scholarly journals CTNI-26. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING

2021 ◽  
Vol 23 (Supplement_6) ◽  
pp. vi65-vi65
Author(s):  
Barbara O'Brien ◽  
Marta Penas-Prado ◽  
Carlos Kamiya-Matsuoka ◽  
Shiao-Pei Weathers ◽  
W K Alfred Yung ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Safety Data ◽  
Standard Of Care ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Adjuvant Setting ◽  
Group 2 ◽  
Initial Starting ◽  
Recurrent Gbm ◽  
Group 1

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard-of-care treatment, with a median survival of 3-9 months after recurrence. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces interstrand DNA cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independently of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated, bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response is assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of May 2021, Group 1 (Recurrent GBM) is fully enrolled: 35 evaluable patients have received 40 mg/m2/d and 48 evaluable patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 35 evaluable patients have been enrolled (30 mg/m2/day). Enrollment, safety data and efficacy updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

scholarly journals CTNI-72. PHASE 2 STUDY OF DIANHYDROGALACTITOL (VAL-083) IN PATIENTS WITH MGMT-UNMETHYLATED, BEVACIZUMAB-NAÏVE GLIOBLASTOMA IN THE RECURRENT AND ADJUVANT SETTING

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii59-ii59
Author(s):  
Barbara O’Brien ◽  
Marta Penas-Prado ◽  
Carlos Kamiya-Matsuoka ◽  
Shiao-Pei Weathers ◽  
W K Alfred Yung ◽  
...  
Keyword(s):  
Adjuvant Therapy ◽  
Safety Data ◽  
Standard Of Care ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Adjuvant Setting ◽  
Group 2 ◽  
Initial Starting ◽  
Recurrent Gbm ◽  
Group 1

Abstract Current standard-of-care for glioblastoma (GBM) includes surgery followed by concurrent therapy with radiation and temozolomide (TMZ) followed by adjuvant TMZ. Almost all GBM patients experience recurrent/progressive disease despite upfront standard of care treatment, with a median survival after recurrence of 3–9 months. Unmethylated promoter for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for TMZ-resistance and is correlated with poor patient prognosis. VAL-083 is a bi-functional DNA-targeting agent which rapidly induces inter-strand cross-links at N7-guanine inducing double-strand breaks causing cell death and acts independent of MGMT DNA repair. This trial is an open-label two-arm biomarker-driven phase 2 clinical trial in MGMT-unmethylated bevacizumab-naïve GBM patients with either recurrent (Group 1) or newly diagnosed GBM requiring adjuvant therapy after chemo-radiation with temozolomide (Group 2). Patients receive VAL-083 IV at 30 or 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle. The primary objective of this study is to determine the effect of VAL-083 on median overall survival (mOS) in MGMT-unmethylated recurrent GBM patients (Group 1); and progression-free survival (PFS) in newly diagnosed GBM patients requiring adjuvant therapy after chemo-irradiation with temozolomide (Group 2), compared to historical controls in both groups. Tumor response will be assessed by MRI every 42 days, using RANO criteria. The initial starting dose in this study was 40 mg/m2/d on days 1, 2, and 3 of a 21-day cycle, which was subsequently reduced to 30 mg/m2/d to improve tolerance due to myelosuppression. As of June 2-2020, 35 patients with recurrent GBM (Group 1) have received 40 mg/m2/d and 39 patients have received 30 mg/m2/d VAL-083. In the adjuvant setting (Group 2), 25 patients have been enrolled (30 mg/m2/day). Enrollment, safety data and study updates will be presented at the meeting. Clinicaltrials.gov identifier: NCT02717962.

Phase 2, open-label study of pembrolizumab in children and young adults with newly diagnosed classical Hodgkin lymphoma (cHL) with slow early response (SER) to frontline chemotherapy: KEYNOTE-667.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. TPS7567-TPS7567
Author(s):  
Christine Mauz-Körholz ◽  
Kara M. Kelly ◽  
Frank G. Keller ◽  
Rod Ramchandren ◽  
Akash Nahar ◽  
...  
Keyword(s):  
Young Adults ◽  
Risk Group ◽  
Response Assessment ◽  
Early Response ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Deauville Score ◽  
Pet Ct ◽  
Group 2 ◽  
Group 1

TPS7567 Background: High risk for relapse is observed in cHL patients (pts) with SER to initial chemotherapy and organ toxicities may be higher following dose intensification. Methods: The phase 2 KEYNOTE-667 study will enroll 440 pts aged 3 to 17 (children) or 18 to 25 years (young adults) with newly diagnosed, confirmed stage IA, IB, or IIA cHL without bulky disease (Group 1 [low-risk]) or stage IIEB, IIIEA, IIIEB, IIIB, IVA, or IVB cHL (Group 2 [high-risk]); measurable disease; and performance status per Lansky Play-Performance Scale ≥50 (age ≤16 years) or Karnofsky score ≥50 (age >16 years). Pts will receive induction with doxorubicin, bleomycin, vinblastine, dacarbazine (ABVD; Group 1) or vincristine, etoposide/etoposide phosphate, prednisone/prednisolone, doxorubicin (OEPA; Group 2) for 2 cycles, then early response assessment by PET/CT/MRI. Pts with rapid early response (Deauville score 1-3) will receive standard therapy. Pts with SER (Deauville score 4-5) will receive consolidation with pembro 2 mg/kg Q3W up to 200 mg (children) or 200 mg Q3W (young adults) plus 2 cycles AVD (Group 1) or 4 cycles cyclophosphamide, vincristine, prednisone/prednisolone, dacarbazine (COPDAC-28; Group 2). PET/CT for late response assessment (LRA) will be performed after consolidation. After LRA, Group 1 pts with SER and Group 2 pts with Deauville score 4-5 will receive radiotherapy (RT). All pts will receive maintenance with pembro Q3W concomitantly with RT. Pembro will continue up to 17 administrations, with an option to stop after 24 weeks due to CR, or until progression, unacceptable toxicity, or withdrawal. The primary endpoint is ORR per Cheson 2007 IWG criteria by group in SER pts. Secondary endpoints are SERs with PET negativity after consolidation, 2-yr event-free survival (EFS), OS, and RT frequency and details by group, RERs with PET negativity after ABVD induction, 3-yr EFS by investigator, and OS by risk group, and serum TARC levels at screening in SERs by risk group. ORR with 95% CI will be estimated by Clopper-Pearson method. EFS and OS will be estimated by Kaplan-Meier method. Safety will be assessed in all treated pts. Clinical trial information: NCT03407144.

scholarly journals 48 Phase 2 studies of dianhydrogalactitol (VAL-083) in patients with glioblastoma, MGMT-unmethylated

2018 ◽  
Vol 45 (S3) ◽  
pp. S10-S10 ◽  
Author(s):  
JA Bacha ◽  
A Steino ◽  
R Schwartz ◽  
J Langlands ◽  
S Kanekal ◽  
...  
Keyword(s):  
Dna Methyltransferase ◽  
Safety Data ◽  
Standard Of Care ◽  
Primary Objective ◽  
Phase 2 ◽  
Newly Diagnosed ◽  
Current Standard ◽  
In Vivo Models ◽  
Phase 2 Trial

Current standard-of-care for glioblastoma (GBM) includes surgery, radiation and temozolomide. Most tumors recur within a year from diagnosis and median survival for recurrent GBM (rGBM) is 3-9 months. Unmethylated promoter status for O6-methylguanine-DNA-methyltransferase (MGMT) is a validated biomarker for temozolomide-resistance, exhibited by most GBM patients. VAL-083 is a DNA-targeting agent with a mechanism-of-action that is independent of MGMT. VAL-083 overcomes temozolomide-resistance in GBM cell-lines, cancer stem cells, and in vivo models. VAL-083 readily crosses the blood-brain barrier and accumulates in brain-tumor tissue. We recently completed a VAL-083 dose-escalation trial in temozolomide- and bevacizumab-refractory rGBM and determined that 40mg/m2/day given intravenously on days 1,2,3 of a 21-day cycle is generally well-tolerated. This dosing regimen was selected for subsequent GBM trials, including an ongoing single-arm, biomarker-driven Phase 2 trial (N=48) in temolozomide-refractory, bevacizumab-naïve rGBM , MGMT-unmethylated (Clinicaltrials.gov:NCT02717962). The primary objective of this study is to determine if VAL-083 improves OS compared to a historical control of 7.15 months for MGMT-unmethylated rGBM patients treated with lomustine (EORTC26101). In addition, another single-arm, biomarker-driven, Phase 2 study (N=25) of VAL-083 in combination with radiotherapy in newly diagnosed GBM, MGMT-unmethylated is ongoing (Clinicaltrials.gov:NCT03050736). This trial aims to determine a dose for further study of VAL-083 in combination with radiotherapy and explore if VAL-083 improves PFS and OS compared to historical results in newly diagnosed GBM. Enrollment and safety data updates will be provided at the meeting. The results of these studies, if successful, may support VAL-083 as part of a new chemotherapeutic treatment paradigm for GBM.

scholarly journals Hybrid cardiac rehabilitation program as a potential enhancer of adherence to cardiac rehabilitation in smoking patients with coronary heart disease - a retrospective single-centre analysis

2021 ◽  
Vol 28 (Supplement_1) ◽  
Author(s):  
M Cabral ◽  
R Santos ◽  
F Januario ◽  
A Antunes ◽  
R Fonseca-Pinto
Keyword(s):  
Mental Health ◽  
Cardiac Rehabilitation ◽  
Smoking Status ◽  
Rehabilitation Program ◽  
Anxiety And Depression ◽  
Cardiac Rehabilitation Program ◽  
Phase 2 ◽  
Significant Difference ◽  
Group 2 ◽  
Group 1

Abstract Funding Acknowledgements Type of funding sources: None. Cardiac rehabilitation (CR) has well known beneficial effects on physical capacity, health-related quality of life, morbidity and mortality following an acute cardiac event. It is also known that smoking status is a powerful predictor of recurrent cardiovascular disease events. However, it has been noted that smoker patients may be less likely to access or complete CR. The aim of this study was to determine the levels of anxiety and depression and its improvement, depending on the smoking status of patients with coronary artery disease (CAD) on phase 2 of the Cardiac Rehabilitation Program (CRP). Additionally, we intend to investigate the mental health impact on smoker patients" group in conventional CR versus telemonitored CR. A retrospective study was conducted and patients in CRP between 2017 and 2020 were included. Patient selection and information collection were obtained through medical records. The outcomes of anxiety and depression were evaluated through the Hospital Anxiety and Depression Scale (HADS). Patients were divided into two groups: group 1 for non-smokers or ex-smokers and group 2 for smokers. For group 2 patients, a sub-analysis was performed for patients following the conventional CR versus the telemonitored CR, with the use of MOVIDA mobile application. Variables were analysed in the beginning (T0) and in the end (T1) of phase 2, around 3 months after. Group comparisons tests and statistical analysis were performed using SPSS software v25.0. A p-value less than 0.05 is statistically significant.  We analysed 107 patients, which 93 of these were assiduous and 69 concluded the phase 2 of CRP: 39 patients in group 1 and 30 patients in group 2. Two groups have similar baseline characteristics, except for the higher presence of diabetes (p = 0.02) in group 1. It was noted an improvement in both anxiety and depression items for group 1 (p < 0.01 for both), but only for anxiety item for group 2 (p = 0.03). In subgroup analysis, we observed no improvement for smoking patients following the conventional CR for both anxiety and depression items (p = 0.60 and p = 0.71, respectably) versus a significant difference in telemonitored CR patients (p = 0.02 and p = 0.04). We hypothesise that, when compared to conventional CR, cardiac telemonitored exercise using modern communication methods may result in an improved mental health state among smoking patients, which can lead to a better adherence for CRP. Further studies including more patients and phase 3 of CRP are needed to confirm these results.

The combination of venetoclax, lenalidomide, and rituximab in patients with newly diagnosed mantle cell lymphoma induces high response rates and MRD undetectability.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7505-7505
Author(s):  
Tycel Jovelle Phillips ◽  
Alexey Valeryevich Danilov ◽  
David Alan Bond ◽  
Alex Francisco Herrera ◽  
Kami J. Maddocks ◽  
...  
Keyword(s):  
Phase 1 ◽  
Safety Data ◽  
Standard Of Care ◽  
Primary Objective ◽  
Clinical Activity ◽  
Newly Diagnosed ◽  
Grade 5 ◽  
Unrelated Condition ◽  
Mantle Cell ◽  
Grade 3

7505 Background: MCL is a rare lymphoma without a standard of care but several regimens have demonstrated clinical activity, the majority based on traditional chemotherapy. We hypothesized that adding venetoclax (V) to R2 would be safe and effective in MCL pts irrespective of age, morphology or stage. Here we present safety and efficacy data from the on-going phase 1b study of R2 + V in pts with newly diagnosed MCL. Methods: This multi-center phase 1 study (NCT03523975) enrolled pts aged ≥18 yrs with untreated MCL. The primary objective was to characterize the safety and tolerability of R2 + V and determine the MTD. During induction (12 months (m)) pts received lenalidomide (L) 20 mg daily on day 1-21, Rituximab (R) was given weekly during c1 then on day 1 of every even cycle, V was escalated over 4 weeks to 400 mg beginning day 8. Each cycle is 28 days (d). The DLT period was 42 d beginning C1D8. In maintenance, R every 8 weeks for 36m, L at 10 mg or half of last dose during induction for 24 m and V for minimum 12 m. No pts have been transplanted. Pts with progression (PD) came off study. MRD was analyzed in parallel with scans during induction by clonoSEQ assay (Adaptive Biotechnologies). Results: As of Feb. 1st, 2021, we have enrolled all 28 planned pts on study. Pt characteristics/responses are summarized in Table. Among the 28 pts who have received at least one dose, the median treatment duration so far is 278d (IQR 170-560), with 24 pts still on treatment (Tx). 1 pt is off from a unrelated condition. All pts escalated to V 400 mg w/o any DLTs noted. Treatment-emergent adverse events (TEAEs) were reported in 100% of pts, and grade 3+ TEAEs were reported in 26 (93%) patients. The most common all-grade TEAEs (≥50% of pts), regardless of relationship to study Tx, were fatigue, neutropenia and diarrhea. Grade ≥3 TEAEs reported in ≥50% pts were neutropenia (68%) and thrombocytopenia (50%). No pts have withdrawn or d/c Tx due to AEs. There was one grade 5 event, in a non-evaluable pt, related to a PE that occurred prior to DLT period. In the 28 evaluable pts the ORR (CR/PR) was 96% (27/28 pts) with CR/CRu of 89%. Of the responding pts, two had PD, one w/ CR and one w/ PR. All pts with PD had baseline TP53 mutation. MRD testing was successful in all pts. At time of submission 20 of 28 (71%) were MRD - at 10-6. Conclusions: Interim results show that at the MTD the combination of V 400 mg daily, L 20 mg, with R is safe with a manageable toxicity profile and a high ORR and MRD - in pts with newly diagnosed MCL. Safety data is consistent with the AE profile noted for each drug without any unexpected or unique AEs. Updated results including BH3 profiling will be presented at the meeting. Clinical trial information: NCT03523975. [Table: see text]

The Relation Between Epicardial Fat Tissue Thickness and TSH Receptor Antibody in Hyperthyroidism

2018 ◽  
Vol 6 (01) ◽  
pp. 37-40
Author(s):  
Rıza Altunbaş ◽  
Mehmet Eren ◽  
İbrahim Altıparmak ◽  
Hüseyin Karaaslan ◽  
Tevfik Sabuncu
Keyword(s):  
Tsh Receptor ◽  
Newly Diagnosed ◽  
Fat Tissue ◽  
Tissue Thickness ◽  
Receptor Antibody ◽  
Tsh Receptor Antibody ◽  
Epicardial Fat Tissue ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

Abstract Background Although hyperthyroidism may be associated with atherosclerosis, its pathogenesis is not well known. TSH receptor antibody (TRAb) has been shown to be responsible for increased orbital fat tissue in Graves ophthalmopathy. Epicardial fat tissue thickness (EFT) has been found to be increased in case of overt hyperthyroidism. In our study, we aimed to investigate if TRAb is associated with the increased EFT in newly diagnosed hyperthyroidism. Methods Twenty six TRAb positive (group 1) and 26 TRAb negative (group 2) newly diagnosed patients with hyperthyroidism, and 26 healthy control subjects (group 3) were enrolled. EFT was measured by the same cardiologist using an echocardiography device. Serum TRAb levels were measured by the radio-receptor assay and levels above 1.75 IU/L were considered as positive. Results There was no difference among groups in terms of age, gender and body mass index. Although there was no significant difference between group 1 and 2, both group 1 (0.38±0.15 cm) and group 2 (0.4±0.17 cm) had significantly higher EFT levels when compared to group 3 (0.25±0.06 cm) (p=0.004 and p=0.001, respectively). However we did not find any correlation between TRAb and EFT levels. Conclusion The results of our study suggested that EFT was increased in hyperthyroidism and this increasing was not dependent of TRAb level. EFT elevation might be depending directly to the cardiovascular effects of hyperthyroidism.

P1757RITUXIMAB FOR RECURRENCE OF PRIMARY FOCAL SEGMENTAL GLOMERULOSCLEROSIS AFTER KIDNEY TRANSPLANTATION: RESULTS OF A NATIONWIDE STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Camille Lanaret ◽  
Dany Anglicheau ◽  
Audard Vincent ◽  
Celine Lambert ◽  
Lionel Couzi ◽  
...  
Keyword(s):  
Kidney Transplantation ◽  
Focal Segmental Glomerulosclerosis ◽  
Standard Of Care ◽  
High Dose ◽  
Infectious Risk ◽  
Segmental Glomerulosclerosis ◽  
Group 2 ◽  
Retrospective Multicenter Study ◽  
Group 1 ◽  
Rejection Rates

Abstract Background and Aims The indication of rituximab (RTX) in the treatment of primary focal segmental glomerulosclerosis (FSGS) recurrence after kidney transplantation (KT) remains controversial. The objective of our study was to evaluate the benefit and tolerability of adding RTX to the standard of care (SOC) comprising plasmapheresis (PP), corticosteroids, and high-dose anticalcineurins for the treatment of FSGS recurrence after KT. Method This retrospective, multicenter study reports on 148 patients, transplanted between 31 December 2004 and 31 December 2018, aged 39.9 + 13.4 years, who developed FSGS recurrence at 7 [3–23] days. In all 109 patients received a SOC (Group 1). RTX was introduced in this group after more than 28 days of SOC for failure or for therapeutic intensification (n = 19, Group 1a), or for early discontinuation of PP (n = 12, Group 1b); 39 patients received RTX associated at the outset with SOC (Group 2). Results We observed 46.6% complete remission (CR) and 33.1% partial remission (PR). Ten-year graft survival was 65.6% [51.4–76.6] and 13.4% [3.4–30.0] in responders and non-responders respectively. There was no difference in CR + PR rate between G1 (82.5%) and G2 (71.8%), p = 0.08, confirmed by propensity score +4.3% (95% CI [−9.0%-17.5%], p = 0.53). Following addition of RTX (Group 1a), we observed a CR rate of 26.3% and a PR rate of 31.6%. Patients with and without RTX experienced similar rejection rates (18.6% and 28.2%, p = 0.17) and infection rates (71.4% and 79.5%, p = 0.40). In multivariate analysis, the infections were associted with hypogammaglobulinemia <5g/l (OR = 8.04, 95% CI [1.65,39.25], p = 0.01). Conclusion Rituximab could be used in cases of SOC failure or in remission patients for early weaning of plasmapheresis, without increasing infectious risk.

Treatment of Adult T-ALL with a Pediatric Asparaginase-Intensive Protocol Results in Survival Benefit When Compared to Other Adult Based Protocols

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3956-3956
Author(s):  
Murtadha K. Al-Khabori ◽  
Mark Minden ◽  
Vikas Gupta ◽  
Aaron D. Schimmer ◽  
Andre C. Schuh ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Treatment Regimen ◽  
Lymphoblastic Leukemia ◽  
Remission Induction ◽  
Entire Group ◽  
Induction Phase ◽  
Newly Diagnosed ◽  
Significant Difference ◽  
Group 2 ◽  
Group 1

Abstract T cell acute lymphoblastic leukemia (T-ALL) accounts for 14–22% of adult ALL. No prospective comparisons between different chemotherapy protocols have been done. Since 2000 a modified DFCI protocol (Silverman et al, Blood2001;97:121–1218) has been used as standard treatment for all newly diagnosed patients with T-ALL at Princess Margaret Hospital (PMH). This protocol includes a remission induction phase, a CNS prophylaxis phase with intrathecal chemotherapy and 12 Gy cranial irradiation, a 30-week intensification phase including weekly asparaginase, and a 72-week maintenance phase. We compared outcomes using this regimen to previous results for all newly diagnosed T-ALL from 1990 – 2000 at PMH using the standard institutional protocol in use at the time. Between 1990–2000, 44 patients (Group 1) were treated with a variety of protocols, including 9203ALL PMH protocol (11 patients), L10 (2 pts), Protocol C (7 pts), HyperCVAD (15 pts) and ECOG E2993 (9 pts). From 2000–2007, 33 T-ALL patients were treated with modified DFCI protocol (Group 2). The median age for all patients was 31 years (range 14–69 years). There was no significant difference between the two groups with respect to age at diagnosis, presenting WBC (median or percent > 100 ×109/L), CSF positivity, or cytogenetics. More patients from Group 1 underwent allogeneic stem cell transplantation (BMT) in CR-1 (54%) as compared to those in Group 2 (54% vs. 14%, P = 0.001), primarily due to a change in BMT policy in 2002. The median follow up was 23 months (range 1–161 months) for the entire group and 53 months (range 14–161 months) for the surviving patients. Sixty-nine patients (90%) achieved complete remission, and 37 patients have relapsed. The CR rates were not significantly different between the two groups. The 3-year failure-free survival (FFS) was significantly higher in Group 2 (DFCI protocol) as compared with Group 1 (other protocols) (89% vs. 27%, P = 0.0001). Multivariate analysis using Cox proportional hazard model showed only the treatment regimen received (DFCI vs. others) to have a statistically significant impact on FFS (P = 0.0001). The 3-year overall survival (OS) was significantly higher in the DFCI group compared to the group receiving the other protocols (81% vs. 45%, P = 0.0006). On multivariate analysis, only the treatment regimen received (P=0.001) and the CSF status (P=0.014) had a significant impact on OS; BMT did not have a significant impact on OS. When patients were censored at the time of transplant, the FFS and OS analyses still showed statistically significant benefit for patients treated on DFCI protocol (P = 0.0001 and 0.03, respectively). In summary, treatment outcomes have markedly improved from 2000 onward as compared to the previous decade. Although improvements in supportive care and reduced use of allogeneic BMT may have been factors, it is likely that the institution of the DFCI pediatric protocol was the primary factor in the improved outcome. These results support the use of such pediatric asparaginase-intensive pediatric protocols for adult T-ALL.

E7389, a novel anti-tubulin, in patients with refractory breast cancer

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 653-653 ◽  
Author(s):  
J. BlumL. Forero ◽  
M. K. Heiskala ◽  
N. Meneses ◽  
K. Chandrawansa ◽  
F. Fang ◽  
...  
Keyword(s):  
Breast Cancer ◽  
Performance Status ◽  
Safety Data ◽  
Synthetic Analog ◽  
Open Label ◽  
Ecog Performance Status ◽  
Group 2 ◽  
Grade 3 ◽  
Cycle Group ◽  
Group 1

653 Background: E7389 is a synthetic analog of halichondrin B, with a broad anti- proliferative activity against tumor cells. Methods: E7389 was evaluated in an open-label, single-arm Phase II trial as monotherapy for patients with refractory breast cancer (≥2 prior chemotherapy regimens, which must have included an anthracycline and a taxane). E7389 was administered as an IV bolus of 1.4 mg/m2 on Days 1, 8, and 15 of a 28-day cycle (group 1), or on Days 1 and 8 of a 21-day cycle (group 2). The primary efficacy endpoint was ORR. Results: As of 9 December 2005, 88 patients had received treatment, 68 in group 1 and 20 in group 2. Median age was 55 yrs (range 36–84) and ECOG performance status 0–1. Sixty-six percent of the tumors were ductal carcinomas, 6% lobular, and 27% were unclassified. Sixty percent of the tumors were ER+, 47% PR+, and 17% Her2/neu 3+. The patients had received at least two previous regimens, with a median number of 5 (range 2–14). Forty-eight percent of the patients had also used hormonal therapy. Forty-nine patients in group 1 and 12 patients in group 2 had completed their 2nd cycle of treatment, and twenty-one in group1 and 1 in group 2 their 4th cycle. Safety: The major toxicity related to study drug was neutropenia. Among 73 patients with preliminary safety data available, two patients had Grade 3 febrile neutropenia, and 31 had Grade 3 or 4 neutropenia or leukopenia. The other Grade 3 toxicities encountered in more than two patients were dehydration (4 patients) and dyspnea (4 patients). Grade 3 peripheral neuropathy was reported in 2 patients. Efficacy: At the end of cycle four there were 10 (15.2%) confirmed partial responses (PRs) out of 66 evaluable patients in group 1, and 1 confirmed PR (5.6%) out of 18 evaluable patients in group 2. The median duration of confirmed responses was 113 days. Conclusions: Based on the safety and efficacy in this refractory breast cancer population, E7389 appears to be a therapy worthy of continued investigation in patients with heavily pretreated breast cancer. In order to comply with the current demand for individualized cancer care, bio-markers which would predict the sensitivity to E7389 are being searched in the tumor samples of the patients in the current and forthcoming studies. [Table: see text]

ITCC phase I study of erlotinib as single agent in children with refractory and relapsed malignant brain tumors and in combination with irradiation in newly diagnosed brain stem glioma

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 9556-9556 ◽  
Author(s):  
B. Geoerger ◽  
D. Hargrave ◽  
A. Ndiaye ◽  
D. Frappaz ◽  
F. Doz ◽  
...  
Keyword(s):  
Brain Tumors ◽  
Phase I ◽  
Brain Stem ◽  
Phase I Study ◽  
Single Agent ◽  
Glioneuronal Tumor ◽  
Brain Stem Glioma ◽  
Newly Diagnosed ◽  
Group 2 ◽  
Group 1

9556 Background: Erlotinib hydrochloride (OSI-774), a selective inhibitor of the EGFR tyrosine kinase, may be active in childhood brain tumors, particularly in combination with irradiation. Methods: Multicenter, non-randomized phase I study with separate dose findings for erlotinib as single agent in children with refractory or relapsing brain tumors (group 1), and combined to irradiation in newly diagnosed brain stem glioma (group 2). Erlotinib was administered orally daily at 75, 100, 125 or 150 mg/m2. Dose escalation was performed in a classical 3+3 methodology for group 1 and according to the continuous reassessment method for group 2; dose-limiting toxicity (DLT) was evaluated at 3 and 6 weeks, respectively. Results: In total, 31 patients have been entered to date, 30 received treatment, 17 in group 1 (3 relapsing brain stem glioma, 4 ependymoma, 4 oligodendroglioma, 6 other) and 13 in group 2 with a median age of 9 and 6 years (range 4–16 and 2–12), respectively. Median treatment duration was 1.5 and >5 months, respectively. In group 1, 3 patients each were treated at 75 mg/m2 and 100 mg/m2, 7 at 125 mg/m2, 4 at 150 mg/m2. One patient with a glioneuronal tumor treated at 125 mg/m2 experienced G5 intra-tumoral hemorrhage at day 4 which was considered as DLT; at 150 mg/m2, 1 patient with an oligodendroglioma experienced G3 asthenia at day 18 and G3 intratumoral hemorrhage at day 29, and 1 patient with an ependymoma experienced G5 intra-tumoral hemorrhage at day 49. In group 2, 1/6 patients treated with erlotinib 75 mg/m2 and irradiation experienced seizures and died, no DLT occurred in 6 patients at 100 mg/m2. Non-hematological toxicities included G1-G2 erythema, folliculitis, dry skin, trichomegaly, G1 transaminitis, bilirubinemia, G1–3 asthenia, G1–5 intra-tumoral hemorrhage. Minor tumor response was observed in an oligodendroglioma. Pharmacokinetic and biological evaluations are ongoing. Conclusions: Erlotinib was well tolerated in children with cutaneous symptoms being the most frequent treatment toxicity. However, neurological toxicity and intra-tumoral hemorrhage was notable in these children with brain tumors. Inclusion at 125 mg/m2 is ongoing to confirm the MTD. No significant financial relationships to disclose.

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