A Phase II Study of the Farnesyltransferase Inhibitor Tipifarnib Demonstrates Anti-Tumor Activity In Patients with Relapsed and Refractory Lymphomas

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 287-287
Author(s):  
Thomas E. Witzig ◽  
Tang Hui ◽  
Ivana N Micallef ◽  
Stephen M. Ansell ◽  
Brian Link ◽  
...  
Keyword(s):  
T Cell ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Response Duration ◽  
T Cell Lymphoma ◽  
Farnesyltransferase Inhibitor ◽  
Median Response

Abstract Abstract 287 Purpose: Farnesyltransferases are key cellular enzymes involved in the prenylation of proteins. Prenylated proteins are important for malignant cell growth. The purpose of this phase II study (NCT00082888) was to assess tumor response and toxicity associated with the oral farnesyltransferase inhibitor tipifarnib (R115777, Johnson and Johnson) in patients with relapsed aggressive, indolent, or uncommon lymphoma. The uncommon group included low incidence lymphoma types such as Hodgkin lymphoma (HL) and T-cell non-Hodgkin lymphoma- cutaneous T-cell lymphoma (CTCL) and peripheral T-cell lymphoma (PTCL). Patients and Methods: Patients with relapsed or refractory non-Hodgkin (NHL) or Hodgkin (HL) were eligible if they had measurable disease, performance status ≤2, platelet count ≥75,000 × 10(6)/L, an absolute neutrophil count ≥1000 × 10(6)/L and a creatinine ≤2 × upper limit of normal. Patients initially received tipifarnib 300 mg twice daily, days 1–21 every 28 days. The trial was conducted by the University of Iowa/Mayo Clinic Lymphoma SPORE. Results: Ninety-three patients with lymphoma (42 aggressive, 15 indolent, and 36 uncommon) enrolled in the trial between March 2004 and November 2008. The median age was 62 years (range, 18–91). The median number of prior therapies was 5 (range, 1–17). The overall response rate (ORR) was 20% (19/93) with 6% (6/93) complete responses (CR) and 14% (13/93) partial responses (PR). The ORR was 17%, 7%, and 31% for the aggressive, indolent, and uncommon groups, respectively (Table). Among the 19 responders were 7 diffuse large B-cell lymphoma (DLBCL), 7 T-cell NHL, 1 follicular grade II, and 4 HL. The overall median response duration for the 19 responders was 7.5 months (mean, 12.8; range, 1.8 – 48.1 months). The median response duration was 11.3 months (mean, 10.1; range, 1.8 – 18.5 months), 2 months, and 7.5 months (mean, 15.5; range, 1.9 – 48.1 months) for the aggressive (7), indolent (1), and uncommon (11) groups, respectively. Five patients in the uncommon group are still receiving treatment with a range of treatment duration between 25 – 60+ months. Among the 5 still receiving treatment 4 responded and 1 is stable. The range of response duration is 15.4, 17.7, 43.1, and 48.1 months. These five patients (2 with HL, 1 anaplastic large cell cutaneous, and 2 PTCL) are currently receiving doses of 400 (1), 200 (2), and 100 (2) mg twice daily. The median time to progression for all patients was 3.6 months (95% CI: 2.1 – 4.5 months). The grade 3,4 toxicities observed were primarily fatigue (10%) and reversible myelosuppression with 11% anemia, 37% neutropenia, and 32% thrombocytopenia. Correlative studies demonstrated tipifarnib-induced upregulation of Bim, a marker of tipifarnib action in lymphoma cell lines, in 7 of 9 paired lymphoma biopsies. Conclusions: Tipifarnib has activity in lymphoma, with responses in patients with heavily pretreated DLBCL, HL and T-cell types, but little activity in follicular NHL. This agent has an excellent toxicity profile and targets a novel pathway. Further studies in combination with other agents are warranted for patients with DLBCL, HL or T-cell NHL. Disclosures: No relevant conflicts of interest to declare.

CALGB 59901: Results of a Phase II Study of 506U78 in CTCL and PTCL.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 2486-2486 ◽  
Author(s):  
Myron S. Czuczman ◽  
Pierluigi Porcu ◽  
Jeff Johnson ◽  
Donna Niedzwiecki ◽  
George P. Canellos ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Western Hemisphere ◽  
Water Soluble ◽  
T Cell Lymphoma ◽  
Grade 3

Abstract T-cell lymphoma comprises approximately 10% to 15% of all lymphomas seen in the Western hemisphere and may be broadly categorized into 2 main groups: the various histologies of peripheral T-cell lymphoma (PTCL) or cutaneous T-cell lymphoma (CTCL). Overall, PTCL patients (pts) are believed to have a worse prognosis than pts with B-cell lymphoma. Except for the favorable subset of ALK-1-positive anaplastic large cell lymphoma, most PTCL are incurable with standard therapy. Salvage chemotherapy is often ineffective in relapsed PTCL or in pts with advanced CTCL no longer responding to agents that modulate T-cell function (e.g. retinoids, interferons, antibodies). New agents are needed for these pts. 506U78 is a pro-drug of ara-G, a deoxyguanosine analogue. Ara-G itself is difficult to synthesize and poorly water soluble. 506U78 is 10 X more water soluble than ara-G and is rapidly demethoxylated in blood to ara-G, which has been shown to be toxic to T-cells at even micromolar concentrations. Based on positive preliminary data with 506U78 in pediatric pts with recurrent/refractory precursor T-lymphoblastic lymphoma or leukemia (PTLL), we activated CALGB protocol 59901, a Phase II study of 506U78 in pts with systemically untreated CTCL or refractory/relapsed PTCL. Objectives were to determine response rate, remission duration, and safety associated with 506U78 given at 1.5 g/m2/day on Days 1, 3, and 5 as an IV infusion q 21 days for a minimum of 2 cycles and/or to continue for 2 cycles after CR (up to max of 8 cycles). Eligibility included: diagnosis of PTCL or CTCL; measurable disease; no CNS lymphoma; no history of seizure disorder or significant (>grade 1) neurologic dysfunction; age <70; PS 0–2; adequate renal and hepatic function; CTCL pts were originally not permitted to have received systemic chemo, but the protocol was amended on 2/15/02 to allow therapy with one prior course of single-agent chemotherapy in an attempt to increase accrual. Nineteen pts were enrolled between 5-15-00 and 3-15-04: 11 CTCL and 8 PTCL pts. Five of 11 CTCL pts had received no prior therapy and 7 of 7 evaluable PTCL pts had received prior chemo and 2 prior BMT. Adverse event (AE) data are available for 18 pts. Grade 3 or 4 AEs were documented in 50% and 28% of pts, respectively. Thirty-three percent of pts experienced Grade 3 or 4 neurologic toxicities which included: ataxia, vertigo, peripheral neuropathy, confusion, and/or depressed consciousness. There were 2 treatment-related deaths, 1 due to infection and 1 due to CNS hemorrhage (both in pts with CTCL). There were 2 PRs to therapy, one each in the PTCL and CTCL groups, with disease progression at 3m and 5.5m, respectively. The overall response rate is 10.5% (1.3% – 33.1%; 95% CI). Fifteen of 19 pts have died. Median EFS was 1.2m (1.0, 1.6 m; 95% CI) and median OS was 3 months (1.4, 9.8m; 95% CI). Due to lack of efficacy and excessive toxicity the protocol was closed on 3/15/04. In contrast to the favorable results seen in pediatric pts with recurrent PTLL, our data demonstrate that 506U78 has low efficacy, is unacceptably toxic and is not recommended as monotherapy in adult pts with CTCL and PTCL.

A Phase II Clinical Study of Rituximab and High-Dose Biweekly THP-COP (Pirarubicin, Cyclophosphamide, Vincristine and Predonisolone) with G-CSF for Non-Hodgkin Lymphoma: Results of a Multicentric Study of NMLSG (Niigata Malignant Lymphoma Study Group).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4734-4734
Author(s):  
Jun Takizawa ◽  
Sadao Aoki ◽  
Kazue Takai ◽  
Tohri Kurasaki ◽  
Keiichiro Honma ◽  
...  
Keyword(s):  
Clinical Study ◽  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Phase Ii ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
High Dose ◽  
Histological Subtypes ◽  
Non Hodgkin Lymphoma

Abstract Introduction CHOP chemotherapy has been accepted as the standard treatment for patients with non-Hodgkin lymphoma (NHL), but in some histological or clinical subtypes the results are not satisfactory. We have shown the efficacy and safety of high-dose biweekly THP-COP with G-CSF support (HDBW-TCOP(G)) for NHL. In this regimen, we choose pirarubicin in stead of doxorubicin because it was proven high efficacy against NHL and the lower toxicity than doxorubicin. Recently, the combination of rituximab and standard CHOP has been shown to have a synergistic effect for NHL. We performed a phase II multicentric clinical study to assessed the feasibility and toxicity of the combination chemotherapy of rituximab and HDBW-TCOP(G) (HDBW-R-TCOP(G)) compared with those of HDBW-TCOP(G). Patients and methods Between August 1998 and December 2004, Forty-one Japanese patients with previously untreated NHL from whom informed consent was obtained were included in this study. Median age was 45 (range 19–63) years. There were 19 males and 22 females. According to WHO-classification diagnoses, histological subtypes included follicular lymphoma (FL) 15(37%); nodal marginal zone B-cell lymphoma (NMZBCL) 2(5%); mantle cell lymphoma (MCL) 3(7%); anaplastic large cell lymphoma (ALCL) 1(2%), diffuse large B-cell lymphoma (DLBCL) 18(44%); peripheral T-cell lymphoma (PTCL) 1(2%), angioimmunoblastic T-cell lymphoma (AILT) 1(2%). Of 41 patients, one patient was stage 1, stage 2, 11 stage 3 and 16 stage 4. International prognostic index (IPI) included L 6; LI 22; HI 7; H 6. HDBW-TCOP(G) consisted of pirarubicin 70 mg/m2 on day 1; cyclophosphamide 1000 mg/m2 on day 1; vincristine 1.4 mg/m2 on day 1; predonisolone 50 mg/m2 orally from day 1 to 5; lenograstim 2.0 μg/kg/day from day 3. Fifteen patients who enrolled after rituximab was approved in Japan received therapy combined HDBW-TCOP(G) with rituximab 375mg/ m2 on day -2 (HDBW-R-TCOP(G)). Six cycles were administered at intervals of two weeks. Results Of the 41 patients treated, 32 (78.0%) achieved a complete remission (CR) and nine (22.0%) achieved a partial remission (PR), for an overall response rate of 100%. After median follow-up of 36 months (range 2.9– 81.8), progression free survival (PFS) and overall survival (OS) were 68.2% and 97.5%, respectively. PFS was 90.9% for HDBW-R-TCOP(G), and 69.5% for HDBW-TCOP(G), but no significant differences was found among two regimen. There was no significant difference in the PFS and OS between aggressive and indolent histological subtypes. 76% of patients developed Grade4 leukopenia (according to NCI criteria) but no patients experienced febrile neutropenia. 15% of patients developed G4 anemia and 17% of patients G4 thrombocytopenia. Other adverse effects were minimal. Conclusion Both HDBW-TCOP(G) and HDBW-R-TCOP(G) are feasible for NHL with acceptable toxicity. The excellent result suggests they are effective for aggressive NHL patients with poor prognostic factors and advanced stage indolent NHL.

Multicenter Phase II Study of Mogamulizumab (KW-0761), a Defucosylated Anti-CCR4 Antibody, in Patients with Relapsed Peripheral and Cutaneous T-Cell Lymphoma

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 795-795 ◽  
Author(s):  
Takashi Ishida ◽  
Michinori Ogura ◽  
Kiyohiko Hatake ◽  
Masafumi Taniwaki ◽  
Kiyoshi Ando ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Clin Oncol ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Cell Subset ◽  
T Cell Lymphoma ◽  
Cutaneous T Cell Lymphoma ◽  
Multicenter Phase

Abstract Abstract 795 Background: Mogamulizumab (KW-0761) is a humanized anti-CCR4 antibody engineered to exert potent ADCC by defucosylation. In a phase I study for patients with CCR4-positive T-cell malignancies, once weekly administration for 4 weeks of mogamulizumab was well tolerated up to 1.0 mg/kg, and encouraging efficacy was observed (J Clin Oncol 2010;28:1591). In a subsequent phase II study in CCR4-positive relapsed adult T-cell leukemia-lymphoma (ATL) patients, mogamulizumab exhibited an overall response rate (ORR) of 50% (J Clin Oncol 2012;30:837), leading to its approval in Japan in 2012 for relapsed/refractory ATL. In addition, a phase I/IIa study for previously treated cutaneous T-cell lymphoma (CTCL) in the USA showed an ORR of 37% (14/38) (T-CELL LYMPHOMA FORUM 2012). Based on these findings, a phase II study of mogamulizumab for relapsed peripheral T-cell lymphoma (PTCL) and CTCL was conducted in Japan. Methods: A multicenter phase II study of mogamulizumab monotherapy for patients with relapsed CCR4-positive PTCL and CTCL was conducted to evaluate efficacy, pharmacokinetic profile, and safety. The primary endpoint was ORR and secondary endpoints included progression-free survival (PFS) and overall survival (OS). At least 35 patients were needed to detect a lower limit of the 95% confidence interval (CI) exceeding the 5% threshold, with an expected ORR for mogamulizumab of 25% with 90% statistical power. Patients received intravenous infusions of mogamulizumab once per week for 8 weeks at a dose of 1.0 mg/kg. Responses were assessed after the 4th and 8th infusions of mogamulizumab by an independent efficacy assessment committee. The histopathological subtypes of PTCL were confirmed by an independent pathology review committee according to the 2008 WHO classification. In addition, we examined blood T-cell subset distributions. Results: A total of 38 patients were enrolled, and 37 patients (male/female 23/14; median age 64 years, range 33–80) received mogamulizumab. One patient was withdrawn due to an infectious complication. Twenty-nine of the 37 assessable patients had PTCL [PTCL- not otherwise specified (NOS), n=16; angioimmunoblastic T-cell lymphoma (AITL), n=12; anaplastic large cell lymphoma (ALCL)-ALK negative, n=1] and 8 had CTCL [mycosis fungoides (MF), n=7; cutaneous ALCL, n=1]. Performance status at enrollment was 0 (n=24), 1 (n=12), and 2 (n=1). The median number of prior systemic chemotherapy regimens was 2 (range 1–6). Of the 37 patients, 25 completed the schedule of 8 planned infusions. Nine patients (24%) discontinued the treatment protocol due to progressive disease and 3 due to adverse events (AEs). The ORR in 37 patients was 35% (13/37, 95% CI, 20 to 53%) with 14% having a complete response (5/37) (Table 1). By PTCL subtype, the ORR was 34% (10/29) for PTCL (3/16 for PTCL-NOS, 6/12 for AITL, and 1/1 for ALCL-ALK negative) and 38% (3/8) for CTCL (2/7 for MF and 1/1 for cutaneous ALCL). AEs possibly, probably, or definitely related to mogamulizumab monotherapy were as follows. Lymphopenia of all grades and that of grades 3–4 were observed in 78% and 70% of the 37 patients, respectively. Leukopenia of all grades and that of grades 3–4 were observed in 43% and 14% of the 37 patients. For all grades and grades 3–4, neutropenia was observed in 35% and 16%, thrombocytopenia in 35% and 3%, ALT increases in 22% and 3%, and skin eruptions in 49% and 8% of patients, respectively. Infusion-related toxicities occurred in 22%, which were all within grade 2 or lower. Fourteen severe AEs were observed in 7 patients, including a grade 3 polymyositis in 1 and grade 2 cytomegalovirus retinitis in 2. All severe AEs were improved. No grade 5 AEs were observed. Pharmacokinetic analysis demonstrated that Cmax and trough (C168h) after the 8th infusion were 45.9 ± 9.3 and 29.0 ± 13.3 μg/mL, respectively. No anti-mogamulizumab antibody has been detected. Updated results of PFS, OS, and T-cell subset analysis are being analyzed for presentation. Conclusions: Mogamulizumab monotherapy showed promising antitumor activity with acceptable toxicity profiles in patients with relapsed PTCL and CTCL, warranting further investigation. Disclosures: Ishida: Kyowa Hakko Kirin Co., Ltd,: Honoraria, Research Funding, Speakers Bureau. Ogura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Suzumiya:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Inagaki:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Tamura:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Akinaga:Kyowa Hakko Kirin Co., Ltd,: Employment. Tomonaga:Kyowa Hakko Kirin Co., Ltd,: Consultancy. Ueda:Kyowa Hakko Kirin Co., Ltd,: endowed chair Other.

Phase II study of SMILE chemotherapy for newly-diagnosed stage IV, relapsed or refractory extranodal NK/T-cell lymphoma, nasal type: NKTSG study.

2010 ◽  
Vol 28 (15_suppl) ◽  
pp. 8044-8044 ◽  
Author(s):  
M. Yamaguchi ◽  
Y. Kwong ◽  
Y. Maeda ◽  
C. Hashimoto ◽  
W. Kim ◽  
...  
Keyword(s):  
T Cell ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Stage Iv ◽  
T Cell Lymphoma ◽  
Newly Diagnosed ◽  
Nasal Type ◽  
Nk T Cell

scholarly journals Imaging of Chemokine Receptor-4 Targeted PET/CT with 68Ga-Pentixafor in Non-Hodgkin Lymphoma: Comparison to 18F-FDG

2020 ◽  
Author(s):  
Qingqing Pan ◽  
Yaping Luo ◽  
Yan Zhang ◽  
Long Chang ◽  
Ji Li ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
Hodgkin Lymphoma ◽  
Marginal Zone ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Lymphoplasmacytic Lymphoma ◽  
Non Hodgkin Lymphoma ◽  
Pet Ct

Abstract Background: In order to study the CXCR4 expression with 68Ga-Pentixafor PET in different types of non-Hodgkin lymphoma, we performed a retrospective study to describe the 68Ga-Pentixafor PET/CT imaging in a spectrum of lymphomas and to compare it with 18F-FDG PET/CT. Results: Twenty-seven patients with newly diagnosed non-Hodgkin lymphoma were recruited retrospectively. 68Ga-Pentixafor PET showed increased radioactivity in lymphoplasmacytic lymphoma (n = 8), marginal zone lymphoma (n = 4), diffuse large B cell lymphoma (n = 3), follicular lymphoma (n = 2), mantle cell lymphoma (n = 1), unclassified indolent B cell lymphoma (n = 3) and enteropathy associated T cell lymphoma (n = 3). However, peripheral T cell lymphoma, not otherwise specified (n = 1), and NK/T cell lymphoma (n = 2) were not avid for 68Ga-Pentixafor. In comparison to 18F-FDG PET, 68Ga-Pentixafor PET demonstrated more extensive disease and higher radioactivity in lymphoplasmacytic lymphoma and marginal zone lymphoma. Conclusion: CXCR4 expression varies in different types of non-Hodgkin lymphoma. Overexpression of CXCR4 was detected with 68Ga-Pentixafor PET/CT in lymphoplasmacytic lymphoma, marginal zone lymphoma, diffuse large B cell lymphoma, follicular lymphoma, mantle cell lymphoma, unclassified indolent B cell lymphoma, and enteropathy associated T cell lymphoma.

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