Results of a Phase I Dose Escalation Study of the Novel, Oral CRM1 Selective Inhibitor of Nuclear Export (SINE) KPT-335 in Dogs with Spontaneous Non-Hodgkin's Lymphomas (NHL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 161-161 ◽  
Author(s):  
Sharon Shacham ◽  
Sandra Barnard ◽  
William Kisseberth ◽  
Daisuke Ito ◽  
Kiersten Jensen ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Large Animal ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Good Tolerability ◽  
Optimal Dosing

Abstract Abstract 161 Introduction. Nuclear-cytoplasmic transport is highly regulated by karyopherin proteins – importins and exportins – through the nuclear pore complex. Of the seven known exportins, most tumor suppressor proteins (TSP) and IkB, the inhibitor of NF-kB, are transported out of the nucleus exclusively by exportin 1 (XPO1), more commonly called CRM1. SINE compounds bind irreversibly CRM1/XPO1, forcing the nuclear retention and activation of TSP and IkB, leading to selective tumor cell death. In vitro, SINEs demonstrate potent cytotoxic activity against tumor cells at nanomolar concentrations with minimal effects on normal cells in vitro. KPT-335 and related SINEs show oral bioavailability, good tolerability, and potent activity in multiple mouse xenograft models. Hematologic cancers are particularly vulnerable to SINE induced apoptosis, and effects on normal tissues are minimal at antitumor doses. Methods. Cytotoxicity was assessed in vitro with MTT and apoptosis assays. In order to evaluate the therapeutic potential of SINE in a spontaneous, large animal malignancy with many similarities to human disease including NF-kB activation, dogs with relapsed or newly diagnosed NHL were treated with KPT-335 in this dose escalation study. The primary objective was to evaluate the adverse events (AEs) and to establish the maximum tolerated dose (MTD) of KPT-335 orally in capsules. The secondary objectives were to determine the optimal dosing regimen, correlate pharmacodynamic markers and drug levels, and provide evidence of biological activity. We report the interim results defining the MTD and AEs of KPT-335 in dogs with NHL. All dogs had progressive disease (PD) on entry into the trial. Dogs with newly diagnosed or relapsed NHL, metastatic osteosarcoma (OSA), melanoma (MEL) and mast cell tumor (MCT) were eligible with preference given to NHL. The initial KPT-335 dose was 1 mg/kg (equivalent to 20mg/m2) orally with food on a Monday/Thursday schedule. At least 3 dogs were included in each cohort, and dose was escalated by 0.25mg/kg increments. CBC, serum chemistries, clotting times, drug peak plasma level and response to therapy were assessed at each weekly visit. Tumor samples will be obtained before and after treatment in an expansion cohort once the optimal dosing regimen has been determined. Results. Three structurally related SINE compounds including KPT-335 showed potent cytotoxicity of primary and immortalized canine B cell lymphomas in vitro (EC50<100 nM). The Phase 1 dose escalation study with KPT-335 oral included doses of 1mg/kg twice weekly and continued up to 2mg/kg (Table 1). Doses up to 1.75mg/kg were very well tolerated for over 3 months. At 1.75mg/kg, mild to moderate anorexia, weight loss and alkaline phosphatase elevation (possibly related to prednisone use) were observed. DLTs occurred at 2mg/kg including anorexia and vomiting without diarrhea. Laboratory parameters showed minimal or no changes at doses below the DLT. Discussion. Oral KPT-335 shows single agent disease stabilization and tumor reduction in dogs with NHL, the majority of who have diffuse large B cell lymphoma (DLBCL) relapsed after chemotherapy (typically CHOP). The activation of TSP and the neutralization of NF-kB activity by nuclear localization of IkB may contribute to the antitumor activity of SINE in canine NHL. AEs associated with drug administration include primarily anorexia, with vomiting at the DLT dose; diarrhea and significant laboratory changes were not observed. These observations are consistent with the effects of SINEs in other animal species. Conclusion. The novel SINE KPT-335 exhibits single agent biological activity with good tolerability in a relevant spontaneous large animal model of newly diagnosed and chemotherapy refractory cancer. The MTD and no adverse effect level of KPT-335 given by mouth twice weekly to dogs with NHL are ∼1.75 and 1.25 mg/kg, respectively, with anorexia, weight loss and vomiting as DLTs. Additional cohorts at doses of ≥1.25mg/kg given with increased frequency are being enrolled. These data are directly relevant to the development of oral KPT-330, a related SINE, currently in Phase 1 human clinical trials. Disclosures: Shacham: Karyopharm Therapeutics: Employment. Barnard:Karyopharm: Research Funding. Kisseberth:Karyopharm: Research Funding. Ito:Karyopharm: Research Funding. Jensen:Karyopharm: Research Funding. Borgotti:Karyopharm: Research Funding. Henson:Karyopharm: Research Funding. Wilson:Karyopharm: Research Funding. McCauley:Karyopharm Therapeutics Inc: Employment. Modiano:Karyopharm: Research Funding. Kauffman:Karyopharm Therapeutics Inc: Employment. London:Karyopharm: Research Funding.

scholarly journals Phase 1 Study of the IDH1m Inhibitor FT-2102 As a Single Agent in Patients with IDH1m Acute Myeloid Leukemia (AML) or Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1453-1453 ◽  
Author(s):  
Justin Watts ◽  
Maria R. Baer ◽  
Jay Yang ◽  
Shira Dinner ◽  
Sangmin Lee ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Human Tissue ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Phase 2 ◽  
Phase 1 Study ◽  
Grade 3

Abstract Background: Isocitrate dehydrogenase 1 mutations (IDH1m) occur in 7-14% of AML patients and 3% of MDS patients and produce 2-hydroxyglutarate (2-HG), an oncometabolite that impairs differentiation. FT-2102 is an oral, highly potent, selective small molecule inhibitor of mutated IDH1, with the therapeutic potential to restore normal cellular differentiation. Herein, we present preclinical and clinical data from an ongoing Phase 1/2 study of single-agent (SA) FT-2102 in patients with IDH1m AML and MDS (CT.gov: NCT02719574). Methods: Extensive pre-clinical evaluations were performed on FT-2102, including CYP interactions in-vivo in rat and in-vitro in human tissue and in-vivo QTc toxicology in monkeys. The clinical Phase 1 study was initiated to evaluate the safety, PK/PD, and antileukemic activity of FT-2102 in patients with IDH1m AML or MDS and included both dose escalation and expansion phases. FT-2102 was administered daily until disease progression or unacceptable toxicity. Eligibility criteria included: IDH1m AML/MDS [relapsed/refractory (R/R) or treatment naïve (TN) for whom standard therapy was contraindicated], adequate liver and renal function, no prior IDH1 inhibitors, and no restrictions for concomitant non-anticancer medications. Investigator-assessed responses were per modified IWG 2003/2006 criteria. Efficacy was assessed at Cycle 2 Day 1 and as clinically indicated thereafter. Adverse events (AEs) were assessed throughout the study per NCI CTCAE version 4.03. Results: Evaluation of FT-2102 in in-vivo rat and in-vitro human tissue indicated hepatic metabolism by CYP enzymes (CPY3A4, 2C9, 1A1) as the major route of excretion. Animal toxicology studies predicted the threshold for QTc risk occurred at exposures >5.5 fold higher than the murine exposure at which 90% 2-HG reduction was observed. In the clinical study, at the time of the data cutoff, 31 patients (pts) had been treated with SA FT-2102, with a median of 3 mo. on treatment (range: 0.2 to 20 mo.). Of the 31pts treated, 25 had AML (22 R/R; 3 TN) and 6 had MDS (4 R/R; 2 TN). The median number of prior anti-leukemia therapies was 2 (range: 0-9) for AML pts and 1 (range: 0-4) for MDS pts. FT-2102 doses were: 150 mg QD (n=8), 300 mg QD (n=4), 150 mg BID (n=16), and 100 mg QD with food (n=3). Eighteen pts discontinued treatment, most commonly due to death (n=5), progressive disease (n=5), HSCT (n=3), or lack of response (n=3). Severe (≥Grade 3) AEs occurring in >5% of pts included thrombocytopenia (26%), febrile neutropenia (23%), anemia (19%), pneumonia (13%), neutropenia (7%), hypokalemia (7%), pyrexia (7%) and leukocytosis (6%). Three pts had differentiation syndrome (IDH-DS), which resolved with temporary interruption of FT-2102, treatment with dexamethasone, hydroxyurea, and supportive care in all three. One pt had transient QTcF prolongation (Grade 3) which resolved with temporary interruption of FT-2102 and cessation of suspected concomitant medications. Eight pts died on treatment or within 28 days of the last dose, with no deaths considered related to FT-2102. No DLTs were observed during dose escalation. Selection of FT-2102 150 mg BID as the RP2D was supported by PK and PD data. Durable steady-state (Css) achieved by Week 2 was well below the threshold for QTc risk predicted by preclinical studies. The predicted IC90 was confirmed with prompt and durable 2-HG reduction to normal levels by C2D1 at the RP2D. Table 1 shows the Investigator-assessed ORR per IWG. Responses have been observed from 1 to 6 months on treatment, with stable disease observed beyond 6 months; 42% of the patients remain on treatment. Conclusions: FT-2102 preclinical evaluations suggest a low risk of clinically significant CYP-mediated drug-drug interaction and QTc prolongation. SA FT-2102 is well tolerated in AML and MDS, with 150 mg BID selected as the RP2D based on safety, PK and PD (2-HG) response. Significant clinical activity has been observed in heavily pre-treated and in TN patients, both in AML and MDS. FT-2102 continues being investigated at a dose of 150 mg BID in a Phase 2 study. Three SA Phase 2 cohorts are currently open for enrollment in R/R AML, AML/MDS with CR/CRi (i.e., with MRD), and in pts with R/R MDS/AML with prior exposure to an IDH1m inhibitor. Data updates will be available at the time of presentation. Disclosures Lee: LAM Therapeutics: Research Funding; Karyopharm Therapeutics Inc: Consultancy; AstraZeneca: Consultancy; Clinipace: Consultancy; Amgen: Consultancy. Schiller:Celator/Jazz Pharmaceuticals: Research Funding; Pharmacyclics: Research Funding. Ferrell:Incyte: Research Funding. Kelly:Forma Therapeutics Inc.: Employment. Li:Forma Therapeutics Inc.: Employment. Sweeney:Forma Therapeutics Inc.: Employment. Watson:Forma Therapeutics Inc.: Employment. Mohamed:Forma Therapeutics Inc.: Employment. Cortes:Pfizer: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Astellas Pharma: Consultancy, Research Funding; Arog: Research Funding.

scholarly journals Preliminary Results from a Phase 1 Study of Gilteritinib in Combination with Induction and Consolidation Chemotherapy in Subjects with Newly Diagnosed Acute Myeloid Leukemia (AML)

Blood ◽  
2017 ◽  
Vol 130 (Suppl_1) ◽  
pp. 722-722
Author(s):  
Keith Pratz ◽  
Mohamad Cherry ◽  
Jessica K. Altman ◽  
Brenda W. Cooper ◽  
Jose Carlos Cruz ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Advisory Board ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Once Daily ◽  
End Of Treatment

Abstract Background: Gilteritinib is a novel, potent, highly-selective oral fms -like tyrosine kinase 3 (FLT3)/AXL inhibitor with clinical activity in relapsed/refractory (R/R) AML with activating FLT3-ITD and -TKD mutations. In such patients, once-daily gilteritinib ≥80 mg/day, as a single agent, elicited a response rate of 52% and median overall survival (OS) of 31 weeks (Perl AE, et al. Lancet Oncol . 2017.). Here we examined the safety/tolerability and antitumor activity of gilteritinib combined with front-line intensive chemotherapy in newly diagnosed AML patients. Methods: The primary objective of this open-label, dose-escalation/expansion Phase 1 study (NCT02236013) was to assess the safety/tolerability profile (including dose-limiting toxicities [DLTs] and maximum tolerated dose [MTD]) of gilteritinib when combined with 7+3 induction and high-dose cytarabine (HiDAC) consolidation, and administered as single-agent maintenance therapy in subjects aged ≥18 years with newly diagnosed AML. Assessment of antitumor effects of this combination therapy was an exploratory objective. Dose escalation followed a 3+3 design where successive cohorts of 3-6 subjects received gilteritinib doses of 40, 80, or 120 mg/day. Dose-escalation decisions were made based on DLTs that occurred during remission induction. A DLT was defined as any grade ≥3 non-hematologic or extramedullary toxicity (with exceptions) or hematologic toxicity that occurred after the first gilteritinib dose and did not resolve by Day 42 of the last induction cycle or before initiation of consolidation therapy. Subjects received up to 2 cycles of a 7+3 induction regimen (cytarabine 100 mg/m2/day, days 1-7 plus idarubicin 12 mg/m2/day, days 1-3) plus once-daily oral gilteritinib, which was initially administered on days 1-14 but was subsequently changed to administration on days 4-17 at the designated dose. During consolidation, subjects received cytarabine (1.5 g/m2 every 12 hours, days 1, 3, and 5) and once-daily gilteritinib (days 1-14) at the induction dose, for up to 3 cycles. Subjects in the dose-expansion cohort, received gilteritinib at the recommended expansion dose established during dose escalation. After consolidation, subjects received maintenance therapy with once-daily gilteritinib (28-day cycles; up to 26 cycles). Results: As of July 9, 2017, 50 subjects had been enrolled (n=17, dose-escalation cohort; n=33, dose-expansion cohort); 49 had received at least 1 dose of gilteritinib. Most subjects were male (67.3%; n=33); median age was 59 years (range, 23-77 years). Of the 48 subjects with known FLT3 mutation status, 23 (47.9%) were FLT3mut+, of whom 15 (65.2%) had internal tandem duplications. During dose-escalation, 2 subjects in the 40 mg/day cohort who had received gilteritinib on days 1-14 experienced DLTs (neutropenia, thrombocytopenia, and decreased ejection fraction). After gilteritinib induction schedule modification, no additional DLTs were observed. The MTD was not reached; gilteritinib 120 mg/day was chosen as the recommended expansion dose. Grade ≥3 treatment-emergent adverse events (TEAEs) occurring in ≥10% of subjects were febrile neutropenia (53.1%), thrombocytopenia (18.4%), neutropenia (16.3%), decreased platelet count (12.2%), sepsis (10.2%), and decreased white blood cell count (10.2%). Serious drug-related TEAEs occurring in &gt;1 subject were febrile neutropenia (16.3%), sepsis (6.1%), and decreased ejection fraction (4.1%). The end of treatment investigator-reported composite complete remission (CRc) rate for all subjects was 71.4% and 57.1% achieved complete remission (Table). In FLT3mut+ and FLT3 mutation-negative (FLT3mut−) subjects, end-of-treatment CRc rates were 91.3% and 56%, respectively. Among subjects who received ≥80 mg/day gilteritinib (n=40), end-of-treatment CRc rates were 90% (n=18/20) for FLT3mut+ and 60% (n=12/20) for FLT3mut− subjects. Median OS and duration of response have not been reached. For the total study population, median event-free survival (EFS) was 327 days and median disease-free survival (DFS) was 297 days; FLT3mut+ subjects had a longer median EFS (327 days) and DFS (134 days) than FLT3mut− subjects (EFS, 80 days; DFS, not estimable). Conclusions: In subjects with newly diagnosed AML, gilteritinib combined with intensive chemotherapy was well tolerated (MTD &gt;120 mg/day) with seemingly high response rates in FLT3mut+ subjects. Disclosures Cherry: Pfizer: Membership on an entity's Board of Directors or advisory committees; Astellas: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Ariad: Membership on an entity's Board of Directors or advisory committees. Altman: NCCN: Other: Educational speaker; Syros: Consultancy; BMS: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Ceplene: Consultancy; Janssen Pharmaceuticals: Consultancy; Novartis: Consultancy; ASH: Other: Educational speaker. Cooper: Novartis: Research Funding. Jurcic: Syros Pharmaceuticals: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy; Kura Oncology: Research Funding; Incyte: Consultancy; Genentech: Research Funding; Forma Therapeutics: Research Funding; Celgene: Research Funding; Alexion Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy, Research Funding; Actinium Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi-Sankyo: Research Funding; Astellas Pharma, Inc: Research Funding; Amgen: Consultancy. Levis: Astellas Pharma Us: Consultancy, Research Funding; Daiichi Sankyo, Inc.: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Research Funding; FujiFilm: Research Funding. Lin: Jazz Pharmaceuticals: Consultancy. Perl: Arog Pharmaceuticals: Consultancy; Asana Biosciences: Other: Scientific advisory board; Astellas: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Other: Advisory Board; Novartis: Other: Advisory Board; Actinium Pharmaceuticals: Other: Scientific Advisory Board; Seattle Genetics: Other: Advisory board. Podoltsev: Alexion: Consultancy; CTI biopharma/Baxalta: Consultancy; Incyte: Consultancy; Ariad: Consultancy. Schiller: Celator/Jazz: Research Funding. Liu: Astellas Global Pharma, Inc.: Employment. Bahceci: Astellas Pharma Global Development: Employment.

scholarly journals Results of the Phase 1b Dose Escalation Study of OPB-111077, Decitabine, and Venetoclax for the Treatment of Newly Diagnosed or Relapsed/Refractory AML

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 10-10
Author(s):  
Lindsay Wilde ◽  
Ubaldo Martinez-Outschoorn ◽  
Neil Palmisiano ◽  
Gina Keiffer ◽  
Margaret Kasner
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Acid Metabolism ◽  
Pharmaceutical Research ◽  
Refractory Disease ◽  
Newly Diagnosed ◽  
Dose Escalation Study ◽  
Phase Ib ◽  
Otsuka Pharmaceutical ◽  
Refractory Aml

Background: The combination of a hypomethylating agent (HMA) and the Bcl-2 inhibitor venetoclax (VEN) has revolutionized the treatment of elderly patients with newly diagnosed acute myeloid leukemia (AML). However, patients treated with this regimen inevitably relapse and subsequent treatment options are limited. Furthermore, the success of this combination in the relapsed/refractory setting has been less impressive. Mechanisms of resistance to HMA/VEN are of great interest, and alterations in leukemic cell metabolism have been implicated. It is hypothesized that drugs that target oxidative phosphorylation (OXPHOS), fatty acid metabolism, and /or amino acid metabolism may be successful in overcoming HMA/VEN resistance. OPB-111077 is a novel, oral, low-molecular-weight compound that was shown in preclinical models to inhibit mitochondrial electron transport and have an inhibitory effect on the growth of AML cells. When given in combination with decitabine, OPB-111077 showed a more potent antitumor effect in a KG-1 tumor-bearing mouse model, thus providing support for conducting clinical trials of this combination. AML cells treated with OPB-111077 and venetoclax have also been shown to have decreased proliferation and increased apoptosis. The effects on proliferation and apoptosis of the combination of OPB-111077 and venetoclax were more pronounced in AML cells that were genetically engineered to increase OXPHOS. These data formed the basis for the development of a clinical trial utilizing the triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML. Herein, we report results from the Phase Ib dose escalation study. Methods: In this phase Ib single center study (NCT03063944), OPB-111077 is administered daily starting on day 1 and continuing throughout the treatment cycle. Decitabine 20mg/m2 is given for 5 days starting on day 4 of cycle 1. Venetoclax 70mg daily (if receiving posaconazole prophylaxis) or 100mg daily (if receiving voriconazole) is started on day 4 and given continuously until day 28. If a response is seen within 2 cycles, treatment continues until toxicity, disease progression, or availability of an alternative therapy. Patients were enrolled in cohorts of escalating dose levels of OPB-111077 using a traditional 3+3 design. The primary objectives were to determine preliminary safety and tolerability as well as maximum tolerated dose (MTD) of OPB-111077. The secondary objective was to measure preliminary efficacy. Correlative studies including metabolomics, ATP measurement, apoptosis, and proliferative assays were performed on samples of blasts and non-cancerous cells that were collected from blood or marrow. Results: As of July 15, 2020, 2 patients with newly diagnosed AML and 7 patients with relapsed/refractory AML were treated with the triplet. Patients received OPB-111077 at 150mg (n=3), 200mg (n=3), and 250mg (n=3). Median age was 73 years (range, 23-79) and 7 patients (78%) were male. The median number of prior systemic anticancer regimens for patients with relapsed/refractory disease was 2 (range, 1-5); no patients had undergone prior stem cell transplant. The median treatment duration has not yet been reached; 3 patients are receiving ongoing treatment. No patients experienced a dose limiting toxicity. The most common Grade ≥3 adverse event (AE) was febrile neutropenia (56%). No patients discontinued due to AEs. No pts experienced tumor lysis syndrome. Three patients died after completing their study treatment, all due to progressive AML. The best overall response to therapy was a complete remission in 2 (22%) patients (1 with newly diagnosed AML and 1 with relapsed/refractory disease). Metabolomics using liquid chromatography/mass spectrometry was performed on paired pre- and post-treatment samples and intracellular metabolic changes in glycolysis and the tricarboxylic acid (TCA) cycle were observed consistent with on-target effects. Conclusion: The triplet of OPB-111077, decitabine, and venetoclax for the treatment of newly diagnosed or relapsed/refractory AML was safe and well tolerated, and showed preliminary anti-leukemic efficacy. A planned expansion phase is underway utilizing the 250mg daily dose of OPB-111077. Disclosures Martinez-Outschoorn: Otsuka Pharmaceutical: Research Funding. Palmisiano:AbbVie: Research Funding; Genentech: Research Funding. Kasner:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Otsuka Pharmaceutical: Research Funding.

scholarly journals A phase 1 dose-escalation study of intraperitoneal cisplatin, intravenous/intraperitoneal paclitaxel, bevacizumab, and olaparib for newly diagnosed ovarian cancer

2020 ◽  
Vol 157 (1) ◽  
pp. 214-221
Author(s):  
Karen A. Cadoo ◽  
Rachel N. Grisham ◽  
Roisin E. O'Cearbhaill ◽  
Nicole N. Boucicaut ◽  
Melissa Henson ◽  
...  
Keyword(s):  
Ovarian Cancer ◽  
Dose Escalation ◽  
Phase 1 ◽  
Newly Diagnosed ◽  
Dose Escalation Study

A Phase I/II Trial of the KSP Inhibitor ARRY-520 In Relapsed/Refractory Multiple Myeloma

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 1959-1959 ◽  
Author(s):  
Jatin J Shah ◽  
Jeffrey A. Zonder ◽  
Adam Cohen ◽  
Donna Weber ◽  
Sheeba Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Single Agent ◽  
Clinical Activity ◽  
Employment Equity ◽  
Heavily Pretreated ◽  
Equity Ownership ◽  
Ksp Inhibitor

Abstract Abstract 1959 Background: Kinesin Spindle Protein (KSP) is required for cell cycle progression through mitosis. Inhibition of KSP induces mitotic arrest and cell death. ARRY-520 is a potent, selective KSP inhibitor. Cancers such as multiple myeloma (MM) which depend on the short-lived survival protein MCL-1 are highly sensitive to treatment with ARRY-520. ARRY-520 shows potent activity in preclinical MM models, providing a strong rationale for its clinical investigation in this disease. Methods: This Phase 1 study was designed to evaluate the safety and pharmacokinetics (PK) of ARRY-520 administered intravenously (IV) on Day 1 and Day 2 q 2 weeks without/with granulocyte-colony stimulating factor (G-CSF). Patients (pts) with relapsed/refractory (RR) MM with 2 prior lines of therapy (including both bortezomib and an immunomodulatory agent, unless ineligible for or refusing to receive this therapy) were eligible. Cohorts of at least 3 pts were enrolled in a classical 3 + 3 dose escalation design. Pts were treated for 2 cycles (4 weeks) to evaluate safety prior to dose escalation. Results: Twenty five pts have been treated to date, with a median age of 60 years (range 44–79) and a median of 5 prior regimens (range 2–16). All pts received prior bortezomib or carfilzomib, 21 pts received prior lenalidomide, 17 pts prior thalidomide, and 18 pts had a prior stem cell transplant. Pts received ARRY-520 without G-CSF at 1 mg/m2/day (n = 3), and at 1.25 mg/m2/day (n = 7, 6 evaluable). A dose-limiting toxicity (DLT) of Grade 4 neutropenia was observed at 1.25 mg/m2/day, and this was considered the maximum tolerated dose (MTD) without G-CSF. As neutropenia was the DLT, dose escalation with prophylactic G-CSF support was initiated, at doses of 1.5 mg/m2/day (n = 7, 6 evaluable), 2.0 mg/m2/day (n = 6) and 2.25 mg/m2/day (n = 2) with G-CSF. Both the 2.0 mg/m2/day and 2.25 mg/m2/day dose levels were determined to be non-tolerated, with DLTs of febrile neutropenia (FN) (2 pts at 2.0 mg/m2/day and both pts at 2.25 mg/m2/day) and Grade 3 mucositis (both pts at 2.25 mg/m2/day). One out of 6 evaluable pts at 1.5 mg/m2/day also developed a DLT of FN. In an attempt to optimize the Phase 2 dose, an intermediate dose level of 1.75 mg/m2/day with G-CSF is currently being evaluated. The most commonly reported treatment-related adverse events (AEs) include those observed with other KSP inhibitors, such as hematological AEs (thrombocytopenia, neutropenia, anemia, leukopenia), fatigue, mucositis and other gastro-intestinal AEs. Pts displayed linear PK, a low clearance and a moderate volume of distribution, with moderate-to-high inter-individual variability in PK parameters. The median terminal elimination half life is 65 hours. The preliminary efficacy signal as a single agent is encouraging with 2 partial responses (PR) observed to date per IMWG and EBMT criteria in a heavily pretreated population (23 evaluable pts). A bortezomib-refractory pt with 8 prior lines of therapy, including a tandem transplant, treated at 1 mg/m2/day of ARRY-520 obtained a PR after Cycle 6, with urine protein and kappa light chain levels continuing to decline over time. He remains on-study after 15 months of ARRY-520 treatment. A pt with 2 prior lines of therapy, including prior carfilzomib, has obtained a PR after Cycle 8 at 2 mg/m2/day of ARRY-520, and she is currently ongoing after 4.5 months on therapy. Fifteen pts had a best response of stable disease (SD), including 1 pt with a thus far unconfirmed minimal response, and 6 had progressive disease. A total of 10 pts (43%) achieved a PR or SD lasting > 12 weeks. Several additional pts have shown other evidence of clinical activity, with decrease in paraproteins, increase in hemoglobin levels and regression of plasmacytomas. The median number of cycles is 4 (range 1–28+). Treatment activity has not correlated with any baseline characteristics or disease parameters to date. Conclusions: : The selective KSP inhibitor ARRY-520 has been well tolerated, and shows promising signs of single agent clinical activity in heavily pretreated pts with RR MM. Prophylactic G-CSF has enabled higher doses to be tolerated. No cardiovascular or liver enzyme toxicity has been reported. Enrollment is ongoing at 1.75 mg/m2/day with G-CSF support, and a planned Phase 2 part of the study will be initiated as soon as the MTD is determined. Complete Phase 1 data will be disclosed at the time of the meeting. Disclosures: Shah: Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium: Research Funding. Off Label Use: Revlimid (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma patients who have received at least one prior therapy. Zonder:Millennium: Consultancy, Myeloma and Amyloidosis Patient Day Symposium – Corporate support from multiple sponsors for a one-day educational event, Research Funding; Celgene:; Novartis:; Proteolix: . Weber:novartis-unpaid consultant: Consultancy; Merck- unpaid consultant: Consultancy; celgene- none for at least 2 years: Honoraria; millenium-none for 2 years: Honoraria; celgene, Millenium, Merck: Research Funding. Wang:Celgene: Research Funding; Onyx: Research Funding; Millenium: Research Funding; Novartis: Research Funding. Kaufman:Celgene: Consultancy, Honoraria, Research Funding; Millenium: Consultancy, Honoraria; Merck: Research Funding; Genzyme: Consultancy. Walker:Array Biopharma: Employment, Equity Ownership. Freeman:Array Biopharma: Employment, Equity Ownership. Rush:Array Biopharma: Employment, Equity Ownership. Ptaszynski:Array Biopharma: Consultancy. Lonial:Millennium, Celgene, Bristol-Myers Squibb, Novartis, Onyx: Advisory Board, Consultancy; Millennium, Celgene, Novartis, Onyx, Bristol-Myers Squibb: Research Funding.

Phase 1 study of CPX-1, a fixed ratio formulation of irinotecan (IRI) and floxuridine (FLOX), in patients with advanced solid tumors

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 2014-2014 ◽  
Author(s):  
G. Batist ◽  
K. Chi ◽  
W. Miller ◽  
S. Chia ◽  
F. Hasanbasic ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Phase 1 ◽  
Fixed Ratio ◽  
Compression Fracture ◽  
Drug Combinations ◽  
Molar Ratio ◽  
Open Label ◽  
Dose Escalation Study ◽  
Grade 3

2014 Background: In vitro studies have shown that varying the ratio of individual agents in drug combinations can result in synergistic, additive or antagonistic activity against tumor cells. CPX-1 is a liposomal formulation of IRI and FLOX in a fixed 1:1 molar ratio which was selected as optimal in vitro and confirmed to be synergistic in vivo in preclinical tumor models. CPX-1 overcomes the dissimilar pharmacokinetics (PK) of the individual drugs, enables sustained maintenance of this ratio after IV administration, and was evaluated in a Phase I open-label, dose-escalation study. Methods: Starting dose was 30 U/m2 (1 Unit of CPX-1 contains 1 mg IRI + 0.36 mg FLOX) given on day 1 and 15 of each 28-day cycle. Dose escalation was by modified Fibonacci with 4 subjects/cohort. Eligibility included: ≥ 18 yo; advanced solid tumor; ECOG PS ≤ 2; adequate bone marrow/liver/renal function. PK analysis was done on day 1 and 15 of the first cycle. Results: 26 subjects (16M:10F), median age 54.5 y (21–72), all with prior therapy, enrolled in 6 cohorts with the 5th cohort expanded to 6 subjects. Diagnoses: 8 colorectal, 3 pancreatic, 3 ovarian, 2 breast, 2 gastric, 2 esophageal, 2 sarcomas, 1 renal cell, 1 prostate, 1 NSCLC and 1 sphenoid sinus. Response: 20 subjects evaluable: 2 confirmed PRs (NSCLC 8+ wks; Colon 13+ wks, in a patient with prior IRI exposure) and 13 with SD (8–24+wks). Safety: DLTs were observed at the 6th dose level: 4 subjects with DLTs: 3 diarrhea (one resulting in death due to dehydration/ARF) and one neutropenia. Other possibly related grade 3 and 4 events included one each of: grade 3 diarrhea, grade 3 vomiting, grade 3 neutropenia, grade 3 fatigue, grade 3 compression fracture and arthralgia and pulmonary embolism grade 4. PK: In all 14 subjects analyzed to date the 1:1 molar ratio of IRI to FLOX was maintained for 24 hours and metabolites 5-FU and SN-38 were present in the plasma. Conclusions: CPX-1 represents a new approach to developing drug combinations in which drug ratios are pre-selected in vitro based on optimal antitumor activity and maintained systemically through pharmacokinetic control. Phase 2 studies are planned with a recommended dose of 210U/m2 of CPX-1. [Table: see text]

A phase I, first-in-human, open label, dose-escalation and cohort expansion study of MGD019, a bispecific DART protein binding PD-1 and CTLA-4 in patients with unresectable or metastatic neoplasms.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS2661-TPS2661
Author(s):  
Jason J. Luke ◽  
Manish Sharma ◽  
Rachel E. Sanborn ◽  
Gregory Michael Cote ◽  
Johanna C. Bendell ◽  
...  
Keyword(s):  
Antitumor Activity ◽  
Dose Escalation ◽  
Cell Function ◽  
Immune Cell ◽  
Checkpoint Inhibitors ◽  
Phase 1 ◽  
Single Agent ◽  
Open Label ◽  
Biopsy Specimens

TPS2661 Background: Immune checkpoint molecules, including CTLA-4 and PD-1, attenuate the duration and strength of adaptive immune responses to limit immune-mediated tissue damage. Tumors may inhibit cellular immune activation by expressing ligands that bind checkpoint molecules and inhibit T-cell function in the tumor microenvironment. Blockade of these inhibitory pathways is the primary mechanism of action of several novel cancer immunotherapy agents. Combined blockade of PD-1 and CTLA-4 with two checkpoint inhibitors, ipilimumab and nivolumab, increases antitumor activity beyond either single agent alone in patients with metastatic melanoma or other malignancies. MGD019, a novel bispecific molecule that co-engages and coordinately inhibits both PD-1 and CTLA-4 signaling, was developed to potentially improve antitumor activity and/or safety relative to the monoclonal antibody combination. MGD019 is an Fc-bearing tetravalent DART molecule (bivalent for each antigen) that can independently block either checkpoint molecule, with preferential co-blockade in cells co-expressing both molecules demonstrated in vitro. It is hypothesized that MGD019 might be clinically active in either checkpoint naïve or checkpoint experienced patients after prior PD-1/PD-L1 inhibitors. Methods: This Phase 1 study will characterize safety, dose limiting toxicities, and maximum tolerated dose (MTD)/maximum administered dose (MAD) of MGD019. Dose Escalation will enroll patients with advanced solid tumors of any histology in sequential escalating doses in cohorts of 3 to 9 patients in a 3+3+3 design. Once the MTD/MAD is reached, a Cohort Expansion phase will characterize safety and initial antitumor activity per RECIST v1.1 and irRECIST in patients with specific tumor types anticipated to be sensitive to dual checkpoint blockade. Additional endpoints include pharmacokinetics; immunogenicity; impact of MGD019 on various measures of immune-regulatory effects in peripheral blood and biopsy specimens; and relationship between antitumor activity and gene profiles, tumor mutational burden, and PD-1, PD-L1, and CTLA-4 expression on tumor cells and immune cell infiltrates within biopsy specimens. Patients will be followed for survival approximately every 3 months for 2 years. Clinical trial information: NCT03761017.

scholarly journals MM-004: A Phase 1, Dose-Escalation Study to Determine the Maximum Tolerated Dose, Safety, Efficacy, and Pharmacokinetics of Pomalidomide Alone or in Combination with Dexamethasone in Patients with Refractory or Relapsed and Refractory Multiple Myeloma in Japan

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2107-2107
Author(s):  
Shinsuke Iida ◽  
Hiromi Iwasaki ◽  
Takaaki Chou ◽  
Kensei Tobonai ◽  
Kazutaka Sunami ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Single Dose ◽  
Plasma Concentration ◽  
Dose Escalation ◽  
Research Funding ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Refractory Multiple Myeloma ◽  
Multiple Doses ◽  
Dose Levels

Abstract Background: Patients (pts) with refractory or relapsed and refractory multiple myeloma (RRMM) who have exhausted treatment (Tx) with lenalidomide (LEN) or thalidomide (THAL) and bortezomib (BORT) have shortened overall survival (OS; Kumar, Leukemia, 2012). Pomalidomide (POM) is a novel oral IMiDs® immunomodulatory agent with direct antimyeloma and stromal cell inhibitory effects (Quach, Leukemia, 2010; Mark, Leuk Res, 2014). POM 4 mg (± dexamethasone) is approved in some countries for Tx of pts with RRMM based on phase 3 results showing significant improvement vs high-dose dexamethasone in response, progression-free survival (PFS), and OS and phase 1/2 results showing high and durable overall response rates (ORRs; Richardson, Blood, 2013; Richardson, Blood, 2014; San Miguel, Lancet Oncol, 2013). MM-004 is a phase 1, open-label, dose-escalation study designed to assess the tolerated dose (TD), safety, efficacy, and pharmacokinetics (PK) of POM alone or POM + low-dose dexamethasone (LoDEX) in Japanese pts with RRMM. Methods: Pts must have been ≥ 20 yrs old with a documented diagnosis of MM, have had ≥ 2 prior lines of anti-MM Tx including ≥ 2 cycles of LEN and BORT (alone or in combination), and have RRMM defined as progressive disease (PD) during or within 60 days of completing their last anti-MM Tx. Tx consisted of POM 2 mg (Cohort 1) or 4 mg (Cohort 2) day (D) 1-21 of a 28-D cycle and DEX 40 mg (20 mg for pts > 75 yrs) D1, 8, 15, and 22 (starting on cycle 2). Tx was continued until PD, unacceptable adverse event (AE), or voluntary withdrawal. Pts enrolled in Cohort 1 received a single dose of POM 0.5 mg at D7 for PK evaluation. The primary endpoint was TD; secondary endpoints included ORR based on International Myeloma Working Group criteria, objective response, duration of response (DOR), PFS, PK, and safety. Results: Twelve pts were enrolled (6 in each cohort); 2 pts remain on Tx as of June 27, 2014 (Cohort 2, n= 2). Median age was 68 yrs (range, 52-76 yrs); 75% of pts were aged > 65 yrs. Median number of prior anti-MM Tx was 6 (range, 4-10) and baseline creatinine clearance (CrCl) was ≥ 60 mL/min for all pts except one. Six pts received prior THAL-based Tx (Cohort 1, n= 3; Cohort 2, n= 3). TD was determined to be POM 4 mg D1-21 of a 28-D cycle (a dose-limiting toxicity of grade 4 neutropenia for ≥ 7 days was observed in 1 pt in cohort 1). This result showed that the TD of POM in Japanese pts with MM was the same as that in Caucasian pts with MM. Median duration of treatment was 6.5 cycles in all pts. The best ORR (≥ partial response [PR]) was 25% (3/12 pts) across both cohorts; ORR was 17% (1/6) in Cohort 1 and 33% (2/6) in Cohort 2. Overall median PFS was 5.5 months (5.1 months in Cohort 1; not reached in Cohort 2). Maximum POM plasma concentration (Cmax) was 9.1, 35.6, and 70.2 ng/mL after single dose of POM 0.5, 2, and 4 mg, respectively, and was reached at times ranging from 0.9 to 6 h. Cmax was 37.6 and 71.2 ng/mL after multiple doses of POM 2 and 4 mg. Systemic POM exposure as measured by geometric means of area under the plasma concentration time curve (AUC) was 84.9, 364.4, and 685.7 ng•h /mL after a single doses of POM 0.5, 2, and 4 mg, respectively. AUC was 411.5 and 713.8 ng•h /mL after multiple doses of POM 2 mg and 4 mg. Both Cmax and AUC exposures increased in a dose-proportional manner from 0.5 to 4 mg, as assessed by both visual inspection and statistical analysis. Clearance and volume of distribution were similar across dose levels. The mean half-life (t1/2) of POM was comparable across dose levels, with t1/2 of approximately 6.4, 6.9, and 6 h after single doses of POM 0.5, 2, and 4 mg, respectively. After multiple doses of POM 2 mg and 4 mg, t1/2was approximately 7.3 and 5.5 h. Grade ≥ 3 AEs occurred in 11 pts (92%), and the most frequently reported AE was neutropenia (8 pts, 67%). Other frequently reported AEs (all grades) were thrombocytopenia, anemia, leukopenia, and peripheral edema. Conclusions: POM 4 mg was identified as the TD in Japanese pts with RRMM, which is consistent with previous findings in Caucasian pts with MM. However, pts should be monitored for the known AE profile of POM and managed appropriately. The combination of POM with LoDEX was also found to be tolerable in Japanese pts with RRMM. Systemic exposure to POM increased dose proportionally, and limited drug accumulation was observed following multiple doses. Responses (≥ PR) were observed in 25% of pts. Further investigation of the efficacy and safety of POM + LoDEX in Japanese pts with RRMM in a phase 2 trial is warranted. Disclosures Iida: Celgene Corp: Honoraria, Research Funding. Tobonai:Ono: Research Funding; Lilly: Research Funding; Janssen: Research Funding; Celgene Corporation: Research Funding. Sunami:Celgene Corp: Honoraria. Kurihara:Celgene Corporation: Employment. Midorikawa:Celgene: Employment. Zaki:Celgene : Employment, Equity Ownership. Doerr:Celgene Corp: Employment.

scholarly journals Results of a Phase 1, Dose-Escalation Study of FF-10501-01 in Patients with Relapsed/Refractory Acute Myeloid Leukemia (AML) or Hypomethylating Agent (HMA)-Resistant Myelodysplastic Syndrome (MDS)

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1438-1438 ◽  
Author(s):  
Guillermo Garcia-Manero ◽  
Michael R. Kurman ◽  
Courtney D. DiNardo ◽  
Naveen Pemmaraju ◽  
Yesid Alvarado ◽  
...  
Keyword(s):  
Adverse Events ◽  
Oral Mucositis ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Phase 1 ◽  
Dose Escalation Study ◽  
Blood Concentrations ◽  
Genetics Research ◽  
Refractory Aml

Abstract Introduction FF-10501-01 is an orally bioavailable potent inhibitor of inosine-5-monophosphate dehydrogenase (IMPDH). In vitro, FF-10501-01 reduced the proliferation of multiple human-derived myeloid leukemia parent and hypomethylating agent (HMA)-resistant cell lines in a concentration dependent manner. Incubation of cells with FF-01501-01 also reduced intracellular pools of GMP, GDP and GTP, and this effect was reversed by addition of guanosine, demonstrating that the effect was due to inhibition of IMPDH. FF-10501-01 was evaluated in a Phase 1 clinical trial in patients with relapsed/refractory AML and HMA-resistant MDS and results are presented below. Methods This was an open-label, single-institution, Phase 1, dose escalation study in patients with refractory AML and MDS, or in patients with AML > 60 years of age not eligible for other treatment. The study was conducted as a "3+3" design. The objectives of the study were to describe the adverse event profile, pharmacokinetics, pharmacodynamics, recommended Phase 2 dose (RP2D) and preliminary efficacy of FF-10501-01. Oral FF-10501-01 was administered in escalating doses ranging from 50 - 500 mg/m2 twice daily (BID) for periods of 14, 21 or 28 days in a 28-day treatment cycle and dose escalation to the next dose cohort was governed by the decision of a safety review committee. The pharmacokinetics of FF-10501-01 and its primary active metabolite were determined by measuring blood levels at various times after administration; pharmacodynamics were based on measurements of xanthine monophosphate (XMP) at various time points. The institutional review board of the participating institution approved the protocol and all protocol amendments, and all patients provided written informed consent. Results Thirty-seven patients were treated with FF-10501-01. Most (78%) of patients had AML; the median age of all patients was 78 (range: 58 - 88). All patients had received prior therapy (median number 3, range: 1 - 6) and 3 patients had undergone stem-cell transplantation. FF-10501-01 was well tolerated; the most frequently observed treatment-emergent related adverse events were fatigue (22%), diarrhea (11%), nausea (11%) and oral mucositis (8%). Of all adverse events reported, only 3 were Grade 3 in severity (one episode each of neutropenia, thrombocytopenia and oral mucositis); all others were Grade 1 or 2. The RP2D was determine to be 400 mg/m2 given for 21 days every 28 days. In the MDS cohort, 1 of 8 evaluable patients demonstrated a complete bone marrow response that persisted for 19 months and 3 of 24 evaluable patients with AML demonstrated partial responses; in 1 of these patients, the response persisted for 31 months. One additional patient with AML continued treatment with FF-10501-01 for 14 months without evidence of progression. FF-10501-01 displayed dose proportional pharmacokinetics with no evidence of drug accumulation; mean steady-state observed half-lives ranged from 3 - 9 hours. Blood concentrations of XMP were variable between subjects as a function of dose and time. Following a single administration of FF-10501-01, on average, there appeared to be a reduction in XMP from baseline and maximum inhibition of pre-dose blood concentrations of XMP were consistently near or above 50% following the first administration of FF-10501-01. Conclusion FF-10501-01, was well tolerated and demonstrated evidence of efficacy in a heavily pre-treated population of patients with AML and MDS. FF-10501-01 had predictable pharmacokinetics and pharmacodynamic testing verified its mechanism of action as an IMPDH inhibitor. FF-10501-01 in combination with other agents, is currently undergoing additional clinical testing. Disclosures Kurman: Fujifilm Pharmaceuticals USA, Inc.: Consultancy. DiNardo:Abbvie: Honoraria; Bayer: Honoraria; Medimmune: Honoraria; Agios: Consultancy; Karyopharm: Honoraria; Celgene: Honoraria. Pemmaraju:Affymetrix: Research Funding; SagerStrong Foundation: Research Funding; plexxikon: Research Funding; daiichi sankyo: Research Funding; samus: Research Funding; celgene: Consultancy, Honoraria; abbvie: Research Funding; cellectis: Research Funding; stemline: Consultancy, Honoraria, Research Funding; novartis: Research Funding. Ravandi:Macrogenix: Honoraria, Research Funding; Sunesis: Honoraria; Xencor: Research Funding; Orsenix: Honoraria; Seattle Genetics: Research Funding; Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Xencor: Research Funding; Macrogenix: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding; Abbvie: Research Funding; Abbvie: Research Funding; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Jazz: Honoraria; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Orsenix: Honoraria. Madden:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Maier:Fujifilm Pharmaceuticals USA, Inc.: Consultancy. Iwamura:Fujifilm Corporation: Employment.

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