Phase I Study of Combination Treatment with Hydroxyurea and Magnesium Pidolate in Children with Sickle Cell Anemia.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 686-686
Author(s):  
Jane Hankins ◽  
Lynn Wynn ◽  
Carlo Brugnara ◽  
Cheryl Hillery ◽  
Chin-Shang Li ◽  
...  
Keyword(s):  
Abdominal Pain ◽  
Phase I ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Phase I Study ◽  
Hematologic Toxicity ◽  
Transport Activity ◽  
Cell Dehydration ◽  
Grade Ii ◽  
Grade Iii

Abstract Red blood cell (RBC) sickling is promoted by increased intracellular deoxygenated Hb S concentration and via cell dehydration. Magnesium (Mg) can reduce RBC water loss through its negative regulation of K-Cl cotransport, a pathway which mediates cell dehydration. Hydroxyurea (HU) reduces sickling in part by increasing intracellular fetal hemoglobin (Hb F). The combination of HU and Mg pidolate, two drugs with distinct mechanisms of action, could offer additive or synergistic effects. We performed a phase I study of treatment with HU and Mg pidolate in children with sickle cell anemia (SCA), to estimate the maximum tolerated dose (MTD) and toxicity of this drug combination, and obtained preliminary data regarding cellular effects of this treatment. Children with SCA who had been treated with HU on a stable dose for a minimum of 6 months, received 6 months of treatment with Mg pidolate in addition to HU. The Mg dose was 0.6 mEq/kg/day for the first cohort of patients and was escalated by 50 % in each subsequent cohort to a maximum of 1.9 mEq/kg/d. HU was continued at the patients’ pre-study dose. Compliance was measured using returned bottles and pills counts for both HU and Mg pidolate. Hematologic studies were performed at baseline, 3, and 6 months, and 3 months after Mg pidolate discontinuation (9 months). In vitro RBC adhesion to immobilized thrombospondin was measured under low shear flow conditions. Sixteen patients participated in the study; 9 were boys, and the median age was 7 years (range 4 – 12 years). All were African American and had Hb SS. The median HU dose was 28.5 mg/kg/day (range 25 to 30 mg/kg/d) and the median pre-study HU treatment duration was 1.9 years (range 0.7 – 8.4 years). The MTD for Mg pidolate used in combination with HU was 0.9 mEq/kg/day. The dose limiting toxicity (DLT) of Mg pidolate was diarrhea. There were 4 cases of grade III toxicity (all in the first 4 weeks of the study), 2 cases of grade II and one case of grade I diarrhea. There also were grade III (2), and grade II (3) abdominal pain events. There were no cases of hematologic toxicity, and no patients required HU dose reduction or interruption. Compliance was above 85 % for both drugs in 95 % of the visits. At baseline, high density RBC and KCl co-transport activity were much lower, and intracellular K was much higher than in untreated Hb SS RBC; these values remained relatively stable on Mg pidolate therapy. Mean RBC adhesion to thrombospondin at baseline was low (323 ± 286 RBCs/mm2) and decreased even further to 245 ± 161 RBCs/mm2 during Mg pidolate use. No significant changes in Hb, WBC, platelets, reticulocytes, Hb F, and MCV occurred. We conclude: The MTD for Mg pidolate when used in combination with HU for children with SCA is 0.9 mEq/kg/d, The most common dose-limiting toxicities from Mg pidolate are diarrhea and abdominal pain, There is no additional hematologic toxicity from HU therapy when Mg pidolate is added, RBC adhesion to endothelium may be further decreased in SCA patients treated with HU when Mg pidolate is added, HU therapy when used at 30 mg/kg/day in fully compliant patients may promote decreased RBC adhesion, higher intracellular K, and lower KCl co-transport activity.

A Phase I Study of Tipifarnib Combined with Conventional Induction and Consolidation Therapy for Previously Untreated Patients with Acute Myeloid Leukemia Age 60 and Over.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 899-899 ◽  
Author(s):  
Joseph M. Brandwein ◽  
Brian F. Leber ◽  
Kang Howson-Jan ◽  
Aaron D. Schimmer ◽  
Andre C. Schuh ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Phase I ◽  
Dose Level ◽  
Induction Therapy ◽  
Myeloid Leukemia ◽  
Phase I Study ◽  
Single Agent ◽  
Hematologic Toxicity ◽  
Grade Iii ◽  
Acute Myeloid

Standard induction therapy for patients over age 60 with acute myeloid leukemia (AML) has produced complete response (CR) rates of around 55%, but most patients eventually relapse. Tipifarnib (R115777, ZarnestraR) has shown activity as a single agent in AML, and is well tolerated in older patients at doses up to 600 mg BID. This agent also has additive/synergistic effects on AML cell lines when combined with daunorubicin (DNR). From 2005–2007, patients age 60 and over with previously untreated AML (de novo or secondary) were enrolled in a Phase I study combining tipifarnib with standard induction therapy. The regimen consisted of cytarabine 100 mg/m2/day continuous IV infusion on days 1–7, DNR 60 mg/m2/day IV push x 3 on days 6–8 and tipifarnib orally twice daily on days 6–15. Tipifarnib was escalated over four doses levels in successive patient cohorts (200, 300, 400 and 600 mg). Patients achieving CR were eligible to received one consolidation using the same regimen. Dose-limiting toxicity (DLT) was defined as Grade III–IV non–hematologic toxicity or hematologic recovery times > 40 days unless due to persistent leukemia. Up to 2/6 DLTs were permitted at each dose level. The following DLT’s were identified during induction: Dose level I: 2/6 (grade III hyperbilirubinemia, grade IV transient respiratory arrest), dose level II: 0/3, dose level III: 0/3 and dose level IV: 2/6 (grade III typhlitis, grade III supraventricular tachycardia). Four additional patients were enrolled at dose level IV, with one DLT (grade III diarrhea). There were no DLTs during consolidation. There were no cases of delayed hematologic recovery. Of 22 evaluable patients, there were 9 CR, 3 MLFS, 2 PR and 8 non-responders. Of 7 patients with adverse risk cytogenetics, there were 3 CR, 1 MLFS and 1 PR. In summary, this regimen was well tolerated and the DLT was not reached, although somewhat more GI toxicity was seen at dose level IV. Because of the inherent toxicity of the underlying regimen and the elderly population, it was decided not to escalate further, and tipifarnib 600 mg BID has been chosen as the recommended dose for further study using this regimen.

CTNI-47. INTERIM RESULTS OF NCT03011671: A MULTI-INSTITUTIONAL PHASE I STUDY OF ACETAZOLAMIDE WITH TEMOZOLOMIDE IN ADULTS WITH NEWLY DIAGNOSED MGMT-METHYLATED MALIGNANT GLIOMA

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi70-vi70
Author(s):  
Bakhtiar Yamini ◽  
Seán Lyne ◽  
Riley Driscoll ◽  
Giovanna Bernal ◽  
Longtao Wu ◽  
...  
Keyword(s):  
Phase I ◽  
Malignant Glioma ◽  
Phase I Study ◽  
Objective Response ◽  
Controlled Study ◽  
Current Phase ◽  
Newly Diagnosed ◽  
Biomarker Analysis ◽  
Secondary Endpoints ◽  
Grade Iii

Abstract Preclinical studies indicate that up-regulation of carbonic anhydrase (CA) by temozolomide (TMZ), via a mechanism requiring the proto-oncogene BCL-3, promotes resistance to therapy in glioblastoma (GBM) cells. Moreover, the CA inhibitor, acetazolamide (ACZ), sensitizes patient-derived GBM cells and xenografts to TMZ. These findings led to the current Phase I study investigating the safety and efficacy of adding ACZ to adjuvant TMZ in patients with newly diagnosed, MGMT-methylated malignant glioma. 24 patients were enrolled (23 GBM and one Grade III IDH-mutant astrocytoma), median age was 53.5 and mean KPS 91. ACZ was given on days 1-21 of each adjuvant TMZ cycle (250 mg BID days 1-7, increased to 500 mg BID days 8-21). No patient experienced the primary outcome of regimen limiting toxicity (RLT) and there were only three grade III adverse events deemed likely unrelated to ACZ. For the secondary endpoints of overall and progression free survival (OS and PFS, respectively), only the 23 GBM patients were included (22 IDH-wildtype and 1 IDH-mutant). From diagnosis, median PFS was 18.8 months (95% CI: 10.4-23.0) and median OS was 25.0 months (95% CI: 19.9-28.4). Median time from diagnosis to consent was 2.9 months. As of April 2021, only 7 of 23 deaths had occurred. 2-year OS% was 68.2%. Further analysis of secondary endpoints including 6-month objective response rate (ORR) and biomarker analysis of BCL-3 by IHC will be available in the coming months. In sum, the data indicate that addition of ACZ to TMZ is safe and does not lead to reduced TMZ dosing. Also, compared to historical data, interim outcomes suggest that addition of ACZ may substantially improve PFS and 2-year overall survival. These findings support the hypothesis that ACZ acts as a chemosensitizer of alkylating chemotherapy in GBM and support examination of this regimen in a randomized, placebo-controlled study.

scholarly journals Auto-adjusting positive airway pressure in children with sickle cell anemia: results of a phase I randomized controlled trial

Haematologica ◽  
2009 ◽  
Vol 94 (7) ◽  
pp. 1006-1010 ◽  
Author(s):  
M. J. Marshall ◽  
R. S. Bucks ◽  
A. M. Hogan ◽  
I. R. Hambleton ◽  
S. E. Height ◽  
...  
Keyword(s):  
Randomized Controlled Trial ◽  
Phase I ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Airway Pressure ◽  
Positive Airway Pressure ◽  
Controlled Trial ◽  
Randomized Controlled

Phase I Study of Triapine® and Cytarabine (ara-C) in Patients with Relapsed or Refractory Acute Leukemias and High-Risk Myelodysplastic Syndrome (MDS).

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4925-4925
Author(s):  
Karen W.L. Yee ◽  
Jorge Cortes ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
High Risk ◽  
Phase I ◽  
Dose Level ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Hematologic Toxicity ◽  
Cell Transplant ◽  
Acute Leukemias ◽  
Elevated Liver Enzymes ◽  
Synergistic Cytotoxicity

Abstract Triapine is a potent inhibitor of ribonucleotide reductase (RNR), which is required for the conversion of ribonucleotides to deoxyribonucleotides. Two phase I trials in patients with hematologic malignancies demonstrated that Triapine could reduce circulating blasts in the majority of patients without significant non-hematologic toxicity (Giles et al. Leuk Res2003;27:1077–1083; Karp et al. Blood2002;100:560a). Preclinical studies have shown that the combination of Triapine and ara-C produces additive or synergistic cytotoxicity against several tumor cell lines, potentially by increasing intracellular ara-CTP levels when Triapine inhibits RNR. Therefore, a phase I study of Triapine in combination with ara-C was conducted in 32 patients with relapsed or refractory acute leukemia and high-risk MDS (1 MDS, 28 AML, 2 Ph+ ALL, and 1 Ph- ALL) in order to determine the tolerability, safety, and maximum tolerated dose (MTD). Triapine® was administered at a dose of 105 mg/m2/d as a 6-hour infusion for 5 consecutive days (D1–5) followed immediately by ara-C [100 (n=4), 200 (n=6), 400 (n=7), or 800 (n=8) mg/m2/d] as an 18-hour infusion for 5 consecutive days (D1–5). Median age was 59 years (range, 15–83 years). Median ECOG status 1 (range, 0–2). Median number of prior therapies was 2 (range 1–9), including prior autologous (n= 2) and allogeneic stem cell transplant (SCT) (n=4). Dose-limiting toxicities (DLTs) were observed at the 800 mg/m2 ara-C dose level (1 patient each with grade 4 mucositis; grade 4 neutropenic colitis, sepsis and death; grade 4 neuropathy; and grade 4 hyperbilirubinemia). Therefore, the study was amended to include an ara-C dose level of 600 mg/m2/d. Seven patients were treated at this dose level without development DLTs. Thirty-one patients received at least 1 course, 2 received 2 courses, and 4 received 3 courses; 1 patient withdrew prior to completion of 1 course of therapy. Of the 31 evaluable patients, 4 (13%) patients (3 AML, 1 Ph+ ALL) achieved a CR (1 at an ara-C dose of 800 mg/m2; 2 at 600 mg/m2; 1 at 200 mg/m2). Two of the responders also achieved a complete cytogenetic remission (including 1 Ph+ ALL). All responses occurred after 1 induction course. One patient went on to receive an allogeneic (SCT) and continues in CR. Duration of responses was 9, 20, 52+, and 73+ weeks. Mean Cmax and AUC achieved for Triapine were 1.13 μg/mL and 251.5 min•μg/mL. The most frequent toxicities included nausea &/or vomiting (66%), elevated liver enzymes (50%; gr. 3 in 22%), fever (47%), diarrhea (41%; gr. 3 in 6%), rash (31%; gr. 3 in 6%), mucositis (28%), hand-foot syndrome (16%; gr. 3 in 3%), and peripheral edema (16%; gr. 3 in 9%). Triapine and cytarabine has activity in patients with relapsed or refractory acute leukemias. The recommended phase II dose is Triapine 105 mg/m2/day for 5 consecutive days (D1–5) followed by ara-C 600 mg/m2/d for 5 consecutive days (D1–5).

Accelerated conformal radiotherapy for stage I non-small cell lung cancer (NSCLC) in patients with pulmonary dysfunction: A CALGB phase I study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 7556-7556 ◽  
Author(s):  
J. Bogart ◽  
D. Watson ◽  
S. Seagren ◽  
A. W. Blackstock ◽  
X. Wang ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Clinical Stage ◽  
Conformal Radiotherapy ◽  
Stage I ◽  
High Risk Population ◽  
Hematologic Toxicity ◽  
Severe Toxicity ◽  
Pulmonary Dysfunction ◽  
Body Radiosurgery

7556 Background: The optimal treatment for medically inoperable stage I NSCLC has not been defined. Methods: CALGB 39904 is a prospective phase I study assessing accelerated once-daily radiotherapy for early stage NSCLC. The primary objectives were to define the maximally accelerated course of conformal radiotherapy; and to describe the short-term and long-term toxicity of therapy. Entry was limited to patients with clinical stage T1N0 and T2N0 NSCLC (< 4 cm) with pulmonary dysfunction (FEV1 <40% predicted, DLCO 45mmHg, V02 max <15m1/kg/min, O2 requirement). The nominal total radiotherapy dose was held constant at 70 Gy, while the number of daily fractions in each successive cohort was reduced (table). Results: The study was activated on 12/15/2000, and closed on 7/29/2005. Forty patients were accrued with 8 on each cohort. One patient on cohort 5 declined protocol treatment leaving 39 eligible patients. Patients were generally female (53%), white (83%), and ECOG performance status = 1 (67%). The median age was 74 (range 48 to 87), and the majority of the patients (73%) had T1N0M0 disease. Treatment was well tolerated without grade 4+ toxicity. There was one hematologic toxicity (lymphopenia) in cohort 2, and one non-hematologic toxicity each in cohort 3 (dyspnea) and cohort 4 (pain).The major repsonse rate was 74% (31% complete response, 43 % partial response), and 26% of patients had stable disease. After a median follow-up of 38.1 months, 21 patients remain alive. The actuarial median survival of all eligible patients is 38.5 months (95% confidence interval= 19.45 to NE). Conclusion: Accelerated conformal radiotherapy was well tolerated in a high-risk population with clinical stage I NSCLC. Outcomes are comparable to prospective reports of alternative therapies, including stereotactic body radiosurgery and limited resection,with less apparent severe toxicity. Further investigation of this approach is warranted. No significant financial relationships to disclose. [Table: see text]

A UGT1A1 genotype-directed phase I study of irinotecan (CPT-11) combined with fixed dose of capecitabine in patients with metastatic colorectal cancer (mCRC)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2554-2554
Author(s):  
T. Kim ◽  
S. Sym ◽  
S. Lee ◽  
M. Ryu ◽  
J. Lee ◽  
...  
Keyword(s):  
Febrile Neutropenia ◽  
Phase I ◽  
Phase I Study ◽  
Maximum Tolerated Dose ◽  
Fixed Dose ◽  
Severe Toxicity ◽  
Common Polymorphism ◽  
Level I ◽  
Grade Iii ◽  
Ugt1a1 Genotype

2554 Background: The risk of severe toxicity of CPT-11 can be in part explained by polymorphism of UGT1A1. The most common polymorphism in Whites is UGT1A1*28. UGT1A1*6 is another common polymorphism in Asians. We designed a phase I study to investigate UGT1A1 genotype-directed maximum tolerated dose (MTD) of CPT-11 plus fixed dose of capecitabine in patients (pts) with Korean mCRC. Methods: Pts with mCRC screened UGT1A1 genotyping (*28 and *6) and were stratified into one of 3 groups according to the number of defective allele (DA): 0 (none of *28 or *6 allele), 1(only one of *28 or *6 allele), and 2 (*28/*28, *6/*6, or double heterozygous for *28 and *6). The dose of CPT-11 was escalated as following: Level -I:200, I:240, II:280, III:320, IV: 350, V: 380 mg/m2 (IV, once every 3 weeks). Capecitabine (1,000 mg/m2 PO BID) was administered on days 2–15 every 3 weeks. Dose limiting toxicity (DLT) and pharmacokinetic analyses was determined at cycle 1. Results: Forty-two pts, median age 50 years, EOOG performance ≤1 were recruited: 0 DA group (18 pts), 1 DA (18), and 2 DA (6). In 0 DA group, two of six pts experienced DLT at 380 mg/m2 with grade III asthenia (1 pts) and febrile neutropenia (1). In 1 DA group, all of two pts experienced DLT at 380 mg/m2 with grade III asthenia. In 2 DA group, two of three pts experienced DLT at 240 mg/m2 with febrile neutropenia (1) and grade IV neutropenia (1). The MTD was defined as CPT-11 350 mg/m2 for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine. Median SN-38G/SN-38 AUC was 10.45, 8.78, and 1.66 in pts with 0, 1, and 2 DA group, respectively. Conclusions: CPT-11 dosing by UGT1A1*28 and *6 genotypes is feasible in Korean pts with mCRC. A dose of CPT-11 350 mg/m2 IV for pts with 0 and 1 DA group and CPT-11 200 mg/m2 for pts with 2 DA group, with capecitabine every 3 weeks, is recommended for further study. [Table: see text] No significant financial relationships to disclose.

Maintenance of elevated fetal hemoglobin levels by decitabine during dose interval treatment of sickle cell anemia

Blood ◽  
2002 ◽  
Vol 99 (11) ◽  
pp. 3905-3908 ◽  
Author(s):  
Joseph DeSimone ◽  
Mabel Koshy ◽  
Louise Dorn ◽  
Donald Lavelle ◽  
Linda Bressler ◽  
...  
Keyword(s):  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Absolute Neutrophil Count ◽  
Neutrophil Count ◽  
Fetal Hemoglobin ◽  
Dose Interval ◽  
Cell Number ◽  
Drug Dose ◽  
Hematologic Toxicity ◽  
Cumulative Toxicity

We have previously demonstrated that 5-aza-2′-deoxycytidine (decitabine) augments fetal hemoglobin (HbF) levels in patients with sickle cell anemia (SS) who did not respond to hydroxyurea (HU). The present study was designed to determine the effect of repeated decitabine dosing on HbF levels and hematologic toxicity over a 9-month treatment period. Seven patients (5 HU nonresponders) were entered. One patient had α-thalassemia sickle cell anemia. Decitabine was administered by intravenous infusion at a starting dose of 0.3 mg/kg per day, 5 days a week for 2 weeks, followed by a 4-week observation period. If the absolute neutrophil count dropped below 1000, the dose was reduced by 0.05 mg/kg per day in the next cycle. A drug dose was obtained for each patient, and it resulted in an elevated HbF without neutropenia (absolute neutrophil count nadir greater than 1500) or evidence of cumulative toxicity. Average HbF and average maximal HbF levels attained during the last 20 weeks of treatment for the 6 SS patients increased to 13.93% ± 2.75% and 18.35% ± 4.46%, respectively, from a pretreatment mean of 3.12% ± 2.75%. Mean and mean maximal hemoglobin (Hb) levels increased from 7.23 ± 2.35 g/dL to 8.81 ± 0.42 g/dL and 9.73 ± 0.53 g/dL, respectively. Individual maximal F-cell number observed during the trial was 69% ± 10.12%. The absence of cumulative toxicity may allow shorter intervals between drug treatments, which may lead to higher hemoglobin and HbF levels after several treatment cycles and, therefore, to greater clinical improvement.

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