scholarly journals Phase I Study of E7777, a Diphtheria Toxin Fragment-Interleukin-2 Fusion Protein, in Japanese Patients with Relapsed or Refractory Peripheral and Cutaneous T-Cell Lymphoma

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2724-2724 ◽  
Author(s):  
Dai Maruyama ◽  
Kensei Tobinai ◽  
Kiyoshi Ando ◽  
Ken Ohmachi ◽  
Michinori Ogura ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Cd25 Expression ◽  
Dose Levels

Abstract Background: E7777 is a recombinant cytotoxic fusion protein composed of diphtheria toxin fragments A, B and human interleukin-2. E7777 has the same amino acid sequence as denileukin diftitox, approved in the USA for treatment of persistent or recurrent CD25 positive cutaneous T-cell lymphoma on 1999, but with improved purity and an increased percentage of active protein monomer species. Since the specific bioactivity of E7777 is 1.5-2 times higher than that of the prior less purified form, a phase 1 study of E7777 in Japanese patients (pts) with peripheral and cutaneous T-cell lymphoma (PTCL and CTCL) was conducted. Methods: This multicenter, phase 1, dose-escalation (3+3 design) study assessed the safety, maximum tolerated dose (MTD), recommended dose (RD), pharmacokinetics (PK), immunogenicity (IM) and anti-tumor activity in pts with relapsed or refractory PTCL and CTCL. E7777 was administered by IV infusion over 60 min on 5 consecutive days of every 21 day cycle (up to 8 cycles) at planned dose-levels of 6, 12, 15 and 18 μg/kg/day (with evaluation of intermediate dose levels if necessary). Premedication including systemic steroid was required. Dose-limiting toxicity (DLT) was evaluated during the first cycle and MTD was determined as the highest dose at which less than 2 of a total 6 pts experienced a DLT. In the event that 2 of 6 pts experienced DLTs in a dose level, an Independent Safety Committee (ISC) will be consulted on whether that dose can be considered the MTD. Anti-tumor activity was evaluated by IWG-2007 criteria (only CT assessment) for PTCL and mSWAT for CTCL. Tumor CD25 expression was examined by immunohistochemistry in pts with available archival samples. Results: A total of 13 pts were enrolled at E7777 dose-levels of 6, 9 and 12 μg/kg/day. 10 pts had PTCL [PTCL-not otherwise specified (NOS), n=4; angioimmunoblastic T-cell lymphoma (AITL), n=3; anaplastic large cell lymphoma (ALCL)-ALK positive, n=1; ALCL-ALK negative, n=1; enteropathy-associated T-cell lymphoma, n=1] and 3 had CTCL [mycosis fungoides (MF), n=3]. The median age was 64 years (range 23-75), and the median number of prior chemotherapy regimens (excluding PUVA, interferon, retinoid) was 1 (range 0-8). DLTs were observed in 3 of 3 pts in the 12 μg/kg/day cohort; ALT increased, hyponatremia, hypokalemia and lymphopenia in one pt, ALT increased, fatigue, hypoalbminemia, hyponatremia and rash in another, and lipase increased in the third. This dose-level was considered to exceed the MTD and the 9 μg/kg/day dose level was expanded. Per recommendation of the ISC, the DLT definition was modified to not include lymphopenia, Grade 3 abnormality of hepatic enzyme recovered to Grade 2 or lower within cycle 1, and any other Grade 3 clinical abnormal laboratory result without clinical symptoms recovered within 7 days. Two of 6 pts in 9 μg/kg/day cohort experienced DLT of decreased appetite and fatigue, respectively. These events were recovered from within 2-3 weeks while interrupting the treatment. Per protocol, the ISC evaluated the toxicity profile of all the pts, and recommended the MTD and RD to be 9 μg/kg/day. As of 10 May 2015, the common adverse events (AEs) were ALT increased (85%), AST increased (77%), decreased appetite (77%), fatigue (77%), lymphopenia (77%), hypoalbuminemia (69%) and nausea (62%). Serious AEs considered related to study drug were reported in 3 pts; ALT increased, AST increased and fatigue in one pt, decreased appetite and hypoxia in another, and delirium in the third. AEs leading to study discontinuation were reported in 3 pts; AEs were hypersensitivity, respiratory failure (not related) and delirium. Objective response rate as assessed by investigator was 38% (5/13 pts), including response in 4 of 10 pts with PTCL and 1 of 3 pts with CTCL. All responses were PRs including 2 pts (AITL) at 6 μg/kg/day, 1 pt (MF) at 12 μg/kg/day followed by 6 μg/kg/day from 2nd cycle, and 2 pts (PTCL-NOS) at 9 μg/kg/day. Tumor responses were observed regardless of the level of CD25 expression in tumors. PK and IM data will be presented. Conclusions: The MTD and RD of E7777 was 9 μg/kg/day. The common AEs observed were considered manageable. Tumor responses were observed in PTCL, which firstly demonstrated with E7777, and also for CTCL pts regardless of level of tumor CD25 expression. Subsequent phase 2 study to evaluate the efficacy and safety of E7777 in pts with PTCL and CTCL, including evaluation of the relationship with CD25 expression, is warranted. Disclosures Maruyama: Takeda Pharmaceutical Company Limited: Honoraria; Eisai Co., Ltd.: Honoraria. Tobinai:Gilead Sciences: Research Funding. Ando:Eisai Co., Ltd.: Honoraria, Research Funding. Ogura:Kyowa Hakko Kirin co., Ltd.: Research Funding; Eisai Co., Ltd.: Research Funding; Zenyaku Kogyo Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Research Funding; Phizer Japan Inc.: Research Funding; Janssen Pharmaceutical K.K.: Research Funding; GlaxoSmithKline K.K.: Research Funding; MSD K.K.: Research Funding; AstraZeneca K.K.: Research Funding; Takeda Pharmaceutical Company Limited: Research Funding; Symbio Pharmaceuticals Limited: Research Funding; Solasia Phama K.K.: Research Funding; Mundipharma K.K.: Research Funding; Celgene K.K.: Research Funding; Sumitomo Dainippon Pharma Co., Ltd.: Research Funding. Uchida:Eisai Co., Ltd.: Research Funding. Nakanishi:Eisai Co., Ltd.: Employment. Namiki:Eisai Co., Ltd.: Employment.

Cutaneous T Cell Lymphoma: Responses in Phase 1 Trial of Combination Therapy with Liposomal Doxorubicin, Bortezomib, and Gemcitabine.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2466-2466 ◽  
Author(s):  
Navneet Dhillon ◽  
Srinivasa Bakkannagari ◽  
Chaan Ng ◽  
Joann Lim ◽  
Madeline Duvic ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Level ◽  
Liposomal Doxorubicin ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Skin Lesions ◽  
T Cell Lymphoma ◽  
Dose Finding ◽  
Cutaneous T Cell Lymphoma ◽  
Heavily Pretreated

Abstract BACKGROUND: There is preclinical data suggesting pro-apoptotic synergy between the proteosome inhibitor bortezomib, doxorubucin and gemcitabine. Therefore, we are currently conducting a Phase I dose finding trial of this combination. As a part of this trial, high response rates with excellent tolerance were noted in advanced cutaneous T- cell lymphoma, and are presented here. METHODS: A 3+ 3 design was used. There were two cohorts of patients: < 65 and ≥65 years of age. The older cohort was dose escalated after the younger cohort demonstrated safety at a dose level. Initial dose escalations were in bortezomib alone, followed by gemcitabine, and then by liposomal doxorubicin. RESULTS: There were 33 patients who were treated on this trial to date. We are reporting the results of 7 patients with cutaneous T cell lymphoma. These patients had been heavily pretreated with a median of 6 prior therapies (range 1–12). All six of six evaluable patients (100%) achieved a partial remission (PR). Some of these responses are ongoing and the patients are still improving. The most common toxicities were grade 2 thrombocytopenia (50% of patients), grade 1–2 fatigue (44% patients), grade1–2 mucositis (14% patients), and myelosuppression (12% patients). Four patients needed hospitalization early in the course for sepsis. All of these patients had advanced disease with ulcerating skin lesions. Dose limiting toxicity has not been seen. CONCLUSIONS: The above combination is safe up to the doses tested so far- (dose level 5 = doxil 24mg/m2 on day1, gemcitabine 800 mg/m2 on days 1 and 8 and bortezomib 1.0 mg/m2 on days 1,4,8,11) and has activity in heavily pretreated, advanced cutaneous T-Cell lymphoma. Responses in Cutaneous T Cell Lymphoma Age Sex Stage Number of prior therapies Dose Level Response Duration of therapy in months 71 F IV 12 1 PR 4 32 F IV 6 1 PR 3 (sent to BMT) 61 F IV 8 2 Lost to follow up after 2 doses 72 M IV 2 2 PR 7+ 73 M IV B 6 2 PR 4+ 53 M II B 1 5 PR 7+ 60 F IV 5 5 PR 8+

A phase-1 trial of bexarotene and denileukin diftitox in patients with relapsed or refractory cutaneous T-cell lymphoma

Blood ◽  
2005 ◽  
Vol 106 (2) ◽  
pp. 454-457 ◽  
Author(s):  
Francine Foss ◽  
Marie France Demierre ◽  
Gina DiVenuti
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Leukemia Cells ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 1 Trial ◽  
Denileukin Diftitox

Abstract Denileukin diftitox, a genetically engineered fusion protein combining the enzymatically active domains of diphtheria toxin and the full-length sequence for interleukin-2 (IL-2), efficiently targets lymphoma cells expressing the high-affinity IL-2 receptor (IL-2R) consisting of the α/p55/CD25, β/p75/CD122, and γ/p64/CD132 chains. In vitro studies demonstrated that the retinoid X receptor (RXR) retinoid, bexarotene, at biologically relevant concentrations of 10–6M to 10–8 M, upregulated both the p55 and p75 subunits of the IL-2R and enhanced 5- to 10-fold the susceptibility of T-cell leukemia cells to denileukin diftitox. To determine whether this biomodulatory effect could be recapitulated in vivo, we treated 14 patients with relapsed or refractory cutaneous T-cell lymphoma with escalating doses of bexarotene (75 mg/day-300 mg/day) and denileukin diftitox (18 mcg/kg per day × 3 days every 21 days) in a phase 1 trial. Overall response was 67% (4 complete responses, 4 partial responses). Modulation of IL-2R expression was observed at or above a bexarotene dose of 150 mg/day. Four patients experienced grade 2 or 3 leukopenia, and 2 had grade 4 lymphopenia. Our results demonstrate that the combination of denileukin diftitox and bexarotene is well tolerated and that even low doses (150 mg/day) of bexarotene are capable of in vivo upregulation of CD25 expression on circulating leukemia cells.

Use of serum soluble interleukin-2 receptor levels to monitor the progression of cutaneous T-cell lymphoma

1998 ◽  
Vol 38 (2) ◽  
pp. 207-220 ◽  
Author(s):  
Eric C. Vonderheid ◽  
Qian Zhang ◽  
Stuart R. Lessin ◽  
Marcia Polansky ◽  
J.Todd Abrams ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Interleukin 2 ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Interleukin 2 Receptor ◽  
Soluble Interleukin 2 Receptor

IPH4102 in relapsed/refractory cutaneous T cell lymphoma (CTCL): Results of the first-in-human multicenter phase 1 study

2018 ◽  
Vol 101 ◽  
pp. S29 ◽  
Author(s):  
Martine Bagot ◽  
Pierluigi Porcu ◽  
Basem William ◽  
Maarten Vermeer ◽  
Sean Whittaker ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 1 Study ◽  
Multicenter Phase

Pivotal Phase III Trial of Two Dose Levels of Denileukin Diftitox for the Treatment of Cutaneous T-Cell Lymphoma

2001 ◽  
Vol 19 (2) ◽  
pp. 376-388 ◽  
Author(s):  
Elise Olsen ◽  
Madeleine Duvic ◽  
Arthur Frankel ◽  
Youn Kim ◽  
Ann Martin ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Therapeutic Interventions ◽  
Phase Iii ◽  
Cutaneous T Cell Lymphoma ◽  
Denileukin Diftitox ◽  
Grade 3 ◽  
Dose Levels

PURPOSE: The objective of this phase III study was to determine the efficacy, safety, and pharmacokinetics of denileukin diftitox (DAB389IL-2, Ontak [Ligand Phar-maceuticals Inc, San Diego, CA]) in patients with stage Ib to IVa cutaneous T-cell lymphoma (CTCL) who have previously received other therapeutic interventions. PATIENTS AND METHODS: Patients with biopsy-proven CTCL that expressed CD25 on ≥ 20% of lymphocytes were assigned to one of two dose levels (9 or 18 μg/kg/d) of denileukin diftitox administered 5 consecutive days every 3 weeks for up to 8 cycles. Patients were monitored for toxicity and clinical efficacy, the latter assessed by changes in disease burden and quality of life measurements. Antibody levels of antidenileukin diftitox and anti–interleukin-2 and serum concentrations of denileukin diftitox were also measured. RESULTS: Overall, 30% of the 71 patients with CTCL treated with denileukin diftitox had an objective response (20% partial response; 10% complete response). The response rate and duration of response based on the time of the first dose of study drug for all responders (median of 6.9 months with a range of 2.7 to more than 46.1 months) were not statistically different between the two doses. Adverse events consisted of flu-like symptoms (fever/chills, nausea/vomiting, and myalgias/arthralgias), acute infusion-related events (hypotension, dyspnea, chest pain, and back pain), and a vascular leak syndrome (hypotension, hypoalbuminemia, edema). In addition, 61% of the patients experienced transient elevations of hepatic transaminase levels with 17% grade 3 or 4. Hypoalbuminemia occurred in 79%, including 15% with grade 3 or 4 changes. Tolerability at 9 and 18 μg/kg/d was similar, and there was no evidence of cumulative toxicity. CONCLUSION: Denileukin diftitox has been shown to be a useful and important agent in the treatment of patients whose CTCL is persistent or recurrent despite other therapeutic interventions.

Pralatrexate (PDX) IS Active in Cutaneous T-Cell Lymphoma: Preliminary Results of a Multi-Center Dose-Finding Trial.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1569-1569 ◽  
Author(s):  
Steven M. Horwitz ◽  
Madeleine Duvic ◽  
Youn Kim ◽  
Jasmine M. Zain ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Tumor Lysis Syndrome ◽  
T Cell Lymphoma ◽  
Hematological Toxicity ◽  
Cutaneous T Cell Lymphoma ◽  
Phase 1 Study ◽  
Toxic Dose ◽  
Aggressive Lymphomas

Abstract Background: Pralatrexate (PDX) is a novel targeted antifolate that is designed to accumulate preferentially in cancer cells. Pralatrexate has demonstrated activity at a range of doses in patients (pts) with relapsed/refractory T-cell lymphoma. The maximum tolerated dose (MTD) in a trial of pts with aggressive lymphomas was 30 mg/m2 weekly for 6 of 7 weeks. In that Phase 1 study, responses were seen in pts with cutaneous T-cell lymphoma (CTCL). To further explore this activity, we designed PDX-010, a multi-center, open-label, Phase 1 study of pralatrexate with vitamin B12 and folic acid in pts with relapsed/refractory CTCL. As CTCL is often a more indolent disease than peripheral T-cell lymphoma and treatment paradigms use maintenance approaches, we sought to identify the least toxic dose and schedule with activity for this distinct pt population through a dose de-escalation scheme. Methods: Eligible pts were required to have mycosis fungoides (MF), Sézary syndrome (SS), or cutaneous anaplastic large cell lymphoma (ALCL), and progression of disease (PD) after ≥ 1 systemic therapy. The dosing scheme employed 2 schedules: a 3 out of 4 week schedule and a 2 out of 3 week schedule. Doses are reduced in sequential cohorts based on toxicity. Optimal dose and schedule is defined as evidence of anti-tumor activity without Grade (Gr) 4 hematological toxicity, Gr 3–4 infection, or febrile neutropenia. Responses in skin are investigator-assessed using the modified severity weighted assessment tool (mSWAT). Results: From August 2007 to August 2008, 23 pts have enrolled, 17 of whom are evaluable for safety and response. The 17 evaluable pts, 15 with MF, 1 with SS, and 1 with ALCL, were enrolled into 4 cohorts: 30 mg/m2 3 of 4 weeks (n=2), 20 mg/m2 3 of 4 weeks (n=3), 20 mg/m2 2 of 3 weeks (n=7), and 15 mg/m2 3 of 4 weeks (n=5). These pts were heavily pretreated with a median of 6 prior regimens (range 1–25), and a median of 3.5 prior systemic regimens (range 1–9). Dose-limiting toxicities (DLTs) to date have included Gr 2 acute renal failure (1), Gr 3 joint stiffness/muscle weakness (1), and Gr 2–3 stomatitis/mucositis (4). The most common treatment-related AEs include mucositis (10 patients [59%]), nausea (8 patients [47%]), and fatigue (7 patients [41%]). Treatment-related SAEs occurred in 3 pts: stomatitis (Gr 2) at pralatrexate 20 mg/m2 2 of 3 weeks; chills (Gr 1) and exfoliative dermatitis (Gr 2) at pralatrexate 20 mg/m2 2 of 3 weeks; and hypoalbuminemia (Gr 3) and tumor lysis syndrome (Gr 3) at pralatrexate 20 mg/m2 3 of 4 weeks. To date of the 17 evaluable pts, 9 have achieved a response (53%), including partial response (PR) in 7 pts, and complete response (CR) in 2 pts (1 progressed rapidly off treatment). In addition, 6 pts had SD. Eight of the responding pts had MF, and the pt with ALCL had a CR. Seven of the 17 pts remain on treatment, including 3 pts who have been on treatment for 8, 8, and 9 months, respectively. Conclusion: In this preliminary report, pralatrexate shows marked clinical activity in the treatment of CTCL at much lower doses than those used for aggressive lymphomas. Responses have been observed in pts who had previously received up to 8 prior treatment regimens. This study is ongoing to identify a dose and schedule of pralatrexate that can result in maintained responses with minimal toxicity for pts with CTCL.

Pralatrexate Is Active in Cutaneous T-Cell Lymphoma (CTCL): Results of a Multicenter, Dose-Finding Trial.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 919-919
Author(s):  
Steven M. Horwitz ◽  
Madeleine Duvic ◽  
Youn Kim ◽  
Jasmine M Zain ◽  
Mary Jo Lechowicz ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Reduction ◽  
Research Funding ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Single Agent ◽  
Optimal Dose ◽  
T Cell Lymphoma ◽  
Grade 3

Abstract Abstract 919 Background: Pralatrexate enters cancer cells via the reduced folate carrier-1 (RFC-1) and is efficiently polyglutamated by folylpolyglutamyl synthetase (FPGS), leading to high intracellular retention. In a Phase 1/2 study of patients with hematologic malignancies, pralatrexate demonstrated activity in aggressive T-cell lymphoma with a maximum tolerated dose (MTD) of 30 mg/m2 once weekly for 6 of 7 weeks. The generally indolent course of CTCL may be better treated at lower doses in a maintenance fashion if a lower incidence and severity of adverse events can be achieved while preserving activity. PDX-010 is an open-label, single-agent, multicenter, Phase 1 dose-reduction trial in patients with relapsed or refractory CTCL. The primary objective is to identify an optimal dose and schedule of pralatrexate for these patients. Methods: Eligibility included mycosis fungoides (MF), Sézary syndrome (SS), and primary cutaneous anaplastic large cell lymphoma (ALCL); with disease progression after at least 1 prior systemic therapy. The pralatrexate dose and schedule started at 30 mg/m2 by IV push on 3 of 4 weeks and subsequent cohorts received reduced doses (20, 15, 10 mg/m2) and/or schedules (3/4 or 2/3 weeks) of pralatrexate based on tolerability. All patients received supplementation with vitamin B12 1 mg intramuscularly every 8-10 weeks and folic acid 1 mg orally once daily. As we sought a well tolerated regimen the definition of DLTs to trigger dose reduction included toxicities such as grade ≥ 3 neutropenia, grade ≥ 2 thrombocytopenia, febrile neutropenia, grade ≥ 2 mucositis/stomatitis, and any toxicity leading to dose omission or reduction in cycle 1. If DLT occurred and a response was seen, the following cohort was opened at the next lower dose or next less frequent schedule. Response was evaluated by modified severity-weighted adjustment tool (SWAT) every 2 cycles for 6 months and then every 4 cycles. For patients with lymph node involvement, scans were completed at baseline and upon clinical response or end of treatment, whichever occurred first. Results: Thirty-one patients received pralatrexate, with 18 (58%) men and median age of 57 yrs (range, 30-81). Patients had received a median of 6 prior therapies (range, 1-25). Cohorts at the following doses/schedules were enrolled: 30 mg/m2 x 3/4 weeks (n=2), 20 mg/m2 x 3/4 weeks (n=3), 20 mg/m2 x 2/3 weeks (n=7), 15 mg/m2 x 3/4 weeks (n=6), 15 mg/m2 x 2/3 weeks (n=3), and 10 mg/m2 x 3/4 weeks (n=10). Patients received pralatrexate for a median of 72 days (range, 7-491+); 4 patients received >10 cycles of treatment. The most common treatment-related adverse events (all grades) were mucositis (18 patients [58%]), nausea (14 patients [45%]), fatigue (14 patients [45%]), pyrexia (7 patients [23%]), vomiting (6 patients [19%]), anemia (6 patients [19%]), and edema (5 patients [16%]). Grade 3-4 treatment-related toxicities in >1 patient each were mucositis (4 patients [13%]) and anemia (2 patients [6%]). Mucositis was dose limiting (≥ grade 2) in 8 patients (26%). A total of 11 responses were observed, including 2 complete responses and 9 partial responses. In the 18 patients who received pralatrexate at a dose intensity of 15 mg/m2 x 3/4 weeks or greater, the objective response rate was 56% (10/18 patients). This appeared to be the threshold dose for substantial activity in CTCL, below which the incidence of responses decreased in this dose de-escalation trial. Conclusion: Pralatrexate shows impressive activity in the treatment of relapsed CTCL. The optimal dose and schedule that provided activity with tolerability for CTCL was determined to be pralatrexate 15 mg/m2 weekly on 3 of 4 weeks. This cohort is being expanded to better assess efficacy and durability. Disclosures: Horwitz: Allos Therapeutics, Inc: Consultancy, Research Funding. Duvic:Allos Therapeutics, Inc.: Research Funding. Lechowicz:Allos Therapeutics, Inc.: Consultancy. Fruchtman:Allos Therapeutics, Inc.: Employment.

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