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

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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 ◽

10.1182/blood-2018-99-116613 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1438-1438 ◽

Cited By ~ 1

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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Phase I Study of the Antibody-Drug Conjugate Brentuximab Vedotin Combined with Re-Induction Chemotherapy in Patients with CD30-Expressing Relapsed/Refractory Acute Myeloid Leukemia

Blood ◽

10.1182/blood-2018-99-115031 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1431-1431

Author(s):

Amir T. Fathi ◽

Traci M. Blonquist ◽

Ashkan Emadi ◽

Andrew M. Brunner ◽

Gabriela S. Hobbs ◽

...

Keyword(s):

Stem Cell ◽

Phase I ◽

Dose Level ◽

Induction Chemotherapy ◽

Dose Escalation ◽

Research Funding ◽

Antibody Drug Conjugate ◽

Dose Escalation Study ◽

Level 3 ◽

Refractory Aml

Abstract Background: Brentuximab vedotin (BV) is an antibody-drug conjugate (ADC) consisting of an antibody specific for human CD30, an anti-microtubule agent monomethyl auristatin E (MMAE), and a protease-cleavable linker attaching MMAE to the antibody. BV is efficacious therapy against certain CD30-expressing malignancies, including classical Hodgkin lymphoma and anaplastic large cell lymphoma, and is currently approved for use in these diseases. We and others previously demonstrated CD30 expression on a sizeable proportion of primary AML samples as well as cell lines. Given this data, we conducted a phase I dose-escalation trial of BV in combination with re-induction chemotherapy (MEC) for patients with relapsed or refractory AML. Methods: In this phase I, 3+3 cohort dose-escalation study, BV was administered 3 days prior to initiation of MEC re-induction for relapsed or refractory AML. Eligibility for enrollment included adults over age 18, adequate organ function, an ECOG performance status of ≤ 2, and a diagnosis of relapsed or refractory AML with > 20% CD30 expression (as assessed by immunohistochemistry or flow cytometric analysis). On day 1 of the trial, all enrolled participants were initiated on therapy with BV intravenously using three sequential dosing levels (0.9 mg/kg, 1.2 mg/kg, 1.8mg/kg). On day 3, patients were initiated on MEC re-induction chemotherapy (Mitoxantrone 10mg/m2 IV administration for five days [D3-8], etoposide 100mg/m2 IV D3-8, cytarabine 1000mg/m2 IV D3-8). The period of dose limiting toxicity (DLT) assessment occurred during the period of re-induction (approximately D1-35). Once dose escalation for BV reached a dose of 1.8 mg/kg IV, no further escalation would occur. An additional cohort of ten patients were to be treated at this maximum dose, or if a maximum tolerated dose (MTD) was reached, an additional 10 patients were to be treated at this dose. Thereafter, maintenance therapy with BV could be initiated, and administered IV every 21 days, as per dose level during prior re-induction, and continued for up to 12 months. Those eligible for stem cell transplant (SCT) were removed from study for this purpose. Results: 22 eligible patients were enrolled on study. The median age was 58 (range 23-72); 15 (68%) were male, and 20 (91%) were Caucasian. 7 patients (32%) had secondary AML (6 with antecedent MDS and 1 with therapy related AML). 6 (27%) exhibited adverse risk karyotype. FLT3 mutations were seen in 7 (32%), NPM1 in 4 (18%), and CEBPA in 2 (9%). The median degree of blast CD30 expression in those assessed by flow cytometry was 92% (range 30-98%). 6 patients had refractory disease, while the remaining had relapsed AML at time of enrollment. 10 patients (46%) had undergone prior allogeneic stem cell transplantation (SCT), one of whom had undergone two prior stem cell transplants. Three patients were treated at dose level 1, 5 at dose level 2, and 4 at dose level 3. Two of the patients treated at dose level 2 were removed prior to end of DLT period due to lack of response and were replaced, and 1 patient treated at dose level 3 died due to infectious complications prior to end of DLT monitoring period and was replaced. No new attributable toxicities apart from that expected from MEC re-induction alone were seen with the combination therapy. No DLTs were detected, and the recommended phase 2 dose (RP2D) was deemed to be dose level 3 (1.8 mg/kg). An additional 10 patients were treated at the RP2D. Overall, 4 patients achieved a complete remission (CR) and 4 achieved a complete remission with incomplete hematologic recovery (CRi), for a composite remission rate (CCR) of 36% (8/22). Among the 14 patients treated at the RP2D of 1.8mg/kg, 6 achieved a CR or CRi (CCR 43%). Of the remaining cases, one was replaced prior to response assessment and the others experienced progressive disease. The degree of baseline CD30 expression by flow cytometry did not appear to predict for response in this phase 1 dose escalation study, although study of correlative samples is ongoing. Conclusions: BV is well tolerated when administered in conjunction with conventional re-induction chemotherapy in patients with relapsed-refractory AML, in whom CD30 is an intriguing target. Adverse events on this study were predominantly expected and related to marrow suppression from MEC re-induction. No DLT was identified. Additional and larger studies are needed to more comprehensively assess the efficacy of CD30-targeted therapy in AML. Disclosures Fathi: Jazz: Honoraria; Boston Biomedical: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Emadi:NewLink Genetics: Research Funding. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Amrein:Takeda: Research Funding.

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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 ◽

10.1182/blood.v120.21.161.161 ◽

2012 ◽

Vol 120 (21) ◽

pp. 161-161 ◽

Cited By ~ 3

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.

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Phase Ib Multicenter Dose Escalation Study of Carfilzomib Plus Lenalidomide and Low Dose Dexamethasone (CRd) in Relapsed and Refractory Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v114.22.304.304 ◽

2009 ◽

Vol 114 (22) ◽

pp. 304-304 ◽

Cited By ~ 7

Author(s):

Ruben Niesvizky ◽

Luhua Wang ◽

Robert Z Orlowski ◽

William Bensinger ◽

Melissa Alsina ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Low Dose ◽

Alkylating Agents ◽

Single Agent ◽

Data Monitoring Committee ◽

Cell Transplant ◽

Serious Adverse Events ◽

Dose Escalation Study ◽

Phase Ib

Abstract Abstract 304 Introduction: Carfilzomib (CFZ) is a highly specific and irreversible proteasome inhibitor that has demonstrated promising single-agent activity in relapsed/refractory MM and has a favorable side-effect profile with minimal myelosuppression (Vij et.al., ASCO # 8537, 2009). The purpose of this study is to evaluate the safety and activity of CFZ in combination with lenalidomide (LEN) and low dose dexamethasone (loDex). Methods: This phase Ib trial is evaluating 6 dose levels (≥3 subjects each) to define the maximum tolerated dose (MTD) of CRd in relapsed or refractory MM patients. An additional 30 patients will be enrolled at the highest dose level tolerated. Patients who received 1–3 prior therapies, including prior LEN and/or prior bortezomib (BTZ), were eligible for the study. CFZ was administered intravenously (IV) at 15–27 mg/m2 (days 1, 2, 8, 9, 15, 16), LEN at 10–25 mg po (days 1–21), and loDex at 40 mg po (days 1, 8, 15, 22) in 4-week cycles (C). LoDex was reduced to 40 mg once a month starting with cycle 5. The overall response rate (ORR) (≥Partial Remission) was assessed by the IMWG Criteria, with a secondary assessment of Clinical Benefit Response (CBR: ≥ Minimal Response (MR)) using EBMT Criteria for a MR. Results: As of 31 July 2009, 32 subjects have been enrolled in the first 5 cohorts: 26 subjects were evaluable for safety and 20 for response (see Table). Prior therapies (median 2.5) in 26 evaluable subjects included steroids (89%), BTZ (77%), alkylating agents (85%), LEN (54%), thalidomide (46%), anthracyclines (31%) and stem cell transplant (81%). Fifty-four percent (14/26) of subjects had received both LEN and BTZ while 50% of patients were refractory or progressed on one or more prior therapies; 73% of all patients had a history of neuropathy, with two-thirds of the cases related to prior bortezomib or immunomodulatory agents (IMiDs). There have been no dose limiting toxicities in the first 5 dose cohorts. No drug-related serious adverse events (SAEs), peripheral neuropathy or renal events were reported. Hematological AEs have been reversible and manageable including Grade (G) ≥3 thrombocytopenia (4/26), anemia (4/26) and neutropenia (2/26). All but 1 of these events was G3; 1 subject had G4 thrombocytopenia lasting less than 7 days. One subject in Cohort 3 had treatment discontinued due to a non-drug-related infection on day 2 of cycle 1. The current ORR is 55% across all cohorts and the CBR is 65%, (see Table). Initial responses were rapid and occurred within the first 2 cycles, and improved with continuing therapy (≥ 3 months). The median number of days on therapy is currently 183 (range 78-367). Five out of 6 subjects have progressed in cohort 1 but 22 out of 26 subjects enrolled in cohorts 2-5 are still on study. Conclusions: An active dose of CFZ (20mg/m2) in combination with full dose LEN (25 mg) and low-dose dexamethasone (CRd) has been established as a tolerated dose in relapsed MM patients. Dose escalation of CFZ is ongoing in cohort 6 (CFZ 20/27 mg/m2 and LEN 25 mg). The lack of overlapping toxicity of CFZ and LEN allows the use of these agents at full doses and for extended durations >10 months in several cases, despite relapsed or refractory disease. Moreover, prior therapy with BTZ or IMiDs does not preclude a good response to CRd. Based on these data, a Phase 3 trial of CRd vs Rd is planned in relapsed MM in the first half of 2010. Disclosures: Niesvizky: Millenium: Research Funding, Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Seattle Genetics, Inc: Research Funding; Proteolix: Research Funding, data monitoring committee. Wang:Proteolix, Inc.: Research Funding. Bensinger:Celgene: Speakers Bureau. Gutierrez:Proteolix, Inc.: Employment. Kunkel:Proteolix: Consultancy, Employment. Kauffman:Proteolix, Inc.: Employment.

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GEINO 1402: A phase Ib dose-escalation study followed by an extension phase to evaluate safety and efficacy of crizotinib in combination with temozolomide (TMZ) and radiotherapy (RT) in patients with newly diagnosed glioblastoma (GB)

Annals of Oncology ◽

10.1093/annonc/mdz243.011 ◽

2019 ◽

Vol 30 ◽

pp. v147

Author(s):

M. Martinez Garcia ◽

M.J. Gil ◽

E. Pineda ◽

M.C. Martin Soberón ◽

C. Mesia Barroso ◽

...

Keyword(s):

Dose Escalation ◽

Extension Phase ◽

Newly Diagnosed ◽

Dose Escalation Study ◽

Safety And Efficacy ◽

Phase Ib ◽

Newly Diagnosed Glioblastoma

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ASP2215 in Japanese Patients with Relapsed or Refractory Acute Myeloid Leukemia: Preliminary Results from a Phase 1 Open-Label, Dose-Escalation Study

Blood ◽

10.1182/blood.v126.23.1320.1320 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1320-1320

Author(s):

Tomoki Naoe ◽

Toru Sakura ◽

Yukio Kobayashi ◽

Kensuke Usuki ◽

Toshihiro Miyamoto ◽

...

Keyword(s):

Complete Remission ◽

Dose Escalation ◽

Research Funding ◽

Phase 1 ◽

Tumor Lysis Syndrome ◽

Pharmaceutical Research ◽

Japanese Patients ◽

Antileukemic Activity ◽

Dose Escalation Study ◽

Mutation Status

Abstract Background: FMS-like tyrosine kinase 3 (FLT3) mutations in patients with acute myeloid leukemia (AML) are strongly associated with poor prognosis and leukocytosis. Approximately 15-35% of AML patients have internal tandem duplication (ITD) of the juxtamembrane domain-coding sequence and 5-10% have a missense mutation of D835 within the tyrosine kinase domain. ASP2215 potently inhibits FLT3 with established preclinical activity against both ITD and D835 mutations. Preliminary results from a Phase 1/2, first-in-human study suggest ASP2215 is generally well tolerated and associated with antileukemic activity in FLT3 mutation-positive (FLT3+) subjects with relapsed or refractory AML (R/R AML). The safety and antileukemic activity of ASP2215 is currently being evaluated in an ongoing, Phase 1 study in Japanese subjects with relapsed or refractory (R/R) AML. Methods: This open-label, dose-escalation study, conducted in adult Japanese subjects (≥18 years) with R/R AML, consisted of a single- and a repeated-dose periods. ASP2215 (20-300 mg) was orally administered to subjects as a single dose (Cycle 0) and then once daily (Cycle 1 and subsequent cycles, each cycle was 28 days) until one of the discontinuation criteria were met. Dose escalation proceeded in a step-wise manner, based on the onset of dose-limiting toxicity (DLT) during Cycles 0 and 1, with the next dose level determined sequentially using the Bayesian Continual Reassessment Method (CRM). The study design allowed that at least one subject would receive the 20 mg dose and at least three subjects would receive higher doses (40-300 mg) of ASP2215. Primary endpoints included ASP2215 tolerability and determination of maximum tolerated dose (MTD, defined as the dose where posterior mean DLT incidence is ~33% when calculated using Bayesian CRM). Secondary endpoints included clinical response (based on Cheson's criteria) and pharmacokinetic profile. Results: As of June 24, 2015, 18 subjects with a median age of 71.5 years (range: 60-81 years) and 94% with ECOG 0-1 have received ASP2215 at dosages of 20 mg (n=1), 40 mg (n=4), 80 mg (n=4), 120 mg (n=4), and 200 mg (n=5). Three subjects were FLT3-ITD mutation positive, eight were FLT3-ITD negative, and the FLT3-ITD status for the other seven was unknown; FLT3 point mutation status for the majority (94%) of these subjects is not yet available. Only one DLT (tumor lysis syndrome), experienced at the 120 mg dose, has been reported suggesting MTD has not yet been reached. Abnormal hepatic function (n=5) and stomatitis (n=3) were the only treatment-related AEs occurring in ≥3 subjects. Grade ≥3 AEs were thrombocytopenia (n=2), febrile neutropenia (n=1), device-related infection (n=1), tumor lysis syndrome (n=1) and pneumonia (n=1). Five serious AEs deemed to be possibly or probably treatment related by the investigators (febrile neutropenia, edema, pneumonia, device-related infection, subdural hematoma) occurred in three subjects. ASP2215 plasma concentrations increased with doses from 20 mg to 200 mg with median time to maximal concentration of 2-6 hr. A total of 13 subjects had evaluable bone marrow to assess antileukemic activity; six of whom achieved at least partial response (Table). Conclusions: These preliminary findings in Japanese patients with R/R AML suggest ASP2215 is a well-tolerated FLT3 inhibitor with dose dependent increase in PK and has shown antileukemic activity in Japanese patients. ASP2215 tolerability, PK profile, and antileukemic activity are consistent with the ongoing dose-escalation/dose-expansion study being conducted in the US and Europe. Based on the positive findings, randomized Phase 3 trials have been planned. Table 1. Best Clinical Response by ASP2215 Dose and FLT3 Mutation Status Dose (mg) FLT3-ITD mutation status Best response Assessment day with first report of best response 20 Unknown CRi Day 28 40 Negative NR Day 29 Negative PR Day 29 Negative NR Day 29 80 Negative CR Day 28 Negative NR Day 11 Positive PR Day 28 Unknown NR Day 30 120 Negative NR Day 29 Positive CRi Day 57 200 Negative CRp Day 39 Positive NR Day 21 Unknown NR Day 27 CR, Complete remission; CRi, complete remission with incomplete hematologic recovery; CRp, complete remission with incomplete platelet recovery; NR, no response; PR, partial response. Disclosures Naoe: Kyowa Hakko Kirin Co., Ltd.: Patents & Royalties, Research Funding; Pfizer Inc.: Research Funding; Toyama Chemical CO., LTD.: Research Funding; FUJIFILM Corporation: Patents & Royalties, Research Funding; Celgene K.K.: Research Funding; Otsuka Pharmaceutical Co., Ltd.: Research Funding; Chugai Pharmaceutical Co., Ltd.: Patents & Royalties; Nippon Boehringer Ingelheim Co., Ltd.: Research Funding; Astellas Pharma Inc.: Research Funding. Off Label Use: ASP2215 is an investigational product for the treatment of AML. Sakura:Astellas: Other: Principal Investigator of the clinical research; study fee. Kobayashi:Gilead Sciences: Research Funding. Usuki:Kyowa Hakko Kirin: Other: personal fees, Research Funding; Shire: Research Funding; Takeda Pharmaceutical: Research Funding; Fujimoto Pharmaceutical: Research Funding; Shionogi: Other: personal fees; SymBio Pharmaceutical: Other: personal fees, Research Funding; Eisai: Research Funding; Otsuka Pharmaceutical: Research Funding; MSD: Other: personal fees, Research Funding; Sanofi: Other: personal fees, Research Funding; Novartis: Other: personal fees, Research Funding; Nippon Shinyaku: Other: personal fees, Research Funding; GlaxoSmithKline: Other: personal fees, Research Funding; Taiho Pharmaceutical: Other: personal fees, Research Funding; Fuji Film RI Pharma: Other: personal fees; Chugai Pharmaceutical: Other: personal fees; Sumitomo Dainippon Pharma: Other: personal fees, Research Funding; Celgene: Other: personal fees, Research Funding; Boehringer Ingelheim: Other: personal fees, Research Funding; Bristol-Myers Squibb: Other; Astellas: Research Funding. Iida:Astellas: Other: Principal Investigator of the clinical research; study fee. Morita:Astellas: Honoraria, Other: Personal fees. Bahceci:Astellas Pharma Global Development: Employment. Kaneko:Astellas Pharma, Inc.: Employment. Yamada:Astellas Pharma, Inc.: Employment. Takeshita:Astellas Pharma, Inc.: Employment. Miyawaki:Astellas Pharma Inc.: Consultancy, Other: personal fees; Ohtsuka Pharma Co, LTD.: Other: Safety Data Committee.

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