (n= 6) lymphoma have been enrolled in a phase I study. Median prior number of treatment regimens was 2 (range 1–5) comprising 4 patients treated with high-dose chemotherapy supported by autologous stem cell transplantation. The vaccination was started after at least 6-months from the last chemotherapy treatment. All patients were evaluable for toxicity and 16/18 patients for efficacy with a median follow-up of 12.5 months (range 3–29 months). Each patient received 4 intradermal/subcutaneous injections at 2-weekly intervals of 50x10e6 tumor-loaded DCs. Immature DCs were generated by 5-days culture of autologous monocytes in the presence of IL-4 and GM-CSF. After selection by immunomagnetic technique, autologous CD19+ tumor cells, harvested from lymph nodes (n= 12) and/or peripheral blood (n= 6), were heat shocked and then irradiated by UVC. DCs were loaded for 48 hrs with killed tumor cells and then, to induce their maturation, were cultured for 12 hrs in the presence of TNF-alfa. Overall, vaccinations were well tolerated and no autoimmune reactions were observed. Mild erythema in the site of injection developed in the majority of patients (12/18), but only in 2 cases induration and extended erythema was observed. Six of 16 (37.5%) evaluable patients had objective responses. Two patients had partial responses (PR). One is still in PR and the other had a PR lasting 7 months. Four patients had complete remission (CR). Two patients are still in CR and the other 2 patients had a mean CR duration of 14.5 months. The remaining 10 patients had stable disease (n=5) or progressive disease (n=5). The overall monitoring of immune responses is ongoing. However, in one patient in PR, we evaluated the frequency of anti autologous tumor-specific T cells, by ELISPOT assay for IFN-gamma, on pathologic lymph nodes harvested before and after 2 months from the last vaccination. A significant increase of specific T-cell frequency was observed in the post-vaccination lymph node, compared to the tissue sample taken before vaccination. Moreover, evaluation of CD8+ T cell maturation markers, by analysis for CCR7 and CD45RA expression, indicated a shift of tumor-infiltrating T cells towards memory and effector stages in the lymph-node isolated after vaccination. In conclusion, injection of DCs loaded with killed tumor cells is a well-tolerated procedure achieving clinical and immunological responses also in the presence of significant tumor burden. However, further strategies, following DC-vaccination, are needed to ensure durable immune and clinical responses.

A Phase I Trial of Subcutaneous (SQ) Dose-Escalated Alemtuzumab in Patients with T-Cell Lymphoproliferative Disorders (T-LPD).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3417-3417 ◽  
Author(s):  
Pierluigi Porcu ◽  
Robert A. Baiocchi ◽  
Thomas S. Lin ◽  
Kristie A. Blum ◽  
Patricia Curtis ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Level ◽  
Fungal Infections ◽  
Single Agent ◽  
Lymphoproliferative Disorders ◽  
Hematologic Toxicity ◽  
T Cell Clone ◽  
Oral Valganciclovir ◽  
Cmv Reactivation

Abstract BACKGROUND: T-cell lymphoproliferative disorders (T-LPD) are heterogeneous and highly chemoresistant malignancies without standard therapy. With few exceptions, cure rates with combination chemotherapy do not exceed 25–30%. We have shown that alemtuzumab (A), a humanized IgG1 targeting the CD52 antigen expressed on most human leukocytes, is cytotoxic for malignant T-cells in vitro and in vivo, regardless of p53 mutational status (Blood106: 3380–3382, 2005). We initiated a Phase I study with A and CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone) in T-LPD. METHODS: Accrual goal: 18–21 pts with untreated (u) or relapsed (r)T-LPD, excluding untreated ALK-1-positive or primary cutaneous anaplastic large cell lymphoma. CD52 expression was not assessed. Other exclusion criteria: pregnancy, HIV+, HCV+, or HBV+. Primary objective: A maximal tolerated dose (MTD). DLT defined as grade (G) ≥ 3 (or non-reversible grade 2) non-hematologic toxicity or G4 neutropenia or thrombocytopenia requiring >7 day delays in therapy for > 3 times. All pts received single agent SQ A loading (3, 10, 30 mg) over 5 days followed by one SQ A dose with each cycle of CHOP every 21 days for a total of 8 cycles. A dose levels: 3, 10, 20, 30 mg. All pts received valacyclovir, trimethoprim-sulfamethoxasole prophylaxis and G-CSF. Erythropoietin was given according to published guidelines. RESULTS: 18 pts were enrolled (uPTCL=11, uT-PLL=2, rCTCL=3, uSezary Syndrome=2). Enrollment according to dose level: 3mg = 6 pts; 10mg = 3 pts; 20 mg = 6 pts; 30 mg = 3 pts. Median age: 62 years. All pts completed single agent SQ A loading on time with minimal local reactions. Ten pts completed all planned therapy. Six pts did not complete therapy: 2 rCTCL=stable disease, 1 uPTCL=poor compliance, 2 PTCL=pt witdrew, 1 uT-PLL=progression. Two pts (30 mg dose level) are receiving therapy. Toxicity: G4 febrile neutropenia=1; G3 fatigue=2, G3 anemia=2, G3 dyspnea=1, G3 emesis=2, G3 CMV infection=1. Cohort 1 was expanded due to asymptomatic CMV reactivation requiring hospitalization for thrice daily foscarnet. Subsequent asymptomatic CMV reactivations (N=4) were treated with oral valganciclovir until clearance. No symptomatic CMV reactivation or other viral or fungal infections were seen. Out of 107 cycles of A/CHOP given, only 3 had to be delayed. Four pts (1 PTCL, 1 T-PLL and 2 Sezary) are in continuous clinical and molecular (PCR) complete response at 36, 28, 18 and 12 months respectively. CONCLUSIONS: SQ A was safely administerd up to 20 mg with each cycle of CHOP chemotherapy and growth factor support without excessive myelosuppression or infectious AEs. Treatment at 30 mg dose level is in progress. Asymptomatic CMV reactivation can be managed with oral valganciclovir without discontinuation of therapy. Durable responses have been seen, including molecular clearance of the malignant T-cell clone.

Oral HDAC Inhibitor HBI8000 in Japanese Patients with Non-Hodgkin Lymphoma (NHL): Phase I Safety and Efficacy Results

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1827-1827 ◽  
Author(s):  
Makoto Onizuka ◽  
Kiyoshi Ando ◽  
Makoto Yoshimitsu ◽  
Takashi Ishida ◽  
S Yoshida ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase Ii ◽  
Research Funding ◽  
Phase I Trial ◽  
Cell Lymphoma ◽  
Japanese Patients ◽  
Dose Cohort ◽  
Grade 3 ◽  
Anti Tumor Activity

Abstract Background: HBI-8000 is an orally bioavailable member of the benzamide class of histone deacetylase inhibitors (HDACi), that inhibits cancer-associated HDAC enzymes (Class I and IIb). HBI-8000 has anti-tumor activity through various mechanisms of action, including epigenetic reprogramming and immunomodulation. It was recently approved by the Chinese FDA under the name chidamide (Epidaza) for relapsed or refractory (R/R) peripheral T-cell lymphoma (PTCL) with a recommended dose of 30 mg twice weekly (BIW). HBI-8000 is also being manufactured in the USA for clinical development outside of China. The preliminary results of a phase I trial of HBI-8000 to confirm the safety and maximum tolerated dose (MTD) in Japanese patients (pts) with advanced NHL are presented (NCT02697552). Methods: This is a multicenter, prospective phase I trial in Japan. Inclusion criteria: patients are eligible if they have histologically or cytologically proven NHL and no other standard therapy is available. The primary endpoint is the MTD based on the frequency of dose-limiting toxicities (DLTs) observed within 28 days of the first dose. Secondary endpoints include pharmacokinetic (PK) profile and anti-tumor activity. At the time of this abstract submission, the trial is still ongoing. Results: Thirteen out of 14 pts were eligible for the 1st cycle DLT assessment (6 pts in the 30 mg, 7 pts in the 40 mg cohort). Median age was 68 years, gender well balanced, and the majority of pts had ≥ 2 prior treatment regimens. Five pts had the diagnosis of adult T-cell leukemia-lymphoma (ATL), 2 pts presented with PTCL, 3 with diffuse large B-cell lymphoma (DLBLC), 2 with follicular lymphoma (FL), 1 with cutaneous T-cell lymphoma (CTCL), and 1 with marginal zone lymphoma. Overall, the treatment was well tolerated, and adverse drug reactions (ADRs) were predominantly hematologic, consistent with the previous experiences. There were 7 pts in the 40 mg dose cohort because one of the first 3 pts had to be replaced for incomplete dosing due to grade 3 hypertriglyceridemia which was not regarded as DLT by the Data Monitoring Safety Committee (DMC/SMC). In the 40 mg cohort, 2 pts were considered as DLTs by definition in the protocol: grade 4 neutropenia and grade 3 alanine transaminase (ALT) increase. Both pts were asymptomatic. The grade 4 neutropenia promptly resolved with the administration of G-CSF and the grade 3 ALT elevation resolved with dose interruption. The 30 mg dose cohort completed with no DLT after the 1st cycle in 6 pts. The following hematologic grade 3/4 toxicities were noted in the 40 mg dose cohort (N=7): leukopenia (2 pts, 29%), neutropenia (3 pts, 43%), and thrombocytopenia (3 pts, 43%). Non-hematologic ADRs included fatigue, nausea, diarrhea, decreased appetite, erythema and pyrexia. The preliminary pharmacokinetic (PK) results from the 3 patients in the 30 mg cohort, and 7 patients in the 40 mg dose cohort show inter-patient variability as expected of an oral agent. Mean half-life (t ½ ) was between16.5 and 20 hours (h) with a Tmax between 2.5 and 3.5h and consistent with previous findings. Mean Cmax and AUC increased with dose (30 mg: 210 ng/mL; 3660 h*ng/mL and 40 mg: 590 ng/mL; 7200 h*ng/mL). The patient with neutropenia as DLT presented with the highest exposure. Cardiovascular assessments including serial ECGs and troponin assessments did not reveal clinically relevant findings. Best overall response was noted in 40 mg BIW cohort (N=7): 1 CR (10%), 5 PR (30%), 1 SD (20%). Four of the partial responders were ATL patients. In the 30 mg BIW dose cohort, 4/6 patients had stable disease after the 1st cycle. Summary: In this phase l trial evaluating the safety of twice weekly 30 mg and 40 mg doses, HBI-8000 was well tolerated with expected toxicities that could be managed with dose interruptions/reductions. Tumor response results in pts who completed at least one cycle of treatment indicate some clinical benefit especially in pts who started with the 40 mg dose level. The DMC/SMC has provided an opinion that the 2 observed DLTs with HBI-8000 in the phase I trial were clinically manageable and that 40 mg BIW would be recommended as the dosage for subsequent phase II studies. Registration enabling phase II trials to evaluate efficacy and safety in R/R ATL pts (Japan) and R/R PTCL pts (Japan and Korea) are being initiated. Disclosures Ando: SymBio Pharmaceuticals: Research Funding. Yoshimitsu:HUYA Bioscience International: Research Funding. Ishida:Kyowa Hakko Kirin, Co., Ltd.: Honoraria, Research Funding; Celgene KK: Research Funding; Bayer Pharma AG: Research Funding. Hidaka:Chugai-pharm: Research Funding. Nagashima:HUYA Bioscience International: Employment. Miyazato:HUYA Bioscience International: Employment. Schupp:HUYA Bioscience International: Employment. Rolland:HUYA Bioscience International: Employment. Gillings:HUYA Bioscience International: Employment. Lee:HUYA Bioscience International: Employment. Tobinai:Eisai: Honoraria, Research Funding; GlaxoSmithKline: Research Funding; HUYA Bioscience: Honoraria; Janssen Pharmaceuticals: Honoraria, Research Funding; Kyowa Hakko Kirin: Research Funding; Mundipharma: Honoraria, Research Funding; Ono Pharmaceuticals: Research Funding; Servier: Research Funding; Takeda: Honoraria, Research Funding; Zenyaku Kogyo: Honoraria; Chugai Pharma: Research Funding; Celgene: Research Funding; Abbvie: Research Funding.

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