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Report for Clinical Trial NCT03190941

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 G12V Variant of Mutated RAS in HLA-A*11:01 Patients

Background: A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. This therapy is called gene transfer using anti-KRAS G12V mTCR cells. Objective: To see if anti-KRAS G12 V mTCR cells are safe and can shrink tumors. Eligibility: Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors. Design: In another protocol, participants will: Be screened Have cells harvested and grown Have leukapheresis In this protocol, participants will have the procedures below. Participants will be admitted to the hospital. Over 5 days, participants will get 2 chemotherapy medicines as an infusion via catheter in the upper chest. A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter. For up to 3 days, participants will get a drug to make the cells active. A day after getting the cells, participants will get a drug to increase their white blood cell count. This will be a shot or injection under the skin. Participants will recover in the hospital for 1-2 weeks. They will have lab and blood tests. Participants will take an antibiotic for at least 6 months. Participants will have visits every few months for 2 years, and then as determined by their doctor. Visits will be 1-2 days. They will include lab tests, imaging studies, and physical exam. Some visits may include leukapheresis or blood drawn. Participants will have blood collected over several years.

NCT03190941 Pancreatic Cancer Gastric Cancer Gast Gastrointestinal 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

1/Phase I 2/Phase II

Name: Fludarabine

Description: Days -7 to -3: Fludarabine 25 mg/m2/day IVPB daily over 30 minutes for 5 days.

Type: Drug

1/Phase I 2/Phase II

Name: anti-KRAS G12V mTCR

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

1/Phase I 2/Phase II

Name: Aldesleukin

Description: Aldeskeukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every eight 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


Primary Outcomes

Description: Percentage of patients who have a clinical response 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

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

Secondary Outcomes

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

Measure: In vivo survival of mTCR gene engineered cells

Time: Batched and assayed at the conclusion of the study

Purpose: Treatment

Allocation: Non-Randomized

Sequential Assignment


There is one SNP

SNPs


1 G12V

A Phase I/II Study Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients. --- G12V ---

Administering Peripheral Blood Lymphocytes Transduced With a Murine T-Cell Receptor Recognizing the G12V Variant of Mutated RAS in HLA-A*11:01 Patients Background: A new cancer therapy involves taking white blood cells from a person, growing them in the lab, genetically modifying them, then giving them back to the person. --- G12V ---

This therapy is called gene transfer using anti-KRAS G12V mTCR cells. --- G12V ---

Eligibility: Adults at least 18 years old with cancer that has the KRAS G12V molecule on the surface of tumors. --- G12V ---

A few days later, participants will get the anti-KRAS G12V mTCR cells via catheter. --- G12V ---

- INCLUSION CRITERIA: - Measurable metatstatic unresectable malignancy expressing G12V 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. --- G12V ---

Patients shown to have tumors expressing G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12V ---

Patients shown to have tumors expressing G12V mutated NRAS and HRAS will also be eligible as these oncogenes share complete amino acid homology with G12V mutated KRAS for their first 80 N-terminal amino acids, completely encompassing the target epitope. --- G12V --- --- G12V ---

Patients who are receiving any other investigational agents - INCLUSION CRITERIA: - Measurable metatstatic unresectable malignancy expressing G12V 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. --- G12V ---

Patients who are receiving any other investigational agents Pancreatic Cancer Gastric Cancer Gast Gastrointestinal Cancer Colon Cancer Rectal Cancer Gastrointestinal Neoplasms Background: - We generated an HLA-A*11:01-restricted murine T-cell receptor (mTCR) that specifically recognizes the G12V-mutated variant of KRAS (and other RAS family genes), expressed by many human cancers and constructed a single retroviral vector that contains its alpha and beta chains that confers recognition of this antigen when transduced into PBL. --- G12V ---

Objectives: Primary objectives: - Phase I: determine the safety of administering PBL transduced with anti-KRAS G12V mTCR in concert with preparative lymphodepletion and high dose interleukin-2 (IL-2; aldesleukin). --- G12V ---

- Phase II:To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12V mutation. --- G12V ---

- Phase II:To determine if anti-KRAS G12V mTCR-transduced PBL can mediate the regression of tumors harboring the RAS G12V mutation. --- G12V --- --- G12V ---

Eligibility: Patients must be/have: - Age greater than or equal to 18 years and less than or equal to 70 years - HLA-A*11:01 positive - Metastatic or unresectable RAS G12V-expressing cancer which has progressed after standard therapy (if available). --- G12V ---

Design: - This is a Phase I/II, single center study of PBL transduced with anti-KRAS G12V mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12V 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. --- G12V ---

Design: - This is a Phase I/II, single center study of PBL transduced with anti-KRAS G12V mTCR in HLA-A*11:01 positive patients with advanced solid tumors expressing G12V 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. --- G12V --- --- G12V ---

- Transduction is initiated by exposure of these cells to retroviral vector supernatant containing replication-incompetent virus encoding the anti-KRAS G12V mTCR. --- G12V ---

- On day 0 patients will receive their PBL transduced with the anti-KRAS G12V mTCR and will then begin high-dose aldesleukin. --- G12V ---

- 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 G12V pancreatic cancer, and Cohort 2b, patients with RAS G12V non-pancreatic cancer. --- G12V ---

- 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 G12V pancreatic cancer, and Cohort 2b, patients with RAS G12V non-pancreatic cancer. --- G12V --- --- G12V ---



HPO Nodes


HPO:
Malignant gastrointestinal tract tumors
Genes 42
CTNNB1 BUB1 DLC1 STK11 MSH6 BMPR1A SMAD4 PIK3CA POLE FLCN SMAD4 MST1 AKT1 FGFR3 APC WRN EPCAM BMPR1A NRAS MUTYH PMS2 EP300 SRC BUB1B MSH2 APC AXIN2 TGFBR2 GREM1 NTHL1 MLH1 MLH3 STK11 APC PTPRJ DCC TCF4 TP53 APC GPR35 POLD1 APC
Neoplasm of the gastrointestinal tract
Genes 340
GPC3 SDHC SDHC MGMT MS4A1 SUFU APC EPCAM INS NFKB2 ABCC8 CDKN2B PALLD POU2AF1 BRCA2 FH HMBS GREM1 APC NTHL1 PTEN RAD51D MSH3 SLC25A13 PIK3CA RASGRP1 UROD KIT TP53 SDHD PRKCD RNF43 SLC37A4 SDHB BAP1 BMPR1A FAN1 CTNNB1 SDHD NEUROD1 MSH3 RPGRIP1L CDKN2B KEAP1 DICER1 WT1 MSH6 PSAP CDKN2A FGFR3 BMPR1A PTCH2 MUTYH CDKN2C BMPR1A CDK4 RELA EP300 ENG TNFSF15 SMAD7 AXIN2 BRCA2 TREX1 TERF2IP ICOS TNFSF12 CHEK2 COMP PRKAR1A PIK3CA KLF11 GPR35 ENG MLH1 STAT1 CDH1 BLK POLE CASP10 IL1B CASP10 SMAD4 H19-ICR SDHB RAD21 MTOR TRIP13 TRIM28 MEN1 JAG1 TNFRSF13B MDM2 BMP2 BRCA2 BCL10 PTEN POU6F2 GCK BUB1B KCNQ1 DOCK8 SEMA3C ACD KLF6 SMPD1 TP53 BUB3 DCC AXIN1 MEN1 MSH2 KCNJ11 TP53 PTEN JAK2 DIS3L2 MITF SH3KBP1 BMPR1A TP53 BUB1 BLM FAH CDKN1C BARD1 SPIB AAGAB RAD50 PHKG2 TNFRSF13C NBN MST1 MLH3 MSH2 IGF2 FLCN SLC37A4 PALB2 CDKN2A SETBP1 SDHC MSH2 CR2 IGF2 MLH1 MC1R IL12RB1 MEN1 RAD51 MLH3 MET MMEL1 SEMA3D H19 APC RNF6 PMS1 CHEK2 CDKN2A MSR1 CC2D2A APC TJP2 TNPO3 ECE1 TTC37 REST TMEM67 GDF2 AHCY CD19 HNF1A NRTN IL1RN TRIP13 IGF2R AKT1 ASCC1 FLCN BRCA1 SDHC HFE MLH1 PMS2 LMNA SDHC ACVRL1 RAD51C SDHD SRC GNAS BUB1 CHEK2 APC HBB PDGFRA PIEZO2 PMS1 STAT6 SDHB SDHB MSH6 RET APC KRAS INPP5E KRAS SETBP1 SKIV2L POLD1 FAS KRAS ARSA SMAD4 DLEC1 RNF43 DLC1 BMPR1A SDHB MSH2 PIK3CA HMBS SMAD4 EDNRB MUTYH G6PC SPRTN PAX4 RHBDF2 PIK3CA SERPINA1 FOXE1 PDX1 ATP7B CTHRC1 ABCB11 ERBB2 MLH1 CDKN1A RPS20 BRCA1 RPS19 HFE H19 POT1 TRIM28 GDNF TERT APC F5 APC AKT1 WT1 CTNNB1 CEL KIT TP53 GPC4 COL14A1 PRKCD HNF1A ATRX CASP8 HFE SMAD4 POLE DAXX AKT1 MSH6 HABP2 KCNQ1OT1 KIT EDN3 H19 NAB2 NRAS MUTYH CDKN1B BRIP1 TGFBR2 MRE11 HNF4A FAH STK11 TGFBR2 SDHD AXIN2 EPCAM AXIN2 TCF4 KLLN APC IL12A PTPN3 SEC23B TGFBR2 SEMA4A POLD1 PIK3CA PDGFRA MINPP1 FAS APPL1 APC CD81 WWOX SMAD4 STK11 CTNNB1 BMPR1A HBB C11ORF95 NFKB1 IRF1 SEC23B GPC3 WRN PTEN PALB2 SDHA PHKA2 PDGFRL PMS2 TNFSF12 RHBDF2 SDHB BUB1B FGFR2 FASLG CEP57 SLC25A13 IRF5 PIK3CA TP53 PTPRJ CDKN1B PTEN APC PTCH1