SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03696355

Developed by Shray Alag, 2019.
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

Stratum A1 Stratum A2

Name: radiation therapy

Description: Both photon and proton therapy modalities will be allowed.

Type: Radiation

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:
Glioma
Genes 30
CHEK2 PMS1 APC MLH1 CDKN2A KRAS TGFBR2 LRP5 NBN MSH6 C11ORF95 ERBB2 RPS20 TSC1 BMPR1A TSC2 RELA PMS2 MSH2 MSH3 MLH3 IDH1 IDH2 SEMA4A NF1 NF2 EPCAM PIK3CA SETBP1 FAN1
Neoplasm of the central nervous system
Genes 116
ALX3 SOX2 PMS1 GABRD VHL CDKN2A KRAS RAF1 FLI1 TCTN3 ERBB2 FAT4 PMS2 PDE6D NRAS OFD1 PDGFB ADAMTS3 RB1 PDGFRB POLD1 NTHL1 MYO1H POLE MAX KIF1B TMEM216 WRN TUBB KCNAB2 WT1 APC NBN RPS20 TSC1 TSC2 EWSR1 RELA MSH2 MSH3 ZSWIM6 OCRL KEAP1 IDH1 IDH2 RET RUNX1 MDH2 PTCH1 PTEN SKI TMEM127 GDNF DICER1 WDPCP PALB2 BDNF EDN3 KRIT1 BAP1 KIAA0753 KIF7 FAN1 SIX6 NUTM1 TGFBR2 MSH6 BMPR1A CCM2 KLLN PTPN11 MLH3 NF1 ALX1 GPC3 LMNA BRAF NF2 SDHAF2 PIK3CA ASCL1 CCBE1 GLI3 BRD4 ARMC5 SETBP1 GPC4 CHEK2 PTCH2 MLH1 SMARCB1 LRP5 AKT1 C11ORF95 FGFR1 RERE GNAS SEMA4A CTNNB1 NME1 FH PHOX2B CPLANE1 PDCD10 SUFU MAPRE2 EPCAM PRDM16 MN1 SEC23B SDHA TP53 NOTCH3 SDHB SDHC SDHD
Neoplasm of the nervous system
Genes 143
ALX3 SOX2 CDKN1A PMS1 CDKN1B GABRD VHL CDKN2A KRAS MYCN CDKN2B RAF1 CDKN2C FLI1 TCTN3 ERBB2 FAT4 PMS2 PDE6D NRAS OFD1 ATRX PDGFB ADAMTS3 PDGFRA RB1 PDGFRB LIN28B POLD1 NTHL1 MYO1H POLE MAX KIF1B APC2 MAFA TMEM216 WRN TUBB KCNAB2 WT1 APC NSD1 L2HGDH NBN DAXX RPS20 TSC1 TSC2 EWSR1 GCGR RELA MSH2 MSH3 ZSWIM6 OCRL KEAP1 IDH1 IDH2 RET RUNX1 MDH2 PTCH1 PTEN MDM2 SKI TMEM127 GDNF DICER1 RNF43 WDPCP PALB2 BDNF EDN3 KRIT1 BAP1 KIAA0753 KIF7 MEN1 FAN1 SIX6 NUTM1 TGFBR2 MSH6 SETD2 BMPR1A CCM2 KLLN PTPN11 MLH3 KARS NF1 ALX1 GPC3 LMNA BRAF NF2 LMO1 SDHAF2 PIK3CA ASCL1 CCBE1 GLI3 BRD4 ARMC5 SETBP1 HACE1 GPC4 CHEK2 HRAS PTCH2 MLH1 PRKAR1A SMARCB1 LRP5 SPRED1 AKT1 C11ORF95 FGFR1 RERE GNAS SEMA4A CTNNB1 NME1 FH PHOX2B CPLANE1 PDCD10 SUFU MAPRE2 KIT EPCAM PRDM16 MN1 ALK TOP2A SEC23B SDHA TP53 NOTCH3 SDHB SDHC SDHD