Phase I study of AZD1775 with radiation therapy (RT) and temozolomide (TMZ) in patients with newly diagnosed glioblastoma (GBM) and evaluation of intratumoral drug distribution (IDD) in patients with recurrent GBM.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 2005-2005
Author(s):  
Brian Michael Alexander ◽  
Manmeet Singh Ahluwalia ◽  
Arati Suvas Desai ◽  
Jorg Dietrich ◽  
Thomas Joseph Kaley ◽  
...  
Keyword(s):  
Dna Damage ◽  
Brain Tumor ◽  
Phase I ◽  
Cellular Response ◽  
Adult Brain ◽  
Dose Finding ◽  
Newly Diagnosed ◽  
Open Label ◽  
Grade 3 ◽  
Recurrent Gbm

2005 Background: The standard of care treatment for newly diagnosed GBM is maximal safe surgical resection followed by two DNA damaging agents, RT and TMZ. Cellular response to DNA damage involves checkpoints that halt the cell cycle to allow DNA repair. AZD1775 is an oral small molecular inhibitor of a nuclear tyrosine kinase Wee1, a key regulator of the G2/M checkpoint. Abrogation of the G2/M checkpoint prevents repair and pushes cells into mitosis with unrepaired DNA damage. AZD1775 was shown to enhance TMZ and RT effects in preclinical models. Methods: The Adult Brain Tumor Consortium 1202 trial (NCT01849146) is a phase I, open label, multicenter dose-finding study of AZD1775 in combination with standard RT and TMZ followed by an IDD study for patients undergoing surgery for recurrent GBM. The dose finding portion is comprised of two arms, one with AZD1775 given Monday through Friday during concurrent RT/TMZ and a second arm given with adjuvant TMZ qd x 5d/28d cycle. Each arm had standard 3+3 design. A combination cohort with both concurrent and adjuvant AZD1775 at MTD and analysis of PK/PD and IDD at MTD in patients undergoing surgery for recurrent GBM followed. Results: 51 patients enrolled in the dose finding arms. For the concurrent arm, the MTD was 200 mg. At 275 mg one patient had grade 3 fatigue and another had grade 4 thrombocytopenia and neutropenia. Two of 6 total patients enrolled at 200 mg experienced DLTs (grade 4 neutropenia and grade 3 ALT elevation). The MTD for the adjuvant arm was 425 mg as 1 of 6 patients had DLT (grade 4 decrease in ANC). At 500 mg, 2 of 3 patients experienced intolerable diarrhea despite prophylaxis. Enrollment in the combination cohort is completed and evaluation of safety is underway. The drug concentration in contrast enhancing and non-enhancing brain tumor was 4-8 x and 0.5-2.6 x greater than plasma, respectively for patients on IDD portion. Conclusions: The MTD for AZD1775 in combination with RT/TMZ is 200 mg qd M-F with concurrent RT/TMZ and 425 mg qd x 5d/28d cycle in combination with adjuvant TMZ. IDD and PK/PD analysis is ongoing to inform the decision to proceed to phase II testing. Clinical trial information: NCT01849146.

Updated safety phase I trial of anti-LAG-3 alone and in combination with anti-PD-1 in patients with recurrent GBM.

2020 ◽  
Vol 38 (15_suppl) ◽  
pp. 2512-2512
Author(s):  
Michael Lim ◽  
Xiaobu Ye ◽  
Anna F. Piotrowski ◽  
Arati Suvas Desai ◽  
Manmeet Singh Ahluwalia ◽  
...  
Keyword(s):  
Phase I ◽  
Late Onset ◽  
Adult Brain ◽  
Dose Finding ◽  
Open Label ◽  
Safety Study ◽  
Flat Dose ◽  
First Recurrence ◽  
Grade 3 ◽  
Recurrent Gbm

2512 Background: Preclinical GBM data targeting the checkpoint molecule Lag-3 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and in combination with anti-PD-1. Methods: A phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) alone or in combination with anti-PD-1 in patients at first recurrence of GBM was carried out in The Adult Brain Tumor Consortium (ABTC) (1501). The primary objectives were safety and to define MTD (DLT rate < 33%) for both the mono and combination arms. The major secondary objective was efficacy. The key inclusion criteria were: adults with first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, on a stable corticosteroid regimen, measurable disease, and written informed consent. Three pre specified dose levels of anti-Lag-3 at 80mg, 160mg, and 800mg were tested. Anti-PD-1was given at a flat dose of 240 mg in combination with anti-LAG-3 at 80 mg and 160 mg. Results: To date, the phase I portion of study completed its accrual and 33 patients were enrolled into the anti-LAG-3 alone or in combination with anti-PD-1 arms. The median age and KPS was 56 and 90 respectively. 39% tumors were MGMT methylated and the median treatment cycle was 3. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. Two DLT were observed in combination arms of Anti-LAG-3 +anti-PD-1 (80 mg/240mg), a grade 3 muscle weakness and a grade 4 edema. Three DLTs were observed in the higher Anti-LAG-3 + anti-PD-1 group (160 mg/240mg): grade 3 hypertension, syncope, and edema. 80% of the DLTs occurred after cycle 2 of the treatment. The estimated overall mOS was 8 months. Seven (44%) patients in the combination arm are still alive and 3 out of the 7 are living beyond 20 months suggesting a subset benefit. Conclusions: The phase I part of trial has completed enrollment. The MTD is 800mg for anti-LAG-3 as a monotherapy. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 was the MTD. DLTs were late onset events. Clinical trial information: NCT02658981 .

Updated phase I trial of anti-LAG-3 or anti-CD137 alone and in combination with anti-PD-1 in patients with recurrent GBM.

2019 ◽  
Vol 37 (15_suppl) ◽  
pp. 2017-2017 ◽  
Author(s):  
Michael Lim ◽  
Xiaobu Ye ◽  
Anna F. Piotrowski ◽  
Arati Suvas Desai ◽  
Manmeet Singh Ahluwalia ◽  
...  
Keyword(s):  
Phase I ◽  
Elevated Serum ◽  
Adult Brain ◽  
Dose Finding ◽  
Open Label ◽  
Safety Study ◽  
Flat Dose ◽  
First Recurrence ◽  
Safe Dose ◽  
Recurrent Gbm

2017 Background: Preclinical GBM data targeting the checkpoint molecules Lag-3 and CD137 have shown promising anti-tumor immune response with resultant improved survival when combined with anti-PD-1. Here we report our experience from a multi-arm safety study in patients with recurrent GBM treated with anti-Lag-3 and anti-CD137. Methods: The Adult Brain Tumor Consortium (ABTC) 1501 trial is a phase I, open label, multicenter, multi-arm dose-finding/safety study of anti-LAG-3 (BMS-986016) or anti-CD137 (BMS-663513) alone and in combination with anti-PD-1 in patients at first recurrence of GBM. The primary objective is to define MTD for the mono and combinational treatment. The major secondary objective is to explore for a signal in efficacy. The key inclusion criteria are adults, first recurrence of GBM following RT+TMZ, TLC≥1000/ul, KPS≥ 60%, stable corticosteroid regimen, measurable disease, and written informed consent. Sequential allocation was used for the treatment assignment at starting dose of 80mg for anti-LAG-3 and 8mg for anti-CD137. Anti-PD-1was given at a flat dose of 240 mg in the combination treatment arms. The 3+3 design is used for the dose finding with a target DLT rate < 33%. Results: to date 44 patients were enrolled into the trial with median age at 57, median KPS at 90. Median treatment cycle was 3 and 39% tumors were MGMT methylated. The highest safe dose for Anti-LAG-3 alone is 800 mg without a DLT. The safe dose for anti-CD137 alone arm is 8mg with 1 DLT, and 2 grade 3 elevated serum ALT at end of cycle 2. Combination arms of Anti-LAG-3 +anti-PD-1 (160 mg/240mg as the highest dose combination) had one DLT (hypertension) and no toxicities were seen in the combination arm of Anti-CD137+Anti-PD-1 (3 mg/240 mg). mOS was 14 months for anti-CD137 alone, 8 months for Anti-Lag-3, and 7 months for Anti-Lag-3 + Anti-PD-1. Correlative data will be discussed. Conclusions: The trial is ongoing. The RP2D is 800mg for anti-LAG-3 as a monotherapy and 8mg for anti-CD137. For the combination arms, 160 mg of Anti-LAG-3 and 240 mg of anti-PD-1 and 3 mg of anti-CD137 and 240 mg antiPD-1 were the RP2D. Clinical trial information: NCT02658981.

Phase I/II study of dianhydrogalactitol in patients with recurrent malignant glioma or progressive secondary brain tumor.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 2093-2093
Author(s):  
James D. Peyton ◽  
Howard A. Burris ◽  
Jeffrey A. Bacha ◽  
Dennis Brown ◽  
William J. Garner ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase I ◽  
Dose Escalation ◽  
Dna Methyltransferase ◽  
Day Treatment ◽  
Optimum Dose ◽  
Open Label ◽  
Dose Escalation Study ◽  
Who Grade ◽  
Recurrent Gbm

2093 Background: Recurrent glial tumors of the brain continue to be one of the most challenging malignancies to treat, and median survival for patients with recurrent disease is approximately 6 months for glioblastoma multiforme (GBM). The front-line therapy for GBM - temozolomide (TMZ) - is subject to resistance by DNA repair protein O6-methylguanine-DNA methyltransferase (MGMT), leading to poor prognoses for patients with recurrent GBM. Dianhydrogalactitol (VAL-083)is a first-in-class bi-functional N7 DNA alkylating agent shown to cross the blood-brain barrier, accumulate in brain tissue, and have activity against GBM. Studies suggest that VAL-083 overcomes MGMT-driven drug resistance in vitro and targets cancer stem cells. The purpose of this study is to determine the maximal tolerated dose (MTD) of VAL-083 in patients with recurrent GBM or progressive secondary brain tumor, and explore the safety, pharmacokinetics and tumor responses to treatment. Methods: Open-label phase I/II dose-escalation study of VAL-083 in patients with histologically confirmed primary WHO grade 4 malignant GBM, now recurrent, previously treated for GBM with surgery and/or radiation, if appropriate, and have failed both bevacizumab and temozolomide; or progressive secondary brain tumor, has failed standard brain radiotherapy, and has brain tumor progression after at least one line of systemic therapy. The study uses a 3 + 3 dose escalation design, until reaching the MTD or maximum specified dose. Patients receive IV VAL-083 on days 1, 2, and 3 of each 21-day treatment cycle. In phase II, additional patients are treated at the MTD (or selected optimum dose) to measure tumor responses. Results: Cohort 1 (3 patients) and cohort 2 (4 patients) were completed without any DLT’s. Adverse events (AEs) have all been grade 1/2, with only 1 grade 3 AE, unrelated to treatment. Cohort 3 currently has 4 patient enrolled, without reaching the MTD. 1/7 (14.3%) patients in cohorts 1and 2 has prolonged stable disease (15+ cycles) on VAL-083 treatment. Conclusions: VAL-083 up to the 2nd dose level was well tolerated without any safety signals. Dose escalation is continuing. Clinical trial information: NCT01478178.

scholarly journals A phase I/II study of veliparib (ABT-888) with radiation and temozolomide in newly diagnosed diffuse pontine glioma: a Pediatric Brain Tumor Consortium study

2020 ◽  
Vol 22 (6) ◽  
pp. 875-885 ◽  
Author(s):  
Patricia A Baxter ◽  
Jack M Su ◽  
Arzu Onar-Thomas ◽  
Catherine A Billups ◽  
Xiao-Nan Li ◽  
...  
Keyword(s):  
Overall Survival ◽  
Brain Tumor ◽  
Phase I ◽  
Dose Escalation ◽  
Pediatric Brain Tumor ◽  
Newly Diagnosed ◽  
Pontine Glioma ◽  
Historical Series ◽  
Grade 3 ◽  
Pediatric Brain

Abstract Background A Pediatric Brain Tumor Consortium (PBTC) phase I/II trial of veliparib and radiation followed by veliparib and temozolomide (TMZ) was conducted in children with newly diagnosed diffuse intrinsic pontine glioma (DIPG). The objectives were to: (i) estimate the recommended phase II dose (RP2D) of veliparib with concurrent radiation; (ii) evaluate the pharmacokinetic parameters of veliparib during radiation; (iii) evaluate feasibility of intrapatient TMZ dose escalation; (iv) describe toxicities of protocol therapy; and (v) estimate the overall survival distribution compared with historical series. Methods Veliparib was given Monday through Friday b.i.d. during radiation followed by a 4-week rest. Patients then received veliparib at 25 mg/m2 b.i.d. and TMZ 135 mg/m2 daily for 5 days every 28 days. Intrapatient dose escalation of TMZ was investigated for patients experiencing minimal toxicity. Results Sixty-six patients (65 eligible) were enrolled. The RP2D of veliparib was 65 mg/m2 b.i.d. with radiation. Dose-limiting toxicities during radiation with veliparib therapy included: grade 2 intratumoral hemorrhage (n = 1), grade 3 maculopapular rash (n = 2), and grade 3 nervous system disorder (generalized neurologic deterioration) (n = 1). Intrapatient TMZ dose escalation during maintenance was not tolerated. Following a planned interim analysis, it was concluded that this treatment did not show a survival benefit compared with PBTC historical controls, and accrual was stopped for futility. The 1- and 2-year overall survival rates were 37.2% (SE 7%) and 5.3% (SE 3%), respectively. Conclusion Addition of veliparib to radiation followed by TMZ and veliparib was tolerated but did not improve survival for patients with newly diagnosed DIPG. Trial Registration NCT01514201

Alternating irinotecan with oxaliplatin combined with UFT plus leucovorin (LV) (SCOUT) in patients with advanced colorectal cancer (ACRC): A phase I/II study

2007 ◽  
Vol 25 (18_suppl) ◽  
pp. 4084-4084
Author(s):  
H. Sheikh ◽  
J. W. Valle ◽  
K. Palmer ◽  
G. Wilson ◽  
A. Sjursen ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Objective Response ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Open Label ◽  
Hand Foot Syndrome ◽  
Label Dose ◽  
Grade 3

4084 Background: The feasibility of UFT (tegafur-uracil) plus LV with alternating irinotecan and oxaliplatin was investigated in a two-stage, phase I/II, open-label, dose-finding trial in patients with ACRC. The study is now closed. Here we present results from the phase II cohort and overall results from the phase I/II study. Methods: Eligible patients aged =18 years had histologically confirmed, advanced, inoperable, measurable metastatic disease, no prior chemotherapy other than adjuvant bolus 5-FU administered =6 months previously, and adequate hematologic, hepatobiliary, and renal function. Patients in the phase I study received irinotecan 180 mg/m2 on d1, oxaliplatin 85–100 mg/m2 on d15 plus UFT 200–300 mg/m2/d with LV 90 mg/d on d1–21 of a 28-d cycle. Diarrhea, lethargy, and vomiting were dose limiting. The maximum tolerated dose (MTD) established was irinotecan 180 mg/m2, oxaliplatin 100 mg/m2, UFT 250 mg/m2/d, and LV 90 mg/day. Patients were treated at the MTD in the phase II study. Primary endpoints in the phase II study were objective response rate (ORR) and time to progression (TTP). Results: Forty-five patients (median age 62 [range 24–79] years, median 4 marker lesions) were entered, 16 and 29 patients in the phase I and II studies, respectively. The ORR in all 38 evaluable patients was 66% (95% CI 49–80%), with clinical benefit (CB) in 89% (95% CI 75–97%). At a median follow-up of 10.3 months, median TTP was 8.5 months (95% CI -7.6 to 10.4 months) in 40 evaluable patients and median OS (ITT population; n=45) was 16.8 months (95% CI -11.3 to 28.3 months). In the phase II study (n=29) median TTP was 8.1 months (95% CI -6.7 to 11.3 months) and median OS was 19.6 months (95% CI -7.7 to >25.6 months); ORR in 25 evaluable patients was 68% (95% CI -46.5 to 85.1%) with CB in 100% (95% CI -86.3 to 100%). Of 30 patients with confirmed radiologic progression, 21 (70%) had second-line therapy. At the MTD, 3 patients (10%) had grade 3 diarrhea, 1 patient (3%) had grade 3 neurotoxicity, and 2 patients (7%) had grade 2 alopecia. No hand-foot syndrome (HFS) was seen. Conclusions: UFT plus LV with alternating irinotecan and oxaliplatin is an efficacious first-line treatment for patients with ACRC, with minimal alopecia and neurotoxicity and no HFS. No significant financial relationships to disclose.

A phase I trial of surgical resection with biodegradable carmustine (BCNU) wafer placement followed by vaccination with dendritic cells pulsed with tumor lysate for patients with malignant glioma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2033-2033
Author(s):  
J. D. Rudnick ◽  
S. Phuphanich ◽  
R. Chu ◽  
M. Mazer ◽  
H. Wang ◽  
...  
Keyword(s):  
Dendritic Cells ◽  
Dendritic Cell ◽  
Phase I ◽  
Dendritic Cell Vaccination ◽  
Newly Diagnosed ◽  
Tumor Lysate ◽  
Bcnu Wafers ◽  
Bcnu Wafer ◽  
Grade 3 ◽  
Recurrent Gbm

2033 Background: Our prior immunotherapy trials demonstrated efficacy in generating a tumor specific immune response in malignant glioma and the potential for high tumor-specific toxicity and sustained tumoricidal activity. Immunotherapy may synergize with chemotherapy and biodegradable carmustine (BCNU) wafers extend overall survival from 11.6 to 13.9 months. Methods: We exploited this synergistic effect to maintain a cytotoxic environment around the tumor milieu. Patients with high-grade glioma were eligible after maximal resection with biodegradable carmustine (BCNU) wafer placement. Screening leukapheresis is used to isolate mononuclear cells which are differentiated into dendritic cells, pulsed with tumor lysate, and then 3 intradermal vaccines are administered at 2-week intervals. Patients continued systemic chemotherapy after vaccine or at progression. Results: Eighteen patients have been enrolled (7 Male, 11 Female) between April 2007 and February 2009 with one screen failure and two patients with clinical progression prior to vaccination. The median patient age was 57 years (26 to 74 ) and median Karnofsky performance status was 90% (80–100). The histology included 3 newly diagnosed glioblastoma multiforme (GBM), 8 recurrent GBM, 2 newly diagnosed anaplastic astrocytoma (AA), and 2 recurrent AA. 15 patients were successfully treated by vaccine injections with 12 patients receiving vaccine every 2 weeks x 3 followed by adjuvant chemotherapy. Our preliminary data on 15 patients and 39 courses of Dendritic Cell vaccines demonstrate one grade 3 toxicity of fever/chest pain. A stable disease interval of 13 to 90 weeks was observed for patients who received vaccine. The 3 newly diagnosed GBM patients have stable disease (18 to 71 weeks). In the recurrent GBM cohort 7/8 patients had progression within 6 months from the post-vaccination MRI. Conclusions: This phase I study demonstrates the safety, feasibility of dendritic cell vaccination with biodegradable carmustine (BCNU) wafers with one grade 3 AE. Immunological data is pending to determine potential synergy of dendritic cell vaccination with intracranial chemotherapy. No significant financial relationships to disclose.

scholarly journals Afatinib and radiotherapy, with or without temozolomide, in patients with newly diagnosed glioblastoma: results of a phase I trial

2021 ◽  
Author(s):  
Frank Saran ◽  
Liam Welsh ◽  
Allan James ◽  
Catherine McBain ◽  
Rao Gattamaneni ◽  
...  
Keyword(s):  
Phase I ◽  
Dna Methyltransferase ◽  
Receptor Gene ◽  
Methylation Status ◽  
Growth Factor Receptor ◽  
Maximum Tolerated Dose ◽  
Dose Finding ◽  
Newly Diagnosed ◽  
Medication Regimen ◽  
Open Label

Abstract Background Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Amplification or overexpression of the epidermal growth factor receptor gene, part of the ErbB family, occur in approximately 40% and 60% of patients with GBM, respectively. We present data from a dose-finding study of the ErbB inhibitor afatinib in combination with radiotherapy (RT), with or without temozolomide (TMZ), in patients with GBM. Methods This was a phase I, open-label, 3 + 3 dose-escalation trial in patients with newly-diagnosed, histologically-confirmed grade 4 malignant glioma and proven O6-methylguanine-DNA methyltransferase gene promoter methylation status. The primary endpoint was the maximum tolerated dose (MTD) of continuous daily afatinib when given in combination with RT, with (regimen M) or without (regimen U) concomitant TMZ treatment. Results Fifty-five patients were enrolled; 36 received ≥ 1 dose of trial medication (regimen M, n = 20, regimen U, n = 16). Afatinib was discontinued by all patients during the study. Reasons for afatinib discontinuation (regimen M/U) included disease progression (45%/50%), dose-limiting toxicity (10%/0%), and other adverse events (AEs; 35%/38%). The most frequently reported AEs with either regimen were diarrhea and rash, with no new safety signals identified. The MTD was determined as afatinib 30 mg in combination with daily TMZ and RT, and afatinib 40 mg in combination with RT alone. Conclusions This study identified the MTD for afatinib in combination with RT, with and without TMZ, in patients with GBM. Further studies of afatinib in patients with GBM are warranted and should be based on appropriate biomarker-based preselection. Trial registration NCT00977431 (first posted September 15, 2009).

Feasibility and phase I trial of tandutinib in patients with recurrent glioblastoma

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2039-2039 ◽  
Author(s):  
J. G. Supko ◽  
S. A. Grossman ◽  
D. M. Peereboom ◽  
S. Chowdhary ◽  
G. J. Lesser ◽  
...  
Keyword(s):  
Brain Tumor ◽  
Phase I ◽  
Dose Level ◽  
Phase Ii ◽  
Phase I Study ◽  
Tumor Tissue ◽  
Recurrent Glioblastoma ◽  
The Mean ◽  
Grade 3 ◽  
Recurrent Gbm

2039 Background: Platelet-derived growth factor signaling is important in gliomagenesis and PDGFR-β is expressed on >90% of endothelial cells in glioblastoma specimens. Methods: We report the results of a feasibility and phase I study of tandutinib (MLN518), an orally bioavailable, quinazoline-based inhibitor of type III receptor tyrosine kinases including PDGFR-β, FLT-3, and c-Kit, in patients with recurrent glioblastoma (GBM) conducted in the New Approaches to Brain Tumor Therapy (NABTT) consortium. Results: A feasibility study was conducted in 6 recurrent GBM patients in whom resection was clinically indicated. These patients received tandutinib 500-mg BID for 7 days prior to resection. In these patients, the drug was measured in tumor tissue and plasma samples obtained shortly before and after the resection by LC/MS. The mean ± SD concentration of tandutinib in tumor tissue was 7.2 ± 3.2 μg/mL and the mean ratio of its concentration in brain tumor-to-plasma was 9.6 ± 7.7. A phase I study was conducted in 19 patients to determine the MTD in this recurrent GBM population with sequential assessment of the following dose levels: 500-, 600-, and 700-mg BID. Four patients were replaced due to early withdrawal unrelated to toxicity. Dose limiting toxicities were observed in 1/6 patients at 500-mg BID (grade 3 phosphorous, grade 3 fatigue, grade 3 somnolence in 1 patient); 1/6 patients at 600-mg BID (grade 3 phosphorous); 2/3 patients at 700-mg BID (grade 3 fatigue, grade 3 weakness). 600-mg BID was declared the MTD and a phase II study has been initiated at this dose level. Conclusions: The mean brain tumor tissue-to-plasma ratio of tandutinib in GBM patients receiving 500-mg BID exceeded the estimated threshold ratio of 0.33 that was considered as being necessary to achieve local cytotoxic concentrations in brain tumors. The MTD of tandutinib in the recurrent GBM population is 600-mg BID. A phase II trial has been initiated at this dose level. [Table: see text]

Phase I/II study of sorafenib and temsirolimus for patients with recurrent glioblastoma (GBM) (NABTC 05–02)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 2006-2006 ◽  
Author(s):  
P. Y. Wen ◽  
T. Cloughesy ◽  
J. Kuhn ◽  
K. Lamborn ◽  
L. E. Abrey ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Single Agent ◽  
Recurrent Glioblastoma ◽  
Molecular Therapy ◽  
Dose Finding ◽  
Pharmacokinetic Data ◽  
Eligibility Criteria ◽  
Grade 3 ◽  
Recurrent Gbm

2006 Background: The activity of targeted molecular therapy with single agents has been disappointing in GBM. Combination therapy simultaneously targeting both the PI3k/Akt/mTOR and the MAP kinase pathway may be more effective. Methods: The North American Brain Tumor Consortium conducted a phase I/II study of sorafenib (VEGFR/PDGFR/Raf inhibitor) in combination with temsirolimus (mTOR inhibitor) in recurrent GBM. Eligibility criteria included histologically proven GBM, radiologic progression, > 18 years old, KPS > 60, adequate bone marrow reserve, and organ function. There was no limit on the number of prior relapses for phase I and no more than two prior relapses for phase II. No enzyme-inducing antiepileptic drugs were allowed. Dose-finding used a standard 3 + 3 design with the MTD defined as the dose with DLTs in 1/6 or fewer patients. The primary endpoint for the phase II component was PFS6 (p0 = 15%; p1 = 35%). A 2-stage design was used. If > 4 of the initial 19 patients achieved PFS6, an additional 14 patients would be accrued for a total of 33 patients. Results: In phase I, 13 patients were enrolled. Median age was 50 years (32–59); median prior chemotherapy 1 (1–3). The initial doses were sorafenib 200 mg bid and temsirolimus 25 mg intravenously once weekly. The MTD was 400 mg bid of sorafenib daily combined with 25 mg of temsirolimus weekly. At this dose 1/6 patients had a DLT (grade 3 thrombocytopenia). Other grade 3 or 4 toxicities included transaminitis, hypophosphatemia, fatigue, diarrhea, and hyperlipidemia. Pharmacokinetic data were similar to that for single agent sorafenib and temsirolimus suggesting that there were no significant interaction between the two drugs. In phase II, 19 patients were accrued to stage I. Median age 50 years (24–64); median prior relapses 1 (range 1–2). One patient was found not to have GBM on central review. No patient remained progression free at 6 months, although two patients stopped treatment prior to 26 weeks for other than progression (alternative therapy, cerebral ischemia). As result, the study was terminated and did not proceed to the second stage. Conclusions: The combination of sorafenib and temsirolimus was moderately well-tolerated but did not demonstrate sufficient efficacy in recurrent GBM to warrant further investigation. No significant financial relationships to disclose.

scholarly journals EPCT-19. A PHASE I STUDY OF RIBOCICLIB AND EVEROLIMUS FOLLOWING RADIATION THERAPY IN CHILDREN WITH NEWLY DIAGNOSED NON-BIOPSIED DIFFUSE PONTINE GLIOMAS (DIPG) AND RB+ BIOPSIED DIPG AND HIGH GRADE GLIOMAS (HGG)

2020 ◽  
Vol 22 (Supplement_3) ◽  
pp. iii307-iii307
Author(s):  
Mariko DeWire ◽  
James Leach ◽  
Christine Fuller ◽  
Peter de Blank ◽  
Trent Hummel ◽  
...  
Keyword(s):  
Phase I ◽  
Phase I Study ◽  
Single Agent ◽  
Maximum Tolerated Dose ◽  
Pharmacokinetic Studies ◽  
High Grade ◽  
Newly Diagnosed ◽  
High Grade Gliomas ◽  
Grade 3 ◽  
Expansion Cohort

Abstract Genomic aberrations in the cell cycle and mTOR pathways have been reported in diffuse pontine gliomas (DIPG) and high-grade gliomas (HGG). Dual inhibition of CDK4/6 (ribociclib) and mTOR (everolimus) has strong biologic rationale, non-overlapping single-agent toxicities, and adult clinical experience. The maximum tolerated dose (MTD) and/or recommended phase two dose (RP2D) of ribociclib and everolimus administered during maintenance therapy following radiotherapy was determined in the phase I study as a rolling 6 design. Ribociclib and everolimus were administered once daily for 21 days and 28 days, respectively starting two-four weeks post completion of radiotherapy. All HGG patients and any DIPG patient who had undergone biopsy were screened for RB protein by immunohistochemistry. Eighteen eligible patients enrolled (median age 8 years; range: 2–18). Six patients enrolled at dose levels 1,2, and 3 without dose limiting toxicities (DLT). Currently, five patients are enrolled at dose level 3 expansion cohort. The median number of cycles are 4.5 (range: 1–20+). Among the expansion cohort, one dose limiting toxicity included a grade 3 infection and one patient required a dose reduction in course 3 due to grade 3 ALT and grade 4 hypokalemia. The most common grade 3/4 adverse events included neutropenia. Preliminary pharmacokinetic studies on 12 patients suggest an impact of ribociclib on everolimus pharmacokinetics. The MTD/RP2D of ribociclib and everolimus following radiotherapy in newly diagnosed DIPG and HGG is anticipated to be 170 mg/m2/day x 21 days and 1.5 mg/ m2/day every 28 days which is equivalent to the adult RP2D.

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