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Report for Clinical Trial NCT03696355

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

Phase I Study of GDC-0084, a Brain-Penetrant PI3 Kinase/mTOR Inhibitor, in Pediatric Patients With Newly Diagnosed Diffuse Intrinsic Pontine Glioma or Diffuse Midline Gliomas After Radiation Therapy

Pediatric high-grade gliomas are highly aggressive and treatment options are limited. The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and pharmacokinetics of GDC-0084 and to estimate its maximum tolerated dose (MTD) when administered to pediatric patients with diffuse intrinsic pontine glioma (DIPG) or other diffuse midline H3 K27M-mutant gliomas after they have received radiation therapy (RT). GDC-0084 is a brain-penetrant inhibitor of a growth-promoting cell signaling pathway that is dysregulated in the majority of diffuse midline glioma tumor cells. This study is also designed to enable a preliminary assessment of the antitumor activity of single-agent GDC-0084, in the hope of enabling rational combination therapy with systemic therapy and/or radiation therapy (RT) in this patient population, which is in desperate need of therapeutic advances. Primary Objectives 1. To estimate the maximum tolerated dose (MTD) and/or the recommended phase 2 dosage (RP2D) of GDC-0084 in pediatric patients with newly diagnosed diffuse midline glioma, including diffuse intrinsic pontine glioma (DIPG) 2. To define and describe the toxicities associated with administering GDC-0084 after radiation therapy (RT) in a pediatric population 3. To characterize the pharmacokinetics of GDC-0084 in a pediatric population Secondary Objectives 1. To estimate the rate and duration of radiographic response in patients with newly diagnosed DIPG or other diffuse midline glioma treated with RT followed by GDC-0084 2. To estimate the progression-free survival (PFS) and overall survival (OS) distributions for patients with newly diagnosed DIPG or other diffuse midline glioma treated with RT followed by GDC-0084

NCT03696355 Brain and Central Nervous System Tumors
MeSH:Glioma Nervous System Neoplasms Central Nervous System Neoplasms
HPO:Glioma Neoplasm of the central nervous system Neoplasm of the nervous system

2 Interventions

Name: GDC-0084

Description: Given PO
Type: Drug
Group Labels: 2

Stratum A1 Stratum A2

Name: radiation therapy

Description: Both photon and proton therapy modalities will be allowed.
Type: Radiation
Group Labels: 2

Stratum A1 Stratum A2


Primary Outcomes

Description: The MTD is empirically defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose-limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. The MTD estimate will not be available if the lowest dose level studied is too toxic or the highest dose level studied is considered safe. In the latter case, the highest studied safe dose may be considered as the recommended phase 2 dose (RP2D). The MTD estimation will be limited to evaluable patients and toxicity assessments from course 1 (28 days).

Measure: Estimate the maximum tolerated dose (MTD)/recommended phase 2 dose (RP2D) of GDC-0084 after standard-of-care radiation therapy (RT)

Time: 1 month after start of GDC-0084 treatment

Description: Adverse event data will be summarized in tables by dose level.

Measure: Incidence of adverse events at least possibly associated with GDC-0084 after RT by stratum

Time: Up to 2 years after start of GDC-0084 treatment

Description: GDC-0084 area under the curve (AUC0-∞) is estimated based on course 1 day 1 (C1D1) PK samples, and AUC0-24 based on course 1 day 28 (C1D28) PK samples.

Measure: Pharmacokinetics of GDC-0084 by stratum

Time: GDC-0084 treatment course 1 days 1 and 28

Secondary Outcomes

Description: The best overall response is the best response recorded between the start of GDC-0084 treatment and the earliest of initiation of alternative therapy or disease progression/recurrence. Best responses include complete response (CR), partial response (PR), and stable disease (SD). The best response is unknown if the patient does not qualify for a best response of progressive disease and if all objective statuses after the first determination and before progression are unknown.

Measure: Rate of best overall response by stratum

Time: Up to 1 year after completion of GDC-0084 treatment

Description: The duration of best overall response is measured from the time the measurement criteria are met for CR, PR, or SD (whichever is recorded first) until the first day on which recurrent or progressive disease is objectively documented.

Measure: Duration of best overall response by stratum

Time: Up to 1 year after completion of GDC-0084 treatment

Description: Progression-free survival (PFS) is defined from the time of diagnosis until disease progression or until death from any cause for patients who experience an event and until the date of last follow-up for those who are alive and progression free at the time of analysis. PFS is estimated by Kaplan-Meier approach and median PFS is reported.

Measure: Progression-free survival for patients treated with GDC-0084 after RT

Time: Up to 3 years from diagnosis

Description: Overall survival (OS) is defined from the time of diagnosis until death from any cause for patients who experience an event and until the date of last follow-up for those who are alive at the time of analysis. OS is estimated by Kaplan-Meier approach and median OS is reported.

Measure: Overall survival for patients treated with GDC-0084 after RT

Time: Up to 3 years from diagnosis

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 K27M

The purpose of this first-in-pediatrics study is to examine the safety, tolerability, and pharmacokinetics of GDC-0084 and to estimate its maximum tolerated dose (MTD) when administered to pediatric patients with diffuse intrinsic pontine glioma (DIPG) or other diffuse midline H3 K27M-mutant gliomas after they have received radiation therapy (RT). --- K27M ---

- Biopsied typical DIPG: WHO grade II diffuse astrocytoma (IDH WT or IDH NOS), WHO grade III anaplastic astrocytoma (IDH WT or IDH NOS), WHO grade IV glioblastoma (IDH WT or IDH NOS), or diffuse midline glioma, H3 K27M mutant. --- K27M ---

Subjects with a typical DIPG who undergo a biopsy may be eligible for the study if the tumor does not harbor the H3 K27M mutation, yet eligibility is restricted to diffuse astrocytoma, anaplastic astrocytoma or glioblastoma, IDH WT or IDH NOS, tumors. --- K27M ---

- Atypical brainstem glioma: diffuse midline glioma, H3 K27M mutant. --- K27M ---

- Non-brainstem midline glioma, defined as tumors with an epicenter within midline structures, including the thalamus, spinal cord, and cerebellum: diffuse midline glioma, H3 K27M mutant. --- K27M ---



HPO Nodes


HPO:
HP:0004375: Neoplasm of the nervous system
Genes 266
EPAS1 PHOX2B LIN28B PHOX2B GPC4 IDH2 PTEN SDHC PRDM16 SUFU BRCA2 PHOX2B SDHC SIX6 ALX3 KIF1B BRAF SMARCB1 SKI SDHAF2 SDHD RNF43 KCNAB2 GABRD WT1 NF2 GCGR BAP1 GLI3 PHOX2B NF1 L2HGDH NRAS OCRL TP53 TP53 NTHL1 NF1 SDHD MAFA PHOX2B CTNNB1 RET C11ORF95 SETBP1 PDCD10 KIF1B MN1 RELA DAXX LRP5 LZTR1 RAF1 VHL PTCH2 RPS20 MDH2 FLI1 BMPR1A MLH1 NF1 YY1 RERE MSH3 SUFU ASCL1 OFD1 GDNF PRKAR1A ZSWIM6 SDHB WDPCP TP53 KEAP1 SETD2 POLE SMARCB1 AKT1 MEN1 ASCL1 IDH1 PTCH1 NAB2 DNMT3A FAM149B1 STAT6 CCBE1 SMARCE1 PTEN SEMA4A HACE1 SUFU SMARCB1 SDHC SEC23B MYCN FGFR1 KRIT1 KIF7 SDHD NBN MSH6 EPHB2 MEN1 TMEM127 CDKN1B TUBB VHL CDKN2B RET TP53 DLST IFNG FAT4 MDM2 MLH1 SMARCB1 TMEM127 GDNF POT1 KARS1 BMPR1A SDHD NSD1 CDKN1A PTEN PTPN11 EWSR1 EDN3 PMS1 OFD1 TSC1 MSH3 NUTM1 PIK3CA TUBB GLI3 SDHC MSH6 NF1 KIAA0753 RET ADAMTS3 NF2 SOX2 APC ATRX RB1 PIK3CA SDHA CCND1 VHL RET VHL SDHC SDHB ARMC5 CPLANE1 SLC25A11 NF2 SDHB TOP2A PIK3CA EPCAM NF2 PDGFB MSH2 MEN1 KRAS LMNA SDHAF2 CDKN1B BRCA2 SDHB GNAS NOTCH3 TSC2 AKT1 PMS2 APC TSC2 PTEN RUNX1 CPLANE1 ERBB2 DLST SUFU LMO1 SDHB SDHC SDHD CHEK2 TGFBR2 APC PDGFRB MYO1H ALX3 ALK PHOX2B APC2 PDE6D POLD1 CHEK2 FH DICER1 PTEN SDHD CDKN2A SDHD CDKN1B HRAS SLC25A11 TCTN3 KIF1B SDHB USF3 LMNA NTHL1 ALX1 PDGFB FAN1 MAX PTCH2 PIK3CA WRN SPRED1 VHL IDH1 KLLN SMARCA4 GPC3 RET APC BRD4 WRN PTEN MAPRE2 DICER1 GLI3 SDHB MSH2 TMEM216 APC PMS2 KIT CCM2 RET SDHA SDHD NBN ALK MAX BDNF MLH3 PALB2 CDKN2C NF2 GDNF EDN3 RET AKT1 PTCH1 TSC1 CDKN2A SDHB PRKAR1A
Protein Mutations 3
F1174L G156A K27M
SNP 0