scholarly journals RTID-04. A RANDOMIZED PHASE II TRIAL TO COMPARE THE EFFICACY OF STANDARD VERSUS COMBINATION THERAPY (PERAMPANEL, MEMANTINE PLUS STANDARD) IN THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM-A STUDY DESIGN

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii194-ii194
Author(s):  
Xiao-Tang Kong ◽  
Bruce Albala ◽  
Senxi Du ◽  
Xiao-Tang Kong ◽  
Daniela Bota
Keyword(s):  
Radiation Therapy ◽  
Nmda Receptor ◽  
Combination Therapy ◽  
Phase Ii ◽  
Study Design ◽  
Survival Data ◽  
Standard Therapy ◽  
Rank Test ◽  
Newly Diagnosed ◽  
Glioma Invasion

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated neurogliomal synaptic communication through AMPA and NMDA receptors promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential enhancing strategy to prevent and to treat GBM progression given the two blockers act through different anti-glioma mechanisms. OBJECTIVE/HYPOTHESIS We hypothesize that adding AMPA blocker Perampanel (An anti-seizure medication) and NMDA blocker Memantine (An anti-dementia medication) to standard temozolomide plus radiation therapy (Stupp’s regimen) for the treatment of newly diagnosed GBM may prevent tumor progression. It may also reduce the frequency of onset/recurrence of seizure episodes and possibly improve radiation related cognition impairment. STUDY DESIGN This is a randomized, active controlled, open label, two arm phase II study of efficacy of treatment of GBM with combination therapy (dual AMPA and NMDA receptor blockers plus standard therapy) versus standard therapy. In the combination therapy arm, patients take Perampanel 2 mg daily and Memantine 5 mg bid, starting from -14 days to +14 days from initiation of concurrent chemo-radiation therapy. Titrating up at a 2 mg increment for Perampanel and 5 mg bid increment for Memantine until reaching MTD. If the patient has AE >= grade 2, then reduce doses at a decrement of 2 mg for Perampanel and decrement of 5 mg bid for Memantine. In the standard therapy arm, the patients are treated with Stupp’s regimen. PRIMARY AND SECONDARY ENDPOINTS PFS, 12, 24 month survival rates and response duration. Safety will be assessed by CTCAE V5. We will use Kaplan-Meier estimates for survival data and a stratified log-rank test for the randomization strata.

scholarly journals RTID-03. A PHASE I CLINICAL TRIAL TO EVALUATE MTD OF PERAMPANEL AND MEMANTINE IN COMBINATION WITH STANDARD CHEMORADIOTHERAPY FOR THE TREATMENT OF PATIENTS WITH NEWLY DIAGNOSED GBM –A STUDY DESIGN

2020 ◽  
Vol 22 (Supplement_2) ◽  
pp. ii193-ii194
Author(s):  
Xiao-Tang Kong ◽  
Bruce Albala ◽  
Senxi Du ◽  
Maya Hrachova ◽  
Daniela Bota
Keyword(s):  
Radiation Therapy ◽  
Nmda Receptor ◽  
Phase I ◽  
Study Design ◽  
Maximum Tolerated Dose ◽  
Chemoradiation Therapy ◽  
Concurrent Chemoradiation ◽  
Newly Diagnosed ◽  
Glioma Invasion ◽  
Concurrent Chemoradiation Therapy

Abstract BACKGROUND Glioblastoma (GBM) is the most aggressive malignant brain tumor in adults with poor prognosis. Effective treatment is urgently needed. Recent studies demonstrated cross-talk between neuron and glioma through neuro-transmitter glutamate receptors (AMPA and NMDA receptors) promotes glioma invasion and progression in vitro and in vivo. Therefore, dual blocking AMPA and NMDA receptor therapy is a potential strategy to prevent and treat GBM progression, particularly given the fact that the two blockers act through different anti-glioma mechanism. OBJECTIVE/ HYPOTHESIS We hypothesize that adding Perampanel (an AMPA receptor blocker) and Memantine (a NMDA receptor antagonist) to standard temozolomide plus radiation therapy for the treatment of newly diagnosed GBM patients may be well tolerated and have a safe profile to prevent tumor progression, seizure recurrence or cognition impairment from radiation. STUDY DESIGN 3 + 3 DESIGN: Maximum Tolerated Dose (MTD) is dose level at which 0/3 or 1/6 patients experience DLT with the next higher dose having at least 2/3 or 2/6 patients encountering DLT. MTD will not be more than FDA approved maximized doses for Perampanel (12 mg daily) and Memantine (20 mg bid) for the treatment of neurological diseases. Once the MTD is found, the patient will continue at MTD for the completion of concurrent chemoradiation therapy plus completion of 6 cycles of adjuvant temozolomide therapy. SUMMARY A Phase I trial to study the safety and toxicity of combined Perampanel and Memantine with standard chemo-radiation therapy to treat patients with newly diagnosed glioblastoma (GBM). To find Maximum Tolerated Dose (MTD) Levels of Perampanel and Memantine at concurrent chemoradiation therapy phase and adjuvant chemotherapy phase to prepare for future phase II or III trial.

scholarly journals Phase II study of hypofractionated radiation therapy in elderly patients with newly diagnosed glioblastoma with poor prognosis

2018 ◽  
Vol 105 (1) ◽  
pp. 47-54 ◽  
Author(s):  
Pierina Navarria ◽  
Federico Pessina ◽  
Luca Cozzi ◽  
Stefano Tomatis ◽  
Giacomo Reggiori ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Observation Time ◽  
Primary Objective ◽  
Karnofsky Performance Scale ◽  
Newly Diagnosed ◽  
Newly Diagnosed Glioblastoma ◽  
Hypofractionated Radiation Therapy ◽  
Hypofractionated Radiation

Objective: To evaluate hypofractionated radiation therapy (HFRT) given at therapeutic effective doses in a phase II study. Endpoints were progression-free survival (PFS) rate, overall survival (OS), and incidence of toxicity. Methods: Patients with newly diagnosed glioblastoma, age ⩾70 years, Karnofsky performance scale (KPS) score ⩽60, were enrolled. The total dose of HFRT was 52.5 Gy/15 fractions, corresponded to a biological effective dose to the tumor of 70.88 Gy. Results: Thirty patients were treated, with a median age of 75 years. Concurrent and adjuvant temozolomide chemotherapy (TMZ-CHT) was administered in 7 (23.3%) and 11 (40.7%) patients received only adjuvant TMZ-CHT. The median, 6-month PFS, and 12-month PFS were 5.0 months, 43.3%, and 20%, respectively. The median, 6-month OS, and 12-month OS were 8 months, 90%, and 30%, respectively. At the last observation time, 26 patients (86.7%) were dead and 4 (13.3%) were alive. No increase in steroid drugs was required during radiotherapy treatment and a reduction was possible in 12 (40%). Patients with KPS=60, RPA V, MGMT methylated status, neurological status stable or improved after surgery and who underwent HFRT with concurrent and adjuvant CHT, had the better outcome. Conclusion: HFRT has proven to be feasible and effective, with limited morbidity, for selected elderly and frail patients with newly diagnosed glioblastoma. The primary objective of this study was not reached in the whole cohort but only in selected patients, who need more aggressive treatment.

Phase II trial of vorinostat (VOR) combined with temozolomide (TMZ) and radiation therapy (RT) for newly diagnosed glioblastoma (GBM) (Alliance N0874/ABTC-0902).

2014 ◽  
Vol 32 (15_suppl) ◽  
pp. 2030-2030 ◽  
Author(s):  
Evanthia Galanis ◽  
S. Keith Anderson ◽  
C. Ryan Miller ◽  
Jann Nagina Sarkaria ◽  
Kurt A. Jaeckle ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
Phase Ii ◽  
Phase Ii Trial ◽  
Newly Diagnosed ◽  
Newly Diagnosed Glioblastoma

BMX-HGG: Phase II trial of newly diagnosed high-grade glioma treated with concurrent radiation therapy, temozolomide, and BMX-001.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. TPS2577-TPS2577
Author(s):  
Katherine B. Peters ◽  
Adam Louis Cohen ◽  
Nicholas A. Butowski ◽  
John L. Villano ◽  
Pierre Giglio ◽  
...  
Keyword(s):  
Radiation Therapy ◽  
White Matter ◽  
Cancer Therapy ◽  
Phase Ii ◽  
Functional Assessment ◽  
Phase Ii Study ◽  
High Grade Glioma ◽  
High Grade ◽  
Newly Diagnosed ◽  
Who Grade

TPS2577 Background: Patients diagnosed with malignant high-grade gliomas (WHO grade III-IV) experience significant morbidity and mortality associated with these cancers. While the mainstay of therapy for patients with newly diagnosed high-grade glioma is surgery followed by concurrent chemotherapy and radiation therapy (RT), the outcomes remain very poor. BMX-001 (MnTnBuOE-2-PyP5+) is a metalloporphyrin with differential action in response to radiation therapy and chemotherapy-induced oxidative stress. Early preclinical studies demonstrated BMX-001’s ability to act as a radioprotectant to healthy tissue such as a central nervous white matter and as a radiosensitizer to cancer cells, in particular, human glioblastoma xenografts. We evaluated the safety of BMX-001 in combination with concurrent RT and temozolomide (TMZ) in a phase I study of newly diagnosed high-grade glioma patients, and we found that BMX-001 is safe and well-tolerated in this population. The maximum tolerated dose of BMX-001 during concurrent RT and TMZ was determined to be 28 mg delivered subcutaneously (SC) followed by 16 biweekly SC doses at 14 mg (Peters et al., Neuro-Oncology 2018). Methods: For this multi-site, open-label, phase II study (NCT02655601), we will randomize approximately 160 patients 1:1 to concurrent RT and TMZ with BMX-001 versus concurrent RT and TMZ alone. Key eligibility criteria include newly diagnosed histologically confirmed high-grade glioma (WHO III-IV), 18 ≥ years, and Karnofsky performance status ≥ 70%. The primary endpoint is overall survival. Secondary endpoints include cognitive performance as assessed by standardized cognitive testing, bone marrow protection, safety and tolerability, progression-free survival, overall tumor response rate, and plasma pharmacokinetics. Exploratory endpoints are health-related quality of life (as assessed by Functional Assessment of Cancer Therapy–Brain, Functional Assessment of Cancer Therapy-Cognition, and Functional Assessment of Chronic Illness Therapy-Fatigue), qualitative hair loss, and white matter integrity (as measured by MRI diffusion tensor/susceptibility imaging). Since November 2018, this phase II study has enrolled 64 of 160 high-grade glioma patients at six sites with future sites planned to be implemented. Clinical trial information: NCT02655601 .

RTOG 0131: Phase II trial of pre-irradiation and concurrent temozolomide in patients with newly diagnosed anaplastic oligodendrogliomas and mixed anaplastic oligodendrogliomas: Relationship between 1p/19q status and progression-free survival

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 1517-1517 ◽  
Author(s):  
M. A. Vogelbaum ◽  
B. Berkey ◽  
D. Peereboom ◽  
C. Giannini ◽  
R. Jenkins ◽  
...  
Keyword(s):  
Overall Survival ◽  
Radiation Therapy ◽  
Median Time ◽  
Phase Ii ◽  
Progression Free Survival ◽  
Chromosome 8 ◽  
Newly Diagnosed ◽  
Time To Progression ◽  
Durable Response ◽  
Free Survival

1517 Background: In a previous report, we showed in patients with newly diagnosed anaplastic oligodendrogliomas (AOs) and mixed anaplastic oligoastrocytomas (MAOs) that temozolomide (TMZ) can be given concurrently with radiation therapy (RT) with acceptable toxicity. We have now evaluated the efficacy of this regimen and correlated durability of response with tumor 1p/19q genotype. Methods: A phase II study was performed to evaluate the use of pre-RT TMZ followed by concurrent RT and TMZ in patients with newly diagnosed AO or MAO. The primary endpoint was to determine the pre-RT TMZ six-month progression rate, and secondary endpoints included progression-free survival and overall survival. Results: 40 eligible patients were entered into the trial. Thirty-two patients completed 6 months of pre-RT TMZ and concurrent RT and TMZ. Of the remaining eight patients, 4 withdrew due to toxicity and 4 other patients withdrew from study without evidence of toxicity or pre-RT progression. 1p/19q data are available in 37 cases; 23 tumors had loss of heterozygosity (LOH) of both 1p and 19q (double-deleted) while 14 tumors had LOH of either 1p or 19q (n = 3), or no LOH (n = 11). To date, 11 patients have experienced tumor progression; 1p/19q data are available for 10 of these cases (2 are double-deleted (2/23 = 9%), 8 have at least one intact chromosome (8/14 = 57%). Kaplan-Meier analysis demonstrates that progression free survival is significantly better for the double-deleted group (median time to progression not reached) than for the intact group (median time to progression = 15.2 months, p = 0.001). Overall survival is 98% (39/40) with a median follow-up of 17.5 months (2.8 - 31.1 months). Conclusions: LOH of both 1p and 19q is strongly correlated with a durable response of AO and MAO to a combined regimen of chemotherapy and radiation therapy. Tumors that are intact at 1p and/or 19q progress early despite an aggressive therapeutic regimen. These results suggest that future clinical trials should be prospectively stratified by tumor 1p/19q genotype. [Table: see text]

Phase II Clinical and Correlative Study Of Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Extended Dosing (CRD-R) Induces High Rates Of MRD Negativity In Newly Diagnosed Multiple Myeloma (MM) Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 538-538 ◽  
Author(s):  
Neha Korde ◽  
Adriana Zingone ◽  
Mary L Kwok ◽  
Elisabet E. Manasanch ◽  
Manisha Bhutani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Flow Cytometry ◽  
Combination Therapy ◽  
Phase Ii ◽  
Plasma Cells ◽  
Hematologic Toxicity ◽  
Newly Diagnosed ◽  
Color Flow ◽  
Time Points ◽  
Grade 3

Abstract Background An irreversible proteasome inhibitor with decreased peripheral neuropathy compared to bortezomib, Carfilzomib (Cz) has potent anti-MM effects resulting in deep clinical responses and durable remissions. In this two-stage phase II trial of 45 planned patients, we treat newly diagnosed MM patients with Cz, lenalidomide(Ln), and dexamethasone (Dx) followed by 2 years of Ln maintenance. Methods Eight 28-day cycles of combination therapy comprises: Cz IV 20/36 mg/m2 on days 1, 2, 8, 9, 15, 16; Ln oral 25 mg days 1-21; and Dx IV or oral 20/10 mg (C1-4/5-8) on days 1, 2, 8, 9, 15, 16, 22, 23. Transplant eligible patients undergo stem cell collection after 4 cycles of CRd and continue with treatment. After 8 cycles of combination therapy, patients with SD or better receive up to 24 cycles of Ln extended dosing 10 mg days 1-21. Primary endpoint is ≥ grade 3 neuropathy. Bone marrow samples are collected at baseline, C1D2 (single agent Cz exposed), CR/end of cycle 8 (cycles 1-8), CR/end of cycle 20 (cycles 9-20), and CR/end of cycle 32/treatment termination (cycles 21-32). Patients are evaluated for clinical biomarkers, FDG-PET CT, and MRD studies (flow cytometry and PCR) at regular time points. Flow cytometry utilizes 8-color flow panel and analyzes ≥ 3 x 106 events (sensitivity 1 x 10-5). Results Forty-one patients meeting eligibility criteria have been enrolled (24 male, 17 female; median age 60; range 40-88). Among patients enrolled, median M-spike is 2.9 (1.0-7.6 g/dL) and isotypes included 26-IgG, 10 – IgA, 4 – free kappa, and 1 – free lambda. Thirty-eight patients are evaluable for response and toxicity. No patients have had ≥ grade 3 neuropathy. The mean decline in serum M-protein (n=33) was 72% after 1 cycle of CRd received. Best responses after a median of 9 cycles (range 2-20) completed, include 17–sCR/1-CR/6-nCR (63%), 10-VGPR (26%), 3-PR (8%), and 1-SD (3%). Among 18/38 (47%), median time to sCR/CR was 5 cycles. Among 14 CR/sCR + 3 nCR patients who underwent MRD assessment, all were negative. Among patients with ≤ VGPR at the end of 8 cycles of CRd, 5/8 (63%) had evidence of immunophenotypically abnormal plasma cells defined by flow cytometry, and 3 patients had undetectable abnormal plasma cells (1 achieved sCR after 8 additional Ln cycles). After median follow-up of 10 months (3-22), PFS rate was 83.3%. Twenty-five patients have completed 8 cycles of CRd, while 24/25 continued to Ln extension and 1 patient opted to exit study after CRd. Patients with non-hematologic toxicity events (≥ grade 3) include: electrolyte disturbances - 7(18%), LFT elevation - 5(13%), rash/pruritus – 4(11%), fatigue – 4(11%), cardiovascular – 3(8%), dyspnea/respiratory – 3(8%), constitutional symptoms – 2(5%), infections – 2(5%), VTE - 2(5%), and anxiety – 1(3%). Patients with hematologic toxicity events (≥ grade 3) include: lymphopenia –24(63%), anemia – 6(16%), leukopenia - 5(13%), and thrombocytopenia - 4(11%). All patients with baseline FDG avid lesions or extramedullary disease showed decrease or resolution of FDG avidity at MRD assessment time points. Conclusions Beyond traditional clinical response criteria, using a functional imaging and highly sensitive MRD assays, we consistently show high rates of deep remission and MRD negativity among newly diagnosed MM patients treated with carfilzomib, revlimid, dexamethasone (CRd) combination therapy. The results were very similar across age-groups and the oldest patient on this trial was 88 years old. If deep remissions are maintained with a delayed ASCT strategy incorporating extended dosing revlimid therapy, this may be a future strategy available to all patients irrespective of age. Disclosures: Off Label Use: Abstract is in newly diagnosed Multiple Myeloma patients. Carfilzomib is approved for relapsed/refractory patients.

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