Phase I study of lurbinectedin (PM11083) in patients with advanced AML and MDS.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. e18521-e18521 ◽  
Author(s):  
Christopher Brent Benton ◽  
Jose Rodriguez Diaz -Pavon ◽  
Abhishek Maiti ◽  
Naval Guastad Daver ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Phase I ◽  
Single Agent ◽  
Dna Minor Groove ◽  
Oral Herpes ◽  
Risk Patients ◽  
Md Anderson ◽  
Dose Levels

e18521 Background: The FDA-approved drug trabectedin is a DNA minor groove binder (MGB) with activity against translocation-associated sarcomas. Lurbinectedin is a next-generation MGB, with activity against myeloid leukemia cells. A phase I clinical trial was initiated to determine recommended doses in MDS/AML. Further assessment of its safety, tolerability, and pharmacogenetics were studied. Methods: In total, 42 patients with relapsed/refractory MDS/AML received lurbinectedin, using a 3+3 study design. It was administered as a 1-hour IV infusion first at 3.5, 5, 6, and 7mg per dose on days 1 and 8. Subsequently, it was administered on days 1, 2, and 3, using 1, 1.5, 2, or 3mg per dose per patient. Results: Three patients had dose-limiting toxicities (DLTs), which were rhabdomyolysis (up to gr 4), hyperbilirubinemia (gr 3), and oral herpes (gr 3). All DLTs occurred in the 6 and 7mg cohorts. Adverse events included febrile neutropenia/infections (n = 3), GI (n = 6) and pulmonary (n = 2) toxicity, hyperhidrosis (n = 1), and QT prolongation (n = 1). Overall, 33 of 42 patients (79%) had reduction of blasts in peripheral blood (PB) or bone marrow (BM) at nadir, including 23 (55%) with > 50% reduction in PB blasts alone (n = 18) or both BM and PB blasts (n = 5). One patient had PR, 2 patients had morphologic leukemia-free survival, and most (n = 30) were discontinued for progressive disease. Early deaths occurred from disease-related causes, not attributable to lurbinectedin. Thirty-two patients treated at MD Anderson were analyzed for clinical characteristics and responses. Notably, among patients with follow-up bone marrow biopsy, those with a cytogenetic abnormality at chromosome 11q21-23 had significantly greater bone marrow blast reduction than those without such abnormality (change in percentage blasts: -31±14% [n = 4] vs. 8±8% [n = 16], respectively; P= 0.04). Conclusions: Lurbinectedin is generally safe and tolerated at dose levels tested. While no sustained remissions > 3 cycles were observed in these highest-risk patients, single-agent lurbinectedin was transiently leukemia suppressive for some patients, including some with abnormal chr11q or TP53 mutation. Rational combinations and situational uses of lurbinectedin are under consideration. Clinical trial information: NCT01314599.

A Phase I Study of Sequential Azacitidine and Lenalidomide for Elderly Patients with Acute Myeloid Leukemia (AML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3288-3288
Author(s):  
Daniel A Pollyea ◽  
Holbrook E Kohrt ◽  
Leonel Gallegos ◽  
Caroline Berube ◽  
Steven Coutre ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Phase I ◽  
Disease Progression ◽  
Dose Escalation ◽  
Dna Methyltransferase ◽  
Single Agent ◽  
World Health ◽  
Cell Transplant ◽  
Bone Marrow Biopsies

Abstract Abstract 3288 Introduction: The elderly constitute the majority of patients (pts) with AML. Effective and tolerable therapeutic alternatives are necessary for these pts, in whom outcomes with standard induction therapy are poor. Azacitidine (AZA), a DNA methyltransferase inhibitor, decreases methylation of tumor suppressor gene (TSG) promoters, which correlates with clinical responses. Lenalidomide (LEN), an immunomodulatory and anti-angiogenic agent, has anti-leukemic activity when used as a single agent. We hypothesized that combining these two agents would decrease promoter methylation and upregulate TSG expression. We present the Phase I results of a Phase I/II clinical trial that sequentially combines AZA with LEN in elderly, previously untreated AML pts. Methods: Eligible pts were ≥ 60 years, had a World Health Organization-confirmed diagnosis of non-M3 AML, a performance status (PS) ≤ 2, adequate organ function, no prior leukemia therapy and were not candidates for standard induction. All pts had a white blood cell count ≤ 10,000/mm3 at the time of study entry; the use of hydroxyurea to attain this was permitted. Pts were enrolled into 4 cohorts using a 3+3 dose escalation design. In cohort 1, pts received 75 mg/m2 AZA SC/IV on d 1–7, followed by 21 days of observation for a 28-day cycle. At the completion of this “cycle 0,” pts were escalated to cycle 1, in which they received the same dose and schedule of AZA followed by LEN 5 mg PO daily on d 8–28, and then observation on d 29–42. Cohorts 2, 3 and 4 received the same dose and schedule of AZA with LEN doses of 10, 25 and 50 mg respectively, at the same schedule described for cycle 1. Intra-cohort dose escalation after cycle 0 was not permitted. Baseline bone marrow biopsies were compared to biopsies obtained after cycles 0, 1, 3, 6 and 12, and response assessments were based on International Working Group criteria. Adverse events (AEs) were graded according to the NCI CTCAE v 3.0. Pts were eligible for a maximum of 12 cycles, provided they tolerated therapy and achieved a response (defined as a complete response [CR], a CR with incomplete recovery of blood counts [CRi] or a partial response [PR]). Result: Eighteen pts were enrolled between April 2009 and July 2010. The median age was 72 years (64-86), 67% were male and 94% were Caucasian. The median PS was 1 (0-2) and the median hematopoietic cell transplant comorbidity index score was 0.5 (0-4). Six of 18 (33%) required hydroxyurea prior to enrollment. Seven of 18 (39%) had de novo AML and 11/18 (61%) had secondary AML (1 therapy-related, 1 evolved from primary myelofibrosis and 9 with myelodysplasia-related changes). The median bone marrow blast percentage was 63.5% (21-91%). Three of 18 (17%) pts had adverse cytogenetics, while 15/18 (83%) pts exhibited intermediate grade cytogenetics (11/15 with normal karyotype). Grade 3 serious AEs with a suspected relationship to treatment included neutropenic fever (NF) (n=5), fatigue (n=3), renal insufficiency (n=2), hyponatremia (n=1) and bleeding (n=1). In Cohort 4, 1/6 pts experienced grade 4 NF; however, 5/6 did not experience DLT, and therefore, the MTD was not reached. Pts have completed a median of 2 treatment cycles (0-6), with a median follow up of 94 days (21-275). Presently, of the 17 evaluable pts, 9/17 (53%) are alive. The overall response rate (ORR; defined as CR+CRi+PR) is 8/17 (47%) and the CR+CRi rate is 4/17 (24%). Thirty-day mortality was 12% (2/17); both deaths occurred in the first cohort in pts who had not received the drug combination, and were related to disease progression. Of the 5 pts enrolled in cohort 1, none responded, and all ultimately died of disease progression. However, among those in cohorts 2–4, 9 of 12 (75%) evaluable pts are alive with an ORR of 67% (CR+CRi= 4/12 [33%]), a median of 104 days after initiation of treatment (42-275). No responder has relapsed to date. Of the 3 post-cohort 1 deaths, 1 was from disease progression and 2 were from infectious complications. Conclusion: The sequential combination of AZA and LEN was well tolerated in elderly, untreated AML pts. The MTD was not reached at the highest dosing cohort, and the Phase II dose and schedule is AZA 75 mg/m2 d 1–7 and LEN 50 mg d 8–28, on a 6-week cycle schedule. The preliminary ORR of 47% is encouraging, as is the 67% ORR in pts who received ≥10 mg of LEN. Six month follow up will be presented. This trial was registered at ClinicalTrials.gov as NCT00890929. Disclosures: Off Label Use: Azacitidine and lenalidomide for AML. Liedtke:Celgene: Lecture Fee, Research Funding.

scholarly journals SP017ONE-YEAR FOLLOW-UP OF A PHASE I CLINICAL TRIAL ON THE USE OF BONE MARROW MESENCHYMAL STROMAL CELLS IN ADPKD PATIENTS

2016 ◽  
Vol 31 (suppl_1) ◽  
pp. i92-i92
Author(s):  
Atieh Makhlough ◽  
Soroosh Shekarchian ◽  
Reza Moghadasali ◽  
Seyedeh Esmat Hosseini ◽  
Nasser Aghdami
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Phase I ◽  
Mesenchymal Stromal Cells ◽  
Stromal Cells ◽  
Phase I Clinical Trial

scholarly journals DIPG-52. PHASE I CLINICAL TRIAL OF ONC201 IN PEDIATRIC H3 K27M-MUTANT GLIOMA OR NEWLY DIAGNOSED DIPG

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii297-iii297
Author(s):  
Sharon Gardner ◽  
Rohinton Tarapore ◽  
Jeffrey Allen ◽  
Wafik Zaky ◽  
Yazmin Odia ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Body Weight ◽  
Phase I ◽  
Single Agent ◽  
High Grade Glioma ◽  
Newly Diagnosed ◽  
Liquid Formulation ◽  
Open Label ◽  
Dismal Prognosis ◽  
Expansion Cohort

Abstract H3 K27M-mutant gliomas often manifest as midline gliomas, have a dismal prognosis, and have no effective treatments. ONC201 efficacy has been shown in high-grade glioma preclinical models and durable responses with single agent ONC201 have been reported in adults with recurrent H3 K27M-mutant gliomas. These observations led to a Phase I pediatric clinical trial of ONC201 dosed by body weight. This multi-center, open-label, 3 + 3 dose-escalation and dose-expansion clinical trial (NCT03416530) for H3 K27M-mutant glioma or non-biopsied DIPG has 6 arms: arms A and E determine the RP2D in pediatric post-radiation (recurrent or not-recurrent) H3 K27M-mutant glioma patients with ONC201 administered as an oral capsule as well as a liquid formulation, respectively. Both arms have completed accrual. The study is currently enrolling newly diagnosed DIPG patients to determine the RP2D for ONC201 in combination with radiation (arm B). Dedicated assessment of intratumoral ONC201 concentrations in midline gliomas patients (arm C) and the effects of ONC201 in H3K27M DNA levels in circulating CSF (arm D) are currently enrolling patients. ONC201 as a single agent in patients with progressive H3K27M mutant tumors following irradiation (excluding DIPG/spinal cord tumors) was recently opened (arm F). Once the RP2D is confirmed, there is a dose-expansion cohort to confirm the safety, radiographic efficacy and survival with ONC201. The primary endpoints of arms A, B, and E have been established with the RP2D of 625mg scaled by body weight as a capsule or liquid formulation administered alone or in combination with radiation without incidence of dose-limiting toxicity.

scholarly journals Nontransplant therapy for bone marrow failure

Hematology ◽  
2016 ◽  
Vol 2016 (1) ◽  
pp. 83-89 ◽  
Author(s):  
Danielle M. Townsley ◽  
Thomas Winkler
Keyword(s):  
Bone Marrow ◽  
Aplastic Anemia ◽  
Bone Marrow Failure ◽  
Clonal Evolution ◽  
Single Agent ◽  
Telomere Attrition ◽  
Long Term Follow Up ◽  
Treatment Naïve

Abstract Nontransplant therapeutic options for acquired and constitutional aplastic anemia have significantly expanded during the last 5 years. In the future, transplant may be required less frequently. That trilineage hematologic responses could be achieved with the single agent eltrombopag in refractory aplastic anemia promotes new interest in growth factors after years of failed trials using other growth factor agents. Preliminary results adding eltrombopag to immunosuppressive therapy are promising, but long-term follow-up data evaluating clonal evolution rates are required before promoting its standard use in treatment-naive disease. Danazol, which is traditionally less preferred for treating cytopenias, is capable of preventing telomere attrition associated with hematologic responses in constitutional bone marrow failure resulting from telomere disease.

Cell-Based Regenerative Endodontics for Treatment of Periapical Lesions: A Randomized, Controlled Phase I/II Clinical Trial

2020 ◽  
Vol 99 (5) ◽  
pp. 523-529 ◽  
Author(s):  
C. Brizuela ◽  
G. Meza ◽  
D. Urrejola ◽  
M.A. Quezada ◽  
G. Concha ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Stem Cells ◽  
Mesenchymal Stem Cells ◽  
Phase I ◽  
Umbilical Cord ◽  
Root Canal ◽  
Categorical Variables ◽  
Safety And Efficacy ◽  
Randomized Controlled

A randomized controlled phase I/II clinical trial was designed to evaluate the safety and efficacy of encapsulated human umbilical cord mesenchymal stem cells in a plasma-derived biomaterial for regenerative endodontic procedures (REPs) in mature permanent teeth with apical lesions. The trial included 36 patients with mature incisors, canines, or mandibular premolars showing pulp necrosis and apical periodontitis. Patients were randomly and equally allocated between experimental (REP) or conventional root canal treatment (ENDO) groups. On the first visit, cavity access and mechanical preparation of the root canal were performed. Calcium hydroxide medication was used, and the cavity was sealed. Three weeks later, patients were treated following their assigned protocol of ENDO or REP. Clinical follow-up examinations were performed at 6 and 12 mo. Categorical variables were evaluated by Fisher’s exact test. Quantitative variables were compared using the Mann-Whitney test. The evolution over time of the percentage of perfusion units and the dimensions of lesion and cortical compromise were explored. After the 12-mo follow-up, no adverse events were reported, and the patients showed 100% clinical efficacy in both groups. Interestingly, in the REP group, the perfusion unit percentage measured by laser Doppler flowmetry revealed an increase from 60.6% to 78.1% between baseline and 12-mo follow-up. Sensitivity tests revealed an increase of the positive pulp response in the REP group at 12-mo follow-up (from 6% to 56% on the cold test, from 0% to 28% on the hot test, and from 17% to 50% on the electrical test). We present the first clinical safety and efficacy evidence of the endodontic use of allogenic umbilical cord mesenchymal stem cells encapsulated in a plasma-derived biomaterial. The innovative approach, based on biological principles that promote dentin-pulp regeneration, presents a promising alternative for the treatment of periapical pathology (ClinicalTrials.gov NCT03102879).

Phase I study of temozolomide in children and adolescents with recurrent solid tumors: a report from the Children's Cancer Group.

1998 ◽  
Vol 16 (9) ◽  
pp. 3037-3043 ◽  
Author(s):  
H S Nicholson ◽  
M Krailo ◽  
M M Ames ◽  
N L Seibel ◽  
J M Reid ◽  
...  
Keyword(s):  
Phase I ◽  
Children And Adolescents ◽  
Complete Response ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cancer Group ◽  
Grade 3 ◽  
Dose Levels ◽  
Dose Limiting Toxicity

PURPOSE The Children's Cancer Group conducted a phase I trial of temozolomide stratified by prior craniospinal irradiation (CSI). PATIENTS AND METHODS Children and adolescents with recurrent or progressive cancer were enrolled. Temozolomide was administered orally daily for 5 days, with subsequent courses administered every 21 to 28 days after full hematologic recovery. Dose levels tested included 100, 150, 180, 215, 245, and 260 mg/m2 daily. RESULTS Twenty-seven patients on the non-CSI stratum were assessable for hematologic toxicity. During the first three dose levels (100, 150, and 180 mg/m2 daily), only grades 1 and 2 hematologic toxicity occurred. One patient at 215 mg/m2 daily had grade 3 hematologic toxicity. Three of eight patients (38%) treated at 245 to 260 mg/m2 daily had dose-limiting toxicity (DLT), which included both neutropenia and thrombocytopenia. Twenty-two patients on the CSI stratum were assessable for hematologic toxicity. Hematologic DLT occurred in one of six patients (17%) at 100 mg/m2 daily and in two of four patients (50%) at 215 mg/m2 daily. No nonhematologic DLT occurred; nausea and vomiting occurred in more than half of the patients. After two courses of temozolomide, 10 patients had stable disease (SD), and three patients had a partial response (PR), one of whom subsequently had a complete response (CR) that persists through 24 months of follow-up. CONCLUSION The maximum-tolerated dose (MTD) of temozolomide for children and adolescents without prior CSI is 215 mg/m2 daily and for those with prior CSI is 180 mg/m2 daily for 5 days, with subsequent courses that begin on day 28. Temozolomide is well tolerated and should undergo phase II testing in children and adolescents.

scholarly journals Intravenous Bone Marrow Mononuclear Cells for Acute Ischemic Stroke: Safety, Feasibility, and Effect Size from a Phase I Clinical Trial

Stem Cells ◽  
2019 ◽  
Vol 37 (11) ◽  
pp. 1481-1491 ◽  
Author(s):  
Farhaan S. Vahidy ◽  
Muhammad E. Haque ◽  
Mohammad H. Rahbar ◽  
Hongjian Zhu ◽  
Paul Rowan ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Bone Marrow ◽  
Ischemic Stroke ◽  
Phase I ◽  
Acute Ischemic Stroke ◽  
Effect Size ◽  
Mononuclear Cells ◽  
Phase I Clinical Trial ◽  
Bone Marrow Mononuclear Cells

A Phase I Study of Bortezomib in Combination with ICE (BICE) in Patients with Relapsed/Refractory Classical Hodgkin Lymphoma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3048-3048 ◽  
Author(s):  
Michelle A. Fanale ◽  
Luis E. Fayad ◽  
Barbara Pro ◽  
Felipe Samaniego ◽  
Gracy Zachariah ◽  
...  
Keyword(s):  
Hodgkin Lymphoma ◽  
Single Agent ◽  
Cycle Arrest ◽  
Randomized Phase Ii ◽  
Prior Chemotherapy Regimen ◽  
Pet Ct ◽  
Heavily Pretreated ◽  
Dose Levels ◽  
Preclinical Work

Abstract Background: The proteasome inhibitor bortezomib induces cell cycle arrest and apoptosis of Hodgkin lymphoma (HL) cells. We have demonstrated that bortezomib’s single agent efficacy was limited in heavily pretreated HL patients. However, preclinical work has shown that bortezomib may synergize with chemotherapy. Thus, we evaluated the combination of bortezomib plus ICE chemotherapy in patients with relapsed/refractory HL. Methods: Eligibility: Relapsed/refractory classical HL, Only 1 prior chemotherapy regimen, Prior treatment with anthracycline-containing regimen, No prior ASCT. Regimen: ICE (Moskowitz, C et al 2001). Bortezomib on D1 and D4 at dose levels of 0 = 1 mg/m2, 1 = 1.3 mg/m2, 2 = 1.5 mg/m2. Neulasta given on D5. Cycles were repeated on D14 if platelet count is ≥ 100,000/mm3 and ANC is ≥ 1,000/mm3. After 3 cycles CTs and PET/CT were performed to evaluate response. Hematologic DLT was defined as grade 4 thrombocytopenia or neutropenia lasting greater than 2 weeks. Results: 13 patients enrolled (6 primary refractory and 7 relapsed HL). Median age 32 (range 21–39). 3 patients were treated at dose levels 0 and 1 and 7 patients were treated at dose level 2. 12 patients were evaluable for toxicity and response. The ORR was 75% with 25% CR (1 primary refractory, 2 relapsed) and 50% PR (1 primary refractory, 5 relapsed). PET/CT scans showed negativity in all patients who responded to treatment. 8/9 patients who responded to treatment underwent ASCT (1 patient declined ASCT). All patients who underwent ASCT had successful pheresis and engraftment. At median follow-up of 12 months all 8 patients treated with ASCT are free of relapse. Treatment was well tolerated with no DLTs noted. Reversible grade 4 neutropenia and thrombocytopenia occurred respectively in 33% and 50% of the patients. Median day for retreatment for cycle 2 was D20 and for cycle 3 was D21. There have been no toxicities of peripheral neuropathy, febrile neutropenia, or infection. Conclusions: Our data suggests favorable tolerability and efficacy of bortezomib plus ICE in patients with relapsed/refractory Hodgkin lymphoma. We are planning to confirm these promising results in a randomized phase II trial.

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