Peripheral T-cell Lymphoma Pts Research Articles

Abstract PO-008: Phase I/II study of VIP152 (enitociclib), venetoclax, and prednisone (VVIP) in relapsed/refractory (R/R) lymphoid malignancies

Abstract Background: Relapsed/refractory (R/R) aggressive lymphomas, including diffuse large B-cell lymphoma (DLBCL), high-grade B-cell lymphoma double-hit (HGBCL-DH), and peripheral T-cell lymphoma (PTCL), have poor outcomes with standard therapy. VIP152 (enitociclib) leads to rapid depletion of short-lived mRNA transcripts such as MYC and MCL1 through CDK9 inhibition. Preclinical studies have identified BCL2 overexpression as a mechanism of resistance to CDK9 inhibition, and synergistic cytotoxicity has been shown with venetoclax (BCL2 inhibitor), steroids, and CDK9 inhibitors in DLBCL. Based on this preclinical data, we hypothesized that the combination of VIP152 with venetoclax and prednisone (VVIP) would result in acceptable safety and improved efficacy in R/R lymphoid malignancies. Methods: R/R non-GCB DLBCL, MYC-rearranged DLBCL/HGBCL-DH, and PTCL pts after 2 prior systemic therapies are eligible. In phase I, pts are treated at 4 dose levels (DL) of VIP152 and venetoclax in combination with fixed-dose prednisone to identify the recommended phase II dose (RP2D). VIP152 (15mg, 22.5mg, or 30mg) is given IV on days 2 and 9 in combination with venetoclax (600mg or 800mg) PO and prednisone 100 mg PO on days 1-10 every 21 days. Phase II expansion cohorts are included at the RP2D. VVIP x 12 cycles is given for pts who achieve complete response (CR), with a max of 24 cycles for pts not in CR. TLS, G-CSF, and PCP prophylaxis are given to all pts. Baseline CT, PET, and BM are performed with CT after cycles 1 and 2 then every 2 cycles and PET after cycles 6 and 12. CT is then performed q3m x 1y, q4m x 1y, q6m x 1y, then q12m x 2y post-therapy. Results: As of March 26, 2024, 5 pts were enrolled (3 at DL1 and 2 at DL2), including 3 PTCL, 1 non-GCB DLBCL, and 1 HGBCL-DH. Median (range) age was 56 (55-77) yrs, with stage 3/4 disease in 100%, >/=2 extranodal sites in 100%, IPI >/=3 in 80%, and elevated LDH in 40%. Median (range) prior therapies were 3 (3-6), with prior ASCT, allo-HSCT, and CAR-T in 1 (20%) pt each, and 80% of pts refractory per SCHOLAR-1 criteria. All 5 pts completed the dose-limiting toxicity (DLT) window with no DLTs observed. The most common adverse events (AEs) (% pts) included hypokalemia (100%), thrombocytopenia (80%), neutropenia (80%), and anemia (80%). Two (40%) pts had G3-4 neutropenia and 1 (20%) pt had G3 hypokalemia, with no other >/=G3 AEs observed. No dose reductions occurred and only 1 pt required a dose delay due to infection. Tumor reduction was observed in 80% (4/5) of pts, with an overall response rate of 60% (3/5). Partial responses include 1 HGBCL-DH pt refractory to both CAR-T and epcoritamab (71% tumor reduction) and 2 PTCL pts refractory to CHOP and targeted therapy (86% and 91% tumor reduction). Four pts have progressed, and no pts have died. Conclusions: Preliminary results show VVIP to be safe and well tolerated with no DLTs observed. Early activity is noted in pts with HGBCL-DH and PTCL. Enrollment continues to identify the RP2D and to further assess the safety and efficacy of VVIP in R/R aggressive lymphomas. Citation Format: Christopher Melani, Max Gordon, Rahul Lakhotia, Stefania Pittaluga, Jillian Simard, Jagan Muppidi, James D. Phelan, Svetlana Pack, Amynah Pradhan, Candis Morrison, Atekelt Tadese, Anna M. Juanitez, Amy J. Johnson, Melanie M. Frigault, Ahmed Hamdy, Mark Roschewski, Louis M. Staudt, Wyndham H. Wilson. Phase I/II study of VIP152 (enitociclib), venetoclax, and prednisone (VVIP) in relapsed/refractory (R/R) lymphoid malignancies [abstract]. In: Proceedings of the Fourth AACR International Meeting on Advances in Malignant Lymphoma: Maximizing the Basic-Translational Interface for Clinical Application; 2024 Jun 19-22; Philadelphia, PA. Philadelphia (PA): AACR; Blood Cancer Discov 2024;5(3_Suppl):Abstract nr PO-008.

Abstract CT144: Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma

Abstract Background: HMPL-523, a selective oral Syk inhibitor, demonstrated encouraging benefit-risk profile in 2 Phase 1 (P1) studies in relapsed/refractory (R/R) lymphoma patients (pts) in USA/Europe (NCT03779113) and China (NCT02857998). In the 16 response-evaluable pts in the dose-escalation portion (Part 1) of study NCT03779113, 4 responses were noted, including complete responses (CRs) in R/R hodgkin lymphoma (HL) and follicular lymphoma (FL) pts (Strati et al. Blood 2021). Here, we report the results from the dose expansion portion (Part 2) of the study NCT03779113. Methods: Safety and efficacy of HMPL-523, at the recommended phase 2 dose (RP2D) of 700 mg QD, was evaluated in lymphoma pts who have exhausted all approved therapy options. Treatment emergent adverse events (TEAEs) were assessed per NCI CTCAE v5.0. Responses were assessed by investigators at weeks 8, 16, and 24, and then every 12 weeks. Results: As of 14 July 2023, 47 pts were enrolled in the Part 2 [25 HL, 9 Peripheral T cell lymphoma (PTCL), 7 Chronic lymphocytic leukemia (CLL), 2 each of FL and Mantle cell lymphoma (MCL), and 1 each with Marginal zone lymphoma (MZL) and Waldenström's macroglobulinemia (WM)]. Median age was 57 (Range:21-93) years, 55% were males, 85% were Caucasian, 47% had ECOG status of 1, 81% were disease stage ≥3 and 17% had B-symptoms at study entry. Median prior lines of therapy was 4 (range 1 - 12); 86% of CLL pts were prior BTK treated and 88% of HL pts had both a PD-1 inhibitor and Brentuximab vedotin. With a median drug exposure of 2.9 months, the overall response rate (ORR) among 41 efficacy evaluable pts was 26.8% and disease control rate (DCR) was 65.9% [4 CR (9.8%), 7 PR (17.1%) and 16 SD (39.0%)]. The median time-to-response was 1.9 months. Among HL pts (N=24), ORR was 25.0% and DCR was 66.7% [2 CR (8.3%), 4 PR (16.7%) and 10 SD (41.7%)]. Among PTCL pts (N=7), ORR and DCR were 42.9% [2 CR (28.6%) and 1 PR (14.3%)]. The median duration of response (DOR) was not reached for HL pts and was 5.7 months (2.0 - NR) in PTCL. Two pts (one each with HL and PTCL) with disease control were taken off treatment to be consolidated with allogenic stem cell transplant. At cut-off, 1 pt each with CLL (N=5 ) and WM (N=1) demonstrated a PR. Serious TEAEs occurred in 18 pts (38.3%), of which 4 (8.5%) were considered treatment-related (TRAE). Grade≥3 TRAEs were noted in 15 pts (31.9%); the most common Grade≥3 TRAEs (>5%) were alanine aminotransferase increase 4 (8.5%) and febrile neutropenia 3 (6.4%). Dose interruption due to TEAEs occurred in 23 pts (48.9%) and dose reduction in 4 pts (8.5%). Two pts (4.3%), 1 each with TEAE of thrombocytopenia and pruritis had drug discontinued. Conclusion: HMPL-523 was well tolerated at the RP2D of 700 mg QD in R/R lymphoma pts. Encouraging proof of activity was demonstrated in heavily pre-treated HL and PTCL pts. Additional studies are needed to evaluate the value of SYK-inhibitor as either monotherapy or combination in these high unmet-need population. Citation Format: Paolo Strati, Eva Gonzalez-Barca, Daniel Morillo, Sairah Ahmed, Dominik Chraniuk, Sirpa Leppa, Fatima de la Cruz Vicente, Piotr Centkowski, Rathi N. Pillai, Shivani Nanda, Alisha Khullar, Marjo Hahka-Kemppinen, Vijayvel Jayaprakash, Giuseppe Gritti. Safety and efficacy of HMPL-523 (Syk inhibitor) in patients with relapsed or refractory lymphoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr CT144.

Azacitidine for Injection Combined with Chidamide in Relapsed/Refractory Peripheral T-Cell Lymphoma: A Phase I Study

Background: Peripheral T-cell lymphoma (PTCL) is a group of highly heterogeneous malignant tumors with poor prognosis, especially in patients with relapesd/refractory. The efficacy of traditional salvage chemotherapy in the treatment of Relapsed/Refractory (R/R) PTCL was poor, and the median OS and PFS after the first recurrence or progression were only 5.5 months and 3.1 months, respectively. There is an urgent need for more effective treatment regimens to improve the poor prognosis of these patients. Epigenetics, as a new discipline involved in gene expression regulation, provides a new approach for the occurrence, development mechanism research and clinical diagnosis and treatment of PTCL.This phase I study is a prospective, single center clinical study and designed to evaluate the safety, tolerability and efficacy of Azacitidine for injection combined with Chidamide in Relapsed/Refractory peripheral T-cell lymphoma. Methods: Eligible pts (18-75 years of age, ECOG PS 0-2) had histologically confirmed peripheral T-cell lymphoma that was either relapsed or refractory to at least 1 line of therapy. Considering that both Dose Group 2 (Azacitidine 75mg/m 2, Chidamide 20mg) and Group 3 (Azacitidine 50mg/m 2, Chidamide 30mg) adjust the dosage of a single drug based on Dose Group 1 (Azacitidine 50mg/m 2 ih d1-7, Chidamide 20mg po biw; 4 weeks/cycle), this study derived a “3+3” two-dimensional dose increasing design based on the classic “3+3” design, which allows two Dose Groups (Dose Group 2 and Group 3) to start ramp up trials simultaneously according to random principles. Enrollment in dose group 4(Azacitidine 75mg/m 2, Chidamide 30mg) can begin when either group 2 or 3 completes and no DLT occurs. The primary objectives of this study were to evaluate the safety and preliminary anti-tumor activity of Azacitidine for injection combined with Chidamide according to the Lugano 2014 criteria. Adverse events (AEs) were reported according to CTCAE v5.0. Results: Nineteen R/R PTCL pts (median age: 61 years, range: 52-71 years; male: 11 (57.9%) pts; ECOG PS=0: 10 (52.6%) pts) who was either relapsed or refractory to at least 1 line of therapy (median therapy lines:2) were enrolled. Among them, 11 pts were angioimmunoblastic T-cell lymphoma (AITL) and 8 pts were PTCL, NOS. 16 pts could evaluate the efficacy and safety. For 16 treated patients, treatment-related adverse events (TRAEs) of any grade occurred in 15 (93.7%) pts, ≥3 TRAEs occurred in 7 (43.8%) pts. The most frequent TRAEs (≥ 20%) were Pain at the injection site (n=12, 75.0%), Neutropenia (n=9, 56.3%), Erythema at the injection site (n=8, 50.0%), Nausea (n=7, 43.8%), Thrombocytopenia (n=6, 37.5%), Feeble (n=6, 37.5%), Anemia (n=5, 31.3%), Diarrhea (n=5, 31.3%), Neutropenia with fever (n=4, 25.0%). The most frequent grade ≥ 3 TRAEs (≥5%) was Neutropenia (n=3, 18.8%). 3 pts experienced TRAE leading to drug dosage adjustment. The recommended phase II dose (RP2D) was Azacitidine 75mg/m2, Chidamide 20mg (Dose Group 2). As of data cut-off date, 3 pts remained on Azacitidine for injection combined with Chidamide therapy. The objective response rate (ORR) and disease control rate (DCR) were 56.25% (9/16; 95% CI: 31.9-80.5) and 75% (12/16; 95% CI: 53.8-96.2), respectively. For AITL pts, the ORR was and DCR were 60% (6/10; 95% CI: 36.0-84.0) and 80% (8/10; 95% CI: 60.4-99.6), and 4 pts achieved CR. For all PTCL pts enrolled, Median PFS 6.45 months (95% CI: 3.97-12.7); Median OS 17.5 months (95% CI: 2.11-32.9). Conclusion: Azacitidine for injection combined with Chidamide showed a promising anti-tumor effectivity with a manageable safety profile in Relapsed/Refractory peripheral T-cell lymphoma patients, especially for AITL patients.

Phase 1 Pharmacodynamic and Pharmacokinetic Study of the Geranylgeranyltransferase I Inhibitor PTX-100 (GGTI-2418) in Patients with Advanced Malignancies

Introduction: The RAS superfamily of small GTPases mediate hallmarks of cancer cell proliferation, viability, migration, invasion and metastasis. Several GTPases such as RAL, RHO and RAC are required for RAS to induce malignant transformation. RAS post-translational modification (PTM) by farnesyltransferase (FT) as well as RAL, RHO and RAC PTM by geranylgeranyltransferase 1 (GGT-1) are critical for the membrane localization and oncogenicity of these GTPases. Mutations in HRAS, NRAS, KRAS and RHOA are prevalent in solid tumors as well as T-cell lymphomas (TCL) such as peripheral T-cell lymphoma (PTCL), angioimmunoblastic T-cell lymphoma (AITL), PTCL-not otherwise specified and cutaneous T-cell lymphoma (CTCL). PTX-100 is a small molecule inhibitor of GGT-1 that disrupts the oncogenic activity by inhibiting RAL, RHO and RAC PTM. Methods: This ongoing phase 1 study (NCT03900442) in 2 Australian sites, consists of a 3+3 dose escalation with an expansion phase. The aim is to evaluate the pharmacodynamic (PD), pharmacokinetics (PK), preliminary efficacy and safety of 500, 1000 and 2000 mg/m 2 PTX-100 in patients (pts) with advanced malignancies. PTX-100 is administered by IV infusion over 60 minutes days 1 to 5 of a 14 day cycle for 4 cycles. Disease response is assessed via CT, MRI or PET-CT or per SOC after 4 cycles. Pts with a complete response (CR), partial response (PR) or stable disease (SD) may be eligible for continued treatment with PTX 100, dosed in 21 day cycles with response assessment every 3 months. Results: The first pt was enrolled in October 2019 and enrollment is nearly completed in the expansion cohort. The data cutoff was 10 th July 2023. Ten pts were enrolled into Part 1 with 3 dosed at 500 mg/m 2, 3 at 1000 mg/m 2 and 4 at 2000 mg/m 2. The expansion cohort at 2000 mg/m 2 began in May 2022 and there have been 10/15 enrolled to date. Positive long-term responses (32 and 13.8 months) were observed for 2 TCL pts in Part 1 so the decision was made to enroll TCL pts into the expansion cohort. The median age was 67 years (44 to 81), the median number of prior lines was 3 (1-6). The TCL subtypes were PCTL NOS (n=6), AITL (n=3), and CTCL (n=5). Of the 14 enrolled TCL pts, 10 pts had response assessments after 4 cycles, with an overall response rate (ORR) of 40% (4pts), including 10% (1 pt) CR, 30% (3pts) PR. Two CTCL pts (20%) had durable SD >6 months, contributing to a 60% Disease Control Rate. The median Progression Free Survival (PFS) for all TCL pts was 5.3 mos, CTCL pts 13.6 mos and PTCL pts 2.5 mos. No responses were observed in the 5 solid tumor pts. There were 23 Grade ≥3 adverse events in 8 pts including laboratory neutropenia in 2 pts with 1 deemed possibly related. Neutrophil count decreased in 2 pts with 1 deemed possibly related and the platelet count decreased in 2 pts with 1 deemed possibly related. Grade 1-2 adverse events deemed possibly related included, nausea reported in 4 pts and diarrhea in 3 pts. For the PD studies, we determined the effects of PTX-100 on the geranylgeranylation (GG) of the small GTPase RAP1 in peripheral blood monocytes (PBMCs) isolated from pts on cycle 1, day 1 (prior to treatment) and subsequently on days 2, 3, 4, 5, and 8. PTX-100 inhibited GG of RAP1A as early as 1 day after treatment, and with the majority of the pts, the inhibition of RAP1A GG persisted three days after the last dose of PTX-100. Inhibition of RAP1 GG was observed with all doses including the lowest dose of 500 mg/m 2. PK analysis is underway at the time of abstract preparation and the PK parameters will be presented at the meeting. Conclusions: Preliminary data from this phase 1 dose escalation study of PTX-100 indicates promising safety profile in this difficult to treat pt population. PTX-100 demonstrated clinical activity in TCL with an ORR of 40%, and a median PFS for all TCL pts of 5.3 months. PD studies demonstrated that the GGT-1 target was engaged with sustained inhibition of RAP1 GG.

High Rates of Remission with the Initial Treatment of Oral Selinexor Plus CHOP for Newly Diagnosed Peripheral T-Cell Lymphoma (PTCL): Clinical Outcomes Analysis of a Multi-Center Phase II Study in China

CONCLUSIONS Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of aggressive lymphoproliferative disorders with dismal clinical outcomes. In China, PTCLs account for over 20% of non-Hodgkin lymphoma (NHL) cases, representing a relatively high incidence. Although CHOP-like regimens remain the standard frontline therapy, their efficacy is limited (Alain Mina, 2022). Previous studies have demonstrated high expression of XPO1 in T-NHL cell lines and potent anti-proliferative effects of the selective inhibitor selinexor at nanomolar concentrations (Abeykoon JP, 2019). Here, we report the safety and preliminary efficacy of combining selinexor with CHOP as first-line treatment in previously untreated PTCL patients (ChiCTR2200057942). In this open-label, multicentre, phase 2 trial, we enrolled patients with previously untreated peripheral T-cell lymphoma (PTCL). Participants received standard CHOP chemotherapy on day 1 of each cycle for 6 or 8 cycles, along with selinexor priming at 40 or 60 mg on days 1, 8 and 15. Patients achieving a complete response (CR) or partial response (PR) at the end of induction treatement (EOI), with or without autologous stem cell transplantation (ASCT), and then received maintenance treatment with selinexor (days 1, 8, 15 and 22 every 28 days) for up to 12 months. The primary endpoint was overall response rate (ORR) during induction, and secondary endpoints included CR rate, duration of response (DOR), PFS, OS and safety. Between Jul 1, 2022 and May 21, 2023, a total of 17 previously untreated PTCL pts were enrolled and received treatment at six centers, including seven with AITL (41.2%), six with PTCL-NOS (35.3%). The median age was 52 years (range 30-67), 11 (64.7%) had stage III/IV disease, with nine (52.9%) pts having IPI 2-5. As of July 10, 2023, with a median follow-up of 7.3 months (range 1.9-14.8 months), three pts discontinued treatment without efficacy evaluation (two pts due to bone marrow suppression, one pt due to COVID-19 infection), and one pt died due to disease progression. Among 12 pts evaluable for the primary endpoint, seven pts (58.3%) achieved CR, four pts (33.3%) had PR, one pt (9.1%) experienced progressive disease (PD). Based on the analysis of different subtype, the ORR and CR was 100% (5/5) and 80% (4/5) in AITL, 100% (4/4) and 25% (1/4) in PTCL-NOS. One ALK+ALCL and one PTCL-TFH patient achieved CR, while one SPTCL patient experienced progressive disease. Among the 12 pts who received the initial dose of 60mg, two pts did not complete the third course of treatment due to myelosuppression, and two pts reduced the dose to 40mg due to adverse reactions. Five pts in the 40mg group did not require dose reduction or withdrawal. The ORR was 87.5% (7/8) and the CR rate was 62.5% (5/8) in the 60 mg group. The ORR was 100% (4/4) and the CR rate was 50% (2/4) in the 40 mg group. Pts in the 40mg group had better tolerance and similar efficacy compared to those in the 60mg group. The most common (≥10%) Grade 3 or 4 treatment-related adverse events (AEs) were neutropenia (29%), thrombocytopenia (24%), and anemia (18%). No fatal AEs were reported at the end of follow-up, the median PFS and OS were not reached. The integration of Selinexor into the standard tri-weekly CHOP chemotherapy regime has shown a manageable safety profile along with encouraging anti-tumor activity in patients with previously untreated PTCL. The trial is currently ongoing, and this manuscript presents the preliminary findings.

Microenvironment Immune Cells in Bone Marrow and Lymph Node Measured By Flow Cytometry Have Prognostic Impact on Survival in Nodal Non-Hodgkin T-Cell Lymphoma

INTRODUCTION Outcomes in nodal peripheral T-cell lymphomas (PTCL) remain poor. Baseline clinical risk indexes have shown to be prognostic but do not imply a change in therapeutic strategies. Many publications have addressed the role of tumor microenvironment (TME) in lymphomagenesis and disease progression. Particularly in PTCL, TME was shown to be profoundly immunosuppressive. Therefore, TME variables that may aid to improve risk stratification and treatment management are urgently needed. AIMS To determine the prognostic impact on survival in PTCL of: -Conventional clinical risk parameters. -The percentage (%) of immune cells (IC) in the bone marrow (BM) and lymph node (LN) measured by flow cytometry (FC). METHODS We retrospectively collected information of patients (pts) with PTCL and available BM aspiration and/or LN FC data at diagnosis, treated at our center between 2012-2021. FC analysis was performed with 8-color panels according to Euroflow protocols. % of BM and LN IC by FC were compared to normal values determined by Matarraz et al. (Cytometry part B 2010) and Battaglia et al. (Immunology 2003), and analyzed in 3 categories: low, normal and high. Survival analysis was performed with Kaplan-Meier (variables compared with log-rank) and multivariate analysis with Cox regression. RESULTS We included 34 pts, with a median age of 59 years. LN and BM FC data were available in 26 and 28 pts, respectively. Table 1 shows baseline patient characteristics. 85.4% received induction with CHOP or CHOP-like regimens (with etoposide or brentuximab). Complete remission (CR) rate: 52.9%. 14 pts received treatment with new drugs (brentuximab, belinostat, romidepsin or lenalidomide) in the relapsed/refractory setting. Only 10/34 pts underwent consolidation with autologous stem cell transplant (ASCT). Chemorefractory disease was the reason to forgo ASCT in 50% (12/24) of the non- transplanted pts and 3/12 underwent consolidation with allogeneic stem cell transplant in 1st CR. Median progression-free (PFS) and overall survival (OS) for the whole cohort were 15 and 72 months (m) respectively, with a median follow up time of 41.2 m. Pts with ALK+ anaplastic T-cell lymphoma had improved PFS (median of 67 vs 8, 9 and 5.6 m for ALK- anaplastic, PTCL NOS and angioimmunoblastic lymphoma, respectively). Regarding prognostic indexes, PIT score was able to discriminate subgroups with different PFS (median of 15.3 m for pts with at least 1 risk factor vs not reached and PFS rate of 100% in those without, p: 0.012). Other clinical parameters such as BM and CNS compromise were associated with inferior PFS (median of 49.7 in BM not involved vs 6.7 m, p: 0.006; and median of 19.2 in pts without CNS compromise vs 3.45 m, p<0.001, respectively). The only TME variable with prognostic impact on PFS was LN CD4/CD8 ratio (median of 30.8, 5.7 and 2.7 m for the low, normal and high subgroups, respectively, p: 0.045). On multivariate analysis, absence of CNS involvement was the only independent predictor of PFS (HR: 0.009, CI95%: 0-0.235, p: 0.005). The only clinical parameter with prognostic impact on OS was performance status (PS) (median of 72.2 vs 0.2 m in pts with PS≤2 and ≥3, respectively). Regarding TME variables, low BM neutrophil % was associated with improved OS with median not reached vs 27.8 m in pts with normal and high values, p: 0.039). BM neutrophil % did not statistically differ in involved vs not involved BM. Interestingly, only 1/9 pts with normal-high BM neutrophil % with relapse disease could achieve CR with 2nd line treatment vs 6/10 in the low % subgroup (likelihood ratio 5.26, p: 0.022). In contrast, no association was found between peripheral blood neutrophil counts and survival in our cohort. On multivariate analysis, only low BM neutrophil % remained as an independent predictor of OS with a HR of 0.12 (CI95%: 0.015-0.96), p: 0.046. CONCLUSIONS Both clinical risk factors and TME variables showed prognostic impact in our cohort of PTCL pts. A high LN CD4/CD8 ratio and a normal-high BM neutrophil % were associated with decreased PFS and OS, respectively. These TME variables are widely accessible and could help refine prediction of prognosis in pts with nodal PTCL. Manipulating TME with therapeutic strategies that promote effector T-cell function and/or suppress the pro-malignant cell effects of myeloid derived cells may improve patient outcomes in this poor risk disease. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

647TiP A multi-center phase Ib trial evaluating the safety and efficacy of lacutamab in patients with relapsed/refractory peripheral T-cell lymphoma that express KIR3DL2

Peripheral T-cell Lymphoma (PTCL) is a heterogeneous group of mature T-cell lymphomas with adverse outcomes. The majority of patients (pts) with PTCL relapse despite responding to first line systemic therapy. Current treatment options for relapsing PTCL are limited with no generally accepted standard of care to treat these pts. KIR3DL2 is a killer immunoglobulin-like receptor that is expressed across different subtypes of T-cell lymphomas including PTCL. Approximately 40% of PTCL pts expresses KIR3DL2.

Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) with Intention for Curative Therapy Incorporating High Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT)

Outcome of Relapsed and Refractory Peripheral T-Cell Lymphoma (PTCL) with Intention for Curative Therapy Incorporating High Dose Chemotherapy and Hematopoietic Stem Cell Transplant (HDC/SCT)

Next-Generation Sequencing Based Monitoring of Circulating-Tumor DNA in Untreated Peripheral T-Cell Lymphoma

Background: Peripheral T-cell lymphomas (PTCLs) are aggressive lymphomas with a wide range of clinical outcomes. Overall prognosis is worse for PTCL than B-cell lymphomas, but pts who achieve remission can be cured. After initial therapy, controversy exists regarding consolidation with autologous stem cell transplant, and clinical decisions are largely empirical. Circulating-tumor DNA (ctDNA) is emerging as a promising non-invasive biomarker that may aid clinical decision-making. Quantitative baseline levels of ctDNA and kinetics of ctDNA clearance during therapy may provide prognostic information. Further, novel methods that detect disease relapse prior to imaging may improve outcomes. We studied a high-throughput DNA sequencing method of detecting T-cell receptor (TCR) β and γ gene sequences in serum with a sensitivity of 1 lymphoma molecule per million leukocytes. Using this platform, we determined the predictive ability of monitoring ctDNA in pts undergoing frontline therapy for PTCL.Methods: All pts had PTCL undergoing frontline EPOCH-based chemotherapy between May 1993 through December 2015. Pre-treatment FFPE biopsy samples and/or baseline serum samples were sent for VDJ amplification and TCR sequencing calibration. High-throughput TCR sequencing of the CDR3s of TCRβ/TCRγ genes was employed to provide a comprehensive and quantitative analysis of distinct T-cell clones within each sample, the relative frequency of each clone, and the exact unique nucleotide sequences of each clone's CDR3 regions. Pts with a calibrating TCRβ/TCRγ sequence had all available serum samples sent for identification and quantification. Prospectively collected serum sample time points included baseline, start of each cycle, and each follow-up visit until disease progression. Clinic visits after therapy included paired contrast CT scans performed at 3, 4, 6, 12 and 12 mos. intervals for the first 5 years, respectively. All analyses for ctDNA were performed blinded to clinical outcomes.Results: Fifty PTCL pts had a pre-treatment FFPE or serum sample available for calibration. Nineteen of 23 (83%) pts with pre-treatment FFPE had a calibrating rearrangement; Fourteen of 27 (52%) pts with only pre-treatment serum available had a calibrating rearrangement; 1 pt who did not calibrate on FFPE had a dominant sequence identified in serum. Overall, tumor-specific clonotypes were identified in 34 (68%) of 50 pts tested. Ten of 18 (56%) pts with both FFPE and serum available had dominant clones in both compartments. Of the 44 calibrating pre-treatment samples, 1 calibrated for TCRβ only, 15 for TCRγ only, and 28 for both loci. Pt characteristics shown in Table 1. Of 34 study pts, 20 (59%) progressed and 14 (41%) were non-progressors. Quantitative baseline ctDNA levels were significantly higher in pts with stage IV disease compared to stages I-III (p=0.014) but did not correlate with LDH levels (p=0.53).We analyzed the predictive ability of ctDNA as a measure of minimal residual disease (MRD) within 1 month of completing therapy in 28 pts. We compared pts who became MRD- to those who remained MRD+ and identified a trend towards improved PFS in those who became MRD- (median, NR vs. 208 days, p=0.07) (Figure 1). In 20 pts who achieved remission, we studied the use of ctDNA monitoring as a surveillance tool. Of the 10 pts who progressed after remission, ctDNA was detected prior to clinical relapse in 6 cases with a median lead-time of 13.2 mos. (range, 2.7 to 88.5) and 4 with detectable ctDNA > 12 mos. prior to clinical relapse. Four pts progressed without detectable ctDNA prior to clinical relapse. Interestingly, of the 10 non-progressors followed in surveillance, 5 pts developed low-level ctDNA positivity without clinical progression. Results of interim ctDNA kinetics and TCRβ testing is ongoing and will be presented at the meeting.Conclusions: Next-generation based sequencing of the TCR can identify tumor-specific clonotypic sequences in the majority of pts from both FFPE and serum. As a marker of MRD, monitoring TCR sequences in serum may identify pts who do not benefit from treatment intensification, but further studies are needed. Surveillance monitoring of ctDNA in serum identifies TCR sequences months before clinical progression but not all pts with clonotypic sequences progressed clinically in our series. Further studies are needed to investigate surveillance monitoring methods and optimize clinical utility. [Display omitted] DisclosuresJacob:Adaptive Biotechnologies: Employment, Equity Ownership. Chan:Adaptive Biotechnologies: Employment. Vignali:Adaptive Biotechnologies: Employment.

CHOP Chemotherapy Plus Campath-1H (CHOP-C) as First Line Treatment in Patients with Peripheral T-Cell Lymphoma (PTCL).

Malignant T-cells show very high CD 52 expression, and promising results have been obtained in T-PLL and in Sezary patients (pts) treated with alentuzumab (Campath ®). Here we report the preliminary results of standard CHOP therapy plus Campath (CHOP-C) in untreated PTCL pts. Starting from January 2003, 20 consecutive PTCL pts were treated by CHOP for 8 courses, preceded on day -1 by Campath 30 mg. s.c. The diagnosis was PTCL-U in 13 pts, AILD-T in 5, and ALCL Alk- in 2. Clinical characteristics of the 20 pts: mean age 53.3 years (28–69), stage III-IV in 18, bulky in 2, B-symptoms in 9, high LDH in 11, bone marrow attainment in 8, aaIPI 2–3 in 10 pts. 15/20 pts are valuable for the analysis. After a median follow-up of 253 days (105–773), 10/15 pts are still alive and 5/15 have died of lymphoma. 8/15 achieved CR 1 PR and 1 MR; 5 pts showed progression; 3/5 pts in Pro,1 pt in RP, and 1 pt in MR have died of lymphoma. 2 pts. relapsed +62 and +119 days after CR. The median OS and DFS were 461 and 264 days, respectively (Fig. 1). No toxic death was recorded. WHO grade 4 neutropenia was seen in 38/90 courses (42%), grade 4 thrombocytopenia in 4/90 (4%), CMV reactivation in 15/90 (17%), local erythema in 2/90, mild fever in 5/90. Major infections were J-C virus reactivation in 1 pt, pulmonary Invasive Aspergillosis in 1, sepsis in 1, pneumonia in 1. The feasibility of CHOP-C in PTCL pts aged up to 70 years has been proven, and the toxicity acceptable; however the efficacy of this regimen should be confirmed on a larger cohort of pts. [Display omitted]

Nivolumab in Combination with Gemcitabine and Oxaliplatin (GemOx) in Relapse/Refractory T-Cell Lymphoma: Preliminary Results of the Experimental Arm of the Niveau Trial

Nivolumab in Combination with Gemcitabine and Oxaliplatin (GemOx) in Relapse/Refractory T-Cell Lymphoma: Preliminary Results of the Experimental Arm of the Niveau Trial

Proof of Concept for Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study

Proof of Concept for Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study

A Phase 1b/2 Study of Chidamide Combined with CHOP in Previously Untreated Patients with Peripheral T-Cell Lymphoma (PTCL)

Background: CHOP is widely used for untreated PTCL patients (pts), although it has limited efficacy. Chidamide is an oral benzamide class of HDAC inhibitor with subtype specificity in inhibition of HDAC 1, 2, 3 and 10, approved in China for relapsed or refractory PTCL at 30 mg twice per week. A Phase 1b/2 study (NCT02809573) is evaluating the safety, pharmacokinetics and preliminary efficacy of chidamide in combination with CHOP (CHOP-chidamide) in the first-line treatment for PTCL pts. Results from the study are reported. Methods: This open-label, multicenter study enrolled pts (18~65 years) with previously untreated PTCL. Pts received one dose chidamide as the run-in treatment, and 4 days later the induction treatment of CHOP (6 cycles [each 21 days]) with chidamide on days 1, 4, 8 and 11. Pts who achieved a complete response or unconfirmed complete response (CR/CRu) at end of induction (EOI) received consolidation treatment with chidamide on days 1, 4, 8 and 11 every 21 days for 24 months maximum. A 3+3 design was employed in the chidamide dose-escalation stage with the starting dose at 20 mg. The first 21-day treatment cycle was a dose-limiting toxicities (DLTs) observation period (phase 1b; safety and pharmacokinetics), followed by a phase 2 cohort expansion stage. For pharmacokinetic (PK) evaluation, blood samples were collected at pre-dose and 1,2,4,8,12,24,48 and 72 h after the first dose of chidamide in the run-in period and in the first cycle of CHOP-chidamide. Primary endpoints were safety and tolerability of chidamide in combination with CHOP assessed by the incidence of adverse events (AEs) in both phase 1b and 2 and as DLTs during phase 1b. Secondary endpoint was efficacy as determined by the investigator. Results: Between Nov 15, 2016 and Aug 29, 2018, 30 pts were enrolled and received treatment. Pt demographics and disease characteristics are shown in Table 1. Fifteen pts were in the dose-escalation cohort and 15 in the expansion cohort (Table 2).One DLT with grade (Gr) 3 febrile neutropenia occurred in the first three enrolled pts in the 20 mg group, and 1 DLT with Gr 3 vascular access complication in the 35 mg group. Also, in the 35 mg group, 1 pt occurred Gr 2 neutropenia with sustained temperature &gt;38℃, and the dose-escalation was stopped at this dose level. Serious AEs occurred in 7 (23.3%) of 30 pts during the combination treatment, including neutropenia (3 [10%]), leukopenia (2 [6.7%]), interstitial pneumonia (2 [6.7%]), thrombocytopenia (1 [3.3%]), febrile neutropenia (1 [3.3%]), pneumonia (1 [3.3%]), hyponatremia (1 [3.3%]), appendicitis (1 [3.3%]) and vascular access complication (1 [3.3%]). The most common (≥10%) Gr 3 or 4 treatment-related AEs were leukopenia (90%), neutropenia (83.3%), lymphocytopenia (40%), vomiting (13.3%), thrombocytopenia (10%) and febrile neutropenia (10%).No fatal AEs were reported. There were no apparently remarkable differences in frequency and intensity of AEs in pts between chidamide dose groups of 20 mg, 25 mg and 30 mg. Among 28 pts evaluable for response, 13 pts (46.4%) had a CR/CRu, 10 pts (35.7%) had a partial response, 1 pt (3.6%) had stable disease, and 4 pts (14.3%) had progressive disease (Table 3). Fifteen pts entered the consolidation phase (13 pts with CR/CRu, 1 pt with PR, 1 pt not evaluable), and the median treatment time was 189 days (35, 483). There was no AE leading to consolidation discontinuation. Progression-free survival (PFS) and overall survival (OS) at 12 months were 54.3% and 100%. At the data cutoff (Jan 8, 2019), median PFS was 14 months and median OS was not achieved. A total of 16 pts were evaluated in the PK analysis. Over the dose range from 20 to 35 mg, a linear and dose-dependent PK profile of chidamide was characterized in both monotherapy and combination treatment. In addition, co-administration of chidamide and CHOP did not significantly affect the plasma exposure of chidamide, with geometric mean ratio (combination vs monotherapy) values for Cmax and AUC were 97.6% (73.6%, 129.2%) and 97.9% (78.4%, 122.2%), respectively. Conclusions: The combination of 20mg to 30 mg chidamide to a standard 3-week cycle of CHOP chemotherapy showed a manageable safety profile and favourable antitumour activity in pts with previously untreated PTCL. This combination could be further explored in comparison to CHOP alone in a randomized trial. CHOP-chidamide did not significantly alter the chidamide pharmacokinetics. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: Chidamideis an oral benzamide class of HDAC inhibitor with subtype specificity in inhibition of HDAC1, 2, 3 and 10, approved in China for relapsed or refractory PTCL at 30 mg twice per week. This Phase 1b/2 study (NCT02809573) is evaluating the safety, pharmacokinetics and preliminary efficacy of chidamide in previously untreated PTCL patients.

Analysis of a Safety Run-in Cohort from Niveau, a Phase 3 Study for Patients with Aggressive Non-Hodgkin Lymphoma in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx) Plus Rituximab (R) in Case of B-Cell Lymphoma

Analysis of a Safety Run-in Cohort from Niveau, a Phase 3 Study for Patients with Aggressive Non-Hodgkin Lymphoma in First Relapse or Progression Not Eligible for High-Dose Chemotherapy (HDT), Testing Nivolumab in Combination with Gemcitabine, Oxaliplatin (GemOx) Plus Rituximab (R) in Case of B-Cell Lymphoma

S869 TIPIFARNIB IN RELAPSED OR REFRACTORY ANGIOIMMUNOBLASTIC T‐CELL LYMPHOMA (AITL) AND CXCL12+ PERIPHERAL T‐CELL LYMPHOMA (PTCL): PRELIMINARY RESULTS FROM AN OPEN‐LABEL, PHASE 2 STUDY

Background:Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). FT catalyzes post‐translational attachment of farnesyl groups required for localization of signaling molecules to the inner cell membrane. CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors.Aims:Herein we report preliminary efficacy, safety and biomarker data from a Phase 2 study of tipifarnib in angioimmunoblastic T‐cell lymphoma (AITL) and CXCL12+ peripheral T‐cell lymphoma (PTCL) patients (pts).Methods:This Phase 2 study (NCT02464228) is a multi‐institutional, single‐arm, open‐label trial initially designed as a two‐stage (11+7 pts) design to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL age &gt;/ = 18 years and a performance status of 0–2. Based on initial findings, the study was amended to include a cohort of AITL (n = 12) and PTCL (n = 12) pts with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg administered orally twice daily on days 1–21 of 28‐day treatment cycles until progression of disease (PD) or unacceptable toxicity. The primary endpoint of the study is overall response rate (ORR). Ancillary studies are also ongoing to investigate the prognostic value of CXCL12 expression in pts who received tipifarnib and standard of care treatment.Results:As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL‐NOS, 1 ALK‐ ALCL, 1 gamma‐delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least one treatment‐emergent adverse event (TEAE); 39 (90%) had at least 1 study drug‐related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug‐related TEAEs of Grade ≥3 occurring in 10% or more of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n = 3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre‐treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was also retrospectively investigated in 73 pts who received standard of care therapy (AITL N = 50, PTCL NOS = 23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR = 1.8, p = 0.09) was observed using the high CXCL12 subset using the cut‐off point that predicted clinical benefit under tipifarnib therapy. Fifty percent of AITL and 35% of non‐AITL samples overexpressed CXCL12.Summary/Conclusion:Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues.

TIPIFARNIB IN RELAPSED OR REFRACTORY ANGIOIMMUNOBLASTIC T‐CELL LYMPHOMA (AITL) AND CXCL12+ PERIPHERAL T‐CELL LYMPHOMA (PTCL): PRELIMINARY RESULTS FROM A PHASE 2 STUDY

Introduction: Tipifarnib is a potent and selective inhibitor of the enzyme farnesyltransferase (FT). CXCL12 is a chemokine that is essential for T cell homing to lymphoid organs and the bone marrow, and for the maintenance of immune cell progenitors. Tipifarnib has previously been shown to modulate the CXCL12 pathway and to drive clinical activity in CXCL12-expressing T cell lymphomas. Methods: This Phase 2 study (NCT02464228) is a multi-institutional, single-arm, open-label trial initially designed as a two-stage (11+7 pts) study to determine the efficacy, safety and biomarkers of tipifarnib in pts with relapsed/refractory (R/R) PTCL. Based on initial findings, the study was amended to include a cohort of AITL (n=12) and PTCL (n=12) with the CXCL12 rs2839695 A/A genotype (CXCL12+ cohort). Pts received tipifarnib 300 mg orally twice daily on days 1-21 of 28-day treatment cycles. The primary endpoint is overall response rate (ORR). Ancillary studies are ongoing to investigate the prognostic value of CXCL12 expression in pts who received standard of care treatment. Results: As of 20 February 2019, 43 PTCL pts (20 AITL, 21 PTCL-NOS, 1 ALK- ALCL, 1 gamma-delta TCL) have been treated with tipifarnib, 19 pts in stages 1 and 2, and 24 pts in the ongoing AITL histology and CXCL12 cohort. Median number of prior treatment regimens was 3; 19 pts had a prior stem cell transplant. All pts had at least 1 treatment-emergent adverse event (TEAE); 39 (90%) had at least 1 drug-related TEAE and 12 (28%) at least 1 drug related SAE. The most frequently observed drug-related TEAEs of Grade >3 occurring in >10% of pts were blood and lymphatic system disorders, including neutropenia (44%), thrombocytopenia (37%), leukopenia (28%), anemia (21%) and febrile neutropenia (21%). There have been 14 deaths on study; none were related to study drug. Of 18 evaluable pts enrolled in Stages 1 and 2 of the trial, 3 partial responses (PR), 2 of them in pts with AITL histology, and 4 best responses of stable disease (SD) were observed. In the AITL cohort (11 evaluable pts), a 45% ORR and 73% clinical benefit rate (CBR; 3 CR, 2 PR and 3 SD) was observed. In the CXCL12+ cohort (n=3 evaluable pts), 1 PR and 2 SD have been observed, with 4 pts pending cycle 2 response evaluation. CXCL12 expression correlated with favorable outcome to tipifarnib treatment. Pre-treatment high CXCL12 expression had 90% sensitivity and 93% specificity to identify pts who experienced CR/PR/SD on study in a preliminary analysis of 24 pts. The prognosis of CXCL12 was retrospectively investigated in 73 pts who received standard of care therapy (AITL N=50, PTCL NOS=23). A trend for poor prognosis (22 vs 40 months median OS from diagnosis, HR=1.8, p=0.09) was observed in the high CXCL12 subset using the cut-off point that predicted clinical benefit under tipifarnib therapy. Conclusion: Preliminary activity of tipifarnib was observed in PTCL pts, particularly in those with tumors of AITL histology and high CXCL12 expression and enrollment in the CXCL12+ cohort continues. Keywords: angioimmunoblastic T-cell lymphoma (AITL); peripheral T-cell lymphomas (PTCL). Disclosures: Witzig, T: Research Funding: Study Investigator for KO-TIP-002 (Kura Oncology). Sokol, L: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Kim, W: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Foss, F: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Jacobsen, E: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). de la Cruz Vincente, F: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Caballero, D: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Advani, R: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Roncero Vidal, J: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Marin-Niebla, A: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Rodriguez Izquierdo, A: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). de Ona Navarrete, R: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Terol, M: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Domingo-Domenech, E: Research Funding: Investigator for KO-TIP-002 (Kura Oncology Sponsored Clinical Study). Rodriguez, M: Research Funding: Kura Oncology. Piris, M: Research Funding: Kura Oncology. Bolognese, J: Consultant Advisory Role: Kura Oncology. Janes, M: Consultant Advisory Role: Kura Oncology. Burrows, F: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kessler, L: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Mishra, V: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Curry, R: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Kurman, M: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Scholz, C: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology. Gualberto, A: Employment Leadership Position: Kura Oncology; Stock Ownership: Kura Oncology.

PS1073 PRELIMINARY RESULTS OF ASTX660, A NOVEL NON‐PEPTIDOMIMETIC CIAP1/2 AND XIAP ANTAGONIST, IN RELAPSED/REFRACTORY PERIPHERAL T‐CELL LYMPHOMA AND CUTANEOUS T CELL LYMPHOMA

Background:ASTX660 is an oral, novel non‐peptidomimetic, small‐molecule antagonist of cellular/X‐linked inhibitors of apoptosis proteins (cIAP1/2 and XIAP). ASTX660 is currently being evaluated in a first‐in‐human phase 1‐2 study in patients (pts) with advanced solid tumors and lymphoma (ClinicalTrials.gov NCT02503423). In the phase 1 part of the study, the recommended phase 2 dose (RP2D) was identified with a favorable safety profile and initial evidence of clinical activity in a pt with mycoses fungoides (Mita et al, presented at the AACR‐NCI‐EORTC Conference 2017, abs #A091).Aims:Herein, we report preliminary efficacy and safety results from the ongoing relapsed/refractory (r/r) peripheral T‐cell lymphoma (PTCL) and cutaneous T‐cell lymphoma (CTCL) Phase 2 cohorts.Methods:Pts receive treatment with ASXT660 at the RP2D 180 mg/day on Days 1 to 7, and 15 to 22 in a 28‐day cycle. The primary endpoint is response rate as assessed by the investigator according to either the Lugano criteria (PTCL) or Global Assessment (CTCL). Adverse events (AEs) are assessed per CTCAE V4.03.Results:As of 15 January 2019, 16 PTCL pts and 13 CTCL pts have received ASTX660. Pt characteristics: median (range) age: PTCL: 59 (39–81) years and CTCL: 57 (23–75) years; median number of prior therapies: PTCL: 3 (1–7) and CTCL: 3 (1–9). In the PTCL cohort the ORR is 28% (4/14); 2 pts have yet to reach their first assessment. Three responding pts remain on study drug for 7–10 months. Responses have been observed in pts with AITL and PTCL‐NOS. In the CTCL cohort the global response is 25% (3/12); 1 pt has yet to reach their first assessment. Two responding pts remain on study drug for 4–6 months. Responses have been seen in pts with large cell transformation, sezary syndrome and visceral metastases. Among all pts, the most common related AEs of any grade (≥ 15%) were lipase elevation (38%), amylase elevation (34%), ALT elevation (28%), elevation (24%) and rash (24%). Related AEs ≥ Grade 3 occurring in ≥3 pts were rash (n = 5) and lipase elevation (n = 4). Accrual continues; updated efficacy and safety results will be presented at the meeting.Summary/Conclusion:In the ongoing Phase 2 cohorts ASTX660 has shown activity against PTCL and CTCL with manageable safety profile. These early data support continued development of ASXT660 for the treatment of r/r PTCL and CTCL. Correlative studies are aimed at identifying predictors of response.

Response to A+CHP by CD30 expression in the ECHELON-2 trial.

7538 Background: Brentuximab vedotin (BV) is an antibody-drug conjugate that targets CD30. The ECHELON-2 (E-2) study demonstrated significantly longer progression-free and overall survival with BV plus cyclophosphamide, doxorubicin, and prednisone (A+CHP) versus CHOP in frontline treatment of patients (pts) with CD30+ peripheral T-cell lymphoma (PTCL). Complete remission (CR) rate (A+CHP 68%; CHOP 56%) and objective response rate (ORR) (A+CHP 83%; CHOP 72%) were also significantly increased. Expression of CD30 is universal in systemic anaplastic large-cell lymphoma (sALCL) but variable among non-sALCL subtypes. As ORR is a direct measure of antitumor activity, we examined response to A+CHP by CD30 expression. Methods: Pts with CD30+ (≥10% by local review) PTCL were included in E-2. Eligible histologies included ALK+ sALCL (IPI ≥2), ALK− sALCL, PTCL-not otherwise specified (PTCL-NOS), angioimmunoblastic T-cell lymphoma (AITL), adult T-cell leukemia/lymphoma, enteropathy-associated T-cell lymphoma, and hepatosplenic T-cell lymphoma. We analyzed the relationship between CD30 expression (IHC Ber H2 antibody) above and below the median (median CD30=18% PTCL-NOS; 25% AITL) and CR rate, ORR, and duration of CR (DOCR) in pts with AITL and PTCL-NOS treated with A+CHP. Results: Most (26/29, 90%) AITL pts had CD30 expression between 10% and 30%. PTCL-NOS pts were more evenly distributed across levels of CD30 expression ranging from 10% to 100%. CD30 levels were neither predictive of response (Table) nor significantly associated with DOCR in pts with AITL (P=0.30) or PTCL-NOS (P=0.90) (log-rank test). Response by CD30 expression. Clinical trial information: NCT01777152. Conclusions: CD30 expression above vs below median (or at 10%) did not predict response to A+CHP in E-2 non-ALCL subtypes, as responses were seen across CD30 levels. This may be due to intra- and inter-tumoral heterogeneity of CD30 expression, limitations of IHC, the nature of CD30 on the cell surface, and multiple mechanisms of action of BV. Further evaluation of the expression-response relationship in PTCL pts with CD30 &lt;10% is warranted.[Table: see text]

Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study

Tipifarnib in Relapsed or Refractory Angioimmunoblastic T-Cell Lymphoma (AITL) and CXCL12+ Peripheral T-Cell Lymphoma (PTCL): Preliminary Results from an Open-Label, Phase 2 Study

Preliminary Results of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Two Phase IIa Dose Expansion Cohorts in Relapsed/Refractory TP53 Wild-Type Peripheral T-Cell Lymphoma

Preliminary Results of the Stapled Peptide ALRN-6924, a Dual Inhibitor of MDMX and MDM2, in Two Phase IIa Dose Expansion Cohorts in Relapsed/Refractory TP53 Wild-Type Peripheral T-Cell Lymphoma