Study of People With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Gastrointestinal Neoplasm Clinical Trial

Official title:

A Phase I/II Trial in Patients With Metastatic Gastrointestinal Epithelial Cancer Administering Tumor-Infiltrating Lymphocytes in Which the Gene Encoding CISH Was Inactivated Using the CRISPR/Cas9 System

Clinical Trial Details — Status: Withdrawn

Administrative data

• NCT number: NCT03538613
• Other study ID #: 180103
• Secondary ID: 18-C-0103
• Status: Withdrawn
• Phase: Phase 1/Phase 2
• Start date: May 17, 2018
• Est. completion date: September 10, 2018

Study information

• Verified date: September 2018
• Source: National Institutes of Health Clinical Center (CC)
• Contact: n/a
• Is FDA regulated: No
• Study type: Interventional

Clinical Trial Summary

Background:

The gene CISH can weaken immune cells called lymphocytes. It is found in all cells of the body but it most negatively impacts lymphocytes. This study may help people with certain cancers.Lymphocyte cells will be taken from their tumors, the CISH gene will be removed from those cells, then the cells will be returned to the person. Researchers hope this process will help the cells work better and fight the tumors.

Objective:

To see if cells with the CISH gene removed are safe and shrink metastatic gastrointestinal epithelial tumors.

Eligibility:

People 18 70 years old with metastatic gastrointestinal epithelial cancer

Design:

Participants will be screened with physical exam, scans, and heart, lung, blood, and urine tests.

Participants will have cells collected in another protocol. They must tell their doctor of any antibiotic allergy.

The cells will be changed in a lab. Participants will stop therapy 4 6 weeks before getting the cells back.

Participants will have leukapheresis. Blood is sent by a needle in one arm into a machine that takes out the white blood cells. The blood is returned through a needle in the other arm.

Participants will have an IV catheter inserted in their upper chest to receive medicines and the cells.

Participants will stay in the hospital and:

• Have chemotherapy for 1 week

• Get the cells for about a half hour to a little over an hour

• Get a cell growth medicine about every 8 hours for up to 12 doses

• Get medicines to boost blood cells and fight side effects

• Recover for 1 3 weeks.

Participants will have 2 follow-up visits within 12 weeks of treatment, then a couple visits each year. They will repeat screening tests.

Description:

BACKGROUND:

• CISH (Cytokine-induced SH2 protein) is an important negative regulator of T-cell signaling. The knockout or knockdown of CISH in mouse anti-tumor lymphocytes results in a profound increase in the ability of these lymphocytes to mediate tumor regression following administration to tumor bearing mice. These cells have a profound advantage in inducing anti-tumor responses compared to the wild-type anti-tumor lymphocytes.

• We have developed and optimized a CRISPR/Cas9 based strategy for highly efficient gene disruption in primary human T-cells without sacrificing cell viability or function.

• Thus, in this protocol we propose to disrupt the gene encoding CISH in lymphocytes from patients with metastatic cancers that are selected for anti-tumor activity.

OBJECTIVES:

Primary objectives:

• To determine the safety of the administration of mutation reactive autologous lymphocytes with knockout of the CISH gene in patients with refractory metastatic gastrointestinal epithelial cancer.

• To determine the response rate of the administration of mutation reactive TIL with knockout of CISH gene in patients with refractory metastatic gastrointestinal epithelial cancers.

ELIGIBILITY:

• Age greater than or equal to 18 years and less than or equal to 70 years

• Evaluable metastatic gastrointestinal epithelial cancer refractory to standard chemotherapy

• Metastatic cancer lesions suitable for surgical resection for the preparation of TIL

• No allergies or hypersensitivity to high-dose aldesleukin administration

• No concurrent major medical illnesses or any form of immunodeficiency

DESIGN:

• Patients with evaluable metastatic gastrointestinal epithelial cancer will undergo a resection of tumor under the NCI Surgery Branch companion protocol 03-C-0277.

• The study will begin in a standard phase I dose-escalation. After the MTD cell dose has been determined, patients will be enrolled into the Phase II portion of the trial at the MTD established during the Phase I portion of the study.

• Patients will receive a non-myeloablative, lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine followed by intravenous infusion of the CISH knockout lymphocytes plus IV aldesleukin.

• In the Phase II portion, the study will be conducted using a phase II optimal design where initially 21 evaluable patients will be enrolled. If 0 or 1 of the first 21 patients experiences a clinical response, then no further patients will be enrolled but if 2 or more of the first 21

evaluable patients enrolled have a clinical response, then accrual will continue until a total of 41 evaluable patients have been enrolled.

• The objective will be to determine if the treatment regimen is able to be associated with a clinical response rate that can rule out 5% (p0=0.05) in favor of a modest 20% PR + CR rate (p1=0.20).

• Up to 60 patients may be enrolled over 5 years.

Recruitment information / eligibility

• Status: Withdrawn
• Enrollment: 0
• Est. completion date: September 10, 2018
• Est. primary completion date: September 10, 2018
• Accepts healthy volunteers: No
• Gender: All
• Age group: 18 Years to 70 Years

Eligibility

• INCLUSION CRITERIA:

Inclusion Criteria to Enroll and Prepare Cells for Shipping to UMN for Processing:

1. Measurable metastatic gastrointestinal epithelial cancer with at least one lesion that is resectable for TIL generation, plus one other lesion that can be measured.

2. Confirmation of diagnosis of metastatic gastrointestinal epithelial cancer by the NCI Laboratory of Pathology.

3. Patients with 3 or fewer brain metastases that are less than 1 cm in diameter and asymptomatic are eligible. Lesions that have been treated with stereotactic radiosurgery must be clinically stable for 1 month after treatment for the patient to be eligible. Patients with surgically resected brain metastases are eligible.

4. Progressive disease following at least one first line standard therapy.

5. Age greater than or equal to 18 years and less than or equal to 70 years.

6. Clinical performance status of ECOG 0 or 1.

7. Patients of both genders must be willing to practice birth control from the time of enrollment on this study and for up to four months after treatment.

8. Serology:

• Seronegative for HIV antibody. (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who are HIV seropositive can have decreased immune-competence and thus may be less responsive to the experimental treatment and more susceptible to its toxicities.)

• Seronegative for hepatitis B antigen, and seronegative for hepatitis C antibody. If hepatitis C antibody test is positive, then patient must be tested for the presence of antigen by RT-PCR and be HCV RNA negative.

• Blood sample submitted for additional testing per national blood banking standards (e.g., anti-HTLV-I/II, anti-T. cruzi, West Nile Virus NAT, anti-CMV, RPR), for purposes of proper handling and storage

9. Willing to sign a durable power of attorney.

10. Ability of subject or Legally Authorized Representative (LAR) to understand and the willingness to sign a written informed consent document

11. Subjects must be co-enrolled on protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch Adoptive Cell Therapy Protocols).

Inclusion Criteria for Eligibility to Receive Treatment

1. Women of child-bearing potential must have a negative pregnancy test because of the potentially dangerous effects of the treatment on the fetus.

2. Hematology:

• Absolute neutrophil count greater than 1000/mm^3 without the support of filgrastim

• WBC greater than or equal to 3000/mm^3

• Platelet count greater than or equal to 100,000/mm^3

• Hemoglobin greater than 8.0 g/dl. Subjects may be transfused to reach this cut-off.

3. Chemistry:

• Serum ALT/AST less than 5.0 x ULN

• Serum creatinine less than or equal to 1.6 mg/dl

• Total bilirubin less than or equal to 2.0 mg/dl, except in patients with Gilbert s Syndrome, who must have a total bilirubin less than or equal to 3.0 mg/dl.

4. More than four weeks must have elapsed since any prior systemic therapy at the time the patient receives the preparative regimen, and patients toxicities must have recovered to grade 1 or less (except for toxicities such as alopecia or vitiligo).

Note: Patients may have undergone minor surgical procedures within the past 3 weeks, as long as all toxicities have recovered to grade 1 or less.

EXCLUSION CRITERIA:

Exclusion Criteria for Eligibility to Receive Treatment

1. Women of child-bearing potential who are pregnant or breastfeeding because of the potentially dangerous effects of the treatment on the fetus or infant.

2. Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease).

3. Concurrent opportunistic infections (The experimental treatment being evaluated in this protocol depends on an intact immune system. Patients who have decreased immunecompetence may be less responsive to the experimental treatment and more susceptible to its toxicities).

4. Active systemic infections requiring anti-infective treatment, coagulation disorders or any other active major medical illnesses.

5. Concurrent systemic steroid therapy.

6. History of severe immediate hypersensitivity reaction to cyclophosphamide, fludarabine, or aldesleukin.

7. History of coronary revascularization or ischemic symptoms.

8. Documented LVEF less than or equal to 45% tested in patients:

• Age greater than or equal to 65 years

• With clinically significant atrial and/or ventricular arrhythmias, including but not limited to: atrial fibrillation, ventricular tachycardia, second- or third-degree heart block, or have a history of ischemic heart disease and/or chest pain.

9. Clinically significant patient history which in the judgment of the PI would compromise

the patients ability to tolerate high-dose aldesleukin.

10. Documented FEV1 less than or equal to 50% predicted tested in patients with:

• A prolonged history of cigarette smoking (approximately 20 packs/year within the past 2 years).

• Symptoms of respiratory dysfunction

11. Patients who are receiving any other investigational agents.

Related Conditions & MeSH terms

• Cancer of Gastrointestinal Tract
• Cancer, Gastrointestinal
• Digestive System Neoplasms
• Gastrointestinal Epithelial Cancer
• Gastrointestinal Neoplasm
• Gastrointestinal Neoplasms

Intervention

Drug:
• Cyclophosphamide
Days -7 and -6: Cyclophosphamide 60 mg/kg/day X 2 days IV in 250 ml D5W with Mesna 15 mg/kg /day X 2 days over 1 hr.
• Fludarabine
Days -7 to -3: Fludarabine 25 mg /m2/day IVPB daily over 30 minutes for 5 days.
• Aldesleukin
Aldesleukin 720,000 IU/kg IV (based on total body weight) over 15 minutes every 8 hours (+/- 1 hour) beginning within 24 hours of cell infusion and continuing for up to 4 days (maximum 12 doses).

Biological:
• CISH inactivated TIL
Day 0: Each bag of autologous CISH inactivated TIL for infusion will be administered intravenously (IV) on the Patient Care Unit over 10-20 minutes.

Locations

Country	Name	City	State
n/a

Sponsors (1)

Lead Sponsor	Collaborator
National Cancer Institute (NCI)

References & Publications (3)

Osborn MJ, Webber BR, Knipping F, Lonetree CL, Tennis N, DeFeo AP, McElroy AN, Starker CG, Lee C, Merkel S, Lund TC, Kelly-Spratt KS, Jensen MC, Voytas DF, von Kalle C, Schmidt M, Gabriel R, Hippen KL, Miller JS, Scharenberg AM, Tolar J, Blazar BR. Evaluation of TCR Gene Editing Achieved by TALENs, CRISPR/Cas9, and megaTAL Nucleases. Mol Ther. 2016 Mar;24(3):570-81. doi: 10.1038/mt.2015.197. Epub 2015 Oct 27. — View Citation

Palmer DC, Guittard GC, Franco Z, Crompton JG, Eil RL, Patel SJ, Ji Y, Van Panhuys N, Klebanoff CA, Sukumar M, Clever D, Chichura A, Roychoudhuri R, Varma R, Wang E, Gattinoni L, Marincola FM, Balagopalan L, Samelson LE, Restifo NP. Cish actively silences TCR signaling in CD8+ T cells to maintain tumor tolerance. J Exp Med. 2015 Nov 16;212(12):2095-113. doi: 10.1084/jem.20150304. Epub 2015 Nov 2. — View Citation

Tran E, Ahmadzadeh M, Lu YC, Gros A, Turcotte S, Robbins PF, Gartner JJ, Zheng Z, Li YF, Ray S, Wunderlich JR, Somerville RP, Rosenberg SA. Immunogenicity of somatic mutations in human gastrointestinal cancers. Science. 2015 Dec 11;350(6266):1387-90. doi: 10.1126/science.aad1253. Epub 2015 Oct 29. — View Citation

Outcome

Type	Measure	Description	Time frame	Safety issue
Primary	Maximum tolerated cell dose (MTD)	Highest dose at which less than or equal to 1 of 6 patients experienced a DLT or the highest dose level studied if DLTs are not observed at any of the dose levels	Before progression to next higher dose level
Primary	Response rate	Percentage of patients who have a clinical response to treatment (objective tumor regression)	6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 5 years, then per PI discretion
Primary	Frequency and severity of treatment-related adverse events	Aggregate of all adverse events, as well as their frequency and severity	5 years after cell infusion
Secondary	Survival and persistence of CISH inactivated TIL	Assess for any long-term effects resulting from the cell administration. Samples will be batched and analyzed to check for the presence of the transferred cells.	3, 6, and 12 months post cell administration, and then yearly for 15 years