A Phase I Open Label Dose Escalation Study To Evaluate MEDI-507 in Patients with CD2-Positive T-Cell Lymphoma/Leukemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2727-2727 ◽  
Author(s):  
Deborah A. Casale ◽  
Nancy L. Bartlett ◽  
David D. Hurd ◽  
Francine Foss ◽  
Barbara Pro ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Tumor Lysis Syndrome ◽  
Lymphocytic Leukemia ◽  
T Cell Lymphoma ◽  
Cell Recovery ◽  
Open Label ◽  
Dose Escalation Study

Abstract This ongoing multicenter study is a Phase I trial with MEDI-507 (Siplizumab) [a humanized IgG1k class monoclonal antibody that binds to the CD2 receptor on human T- and NK-cells] to determine the maximum tolerated dose (MTD) or the optimum biologic dose (OBD) in patients with relapsed/refractory CD2-positive T-cell lymphoma/leukemia [CD2-positive adult T-cell leukemia (ATL), cutaneous T-cell lymphoma (CTCL), peripheral T-cell lymphoma (PTCL), and large granular lymphocytic leukemia (LGL).] Open label 3+3 dose escalation was conducted in which patients receive bi-weekly infusions of MEDI-507 over 3 consecutive days at total doses of 0.7 mg/kg, 3.4 mg/kg or 4.8 mg/kg. Predose and serial MEDI-507 pharmacokinetics (ELISA) at Visit 2 and anti MEDI-507 antibodies (ELISA), peripheral blood total T-Cell and CD2-positive T-cells (flow cytometry), and C3 and C4 complement are obtained for each patient. Patients are followed for one year after their last dose of MEDI-507 for tumor assessment and CD2-positive T-cell recovery. 16 patients have been enrolled: 3 (0.7 mg/kg); 9 (3.4); 4 (4.8). Three additional patients were added to the 3.4 mg/kg cohort to replace patients who progressed early and one patient with tumor lysis syndrome. Diagnoses of the 16 patients: PTCL (9), CTCL (6) and NK-LGL (1). Frequent adverse events reported, to date, are infusion reaction (7/16) patients; hypertension (4/16); lymphopenia (4/16); fatigue (4/16) and leukopenia (3/16). Two DLT’s have been observed. The first, erythematous confluent dermatitis, occurred in one patient at 3.4 mg/kg and the cohort was expanded with eventual dose escalation. The second, pulmonary edema, occurred in one patient at 4.8 mg/kg and the cohort is currently being expanded without further DLT identified to date. Two responses have been observed, one PR in an NK-LGL patient at 3.4 mg/kg and one CR in a PTCL patient at 3.4 mg/kg. MEDI-507 has been well tolerated and shown anti-tumor activity. Dosing will change to weekly dosing with dose escalation (3+3) starting at 1.2 mg/kg as 0.8 mg/kg was seen to be safe in the single center study. MTD and/or OBD have not been determined.

Phase I Study of Forodesine (BCX1777), An Oral PNP Inhibitor In Patients with Relapsed or Refractory T/NK Malignancies.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1796-1796 ◽  
Author(s):  
Kunihiro Tsukasaki ◽  
Michinori Ogura ◽  
Hirokazu Nagai ◽  
Jun Taguchi ◽  
Tatsuya Suzuki ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Phase I Study ◽  
Conflicts Of Interest ◽  
Cell Lymphoma ◽  
Maximum Tolerated Dose ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Open Label ◽  
Dose Escalation Study

Abstract Abstract 1796 Background: Forodesine is a rationally designed potent inhibitor of purine nucleoside phosphorylase (PNP) that leads to elevation of plasma deoxyguanosine (dGuo) and intracellular accumulation of dGTP levels and then apoptosis mainly in T cells. Oral forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL) (M. Duvic et al, ASH 2007). The objective of this phase I study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with recurrent or refractory T/NK malignancies in Japan. Methods: An open-label dose-escalation study of forodesine, 100 to 300 mg/body qd for 4 weeks, was conducted to evaluate safety profile (dose-limiting toxicities, DLT), tolerability and PK profile as primary endpoints. Forodesine was administered until disease progression or unacceptable toxicity is observed. Relapsed or refractory T/NK malignancies with PS 0 to 1 and without major organ dysfunction were eligible. Results: Overall, 13 Japanese patients, 8 males and 5 females, with a median age of 69 (range 30–77) years were enrolled in the study: 5 patients in the 100mg cohort, 3 in the 200mg cohort and 5 in the 300mg cohort. Patients’ histopathologic subtypes were as follows: peripheral T-cell lymphoma not otherwise specified (PTCL-NOS) (6 patients), anaplastic large cell lymphoma (ALCL) (3), primary cutaneous ALCL (C-ALCL) (2) and mycosis fungoides (MF) (2). Median stage and prior treatment regimen were IIIA (range IA-IVA) and 2 (range 1, 8), respectively. No DLT was observed and a maximum tolerated dose was never defined. The most common toxicities of grade 2 or less were constipation (39 %), rash (31%), lymphopenia (31 %), neutropenia (23 %), nausea (23 %), peripheral edema (23 %), LDH elevation (23 %) and leukopenia (23 %). The toxicities of grade 3 or greater were lymphopenia (62 %), anemia (15 %), leukopenia (8 %), thrombocytopenia (8 %) and viral infection (8 %). Median baseline, nadir, and last visit lymphocytes counts (1,000/μL) were 0.69 (95% CI: 0.56, 1.18), 0.35 (95% CI: 0.14, 0.60) and 0.60 (95% CI: 0.24, 0.95), respectively. Plasma levels for forodesine showed less than dose-proportional increase in exposure as mean AUC at Day 1 was 1,948 (ng·h/mL) in the 100mg cohort, 4,608 (ng·h/mL) in the 200mg cohort, and 4,596 (ng·h/mL) in the 300mg cohort. The levels for dGuo displayed a similar trend, with mean AUC at Day 1 4,023 (ng·h/mL) in the 100mg cohort, 5,705 (ng·h/mL) in the 200mg cohort, and 6,074 (ng·h/mL) in the 300mg cohort. One patient with ALCL reached complete response (CR) in the 100mg cohort and 2 patients with MF reached partial response in the 200mg cohort. In addition, 4 patients with stable disease (SD) were observed: 1 patient with PTCL-NOS in the 100mg cohort, 1 with C-ALCL in the 200mg cohort and 2 with C-ALCL and PTCL-NOS in the 300mg cohort. As of Aug, 2010, 2 patients with ALCL (CR patient in the 100mg cohort) and PTCL-NOS (SD patient in the 300mg cohort) have continued the treatment for more than 510 days and 290 days, respectively. Conclusion: Oral forodesine was well tolerated at all the dose levels tested with similar PK findings to those in the CTCL study in USA, demonstrating potential efficacy against relapsed or refractory T/NK lymphomas including PTCL for the first time. Based on these promising data, we are planning a phase I /II study of forodesine in patients with relapsed or refractory PTCL. Disclosures: No relevant conflicts of interest to declare.

Vorinostat in combination with bexarotene in advanced cutaneous T-cell lymphoma: A phase I study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 8572-8572 ◽  
Author(s):  
R. Dummer ◽  
K. Hymes ◽  
W. Sterry ◽  
M. Steinhoff ◽  
C. Assaf ◽  
...  
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Anticancer Agents ◽  
Cell Lymphoma ◽  
Objective Response ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Cutaneous T Cell Lymphoma ◽  
Open Label

8572 Background: Vorinostat, a histone deacetylase inhibitor, is registered for the treatment of advanced cutaneous T-cell lymphoma (CTCL) in the US. Preclinical studies suggest that vorinostat may enhance the activity of chemotherapeutic or biological anticancer agents in a variety of cancers. This Phase I, multicenter, open-label study systematically evaluated vorinostat combined with the retinoid bexarotene in patients (pts) with advanced CTCL. Methods: Eligible pts were aged ≥18 years with stage ≥IB progressive, persistent, or recurrent CTCL refractory to ≥1 systemic therapy. Primary objective was to determine the maximum tolerated dose (MTD). Phase Ia Part I: dose escalation of vorinostat (200–400 mg/day) and bexarotene (150–300 mg/m2/day); Part II: fixed vorinostat dose (400 mg/day) with bexarotene dose escalation (150–450 mg/day). Cycles were repeated every 28 days for ≤6 cycles. Clinical activity and safety of the combination was also assessed. Results: 23 pts received ≥1 dose of study medication. Three pts in dose level (DL) 2 experienced dose-limiting toxicities (DLTs) ( Table ). No DLTs were observed in the first cycle of DL 2a and 2b. The MTD (Part I) was vorinostat 200 mg/day plus bexarotene 300 mg/m2/day. The Part II MTD was not reached as the study was discontinued early due to low enrollment; no DLTs were observed at DL 6 or 7. The most common drug-related adverse events (DRAEs) were hypothyroidism (35%), fatigue (30%), and hypertriglyceridemia (30%). No Grade 4 or 5 DRAEs were reported and 4 pts had serious DRAEs (Grade ≤3). Eighteen pts have discontinued: 5 due to AEs, 5 due to progressive disease, and 8 withdrew consent. Of 22 pts evaluable for efficacy, 4 (18%) had an objective response, and 7 (32%) derived clinical benefit (pruritis relief). Conclusions: These preliminary data suggest that the vorinostat/bexarotene combination is feasible in pts with advanced CTCL; however, the dosage of either drug must be reduced to avoid unacceptable side effects. [Table: see text] [Table: see text]

scholarly journals Pralatrexate in Combination with Cyclophosphamide, Doxorubicin, Vincristine, and Prednisone (CHOP) in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL): A Phase 1 Dose-Escalation Study

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 818-818 ◽  
Author(s):  
Andrei Shustov ◽  
Patrick B Johnston ◽  
Stefan Klaus Barta ◽  
Gajanan Bhat ◽  
Guru Reddy ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
T Cell Lymphoma ◽  
Peripheral T Cell Lymphoma ◽  
Dose Escalation Study ◽  
Chop Regimen ◽  
Treatment Naïve ◽  
Grade 3

Abstract Background: The prognosis of patients with PTCL remains poor after standard CHOP therapy - the most commonly used combination regimen. Relapses occur in the majority of patients, and curability rates of the relapsed disease are very low. Hence, advances in front-line therapy of PTCL are long overdue. Pralatrexate, a second-generation antifolate, demonstrated a single agent activity in patients with relapsed and refractory PTCL with a response rate of 27%, including complete remissions in 11% of patients (O'Connor et al. J Clin Onc 2011). We conducted a Phase 1 multi-center dose-escalation study of pralatrexate in combination with standard CHOP (Fol-CHOP) in treatment-naïve PTCL patients. Objectives: The primary objective of the study was to determine the maximum tolerated dose (MTD) of pralatrexate when administered with a standard CHOP regimen to patients with newly diagnosed PTCL. The secondary objectives included safety, tolerability, efficacy and pharmacokinetics of pralatrexate in combination with CHOP (Fol-CHOP). Methods: In Part 1 of this 3+3 dose-escalation study, pralatrexate was administered at 10, 15, 20, 25, or 30 mg/m2 as an IV push on days 1 and 8 of a standard 21-day CHOP regimen (cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, vincristine 1.4 mg/m2 [maximum 2 mg] on day 1 and oral prednisone 100 mg on days 1-5). In Part 2 of the study patients were treated at the MTD of pralatrexate established in Part 1, with standard CHOP. In both parts of the study patients were treated with up to 6 cycles of therapy, or until toxicity or disease progression. Patients received antimicrobial prophylaxis, myeloid growth factor support, and "leucovorin rescue" throughout 6 cycles of therapy. Dose-limiting toxicities (DLT) were considered during the 1st cycle of Fol-CHOP and included: Grade 4 infections, treatment-related non-hematological toxicity ≥Grade 3, platelet count < 25 X 109/L at any time, or ANC < 0.5 X 109/L for >7 days despite G-CSF administration. Responses were assessed by the investigator per the Revised Response Criteria for Malignant Lymphoma (Cheson 2007). Results: A total of 31 patients have been enrolled (19 in Part 1; 12 in Part 2). MTD was not reached and pralatrexate dose of 30 mg/m2 in combination with CHOP was selected for Part 2 of the study as predefined by the protocol. The majority of patients were male, White, with the median age of 66 yrs (range, 18-78) at the time of enrolment. PTCL diagnoses included: anaplastic large cell lymphoma, anaplastic lymphomakinase-negative (ALCL, ALK-, n=5), peripheral T-cell lymphoma, not-otherwise specified (PTCL-NOS, n=18), and angioimmunoblastic T-cell lymphoma (AITL, n=5). Fol-CHOP was generally well tolerated with median RDI of 98%. Common (≥ 30%) adverse events (AEs) of any grade were fatigue (n=23), constipation (n=20), nausea (n=16), mucositis (n=14), diarrhea (n=12), anemia (n=9), vomiting (n=10) and oral pain (n=10). Most common (≥ 10%) AEs ≥ grade 3 were anemia (n=6), fatigue (n=4) and neutrophil count decreas (n=5). The only Grade >3 treatment-related AEs (≥10%) was neutrophil count decrease (n=4). SAEs were observed in 13 patients, treatment related SAEs were anemia, febrile neutropenia, dehydration, mucositis and nausea. Five patients withdrew from study: 2 due to disease progression, 1 due to AE and 2 due lapse >28 days between doses. In the 27 patients avaluable for response, the investigator assessed objective response (OR) and complete response (CR) rates were 89% wand 67%, respectively. Conclusions: The combination of pralatrexate and CHOP was well tolerated in treatment-naive PTCL patients. MTD of pralatrexate was not reached, and the protocol-defined maximum dose of 30 mg/m2 on days 1 and 8 of a 21-day CHOP cycle was recomended for future studies. The observed OR and CR rates warrant further evaluation of this regimen in newly diagnosed PTCL patients. Disclosures Shustov: Celgene: Other: Publication assistance; Spectrum Pharmaceuticals: Consultancy, Research Funding. Bhat: Spectrum Pharmaceuticals: Employment. Reddy: Spectrum Pharmaceuticals: Employment.

Oral Forodesine (Bcx-1777) Is Clinically Active in Refractory Cutaneous T-Cell Lymphoma: Results of a Phase I/II Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2467-2467 ◽  
Author(s):  
Madeleine Duvic ◽  
Andres Forero-Torres ◽  
Francine Foss ◽  
Elsie A. Olsen ◽  
Youn Kim
Keyword(s):  
T Cell ◽  
Phase I ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Objective Response ◽  
Safety Data ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Cutaneous T Cell Lymphoma ◽  
Percent Change

Abstract Background: Forodesine is a potent, rationally designed purine nucleoside phosphorylase (PNP) inhibitor that is orally bioavailable. IV forodesine has shown clinical activity in patients with cutaneous T-cell lymphoma (CTCL). The objective of this phase I/II study was to evaluate the safety, PK profile, and efficacy of oral forodesine in patients with refractory CTCL. Methods: An open-label dose-escalation study of fordesine, 40 to 320 mg/m2 qd for 4 weeks, was undertaken to evaluate the safety and PK profile of oral forodesine, followed by an investigation of the expansion of the optimal biologic dose (dose with maximum PNP inhibition and elevation of plasma deoxyguanosine levels) to assess efficacy. Previously treated, refractory CTCL patients with stage IB or greater disease were eligible for participation. The primary end point was objective response (OR) = complete response [CR] plus partial response [PR], as measured by the severity-weighted assessment tool (SWAT; see Figure) and physicians’ global assessment (PGA) Results: Overall, 37 patients were treated, including 14 patients in the dose-escalation portion of the study. No dose-limiting toxicities were observed with target doses of ≤320 mg/m2; thus, a maximum tolerated dose was never defined. Based on PK/PD results, an 80 mg/m2 qd dose was identified as the optimal biologic dose, and this ongoing study was expanded to enroll a total of 28 patients (median age, 64 yr; range, 28–81 yr). The OR rate was 53.6% (15/28 patients; 2 [7.1%] with a CR and 13 [46.4%] with a PR). The proportion of patients with stage IIB or greater disease was 19/28 (67.9%). Response in this population was seen in 10 (52.6%) of the 19 patients (1 [5.3%] with a CR and 9 [47.4%] with a PR). The percent change in SWAT score from baseline as a function of time demonstrated a progressive decrease over a 24-week period. To-date, 12 (42.9%) of 28 patients have completed ≥4 months of treatment. Safety data were recorded for all 37 patients treated with forodesine. The most common adverse events classified as grade 2 or less, without regard to causality, were nausea (30%), dizziness (22%), pruritus (22%), fatigue (19%), headache (19%), peripheral edema (19%), and pyrexia (16%). The only adverse event classified as grade 3 or greater, without regard to causality, and occurring in at least two patients, was lymphopenia, which was observed in two patients (5%). Conclusions: Oral forodesine is effective in the treatment of refractory CTCL patients and has an encouraging safety profile. SWAT SCORE: Percent Change from Baseline SWAT SCORE: Percent Change from Baseline

Phase I Analysis of the Safety and Pharmacodynamics of the Novel Broad Spectrum Histone Deacetylase Inhibitor (HDACi) PCI-24781 in Relapsed and Refractory Lymphoma.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2726-2726 ◽  
Author(s):  
Andrew M Evens ◽  
Weiyun Ai ◽  
Sriram Balasubramanian ◽  
Mint Sirisawad ◽  
Chitra Mani ◽  
...  
Keyword(s):  
Clinical Trial ◽  
T Cell ◽  
Phase I ◽  
Cell Lines ◽  
Phase Ii ◽  
Dose Escalation ◽  
Clinical Benefit ◽  
Cell Lymphoma ◽  
T Cell Lymphoma ◽  
Refractory Lymphoma

Abstract Abstract 2726 Poster Board II-702 Background: PCI-24781 is a novel oral pan-HDACi with potent preclinical anti-tumor activity in lymphoma cell lines and models and has previously demonstrated safety and clinical benefit in solid cancers (Undevia et al, ASCO 2008). In lymphoma cell lines, PCI-24781 was causes increased oxidative stress and NF-κB inhibition that results in caspase-dependent apoptosis (Evens et al, Clin Ca Res 2009). Based in part on this encouraging pre-clinical data, a phase I/II clinical trial was designed for patients with relapsed/refractory lymphoma. Methods: The primary objective of the phase I component of this protocol was to determine the maximum tolerated dose (MTD) for testing in the phase II portion of the trial. PCI-24781 was given orally twice daily at escalating doses of 30–60mg/m2 on a 4-week cycle on two treatment schedules: 5 days/week x 3 weeks (schedule 1) or 7 days/week every other week (schedule 2). A standard 3+3 phase I dose escalation scheme was used. Tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs). Data presented here consists of the completed phase I dose escalation component of the clinical trial. Results: 25 pts enrolled with 7 pts continuing on treatment. The median age was 63 years, while the median number of prior treatments was 3. The histologies included: diffuse large B-cell lymphoma (DLBCL) (9), follicular lymphoma (FL) (4), Hodgkin lymphoma (3), CLL/SLL (2), mantle-cell lymphoma (2), nodal peripheral T-cell lymphoma (2), and cutaneous T-cell lymphoma (1). The best tolerated doses were 30 mg/m2 on schedule 1 and 45 mg/m2 on schedule 2, both with no adverse events (AEs) > grade 2. AEs ≥ grade 3 were thrombocytopenia (n=4) and diarrhea (n=1) and thus were dose limiting. One DLBCL pt with a history of renal insufficiency and renal involvement by lymphoma experienced a serious AE of renal failure, which was deemed possibly related to PCI-24781. Of note, no pericarditis, pericardial effusion, or QT prolongation were seen at any dose level of PCI-24781. Twelve pts were evaluable for response. Two confirmed responses have been seen (1 complete remission (CR), 1 partial remission (PR)), while six patients had stable disease (SD) with the median length of SD being 15 weeks (range, 6–17+). The longest duration of response (CR) was 8 cycles (32+ weeks). Both responses were seen in FL (2/4); one patient (PR) had received prior CHOP, R-ESHAP, and autologous transplant, while the other patient (CR) was rituximab-refractory and had failed 5 prior therapies. Pharmacodynamic monitoring revealed a dose-dependent increase in tubulin acetylation at 4 hours following the first dose, however this did not correlate with response or toxicity. Conclusion: PCI-24781 is a well tolerated pan-HDACi, including complete absence of prolonged QT abnormalities. Preliminary clinical benefit in heavily pre-treated relapsed/refractory lymphoma patients was documented in the phase I portion of this study. Accrual will continue to the phase II component of the clinical trial. Disclosures: Off Label Use: This is a non-FDA approved agent. Balasubramanian:Pharmacyclics: Employment. Sirisawad:Pharmacyclics: Employment. Mani:Pharmacyclics: Employment. Guerra:Pharmacyclics: Employment. Szakacs:Pharmacyclics: Employment. Loury:Pharmacyclics: Employment. Buggy:Pharmacyclics: Employment. Hamdy:Pharmacyclics: Employment, Equity Ownership.

Lenalidomide in relapsed adult T-cell leukaemia-lymphoma or peripheral T-cell lymphoma (ATLL-001): a phase 1, multicentre, dose-escalation study

2016 ◽  
Vol 3 (3) ◽  
pp. e107-e118 ◽  
Author(s):  
Michinori Ogura ◽  
Yoshitaka Imaizumi ◽  
Naokuni Uike ◽  
Norio Asou ◽  
Atae Utsunomiya ◽  
...  
Keyword(s):  
T Cell ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
T Cell Lymphoma ◽  
Cell Leukaemia ◽  
Peripheral T Cell Lymphoma ◽  
Dose Escalation Study

scholarly journals A Dose Escalation Study of RP6530, a Novel Dual PI3K δ/γ Inhibitor, in Patients with Relapsed/Refractory T-Cell Lymphoma

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3004-3004 ◽  
Author(s):  
Yasuhiro Oki ◽  
Auris Huen ◽  
Prajak J Barde ◽  
Kumar Penmetsa ◽  
Alda Ashu ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Dose Escalation ◽  
Cell Lymphoma ◽  
Phase 1 ◽  
Performance Status ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Dose Escalation Study ◽  
Grade 3

Abstract Introduction: The δ isoform of PI3K is highly expressed in cells of hematopoietic origin. The γ isoform is associated with T-lymphocytes and neutrophils and plays a distinct role in T-cell function. Since δ/γ isoforms are synergistic in the growth and survival of certain T-cell malignancies, dual targeting of PI3K δ/γ is an attractive intervention strategy in patients with T-cell lymphoma. RP6530 is a novel, highly specific dual PI3K δ/γ inhibitor with nanomolar inhibitory potency for both isotypes. It has shown acceptable safety profile and efficacy in patients (pts) with advanced hematologic malignancies in a Phase 1 study (ASH 2015). Herein, we present the preliminary results from an ongoing Phase 1/1b, dose escalation study of RP6530 in 11 pts with mature T-cell neoplasms (NCT02567656). Methods: The study consists of dose escalation cohorts to determine the MTD of RP6530 using a standard 3+3 design, followed by two expansion cohorts enrolling 20 pts with peripheral T-cell lymphoma (PTCL) and 20 pts with cutaneous T-cell lymphoma (CTCL). Pts with a diagnosis of PTCL or CTCL who have received at least one prior systemic therapy, ECOG performance status ≤ 2 and measurable/evaluable disease are eligible. This study evaluated the safety, maximum tolerated dose (MTD), pharmacokinetics, pharmacodynamics, and clinical activity of RP6530 administered twice daily (BID) in 28-day cycles. Responses were evaluated for PTCL and CTCL based on IWG criteria (Cheson 2014) and the modified Severity Weighted Assessment Tool (mSWAT) respectively. Dose limiting toxicity (DLT) was defined by a toxicity of grade 3/4 that is considered related to treatment during the first cycle of treatment. Results: To date eleven pts (6 PTCL and 5 CTCL) (5 males and six females) have been enrolled at three dose levels: 200 mg BID, 400 mg BID and 800 mg BID. ECOG performance status score was 0/1/2 in 10/1/0 pts, respectively, with a mean age of 68 yrs (range 52-76). Pts had a median of 3 (range: 3-6) prior treatment regimens, and 5 pts had refractory disease and 6 relapsed on prior treatments. RP6530 was well tolerated without any DLT or related serious adverse event reported to date. A total of 52 non-serious adverse events were reported: 41 Grade 1/2 and 11 Grade 3/4. The most common adverse events included mild vomiting (18%), diarrhoea (18%), fatigue (18%), and rash (18%). No Grade 3/4 adverse events were deemed related to RP6530 except for ALT/AST elevation in one pt. No pt discontinued treatment due to a safety issue. Dose-proportional increases in plasma concentrations were observed in PKs. Dose escalation is currently ongoing at 800 mg BID. Five pts were evaluated for responses at Cycle 3, Day1. Two pts (1 PTCL and 1 CTCL) experienced PR (40%) that are ongoing >5 months, and three pts experienced stable disease lasting for >3 months (60%). Three pts experienced rapid disease progression during first cycle, and discontinued treatment prematurely. Conclusion: This ongoing study of RP6530 demonstrated an acceptable safety profile at doses evaluated, with a promising clinical activity. The results support further evaluation of RP6530 in pts with mature T-cell neoplasms. Disclosures Oki: Novartis: Research Funding. Barde:Rhizen Pharmaceuticals SA: Employment. Penmetsa:Rhizen Pharmaceuticals SA: Employment. Viswanadha:Incozen Therapeutics: Employment.

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