A Phase II Study of the HDAC Inhibitor Givinostat In Combination with Hydroxyurea In Patients with Polycythemia Vera Resistant to Hydroxyurea Monotherapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1748-1748 ◽  
Author(s):  
Alessandro Rambaldi ◽  
Guido Finazzi ◽  
Alessandro M. Vannucchi ◽  
Vincenzo Martinelli ◽  
Francesco Rodeghiero ◽  
...  
Keyword(s):  
Polycythemia Vera ◽  
Phase Ii ◽  
Hdac Inhibitor ◽  
Phase Ii Study ◽  
Jak2v617f Mutation ◽  
Response Criteria ◽  
Weekly Dose ◽  
Daily Dose ◽  
Group A ◽  
Group B

Abstract Abstract 1748 Background and purpose. Several agents inhibiting the JAK2V617F mutation are actively investigated in patients with polycythemia vera (PV) and other chronic myeloproliferative neoplasms (MPN) with promising results. Givinostat, an HDAC inhibitor, specifically inhibits proliferation of cells bearing the JAK2V617F mutation and has shown significant activity with good tolerability in clinical studies in MPN patients. The aim of the present study was to evaluate safety and efficacy of two oral doses of Givinostat (50 or 100 mg daily) in combination with hydroxyurea (HU) in PV patients. Methods. In this multicenter, randomized, open-label, phase II study, we treated 44 patients with JAK2V617F positive PV, non-responders (NR) to the maximum tolerated doses of HU monotherapy for at least 3 months. The clinical -hematological response criteria developed by the European LeukemiaNet (ELN) consensus conference (complete and partial response) were used to assess the primary endpoint after 12 weeks of treatment. Recruited patients were randomly assigned to receive Givinostat (50 or 100 mg/die) in combination with the maximum tolerated dose of HU. After week 12, NR patients increased the initial daily dose of Givinostat by 50 mg, while responders continued Givinostat at the initial daily dose. Overall, the treatment lasted up to a maximum of 24 cumulative weeks of drug administration. Results. Baseline demographic and hematological parameters were balanced between the two randomized groups. The mean weekly dose of HU at baseline was 6.75 (range 1.75–14) and 6.25 (1–14) grams and was reduced during the study to 6.25 (range 1.75–14) and 5.75 (0.75-12.25) grams, in the 50 (group A) and 100 mg (group B) Givinostat groups, respectively. Safety. The combination of Givinostat and HU was well tolerated. Only five out of 44 evaluable patients dropped-out before week 12, respectively 2 in group A and 3 in group B. Reasons for treatment discontinuation were grade 2 thrombocytopenia and iperkalemia in group A and panic attack, withdrawal of consent and investigator decision due to safety reason (detection of familiar cardiac disorder unknown at recruitment) in group B. Only two grade 3 not drug related adverse events (AEs) were observed (hyperkalemia and platelet count increase), both occurring in group B. The most frequent grade 2 AEs were thrombocytopenia (4 cases, two in each group), leukopenia (2 cases both in group B) and diarrhea (2 cases, one in each group). Efficacy. Complete (CR) plus partial (PR) response according to ELN response criteria was observed in 50% and 45% of patients in group A and B respectively. Moreover, a notable control of itching was observed at week 12 in most of the 21 evaluable patients affected by severe itching (grade ≥ 2) at baseline. Seven out of 11 (64%) and 8 out of 10 (80%) patients had a complete itching relief, in group A and B respectively. Conclusions. The combined use of Givinostat and HU is well tolerated and about 50% of patients resistant to HU monotherapy achieved an overall ELN response (PR or CR). At week 12 no differences were found in the two randomized arms in term of hematological responses and itching relief. Givinostat confirms to be active in PV through the control of myeloproliferation and of some specific clinical needs, such as severe itching. Completed clinical and molecular data (after 24 cumulative weeks of treatment) will be presented at the meeting. Disclosures: Rambaldi: Italfarmaco S.p.A.: Consultancy, Honoraria. Vannucchi:Italfarmaco S.p.A.: Consultancy, Honoraria. Barbui:Italfarmaco S.p.A.: Consultancy, Honoraria.

Randomized Phase II Study of Temozolomide and Radiotherapy Compared With Radiotherapy Alone in Newly Diagnosed Glioblastoma Multiforme

2005 ◽  
Vol 23 (10) ◽  
pp. 2372-2377 ◽  
Author(s):  
Helen Athanassiou ◽  
Maria Synodinou ◽  
Evagelos Maragoudakis ◽  
Mihalis Paraskevaidis ◽  
Cosmas Verigos ◽  
...  
Keyword(s):  
Phase Ii ◽  
Phase Ii Study ◽  
Malignant Gliomas ◽  
Progression Free Survival ◽  
Combined Modality Treatment ◽  
Newly Diagnosed ◽  
Randomized Phase Ii ◽  
Group A ◽  
One Year ◽  
Group B

Purpose Surgery remains the standard treatment for glioma, followed by radiotherapy (RT) with or without chemotherapy. Despite multidisciplinary approaches, the median survival time for patients with glioblastoma multiform (GBM) remains at less than 1 year from initial diagnosis. Temozolomide (TMZ), an oral alkylating agent, has shown promising activity in the treatment of malignant gliomas. We conducted a multicenter randomized phase II study comparing the efficacy and safety of TMZ administered concomitantly and sequentially to RT versus RT alone in patients with newly diagnosed GBM. Patients and Methods One hundred thirty patients with pathologically confirmed, newly diagnosed GBM were randomly assigned (110 assessable patients) to receive either TMZ 75 mg/m2/d orally, concomitantly with RT (60 Gy in 30 fractions; group A, n = 57), followed by six cycles of TMZ (150 mg/m2 on days 1 through 5 and 15 to 19 every 28 days), or RT alone (60 Gy in 30 fractions; group B, n = 53). Results Median time to progression was 10.8 months in group A and 5.2 months in group B (P = .0001). One-year progression-free survival rate was 36.6% in group A and 7.7% in group B. Median overall survival (OS) time was also significantly better in group A versus group B (13.4 v 7.7 months, respectively; P < .0001), as was the 1-year OS at 56.3% v 15.7% (P < .0001), respectively. Toxicity was mainly hematologic. One patient with grade 4 myelotoxicity died as a result of sepsis. The other side effects were mild. Conclusion TMZ combined with RT (concomitantly and sequentially) seems to be more effective than RT alone in patients with newly diagnosed GBM. The combined-modality treatment was well tolerated.

scholarly journals IMMU-08. reMATCH PROTOCOL: PHASE II STUDY OF EX-VIVO EXPANDED AUTOLOGOUS TUMOR SPECIFIC LYMPHOCYTE TRANSFER (X-ALT) + TOTAL TUMOR RNA DC VACCINE (TT-RNA DC) DURING RECOVERY FROM MYELOABLATIVE CHEMOTHERAPY (MAC) AND PERIPHERAL BLOOD STEM CELL (PBSC) RESCUE OR NON-MYELOABLATIVE CHEMOTHERAPY (NMAC) AND PBSC IN PATIENTS (PTS) WITH RECURRENT PNET (R-PNET)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii361-iii361
Author(s):  
Sridharan Gururangan ◽  
Eugene Hwang ◽  
Girish Dhall ◽  
Oleg Yegorov ◽  
Lance Governale ◽  
...  
Keyword(s):  
Rna Sequencing ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Bone Marrow Involvement ◽  
Autologous Tumor ◽  
Myeloablative Chemotherapy ◽  
Dc Vaccine ◽  
Group A ◽  
Correlative Studies ◽  
Group B

Abstract A phase II study was performed to assess vaccine-related toxicities and efficacy of x-ALT+tt-RNA DC following MAC +PBSC (group A) or NMAC +PBSC (group B) in pts with r-PNET. METHODS: Eligible pts underwent biopsy to confirm r-PNET and obtain tumor for vaccine preparation. Pts with local (group A) or metastatic (group B) disease received cytoreductive induction chemotherapy prior to either MAC (carboplatin+ thiotepa+ etoposide) or NMAC (cyclophosphamide + fludarabine) respectively and then received one dose of x-ALT (3 x 107cells/kg), PBSC, and 3 doses of bi-weekly intradermal tt-RNA DCs (107cells each). Patients were followed for survival and vaccine-related toxicities. Correlative studies included TCR RNA sequencing and measurement of serum cytokines. RESULTS: 20 evaluable pts (75% males) [Medulloblastoma 17, PNET 3; unifocal 40%] were treated on protocol (group A 7, group B 13). There were no significant vaccine-related toxicities. At a median follow-up of 8.5 months, 5 patients (all with medulloblastoma) are alive following vaccine therapy; 2 pts with SD (3.5+ and 6.5+ months) and 3 pts with PD that stabilized with salvage therapies (26+, 31+, and 46+ months respectively). One patient with medulloblastoma and bone marrow involvement who had PD despite MAC, had an almost complete response one month following x-ALT + tt-RNA DCs and TCR RNA sequencing demonstrated massive clonal expansion of T cells. Correlative studies are ongoing. CONCLUSIONS: x-ALT+tt-RNA DC following either MAC or NMAC is safe and shows signs of biologic and possible clinical activity in some pts with r-PNET.

Updated survival results of the randomized phase II study of S-1, oral leucovorin, and oxaliplatin combination therapy (SOL) versus mFOLFOX6 in patients with untreated metastatic colorectal cancer (mCRC).

2012 ◽  
Vol 30 (4_suppl) ◽  
pp. 586-586 ◽  
Author(s):  
Toshio Otsuji ◽  
Kentaro Yamazaki ◽  
Hitoshi Ojima ◽  
Hiroyuki Kuwano ◽  
Takeshi Kato ◽  
...  
Keyword(s):  
Phase Ii ◽  
Survival Data ◽  
Phase Ii Study ◽  
Performance Status ◽  
Molecular Target ◽  
Phase Iii ◽  
Randomized Phase Ii ◽  
Group A ◽  
Group B

586 Background: We previously reported short term results of a randomized phase II study comparing SOL with mFOLFOX6 in terms of progression-free survival (PFS) by central review. The median PFS for SOL and mFOLFOX6 was 9.6 and 6.9 months (HR= 0.83; 95%CI, 0.49-1.40) with median follow-up time 14 months (Ojima et al, ESMO 2011). Here, we report updated overall survival (OS) results with 29 months follow-up. Methods: The inclusion criteria were; 1) histologically proved adenocarcinoma of colon or rectum, 2) age ≥ 20 years, 3) no prior treatment, 4) at least one target lesion by RECIST ver1.0 criteria, 5) ECOG Performance Status 0-1. Patients (Pts) were randomized to receive either S-1 (40-60 mg bid) and oral LV (25 mg bid) for one week and L-OHP (85 mg/m2) on day 1, repeated every 2 weeks (SOL; Group A) or L-OHP (85 mg/m2), l-LV (200 mg/m2), and 5-FU (400 mg/m2, bolus) on day 1, followed by 5-FU (2400 mg/m2, ci, 46 hours), repeated every 2 weeks (mFOLFOX6; Group B). This trial was supported by Taiho Pharmaceutical CO., LTD and Yakult Honsha CO., LTD. ClinicalTrials.gov Identifier: NCT00721916 Results: From July 2008 to July 2009, 107 pts were randomized, and 105 were eligible (56 to Group A and 49 to Group B). When survival data were updated 2 years after the last patient’s enrollment, with no lost cases, median OS for Group A and Group B was 28.5 and 25.9 months (HR= 0.76; 95%CI, 0.45-1.31), 2-year survival rate was 71.4% and 59.2%, respectively. The incidences of grade 3/4 adverse drug reactions were; neutropenia (19.6% Group A, 41.2% Group B), lymphopenia (14.3% and 5.9%), sensory neuropathy (19.6% and 2.0%), anorexia (12.5% and 7.8%), fatigue (10.7% and 5.9%) and diarrhea (10.7% and 3.9%). Post treatments with or without molecular target agents were performed for 80.4 % of Group A, and 75.5 % of Group B. Conclusions: The results of the present analysis show that SOL might be more effective than mFOLFOX6 in terms of both PFS and OS as the first line chemotherapy for mCRC. Further investigation of the SOL regimen, a phase III trial of its combination with molecular target agents should be considered.

Efficacy and safety of nivolumab and trabectedin in pretreated patients with advanced soft tissue sarcomas (STS): Preliminary results of a phase II trial of the German Interdisciplinary Sarcoma Group (GISG-15, NitraSarc) for the non-L sarcoma cohort.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 11545-11545
Author(s):  
Daniel Pink ◽  
Dimosthenis Andreou ◽  
Anne Flörcken ◽  
Alexander Golf ◽  
Stephan Richter ◽  
...  
Keyword(s):  
Phase Ii ◽  
Single Agent ◽  
Primary Efficacy ◽  
Primary Efficacy Endpoint ◽  
Efficacy And Safety ◽  
Disease Stabilization ◽  
Group A ◽  
Pretreated Patients ◽  
Grade 3 ◽  
Group B

11545 Background: Single-agent PD-1 inhibitors have modest activity in the treatment of most STS. Potential strategies to increase efficacy include combination therapies targeting the tumor microenvironment. Considering that apart from direct growth inhibition and death of malignant cells, trabectedin (Tr) also induces macrophage depletion and/or different immunologic effects, suggesting a possible synergistic effect of combined Tr plus anti-PD-1 treatment. We therefore aimed to evaluate the efficacy and safety of combined Tr and nivolumab (Ni) as a second-line treatment in STS. Methods: The prospective, explorative, two group, non-randomized phase II NiTraSarc trial enrolled pretreated patients (pt) with advanced STS (Group A: lipo- or leiomyosarcomas, Group B: non-L-sarcomas). Pt were initially treated with 3 cycles of Tr 1.5 mg/m2, followed by the combination of Tr 1.5 mg/m2 + Ni 240 mg (“late combination cohort” (LCC)) for up to 16 cycles. After positive results of a preplanned interim analysis, pt received the combination therapy starting with cycle 2 (“early combination cohort” (ECC)). 92 pt were recruited to the trial (55 in Group A, 37 in Group B). Primary efficacy endpoint is progression-free survival rate after 6 months (PFSR6) according to RECIST v.1.1. This is a first analysis of the primary efficacy endpoint in Group B based on a modified intention-to-treat (mITT) population of evaluable 36 pt: 23 and 13 pt from the LCC and ECC, respectively. Results: The most common Group B subtypes comprised undifferentiated pleomorphic/not otherwise specified sarcoma (UPS/NOS, 13pt) and fibromyxoid sarcoma (FMS, 6pt). After a median follow-up of 5 months (m) PFSR6 was 13.9% for all pt, 8.7% in LCC and 23.1% in ECC. Median duration of disease stabilization (DoDS) was 4m in all pt, the LCC and the ECC. Two pt had a partial response (PR), 10 had disease stabilization (SD), while 13 pt progressed, and 11 had missing data. By subtype: PR- UPS/NOS=2 (DoDS 12.7m/12.5m). SD: UPS/NOS=3, epithelioid=2, synovial=2, FMS=1, fibrosarcoma=1, other=1. All 36 pt experienced at least one adverse event (AE) reaching a total of 579 AEs, 141 (24.4%) of which were considered to be grade ≥3 treatment-related AEs. The main grade ≥3 AEs were: leukopenia (47.2% of pt), neutropenia (41.7% of pt), thrombocytopenia (33.3% of pt), increased ALT (30.6% of pt), and anemia (27.8% of pt). Conclusions: Tr+Ni was well tolerated and showed activity in at least some patients with non-L-sarcomas (mostly UPS/NOS) especially in the ECC. Analyses of the collected data, including PD-L1 expression profile, with the goal to establish whether Tr+Ni should be further pursued in these patients, are ongoing. ClinicalTrials.gov Identifier: NCT03590210; EudraCT: 2017-001083-38. Clinical trial information: NCT03590210.

scholarly journals Time out: should vitamin D dosing be based on patient's body mass index (BMI): a prospective controlled study

2021 ◽  
Vol 10 ◽  
Author(s):  
Mir Sadat-Ali ◽  
Khalid W. AlTabash ◽  
Haifa A. Al-Turki ◽  
Sulaiman A. AlMousa ◽  
Hasan N. AlSayed
Keyword(s):  
Vitamin D ◽  
Vitamin D3 ◽  
Standard Dose ◽  
Demographic Data ◽  
Controlled Study ◽  
Daily Dose ◽  
Calcium Phosphorus ◽  
Group A ◽  
Pre Treatment ◽  
Group B

Abstract The recommended daily dose of vitamin D is 2000 IU was found to be insufficient in many patients. The objective of the present study is to find whether the daily dose of vitamin D should be based on BMI. Two hundred and thirty patients with an established vitamin D deficiency (serum level of 25 Hydroxy vitamin D3 (25OHD3) of ≤20 ng/ml) and patients with BMI ≥30 kg/m2 were included in the study. Demographic data, comorbidities and BMI were recorded. Pre-treatment and post-treatment serum 25OHD3, calcium, phosphorus and parathyroid hormone (PTH) were tested at 0-, 3- and 6-month periods. Patients were treated with a standard dose of 50 000 IU of vitamin D weekly and 600/1200 mg of calcium a day. Once their level of 25OHD3 reached ≥30 ng/ml, patients were randomised into two groups. Group A received a standard recommended maintenance dose of 2000 IU daily and Group B patients received 125 IU/kg/m2 of vitamin D3. The data were entered in the database and analysed. The mean age of Group A was 50⋅74 ± 7⋅64 years compared to 52⋅32 ± 7⋅21 years in Group B. In both groups, pre-treatment vitamin D level was ≤15 ng/ml and increased to 34⋅6 ± 2⋅6 and 33⋅7 ± 2⋅4 ng/ml at the end of 3 months treatment with a dose 50 000 IU of vitamin D3 and calcium 600/1200 mg once a day for group A and group B, respectively. At 6 months, patients in Group A 25OHD3 level was 22⋅8 ± 3⋅80 and in Group B was 34⋅0 ± 1⋅85 ng/ml (P < 0⋅001). This preliminary study suggests that obese patients need higher dosage of vitamin D than the recommended dose. It is prudent that the dosage should be based on the BMI to maintain normal levels for a healthy musculoskeletal system.

THE THROMBOTIC COMPLICATIONS OF TWO GROUPS OF PATIENTS WITH DIFFERENT INR THERAPEUTIC RANGES. THE NECESSITY OF INTENSE ORAL ANTICOAGULANT TREATMENT

1987 ◽  
Author(s):  
Ir Kontopoulou-Griva ◽  
J Spiliotopoulou ◽  
L Digenopoulou ◽  
J Georgopoulos
Keyword(s):  
High Risk ◽  
Oral Anticoagulant ◽  
Heart Valves ◽  
Oral Anticoagulants ◽  
Anticoagulant Treatment ◽  
Oral Anticoagulant Treatment ◽  
Daily Dose ◽  
Group A ◽  
Thrombotic Complications ◽  
Group B

One of the reasons why oral anticoagulants fell into disrepute is the absence of internationally acceptable standarised procedures for controlling the level of anticoagulation. This deplorable situation resulted in over and under coagulation and uncertainty in the therapeutic range. The International Normalised Ratio (INR) can safely be applied in patients on oral anticoagulants.We present two Groups of patients under long term anti coagulation, mainly because of prosthetic heart valves that have recently been added to our outpatients clinic. These patients were till then attended by two cardiologists with different attitudes on the intensity of the anticoagulant treatment. The thromboplastin reagent used is that of ox origin and the results are expressed on INR.The Group A with 32 patients had at the time that we started attending them an INR x = 1,80 ± 0,48 and a daily dose of acenocoumarol x = 1,65 ± 0,51.The Group B with 49 patients had an INR x = 2,75 ± 0,51 and a daily dose of acenocoumarol x = 2,52 ± 1,53.Seven patients of the Group A referred thrombotic complications, while three patients of the Group B referred transiant thrombotic complications.The statistical analysis with the t-test of the INR between the two Groups is p<0,001 while that of the thrombotic complication with the x2 is p<0,05.The introduction of the INR and the acceptance by the medical people of the necessity of the intense oral anticoagulant treatment especially on high risk patients with mechanical heart valves as is the majority of the presented patients, will minimize the thromboembolic complications without high risk of bleeding.

Trimetrexate in malignant mesothelioma: A Cancer and Leukemia Group B Phase II study.

1994 ◽  
Vol 12 (7) ◽  
pp. 1436-1442 ◽  
Author(s):  
N J Vogelzang ◽  
L B Weissman ◽  
J E Herndon ◽  
K H Antman ◽  
M R Cooper ◽  
...  
Keyword(s):  
Treatment Group ◽  
Phase Ii ◽  
Malignant Mesothelioma ◽  
Phase Ii Study ◽  
Survival Rates ◽  
Complete Response ◽  
Large Trial ◽  
Treatment Groups ◽  
Group B ◽  
Leukemia Group

PURPOSE Folic acid antagonists are reported to have activity against mesothelioma. The Cancer and Leukemia Group B (CALGB) undertook this phase II study of the new antifolate, trimetrexate (TMTX), to evaluate its response rate and toxicity in chemotherapy-naive patients with malignant mesothelioma. PATIENTS AND METHODS Fifty-two patients were accrued to this protocol. Because of concerns about TMTX toxicity in patients with malignant effusions and/or hypoalbuminemia, the first 17 patients were treated at a dose of 6 mg/m2 daily for 5 days every 21 days. Because minimal toxicity was observed, the subsequent 35 patients were treated at a dose of 10 mg/m2. RESULTS Two of 17 patients (12%) in the 6-mg/m2 treatment group had a partial response (PR) and four of 34 eligible patients (12%) in the 10-mg/m2 treatment group had a PR or regression (R) of assessable disease. No patient achieved a complete response (CR). Median survival durations were 5.0 and 8.9 months in the 6- and 10-mg/m2 treatment groups, respectively, while the 2-year survival rates were identical at 18%. At the 10-mg/m2 dose, toxicity was tolerable, with one toxic death from sepsis and a 12% rate of grade 4 thrombocytopenia and granulocytopenia. CONCLUSION In this large trial, TMTX showed minor activity in the treatment of malignant mesothelioma. Myelosuppression was mild and dose-related. Future studies of higher doses of TMTX should be considered.

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