CTIM-07. A PHASE I/II STUDY EVALUATING THE SAFETY AND EFFICACY OF A NOVEL LONG-ACTING INTERLEUKIN-7, NT-I7, FOR PATIENTS WITH NEWLY DIAGNOSED HIGH-GRADE GLIOMAS AFTER CHEMORADIOTHERAPY

Abstract BACKGROUND Lymphopenia is common after standard radiation therapy (RT) and temozolomide (TMZ) in high-grade gliomas (HGG) and correlates with shorter survival. Interleukin-7 (IL-7), a T-cell proliferation cytokine, is inappropriately low in HGG patients. Our previous preclinical studies demonstrated that NT-I7 (efineptakin alfa), a recombinant human IL-7, corrects lymphopenia and improves survival in murine glioma models. This study examines the safety and absolute lymphocyte counts (ALCs) following administration of NT-I7 patients with newly diagnosed HGG. METHODS Patients with HGG receiving RT/TMZ with ALC ≥600 were eligible. NT-I7 was administered intramuscularly within 1 week after completion of concurrent RT/TMZ and then every 12 weeks, for up to 4 total doses. Phase I examined 6 dose levels (60, 120, 240, 540, 720, and 960 mcg/kg) using the accelerated-titration design for the first 2 doses and 3 + 3 design thereafter to identify the maximum tolerated dose (MTD). Phase II is a double-blinded, placebo-controlled study with 10 HGG patients per arm comparing changes in ALC. Immune profiling will be performed with CyTOF and cytokine analysis. RESULTS Phase I is complete, with 19 patients (89% GBM, median age: 58 (range: 25-78), median baseline ALC: 1000 cells/mm3, median dexamethasone: 0 mg/day (range: 0-12)). The median number of NT-I7 doses administered was 2 (range: 2-4). The most common treatment-related adverse event was grade 1 or 2 injection site reactions (42%). Two patients had dose-limiting toxicities at 960 mcg/kg (grade 3 elevated alanine aminotransferase and grade 3 back pain), prompting selection of 720 mcg/kg for phase II. Dose-dependent increases in ALC were observed at 4 weeks ranging from 1.3x to 4.1x. Phase II enrollment is ongoing. CONCLUSIONS NT-I7 is well tolerated when administered after chemoradiotherapy for HGG patients with MTD of 720 mcg/kg and demonstrates dose-dependent increase of ALC. Phase II and immune profiling are ongoing. Clinical Trial ID: NCT03687957.

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A phase I/II study to evaluate the safety and efficacy of a novel long-acting interleukin-7, NT-I7, for patients with newly diagnosed high-grade gliomas after chemoradiotherapy: The interim result of the phase I data.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.2040 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 2040-2040

Author(s):

Jian Li Campian ◽

Jingqin Luo ◽

Chai Avvaru ◽

Ruth Katumba ◽

Albert H Kim ◽

...

Keyword(s):

Phase I ◽

Phase Ii ◽

Randomized Study ◽

Newly Diagnosed ◽

Interleukin 7 ◽

Cytokine Analysis ◽

Grade 3 ◽

Long Acting ◽

Dose Dependent ◽

Immune Profiling

2040 Background: High-grade gliomas (HGG) patients can develop prolonged lymphopenia after standard radiation therapy (RT) and temozolomide (TMZ), which has been shown to correlate with worse survival. Interleukin-7 (IL-7) level, a cytokine that stimulates T-cell homeostasis and proliferation, is disproportionally low in HGG patients with lymphopenia. NT-I7 (efineptakin alfa) is the first-in-class long-acting recombinant human IL-7 that supports proliferation and survival of CD4+ and CD8+ T-cells in humans and mice. Our previous study demonstrated that NT-I7 could correct lymphopenia and improve the survival of orthotopic murine glioma models. The current study aims to examine the safety of administering NT-17 after chemoradiotherapy to HGG patients and its effect on systemic absolute lymphocyte count (ALC). Methods: All patients with newly diagnosed HGG who have completed concurrent RT/TMZ were considered eligible, regardless of ALC. NT-I7 was initially administered intramuscularly within 1 week after completion of RT/TMZ and then every 12 weeks for up to 4 doses. Patients also received adjuvant TMZ 4 weeks after RT/TMZ. The phase I study tested 6 dose levels of NT-I7, including 60, 120, 240, 540, 720, and 960 mcg/kg, adopting an accelerated phase for the first two doses followed by the standard 3+3 design. The primary endpoint was the safety of NT-I7 in HGG. The Phase II study is a double-blinded randomized study with 10 patients per arm to evaluate the effect of NT-I7 on ALC compared to placebo controls. Blood samples at baseline and during the NT-I7 administrations will be collected for immune profiling by CyTOF, single-cell RNA-sequencing, and cytokine analysis. Results: Phase I was completed with 19 patients (2 anaplastic oligodendrogliomas and 17 glioblastomas), with a median age of 58 years (range: 25-78). Median baseline ALC was 1000 cells/mm3 before NT-I7 administration, and the median baseline dexamethasone use was 0 mg/day (range 0-12). The median number of NT-I7 doses given was 2 (range: 2-4). Treatment-related adverse events (TRAEs) were dose-dependent. The most common TRAEs were grade 1/2 injection site reactions (50%), flu-like symptoms (26%), rash (21%), and fatigue (21%). Two patients had dose-limiting toxicities at 960 mcg/kg (a grade 3 elevated alanine aminotransferase and a grade 3 muscle pain). ALC was increased in a dose-dependent manner with a range of 1.3 – 4.1 fold at week 4 after NT-I7 injection and lasted up to 12 weeks. Thus, 720 mcg/kg was identified as the recommended phase II dose (RP2D). Conclusions: NT-I7 is well tolerated for HGG patients after chemoradiotherapy and has a RP2D of 720 mcg/kg. Immune profiling and cytokine analysis are ongoing and will be updated. The Phase II randomized study to evaluate the effect of NT-I7 vs placebo on ALC and survival is ongoing. Clinical trial information: NCT03687957.

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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)

Neuro-Oncology ◽

10.1093/neuonc/noaa222.141 ◽

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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Phase I study of erlotinib administered concurrently with and after irradiation (RT) in the treatment of children, adolescents, and young adults with newly diagnosed intracerebral high-grade glioma

Journal of Clinical Oncology ◽

10.1200/jco.2007.25.18_suppl.9553 ◽

2007 ◽

Vol 25 (18_suppl) ◽

pp. 9553-9553

Author(s):

A. Broniscer ◽

S. J. Baker ◽

T. E. Merchant ◽

F. H. Laningham ◽

M. Kocak ◽

...

Keyword(s):

Phase I ◽

Phase I Study ◽

High Grade Glioma ◽

Maximum Tolerated Dose ◽

Exclusion Criterion ◽

Pharmacokinetic Studies ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas ◽

Grade 3

9553 Background: High-grade gliomas are uncommon neoplasms in childhood that portend a poor prognosis. Because of the promising activity of erlotinib in adults with high-grade glioma, we conducted this Phase I study to determine the maximum tolerated dose and dose limiting toxicity (DLT) of erlotinib administered concurrently with and after RT. Methods: Patients between 3 and 25 years of age with newly diagnosed high-grade glioma received erlotinib continuously once daily during and after RT for a maximum of 52 weeks. Pharmacokinetic studies of erlotinib and its metabolite OSI-420, and genotyping were performed during course 1 in consenting patients. Use of enzyme-inducing anticonvulsants was an exclusion criterion. Dose escalation followed a typical Phase I design (dosage levels of 70, 90, and 120 mg/m2 per day). The DLT-evaluation period comprised the first 8 weeks of erlotinib. Results: Seventeen patients (median age 10.4 yrs; 10 males) were enrolled. Diagnoses consisted of glioblastoma (n=9), anaplastic astrocytoma (n=4), and other high-grade gliomas (n=4). Two of seven patients experienced reversible grade 3 hypokalemia / hypophosphatemia at the 70 mg/m2 level. Once electrolyte abnormalities were excluded as DLT, only one of seven patients at the 120 mg/m2 level has experienced grade 3 diarrhea so far. Pharmacokinetic studies were obtained in 14/17 patients. At the 70 mg/m2 dosage level, the median (range) erlotinib and OSI-420 Cmax and Tmax were 1,405 ng/ml (937–2,180) and 4.1 hr (2.2–8.2) and 158.5 ng/ml (45–203) and 4.1 hr (2.2–7.9), respectively. Three patients have received erlotinib for more than 1 year with disease stabilization. Six patients have already experienced disease progression. Conclusions: Erlotinib administered concurrently with RT on this schedule has been well tolerated. Preliminary pharmacokinetic results are comparable to those observed in adults. Rather than continue to escalate erlotinib dosages, we plan to complete this study and open a phase II study of erlotinib and RT for this same patient population. No significant financial relationships to disclose.

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Phase II Trial of Erlotinib during and after Radiotherapy in Children with Newly Diagnosed High-Grade Gliomas

Frontiers in Oncology ◽

10.3389/fonc.2014.00067 ◽

2014 ◽

Vol 4 ◽

Cited By ~ 19

Author(s):

Ibrahim Qaddoumi ◽

Mehmet Kocak ◽

Atmaram S. Pai Panandiker ◽

Gregory T. Armstrong ◽

Cynthia Wetmore ◽

...

Keyword(s):

Phase Ii ◽

Phase Ii Trial ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas

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P09.50 Phase I trial of temozolomide plus bevacizumab for newly diagnosed high-grade gliomas in the elderly: Interim report

Neuro-Oncology ◽

10.1093/neuonc/nox036.306 ◽

2017 ◽

Vol 19 (suppl_3) ◽

pp. iii81-iii81 ◽

Cited By ~ 1

Author(s):

M. Kono ◽

Y. Arakawa ◽

Y. Mineharu ◽

F. Ohka ◽

M. Kinoshita ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

The Elderly ◽

High Grade ◽

Newly Diagnosed ◽

Interim Report ◽

High Grade Gliomas

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A phase I trial of temozolomide and lomustine in newly diagnosed high-grade gliomas of childhood

Neuro-Oncology ◽

10.1215/15228517-2008-019 ◽

2008 ◽

Vol 10 (4) ◽

pp. 569-576 ◽

Cited By ~ 22

Author(s):

Regina I. Jakacki ◽

Allan Yates ◽

Susan M. Blaney ◽

Tianni Zhou ◽

Robert Timmerman ◽

...

Keyword(s):

Phase I ◽

Phase I Trial ◽

High Grade ◽

Newly Diagnosed ◽

High Grade Gliomas

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Phase I/randomized phase II trial of either dasatinib or placebo combined with standard chemoradiotherapy for newly diagnosed glioblastoma multiforme (GBM): Final results of phase I study.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.2032 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. 2032-2032 ◽

Cited By ~ 2

Author(s):

Nadia N. Laack ◽

Evanthia Galanis ◽

Clinton Leinweber ◽

Jan C. Buckner ◽

Caterina Giannini ◽

...

Keyword(s):

Phase I ◽

Dose Level ◽

Phase Ii ◽

Progressive Disease ◽

Phase Ii Trial ◽

Newly Diagnosed ◽

Entire Study ◽

Randomized Phase Ii ◽

Level 1 ◽

Grade 3

2032 Background: Dasatinib is a potent oral ATP competitive multi-targeted kinase inhibitor of multiple members of the Src kinase family, known to be involved in gliomagenesis and invasion. N0877 is a phase I/randomized phase II trial evaluating the combination of dasatinib, radiation (RT) and temozolomide (TMZ) in newly diagnosed GBM. The phase I portion has been completed and is the focus of this report. Methods: A cohorts-of-3 design was used to assess the safety of dasatinib in combination with RT and concomitant TMZ, and establish the phase II dose of the combination. Dasatinib was given orally for 42 days, beginning with the first day of RT (total dose 60 Gy) and first dose of TMZ (75 mg/m2/d). A 24 - 42 day rest (cycle 2) followed the RT/TMZ/dasatinib. Patients (pts) were observed for DLT to the end of cycle 2. Patients then received 6 cycles (28 day cycles) of dasatinib (once daily) and TMZ (days 1-5). At the completion of 6 cycles of TMZ + dasatinib, pts stay on dasatinib only (28 day cycles) until progressive disease. Results: Phase I component is complete with 13 patients (3 at dose level 0, 3 at dose level 0-A, 7 at dose level 1). One patient in dose level 1 had to be replaced due to the development of unrelated medical issues. One DLT (grade 4 pancytopenia) was observed in 1 patient at dose level 0 (50mg bid) and one DLT (grade 3 rash) was observed in 1 patient at dose level 1 (150mg qd). MTD of dasatinib was determined to be 150mg daily. Most common adverse events throughout the entire study period were hematologic with the most common toxicity being lymphopenia (grade 3 in 69% of patients, grade 4 in 8%). Other toxicities attributed to treatment and occurring in > 10% of patients included anemia (31%), neutropenia (15%), and fatigue(15%). Best response was stable disease in 10 patients, progressive disease in 1 patient, and not evaluable in 2. Conclusions: MTD for dasatinib in combination with TMZ and RT in newly diagnosed GBM patients is 150mg daily. Toxicity was primarily hematologic with minimal non-hematologic events. This dose is currently being used in the ongoing placebo-controlled, randomized phase II trial.

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