scholarly journals Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination With Fludarabine and Cytarabine, in Pediatric Relapsed or Refractory Acute Leukemia

2016 ◽  
Vol 34 (34) ◽  
pp. 4094-4101 ◽  
Author(s):  
Thomas B. Alexander ◽  
Norman J. Lacayo ◽  
John K. Choi ◽  
Raul C. Ribeiro ◽  
Ching-Hon Pui ◽  
...  
Keyword(s):  
Acute Leukemia ◽  
Nuclear Export ◽  
Complete Response ◽  
Selective Inhibitor ◽  
Pharmacokinetic Parameters ◽  
Inhibition Response ◽  
Nonhematologic Toxicity ◽  
Common Grade ◽  
Heavily Pretreated ◽  
Grade 3

Purpose To characterize the toxicity, pharmacokinetics, and pharmacodynamics of selinexor, a selective inhibitor of nuclear export, when combined with fludarabine and cytarabine, in children with relapsed or refractory leukemia. Patients and Methods Eighteen patients with relapsed or refractory acute leukemia were enrolled in the SELHEM (Selinexor With Fludarabine and Cytarabine for Treatment of Refractory or Relapsed Leukemia or Myelodysplastic Syndrome) clinical trial (NCT02212561). Selinexor, initially at 30 mg/m2 per dose, was given orally on days 1, 3, 8, 10, 22, and 24 and was escalated according to a rolling-six design. Fludarabine 30 mg/m2 and cytarabine 2 g/m2 were administered on days 15 to 19. Pharmacokinetic and pharmacodynamic studies were performed on days 1 and 22. Response evaluations were performed on day 15 and at the completion of course 1. Results Among the 17 patients who were evaluable for toxicity, three were treated at 30 mg/m2, three at 40 mg/m2, six at 55 mg/m2, and five at 70 mg/m2. The most common grade 3 nonhematologic toxicity was asymptomatic hyponatremia. Two patients who were treated at 70 mg/m2 experienced reversible cerebellar toxicity, thereby defining the dose-limiting toxicity. Pharmacokinetic parameters demonstrated that plasma exposure was dose proportional. Fifteen of 16 patients demonstrated at least a twofold increase of XPO1 mRNA, indicating inhibition of the XPO1 protein. In this group of heavily pretreated, relapsed, and refractory patients, seven of 15 evaluable patients (47%) achieved complete response or complete response with incomplete count recovery. Conclusion Selinexor, in combination with fludarabine and cytarabine, is tolerable at doses up to 55 mg/m2 in pediatric patients with relapsed or refractory leukemia. All patients who received selinexor at ≥ 40 mg/m2 demonstrated XPO1 target inhibition. Response rates are promising and will be further explored in a phase II trial.

Phase I evaluation of AZD2171, a highly potent and selective inhibitor of VEGFR signaling, in combination with selected chemotherapy regimens in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 3034-3034 ◽  
Author(s):  
P. M. Lorusso ◽  
E. Heath ◽  
M. Valdivieso ◽  
M. Pilat ◽  
A. Wozniak ◽  
...  
Keyword(s):  
Phase I ◽  
Solid Tumors ◽  
Growth Factor Receptor ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Primary Objective ◽  
Selective Inhibitor ◽  
Minor Response ◽  
Heavily Pretreated ◽  
Grade 3

3034 Background: AZD2171 is an oral, potent, selective inhibitor of vascular endothelial growth factor receptor (VEGFR). Trials have demonstrated that inhibition of the VEGF pathway, in combination with certain chemotherapy, provides benefit to patients with a broad range of solid tumors. Methods: This Phase I trial was conducted in heavily pretreated solid tumor patients. In a single protocol, escalating doses of AZD2171 were evaluated (20, 30 and 45 mg) in combination with four separate chemotherapy regimens: mFOLFOX6 (oxaliplatin 85 mg/m2; 5-FU 400 mg/m2; leucovorin 400 mg/m2 q2 weeks; Arm 1); irinotecan 300 mg/m2 q3 week (Arm 2); docetaxel 75 mg/m2 (Arm 3) and pemetrexed 500 mg/m2 (Arm 4). The primary objective was to evaluate safety and tolerability of the combinations and secondary objective to evaluate pharmacokinetic (PK) interaction and clinical efficacy. Maximum tolerated dose (MTD) toxicity was defined through two cycles. Results: 46 patients have been enrolled: 28/35 evaluable for efficacy/toxicity. The MTD has been reached in two arms: Arm 2 - 20 mg AZD2171 and Arm 4 - 30 mg AZD2171. Arm 3 enrollment continues at 45 mg AZD2171. Two dose-limiting toxicities (DLTs) were observed in eight patients at 30 mg AZD2171 in Arm 1. Enrollment of an additional cohort of less heavily pre-treated patients is ongoing to determine the tolerability of 30 mg AZD2171 with FOLFOX. DLTs have included grade 3 fatigue in Arms 1, 2 & 4; grade 3 diarrhea in Arm 1; grade 3 hand-foot syndrome & grade 4 neutropenic fever in Arm 2; and grade 3 hypertension in Arm 4. AZD2171 did not appear to have a major effect on the PK profile of any chemotherapy regimen tested. Steady-state values are comparable with AZD2171 monotherapy. There have been 13 responses (minor response, n=5; partial response, n=6; complete response, n=2; stable disease ≥ 4 cycles, n=6) in heavily pretreated patients, some having demonstrated resistance to identical chemotherapies. Duration of response has been impressive (4-22+ cycles). Conclusions: AZD2171 combinations have been well tolerated with expected toxicities and encouraging responses. [Table: see text]

scholarly journals Selective Inhibition of Nuclear Export With Oral Selinexor for Treatment of Relapsed or Refractory Multiple Myeloma

2018 ◽  
Vol 36 (9) ◽  
pp. 859-866 ◽  
Author(s):  
Dan T. Vogl ◽  
David Dingli ◽  
Robert Frank Cornell ◽  
Carol Ann Huff ◽  
Sundar Jagannath ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Nuclear Export ◽  
Selective Inhibition ◽  
Refractory Disease ◽  
Nuclear Retention ◽  
Common Grade ◽  
Duration Of Response ◽  
Heavily Pretreated ◽  
Grade 3

Purpose Selinexor, a first-in-class, oral, selective exportin 1 (XPO1) inhibitor, induces apoptosis in cancer cells through nuclear retention of tumor suppressor proteins and the glucocorticoid receptor, along with inhibition of translation of oncoprotein mRNAs. We studied selinexor in combination with low-dose dexamethasone in patients with multiple myeloma refractory to the most active available agents. Patients and Methods This phase II trial evaluated selinexor 80 mg and dexamethasone 20 mg, both orally and twice weekly, in patients with myeloma refractory to bortezomib, carfilzomib, lenalidomide, and pomalidomide (quad-refractory disease), with a subset also refractory to an anti-CD38 antibody (penta-refractory disease). The primary end point was overall response rate (ORR). Results Of 79 patients, 48 had quad-refractory and 31 had penta-refractory myeloma. Patients had received a median of seven prior regimens. The ORR was 21% and was similar for patients with quad-refractory (21%) and penta-refractory (20%) disease. Among patients with high-risk cytogenetics, including t(4;14), t(14;16), and del(17p), the ORR was 35% (six of 17 patients). The median duration of response was 5 months, and 65% of responding patients were alive at 12 months. The most common grade ≥ 3 adverse events were thrombocytopenia (59%), anemia (28%), neutropenia (23%), hyponatremia (22%), leukopenia (15%), and fatigue (15%). Dose interruptions for adverse events occurred in 41 patients (52%), dose reductions occurred in 29 patients (37%), and treatment discontinuation occurred in 14 patients (18%). Conclusion The combination of selinexor and dexamethasone has an ORR of 21% in patients with heavily pretreated, refractory myeloma with limited therapeutic options.

Phase I Study of Selinexor, a Selective Inhibitor of Nuclear Export, in Combination with Fludarabine and Cytarabine in Pediatric Patients with Relapsed or Refractory AML

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1345-1345
Author(s):  
Jeffrey E Rubnitz ◽  
Ronda Kaufman ◽  
Raul C. Ribeiro ◽  
Boris Klebanov ◽  
Joel Ellis ◽  
...  
Keyword(s):  
Stem Cell ◽  
Dose Level ◽  
Nuclear Export ◽  
Pediatric Patients ◽  
Selective Inhibitor ◽  
Pharmacokinetic Parameters ◽  
Plasma Exposure ◽  
Grade 3 ◽  
Dose Proportional ◽  
Refractory Aml

Abstract Background and Purpose: Although novel approaches to the treatment of acute myeloid leukemia (AML) are urgently needed, the heterogeneity of AML and the paucity of known actionable targets indicate that there is an important need for broadly active treatment approaches that are not limited to specific genetic subtypes. Selinexor, an oral selective inhibitor of nuclear export, inhibits XPO1 and causes differentiation and apoptosis of a variety of AML subtypes while sparing normal hematopoiesis. We therefore undertook a pilot study to determine the safety and to explore the efficacy of selinexor in combination with fludarabine and cytarabine in pediatric patients with relapsed leukemia. Patients and Methods: Twelve children and adolescents with relapsed or refractory AML (n=10) or mixed phenotype leukemia (n=2) have been enrolled on the study to date. Four patients previously received only chemotherapy, whereas eight had undergone at least one prior stem cell transplant. High-risk features included t(6;9), t(6;12), t(4;11), -7 (2 cases), and megakaryoblastic leukemia. Selinexor, initially at 30 mg/m2/dose, was given orally on days 1, 3, 8, 10, 22, and 24 and escalated according to a rolling-6 design. Fludarabine (30 mg/m2) and cytarabine (2 g/m2) were administered on days 15-19. Results: Among 11 patients who completed at least one cycle and were evaluable for toxicity and response, 3 were treated at dose level 1 (30 mg/m2), 3 at dose level 2 (40 mg/m2), 4 at dose level 3 (55 mg/m2), and 1 at dose level 4 (70 mg/m2). No dose-limiting toxicities were observed at any dose level. The most common Grade 3 non-hematologic toxicity related to selinexor was hyponatremia, which was observed in 10 patients and easily corrected in all cases. As expected, the combination of selinexor plus fludarabine and cytarabine resulted in Grade 3 neutropenia and thrombocytopenia in all patients. Mean pharmacokinetic parameters indicate that plasma exposure is generally dose proportional across selinexor doses, with no apparent accumulation. Plasma exposure in pediatric patients is similar to adult patients treated in phase I trials. Inhibition of XPO1 was assessed by qRT-PCR of XPO1, which is upregulated at the RNA level in response to XPO1 protein inactivation (PDn). Six of the first seven patients enrolled on the trial demonstrated at least 2-fold induction of XPO1 that persisted for at least 48 hours (see figure), indicating prolonged inhibition of the protein by selinexor. The overall response rate in this group of heavily pretreated, relapsed, and refractory patients was 55%. Five patients achieved complete remission (4 with complete count recovery) and 1 had a partial response. Eight of the 11 patients underwent subsequent stem cell transplantation. A trend toward stronger and persistent XPO1 inhibition (measured by PDn) was observed among patients who achieved CR compared to those who did not. Conclusion: Selinexor, given in combination with fludarabine and cytarabine, is tolerable in pediatric patients with relapsed leukemia. Selinexor pharmacokinetic parameters are generally dose proportional and are similar to those seen in adult patients. Most patients demonstrate XPO1 target inhibition. Response rates are encouraging and will be further explored in the Phase II portion of this trial. Figure 1. Figure 1. Disclosures Kaufman: Karyopharm Therapeutics Inc: Employment. Klebanov:Karyopharm Therapeutics Inc: Employment. Ellis:Karyopharm Therapeutics Inc: Employment. Landesman:Karyopharm Therapeutics: Employment. Youssoufian:Karyopharm Therapeutics Inc: Employment. Rashal:Karyopharm Therapeutics Inc: Employment. Shacham:Karyopharm: Employment, Equity Ownership.

Results of a phase II study evaluating trifluridine/tipiracil plus nivolumab in patients with heavily pretreated microsatellite-stable (MSS) metastatic colorectal cancer (mCRC).

2019 ◽  
Vol 37 (8_suppl) ◽  
pp. 48-48 ◽  
Author(s):  
Manish R. Patel ◽  
Gerald Steven Falchook ◽  
Kensuke Hamada ◽  
Lukas Makris ◽  
Robert E. Winkler ◽  
...  
Keyword(s):  
Colorectal Cancer ◽  
Locally Advanced ◽  
Progression Free Survival ◽  
Complete Response ◽  
Phase 2 ◽  
Phase 2 Study ◽  
Common Grade ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Additional Clinical Benefit

48 Background: Patients (pts) with colorectal cancer (CRC) with microsatellite instability (MSI) have recently been shown to respond to anti–programmed death (PD)-1 drugs. Preclinical data suggest that trifluridine/tipiracil (FTD/TPI) treatment converts MSS CRC cells to MSI, sensitizing them to the activity of anti–PD-1 drugs. The aim of this phase 2 study was to evaluate this hypothesis. Methods: This was a multicenter, single-arm, safety lead-in, phase 2 study that used Simon’s 2-stage design to evaluate the safety and efficacy of FTD/TPI (35 mg/m2 twice daily on days 1-5 and 8-12 every 28 days) plus nivolumab (3 mg/kg every 2 weeks) in pts with heavily pretreated MSS mCRC. Pts had histologically proven metastatic or locally advanced colorectal adenocarcinoma that was MSS (assessed by a local laboratory based on either previous or fresh biopsy), ≥1 measurable lesion for RECIST and immune-related response criteria (irRC) assessment, and failure of ≥2 previous lines of chemotherapy. Six pts were to be enrolled in the safety lead-in, and in order to proceed to Simon’s stage 2, ≥2 of the first 15 pts had to demonstrate a partial or complete response within 6 months based on irRC assessment. Results: The first 6 dose-limiting toxicity (DLT)-evaluable pts enrolled tolerated dosing with no DLTs. A total of 18 pretreated pts enrolled in the first stage (50% males; median age 56.5 yr), among whom 72% had colon cancer and 100% had MSS disease, 56% with RAS mutations. Pts received a median of 2.5 cycles of study therapy (range 1-8). The most common grade 3/4 adverse events (AEs) were neutropenia (28%); diarrhea (17%); and nausea, abdominal pain, fatigue, and anemia (11% each). No pts discontinued treatment due to AEs. No pts achieved a tumor response (either per RECIST or irRC), and the study did not progress to the second stage. Median (6-month) progression-free survival was 2.8 months (21%) per RECIST and 2.2 months (30%) per irRC. Conclusions: The combination of FTD/TPI and nivolumab was feasible and tolerated at the full dose of both compounds. Adding nivolumab to FTD/TPI did not provide additional clinical benefit in pts with previously treated MSS mCRC. Clinical trial information: NCT02860546.

Lenalidomide Monotherapy in Relapsed or Refractory Aggressive Non-Hodgkin's Lymphoma

2008 ◽  
Vol 26 (30) ◽  
pp. 4952-4957 ◽  
Author(s):  
Peter H. Wiernik ◽  
Izidore S. Lossos ◽  
Joseph M. Tuscano ◽  
Glen Justice ◽  
Julie M. Vose ◽  
...  
Keyword(s):  
Adverse Events ◽  
B Cell ◽  
Hodgkin’S Lymphoma ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Non Hodgkin's Lymphoma ◽  
Common Grade ◽  
Duration Of Response ◽  
Grade 3 ◽  
Large B Cell

PurposeThe major cause of death in aggressive lymphoma is relapse or nonresponse to initial therapy. Lenalidomide has activity in a variety of hematologic malignancies, including non-Hodgkin's lymphoma (NHL). We report the results of a phase II, single-arm, multicenter trial evaluating the safety and efficacy of lenalidomide oral monotherapy in patients with relapsed or refractory aggressive NHL.Patients and MethodsPatients were treated with oral lenalidomide 25 mg once daily on days 1 to 21, every 28 days, for 52 weeks, until disease progression or intolerance. The primary end point was response; secondary end points included duration of response, progression-free survival (PFS), and safety.ResultsForty-nine patients with a median age of 65 years received lenalidomide in this study. The most common histology was diffuse large B-cell lymphoma (53%), and patients had received a median of four prior treatment regimens for NHL. An objective response rate of 35% was observed in 49 treated patients, including a 12% rate of complete response/unconfirmed complete response. Responses were observed in each aggressive histologic subtype tested (diffuse large B-cell, follicular center grade 3, mantle cell, and transformed lymphomas). Of patients with stable disease or partial response at first assessment, 25% improved with continued treatment. Estimated median duration of response was 6.2 months, and median PFS was 4.0 months. The most common grade 4 adverse events were neutropenia (8.2%) and thrombocytopenia (8.2%); the most common grade 3 adverse events were neutropenia (24.5%), leukopenia (14.3%), and thrombocytopenia (12.2%).ConclusionOral lenalidomide monotherapy is active in relapsed or refractory aggressive NHL, with manageable side effects.

Clofarabine in Combination with Etoposide and Cyclophosphamide (CLOVE) in Pediatric Patients with Relapsed Acute Leukemia: 4 Italian Pediatric AIEOP Centers’ Experience

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3953-3953
Author(s):  
Concetta Micalizzi ◽  
Rosanna Parasole ◽  
Maria Caterina Putti ◽  
Matteo Luciani ◽  
Laura Banov ◽  
...  
Keyword(s):  
Complete Remission ◽  
Acute Leukemia ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Intrathecal Methotrexate ◽  
Unrelated Donor ◽  
Platelet Recovery ◽  
Heavily Pretreated ◽  
Grade 3 ◽  
Induction Cycle

Abstract Clofarabine is a new promising chemotherapic agent active in the treatment of pediatric acute leukemia. We planned to utilize the same drugs’ combination currently evaluated in USA as phase II study salvage therapy: clofarabine (40mg/m2/day) in combination with etoposide (100mg/m2/day) and Cyclophosphamide (440mg/m2/day) (CLOVE). We planned to treat the patients (pts) (aged 1–18) with relapsed or refractory acute lymphoblastic leukemia (ALL) or acute myeloblastic leukemia (AML) with 1 or 2 induction cycles (5 days chemotherapy) to reach complete remission (CR) or complete remission without platelet recovery (CRp) and with 1 or 2 consolidation cycles (4 days chemotherapy). ALL patients (pts) received intrathecal methotrexate at day 6 and AML patients intrathecal cytarabine at Day 0. Prednisone was added (0,5 mg/Kg/day) to prevent systemic inflammatory response syndrome (SIRS). Fourteen children (5 AML, 9 ALL) were treated, median age 5,7 years (range 1,75–16,5), 7 pts in first, 3 pts in second and 4 pts in third relapse. Four AML pts had one prior bone marrow transplantation (BMT): 1 autologous, 1 matched familiar donor and 2 matched unrelated donor (MUD) transplants. Five ALL pts had one prior BMT : 2 autologous, 1 syngenic and 2 MUD. The AML pts were in first relapse, and three of them were refractory to FLAG-X protocol: 3/5 (60%) achieved remission (1CRp, 2 CR), response data are currently pending for1 patient (day + 20 first induction), and 1 patient died for disease progression. The remission rate of nine ALL pts was 66% (4 CR, 2CRp). Infection grade 3 was observed in one patient, diarrhea and abdominal pain occurred in 4 pts. Febrile neutropenia was e common toxicity. Severe muscles pain with functional impairment was observed in two pts (1 AML, 1 ALL) 7 days post induction cycle: the gabapentin therapy in association with prednisone was efficient and the symptom quickly disappeared. One ALL patient refractory to first induction cycle, died after second cycle (day + 6) for cardiac failure. One ALL patient relapsed after CLOVE induction, after two more cycles he obtained partial response (BM Blast cells 10% ), and he underwent MUD transplantation and died for infection. The overall survival is 58 %, 7/9 (77 %) responders are alive. The median survival is 3 months (range 20 days –10 months). Four out 9 responding patients proceeded to BMT from unrelated donor, and three of them are alive and in CR. No unexpected transplant related toxicity was encountered. We confirm that the association of Clofarabine with Etoposide and Cyclophosfamide is active in heavily pretreated relapsed or refractory pediatric acute leukemia. patients.

Induction chemotherapy with S-1 plus cisplatin in patients with locally advanced squamous cell carcinoma of the head and neck (SCCHN)

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 15501-15501
Author(s):  
J. Chung ◽  
Y. Choi ◽  
H. Shin ◽  
G. Choi ◽  
W. Lee ◽  
...  
Keyword(s):  
Performance Status ◽  
Locally Advanced ◽  
Local Treatment ◽  
Complete Response ◽  
Hematological Toxicity ◽  
Common Grade ◽  
Adequate Organ Function ◽  
Grade 3 ◽  
And Performance ◽  
Mild Toxicity

15501 Background: This study was to assess the efficacy and safety profiles of the combination treatment with S-1 and Cisplatin in patients with locally advanced SCCHN. Methods: Eligible patients were defined as histologically confirmed SCCHN, stage III or IV with no evidence of distant metastasis, evaluable lesions, adequate organ function, age of 20–80 years, and performance status 0,1 or 2. Cisplatin was infused over 1 hour on day 1 (75 mg/m2) and S-1 was administered orally for 14 consecutive days (day 2–15). The dosages of S-1 were assigned according to the patients’ body surface area (BSA): 50 mg twice a day (BSA < 1.5m2), 60 mg twice a day (BSA > 1.5m2). Each course was repeated every 3 weeks. After 2 course, tumor response were evaluated by CT scan and laryngoscopy. If the patients achieved a response (complete response: CR, or partial response: PR), they received one more course of chemotherapy before undergoing the radiotherapy or operation as a definitive local treatment. Results: All 22 patients were assessable for response and toxicity. The overall response was 80.9% (CR: 3, PR: 14). The adverse reactions occurred 120 times in 54 courses of 22 cases. The most common grade 3/4 adverse events were neutropenia, which occurred in 8 patients. Non-hematological toxicity of grade 3 and 4 included nausea and vomiting in 4 patients, fever in one patient and, fatigue in one patient. Since the observation period is short, the analysis about survival rate is not obtained so far. Conclusions: S-1 plus Cisplatin combination chemotherapy is effective against locally advanced SCCHN with mild toxicity. No significant financial relationships to disclose.

A phase II study of capecitabine and oxaliplatin (CAPOX) in metastatic adenocarcinoma of the small bowel (SBA) or ampulla of Vater

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 14025-14025
Author(s):  
M. J. Overman ◽  
S. Chedid ◽  
J. Morris ◽  
S. Waldrum ◽  
R. A. Wolff
Keyword(s):  
Small Bowel ◽  
Performance Status ◽  
Complete Response ◽  
Ampulla Of Vater ◽  
Ecog Performance Status ◽  
Ampullary Adenocarcinoma ◽  
Highly Active ◽  
Common Grade ◽  
Grade 3 ◽  
Tumor Types

14025 Background: Metastatic SBA and ampullary adenocarcinoma (AAC) are incurable, aggressive malignancies. Limited data exists regarding the role of systemic chemotherapy in these diseases. Given the marked activity of CAPOX in other cancers of the gastrointestinal tract, we have investigated the activity of this combination in these two tumor types. Methods: Patients (pts) with either metastatic or unresectable SBA and AAC who had adequate organ function, ECOG performance status (PS) ≤2 and measurable disease per modified RECIST criteria were enrolled. Prior use of 5-FU or capecitabine as adjuvant therapy, neoadjuvant therapy, or with radiation was allowed. CAPOX was administered as a 21 day cycle with oxaliplatin 130mg/m2 IV on day 1 and capecitabine 750mg/m2 PO BID days 1–14. Up to 30 pts will be enrolled. The primary endpoint is overall response rate (ORR). Results: Eleven pts have been enrolled from 11/04 to 12/05 (6 with AAC and 5 with SBA). Ten pts have received ≥2 cycles and are evaluable for response. All pts had metastatic disease and none had received prior chemotherapy. Patient (pt) characteristics: median age 59 (49–76); M/F (4/7); 91% PS 0–1. Grade 3/4 toxicities included fatigue (5), neuropathy (1), anorexia (1), thrombocytopenia (1), hypokalemia (1), hyponatremia (1), and musculoskeletal (1). Common grade 1/2 toxicities included neuropathy (8), nausea (8), diarrhea (6), and fatigue (5). Four pts required dose reduction and 1 pt discontinued due to toxicity (grade 3 fatigue). Six pts, 3 AAC and 3 SBA, responded with an ORR of 60% (95% CI 31 to 83%). Five responses have been confirmed and 1 AAC pt obtained a complete response after 5 cycles of treatment. Median time to progression was 6.8m (95% CI 4.4 to 9.3+m). Conclusions: The combination of CAPOX is both well-tolerated and highly active. The ORR of 60% is one of the highest yet reported in the literature for the treatment of adenocarcinoma of the small bowel and ampulla of Vater. Enrollment continues on this trial. (Supported by a research grant from Sanofi-Aventis). [Table: see text]

Preliminary phase II results of selinexor, an oral selective inhibitor of nuclear export in patients with heavily pretreated gynecological cancers.

2015 ◽  
Vol 33 (15_suppl) ◽  
pp. 5565-5565 ◽  
Author(s):  
Ignace Vergote ◽  
Bente Lund ◽  
Hanne Havsteen ◽  
Zaza Ujmajuridze ◽  
Karin Leunen ◽  
...  
Keyword(s):  
Phase Ii ◽  
Nuclear Export ◽  
Selective Inhibitor ◽  
Gynecological Cancers ◽  
Heavily Pretreated ◽  
Preliminary Phase

scholarly journals XPO1 Inhibitor (ATG-010) Plus Chemotherapy per Investigator's Choice for Heavily Pretreated Patients with Relapsed or Refractory (R/R) Peripheral T-Cell Lymphoma (PTCL) and Extranodal NK/T-Cell Lymphoma (ENKTL)：Preliminary Results from a Multicenter, Single-Arm, Phase Ib Study (TOUCH Trial)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2452-2452
Author(s):  
Huiqiang Huang ◽  
Yan Gao ◽  
Huilai Zhang ◽  
Keshu Zhou ◽  
Jianqiu Wu ◽  
...  
Keyword(s):  
T Cell ◽  
Adverse Events ◽  
Disease Progression ◽  
Nuclear Export ◽  
Cell Lymphoma ◽  
Fatal Outcome ◽  
T Cell Lymphoma ◽  
Clinical Activity ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background The prognosis of R/R PTCL and ENKTL remains poor. Current therapeutic options are limited, highlighting the need for novel approaches. ATG-010 (selinexor) is a novel, oral selective inhibitor of nuclear export, which blocks exportin 1. It has demonstrated clinical activity in different hematological malignancies. Preclinical synergistic anti-tumor effects are confirmed when combined with gemcitabine, cisplatin, or etoposide. Method The aim of this study was to evaluate safety and efficacy of ATG-010 plus GemOx or ICE regimen followed by ATG-010 maintenance in patients (pts) with R/R PTCL or ENKTL in China. The study planned to enroll 30 pts with PTCL-NOS, AITL, ALCL, PTCL-TFH, FTL and ENKTL. Pts must have had prior exposure to an anthracycline-based regimen for PTCL or an asparaginase-based regimen for ENKTL, and were relapsed or refractory from the last therapy. ATG-010 was administered orally (60 mg day 1, 8) plus standard-dose of either ICE or GemOx regimen every 3 weeks as per investigator's choice. If response was achieved after initial 2-6 cycles, pts continued to receive ATG-010 maintenance at the dose of 60 mg weekly until disease progression, intolerability or withdrawal of consent. Primary endpoints included safety according to the NCI CTCAE 5.0 and overall response rate (ORR) evaluated by investigators according to the Lugano criteria (2014). Secondary endpoints included duration of response (DOR), progression-free survival (PFS) and overall survival (OS). This trial was registered at ClinicalTrials.gov (NCT04425070). Results From Aug 18, 2020 to June 25, 2021, 24 pts (20 in GemOx cohort, 4 in ICE cohort) were enrolled and received at least one cycle of treatment. In this abstract, we report results of the GemOx cohort with 9 (45%) PTCL-NOS, 6 (30%) ENKTL, 4 (20%) AITL, and 1 (5%) ALCL ALK-. At study entry, median age was 55 years (range 35-69); 17 (85%) had stage III/IV disease. Five (36%) pts with PTCL had IPI score ≥3, and 5 (83%) ENKTL pts with had PINK-E score ≥2. Median number of prior regimens was 3.5 (range 1-7) with 5.5 for ENKTL and 2 for PTCL. All pts were refractory from last therapy; 11 (55%) pts had received gemcitabine-based regimens. Median time from last-line therapy to this trial was 1.5 months (range 1.0-16.7). The most common treatment-emergent adverse events (TEAEs) were hematological toxicities. All grade hematological TEAEs were neutropenia (90%), thrombocytopenia (90%) and anemia (85%). Grade≥3 hematological TEAEs included neutropenia (85%), thrombocytopenia (80%) and anemia (40.0%). The most common (&gt;30%) non-hematological TEAEs were nausea (70%), diarrhea (65%), decreased appetite (65%), asthenia/fatigue (60%), vomiting (50%), pyrexia (40%), and hyponatremia (35%). Grade≥3 non-hematological TEAEs (≥10%) were diarrhea (15%) and pyrexia (10%). Serious TEAEs occurred in 7 (35%) pts with the most common being thrombocytopenia (20%). Three (15%) pts discontinued treatment due to TEAEs. TEAEs with a fatal outcome occurred in 1(5%) patient, who experienced rapid disease progression before death. The majority of adverse events were manageable by dose modification and supportive care. Of 17 efficacy evaluable pts, ORR was 52.9% (9/17), and CR rate was 35.3% (6/17). ORR of PTCL-NOS, ENKTL, AITL, ALCL were 62.5% (5/8), 60% (3/5), 0 (0/3), 100% (1/1); CR rate were 37.5%, 40%, 0, 100%, respectively. At a median follow-up of 6.1months, median PFS, DOR and OS of the whole cohort was 2.9, 3.1 months, and not reached (6-month OS rate 68.9%), respectively. Patients with ENKTL enjoyed a relatively longer median PFS (4.7 months). Conclusions ATG-010 plus GemOx regimen showed a manageable safety profile, and favorable activity with impressive CR rate in refractory pts, potentially offering a new therapeutic option for heavily pretreated pts with refractory PTCL or ENKTL. Disclosures Lou: Antengene Therapeutics Ltd.: Current Employment. Fei: Antengene Therapeutics Ltd.: Current Employment. Wang: Antengene Therapeutics Ltd.: Current Employment. Lynch: Antengene Therapeutics Ltd.: Current Employment.

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