SNPMiner Trials by Shray Alag


SNPMiner Trials: Clinical Trial Report


Report for Clinical Trial NCT03745326

Developed by Shray Alag, 2019.
SNP Clinical Trial Gene

Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients

Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. Researchers think this may help attack tumors in people with certain cancers. It is called gene transfer using anti-KRAS G12D mTCR cells. Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. Eligibility: Adults ages 18-70 who have cancer with a molecule on the tumors that can be recognized by the study cells Design: Participants will be screened with medical history, physical exam, scans, photography, and heart, lung, and lab tests. An intravenous (IV) catheter will be placed in a large vein in the chest. Participants will have leukapheresis. Blood will be removed through a needle in an arm. A machine will divide the blood and collect white blood cells. The rest of the blood will be returned to the participant through a needle in the other arm. A few weeks later, participants will have a hospital stay. They will: - Get 2 chemotherapy medicines by IV over 5 days. - Get the changed cells through the catheter. Get up to 9 doses of a medicine to help the cells. They may get a shot to stimulate blood cells. - Recover in the hospital for up to 3 weeks. They will provide blood samples. Participants will take an antibiotic for at least 6 months. Participants will have several follow-up visits over 2 years. They will repeat most of the screening tests and may have leukapheresis. Participants blood will be collected for several years.

NCT03745326 Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer
MeSH: Pancreatic Neoplasms Gastrointestinal Neoplasms
HPO: Malignant gastrointestinal tract tumors Neoplasm of the gastrointestinal tract Neoplasm of the pancreas

4 Interventions

Name: Cyclophosphamide

Description: Days -7 and -6: Cyclophosphamide 60 mg/kg/day x 2 days IV in 250 mL D5W infused simultaneously with mesna 15 mg/kg/day over 1 hour x 2 days.

Type: Drug

1/Phase I 2/Phase II

Name: Fludarabine

Description: Days -7 to -3: Fludarabine 25 mg /m^2/day IVPB daily over 30 minutes for 5 days.

Type: Drug

1/Phase I 2/Phase II

Name: Aldesleukin

Description: Aldesleukin 720,000 IU/kg (based on total body weight) IV over 15 minutes approximately every 8 hours beginning within 24 hours of cell infusion and continuing for up to 3 days (maximum 9 doses).

Type: Drug

1/Phase I 2/Phase II

Name: anti-KRAS G12D mTCR PBL

Description: Day 0: Cells will be infused intravenously on the Patient Care Unit over 20-30 minutes.

Type: Biological

1/Phase I 2/Phase II


Primary Outcomes

Description: Aggregate of all adverse events, as well as their frequency and severity

Measure: Frequency and severity of treatment-related adverse events

Time: 5 years following cell infusion

Description: Percentage of patients who have a clinical response to treatment (objective tumor regression)

Measure: Response rate

Time: 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x2 years, then per PI discretion

Secondary Outcomes

Description: TCR and vector presence will be quantified in PBMC samples using established PCR techniques

Measure: In vivo survival of mTCR geneengineered cells

Time: Batched and assayed at the conclusion of the study

Purpose: Treatment

Allocation: Non-Randomized

Parallel Assignment


There is one SNP

SNPs


1 G12D

Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients. --- G12D ---

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12D Variant of Mutated RAS in HLA-A*11:01 Patients Background: A new cancer therapy takes white blood cells from a person, grows them in a lab, genetically changes them, then gives them back to the person. --- G12D ---

It is called gene transfer using anti-KRAS G12D mTCR cells. --- G12D ---

Objective: To see if anti-KRAS G12D mTCR cells are safe and cause tumors to shrink. --- G12D ---

-INCLUSION CRITIERIA: 1. Measurable (per RECIST v1.1 criteria), metastatic, or unresectable malignancy expressing G12D mutated KRAS as assessed by one of the following methods: RT-PCR on tumor tissue, tumor DNA sequencing, or any other CLIA-certified laboratory test on resected tissue. --- G12D ---

Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D ---

Patients shown to have tumors expressing G12D mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12D mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12D --- --- G12D ---

2. Confirmation of G12D mutated KRAS, NRAS, or HRAS by the NCI Laboratory of Pathology. --- G12D ---

Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer Pancreatic Neoplasms Gastrointestinal Neoplasms Background: - We generated an HLA-A11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12D-mutated variant of KRAS (and other RAS family genes) expressed by many human cancers and constructed a single retroviral vector that contains alpha and beta chains that confer recognition of this antigen when transduced into PBL. --- G12D ---

Objectives: -Primary objectives: - Phase I: Determine the safety of administering PBL transduced with anti-KRAS G12D mTCR in concert with preparative lymphodepletion and high-dose interleukin-2 (IL-2; aldesleukin). --- G12D ---

- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D ---

- Phase II: Determine if anti-KRAS G12D mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12D mutation. --- G12D --- --- G12D ---

Eligibility: - Patients must be/have: - Age greater than or equal to 18 years and less than or eqaul to 70 years - HLA-A*11:01 positive - Metastatic or unresectable RAS G12D-expressing cancer which has progressed after standard therapy (if available). --- G12D ---

Design: - This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. - PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D ---

Design: - This is a phase I/II, single center study of PBL transduced with anti-KRAS G12D mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12D mutated RAS. - PBMC obtained by leukapheresis will be cultured in the presence of anti-CD3 (OKT3) and aldesleukin in order to stimulate T-cell growth. --- G12D --- --- G12D ---

- Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12D mTCR. --- G12D ---

- On Day 0, patients will receive PBL transduced with the anti-KRAS G12D mTCR and will then begin high-dose aldesleukin. --- G12D ---

- The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. --- G12D ---

- The study will be conducted using a phase I/II Simon minimax design, with two separate cohorts for the Phase II component: Cohort 2a, patients with RAS G12D pancreatic cancer, and Cohort 2b, patients with RAS G12D non-pancreatic cancer. --- G12D --- --- G12D ---



HPO Nodes


HPO:
Malignant gastrointestinal tract tumors
Genes 32
APC MLH1 MST1 FLCN TGFBR2 STK11 MSH6 TCF4 AKT1 BMPR1A PMS2 MSH2 FGFR3 MLH3 GREM1 CTNNB1 DLC1 NRAS DCC EPCAM PIK3CA GPR35 POLD1 EP300 NTHL1 POLE MUTYH AXIN2 SMAD4 SRC BUB1B WRN
Neoplasm of the gastrointestinal tract
Genes 211
CDKN1A CDKN1B CDKN1C CDKN2A HFE CDKN2B CDKN2C CDKN2D IL12A H19-ICR TMEM67 IL12RB1 TREX1 ERBB2 POU6F2 BRIP1 DIS3L2 ATP7B PSAP WWOX CEL SPIB ACD ATRX PDGFRA PDGFRL TNFSF12 INS SRC MC1R PDX1 BARD1 HMBS IRF1 NBN IRF5 RPS19 DAXX RPS20 GCK KEAP1 ACVRL1 DCC PTCH1 PTEN MDM2 GDF2 HNF4A TRIP13 GDNF RNF43 TERF2IP STAT1 AXIN1 AXIN2 BAP1 MEN1 BLK BLM FAH MET STK11 PTPN3 BMPR1A SERPINA1 NEUROD1 DLC1 ICOS GPC3 MGMT BRCA1 BRCA2 PIK3CA ABCC8 JAG1 NFKB1 KCNJ11 NFKB2 BUB1 BUB1B MITF AHCY GPC4 MLH1 CTHRC1 TJP2 KCNQ1 CC2D2A COL14A1 AKT1 BCL10 DLEC1 FGFR3 FGFR2 GNAS SEMA4A UROD FH KIT KCNQ1OT1 TNFSF15 SEC23B SDHA SDHB SDHC SDHD RAD21 FOXE1 RAD51 RAD51C PMS1 RAD51D KRAS MRE11 TCF4 KLF11 HNF1A SEMA3C PMS2 RPGRIP1L NRAS COMP RHBDF2 KLF6 NRTN DOCK8 GPR35 INPP5E POLD1 NTHL1 POLE POT1 SH3KBP1 WRN ASCC1 WT1 APC CASP8 POU2AF1 CASP10 RELA MSH2 MSH3 MINPP1 REST RET ECE1 FAS FASLG CR2 AAGAB TERT DICER1 PALB2 EDN3 EDNRB FAN1 RAD50 MSR1 MST1 TGFBR2 MSH6 RASGRP1 SEMA3D KLLN MLH3 PIEZO2 IGF2 ARSA IGF2R MMEL1 LMNA RNF6 CD19 MS4A1 TRIM28 SLC25A13 SETBP1 CHEK2 PTCH2 TNFRSF13C PRKAR1A ABCB11 TNFRSF13B FLCN APPL1 PRKCD C11ORF95 CD81 HABP2 PAX4 GREM1 CTNNB1 SPRTN BUB3 HBB SUFU CEP57 ENG CDH1 EPCAM G6PC SLC37A4 PALLD TNPO3 EP300 MUTYH H19 TP53 SMAD4 CDK4
Neoplasm of the pancreas
Genes 80
RAD51 RAD51C CDKN1A PMS1 CDKN1B RAD51D VHL CDKN2A NUTM1 KRAS CDKN2B CDKN2C CDKN2D TGFBR2 FLI1 MRE11 STK11 MSH6 BMPR1A PMS2 MLH3 BRIP1 MGMT SLC12A3 BRCA1 ACD SPINK1 BRCA2 USB1 CLCNKB TINF2 RTEL1 PDGFRB CTC1 PIK3CA NTHL1 BRD4 POT1 MAFA MC1R MITF CHEK2 WT1 APC BARD1 MLH1 PRKAR1A DKC1 NBN COL14A1 RPS20 TSC1 PARN NOP10 TSC2 EWSR1 GCGR MSH2 CDC73 SEMA4A WRAP53 PTEN MDM2 NHP2 TERC AAGAB TERT EPCAM RNF43 PALLD PALB2 TERF2IP TP53 NOTCH3 SMAD4 BAP1 CDK4 MEN1 FAN1 RAD50