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Report for Clinical Trial NCT03745326

Developed by Shray Alag, 2020.
SNP Clinical Trial Gene

A 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:Gastrointestinal Neoplasms
HPO:Malignant gastrointestinal tract tumors Neoplasm of the gastrointestinal tract

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
Group Labels: 2

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
Group Labels: 2

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
Group Labels: 2

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. (2-4 days after the last dose of fludarabine).
Type: Biological
Group Labels: 2

1/Phase I 2/Phase II


Primary Outcomes

Description: Grade and type of toxicity per dose level; fraction of patients who experience a DLT at a given dose level, and number and grade of each type of DLT

Measure: Frequency and severity of treatment-related adverse events

Time: From time of cell infusion to two weeks after cell infusion

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

Measure: Response rate

Time: 6 weeks and 12 weeks following administration of the cell product, then every 3 months x3, then every 6 months x 2 years, then per PI discretion

Purpose: Treatment

Allocation: Non-Randomized

Sequential Assignment


There is one SNP

SNPs


1 G12D

A 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 ---

Gastrointestinal Cancer Pancreatic Cancer Gastric Cancer Colon Cancer Rectal Cancer 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:
HP:0007378: Neoplasm of the gastrointestinal tract
Genes 342
DOCK8 CTHRC1 WT1 APC ABCC8 GPC4 PTEN TNFSF15 SMPD1 PRKCD SDHC APPL1 SUFU TCF4 STK11 SMAD7 TTC37 TP53 AHCY POLE H19 RAD51D SDHD RNF43 FASLG CC2D2A SDHC BUB1 PIK3CA TP53 BAP1 ENG SDHD PMS2 CTNNB1 CR2 C11ORF95 PTPN3 PIEZO2 ABCB11 SETBP1 SLC37A4 RELA DAXX MST1 RAD51C SMAD4 FGFR3 PTCH2 SH3KBP1 RPS20 BMPR1A TNFSF12 BMPR1A SMAD4 RAD50 WWOX EP300 SPRTN MSH3 RHBDF2 TP53 FAH GREM1 APC TRIM28 SETBP1 TP53 HNF1A KEAP1 COL14A1 RHBDF2 POLE INS HBB MEN1 NAB2 PMS1 WT1 HFE KRAS EDN3 POLD1 ARSA STAT6 CDKN1C KRAS PTEN PALB2 SEMA4A HABP2 CD81 POU2AF1 TNFSF12 SMAD4 CDH1 IRF1 SEC23B MGMT H19 SDHD IGF2 PDGFRA RET MUTYH NBN MEN1 BRCA2 FAS BRIP1 NFKB2 GNAS RNF6 EDNRB BUB1B CDKN2B DCC TJP2 TP53 PAX4 BUB1B MC1R GCK MDM2 ERBB2 SMAD4 MLH1 STAT1 SRC IL12RB1 IRF5 TNFRSF13C TNFRSF13B ICOS BMPR1A CASP8 INPP5E RAD21 NFKB1 CDKN1A POT1 MINPP1 HNF1A IL12A H19 TRIP13 TMEM67 PMS1 MSH3 PIK3CA KCNQ1 ASCC1 IGF2R BARD1 MLH3 CDK4 SDHC IGF2 MLH1 MSH6 BRCA2 POU6F2 EPCAM ACD TNPO3 APC ATRX PIK3CA SKIV2L PALB2 IL1B MLH1 APC SDHC FOXE1 APC FLCN SDHB PIK3CA EPCAM MEN1 KLF6 TERT SDHB KRAS GDNF LMNA ACVRL1 CTNNB1 CDKN1B CCND1 TRIP13 SDHB DIS3L2 APC STK11 MSH2 AKT1 SLC25A13 BMP2 SDHA GDF2 F5 PMS2 APC APC PTEN IL1RN HBB MITF RASGRP1 CASP10 SMAD4 MRE11 COMP DLEC1 TRIM28 SDHB CHEK2 SDHC BRCA2 BRCA1 SEMA3D DLC1 CHEK2 MSH6 TGFBR2 PIK3CA HFE APC SLC37A4 BLM CDKN2A FH KCNJ11 SLC25A13 JAG1 POLD1 CHEK2 PHKA2 DICER1 PIK3CA HFE MSH2 REST AXIN2 HMBS MS4A1 RPS19 PTEN UROD BMPR1A GPR35 PRKCD JAK2 SDHD SEC23B CTNNB1 CDKN1B AXIN2 HMBS KIT RAD51 TP53 MUTYH SDHB AXIN1 SEMA3C PSAP FGFR2 BMPR1A USF3 TGFBR2 AKT1 PDX1 NTHL1 BUB3 H19-ICR KCNQ1OT1 BLK RPGRIP1L RNF43 NRAS MTOR AAGAB BMPR1A TERF2IP SERPINA1 FAH FAN1 NEUROD1 TGFBR2 MLH1 KLLN GPC3 MSH6 APC G6PC PALLD BCL10 CD19 WRN PTEN KIT GPC3 MSH2 ECE1 CEP57 TREX1 CDKN2B APC PDGFRA KIT MMEL1 NRTN PHKG2 CDKN2A HNF4A KLF11 FAS MET MLH3 BUB1 CASP10 CDKN2C MSH2 SPIB ATP7B PDGFRL PTPRJ AXIN2 AKT1 ENG MUTYH BRCA1 FLCN PTCH1 CEL CDKN2A SDHB MSR1 PRKAR1A
Protein Mutations 5
C10D G12D G12V G34A V600E