Description:
Background:
A person s tumor is studied for mutations. When cells are found that can attack the mutation
in a person s tumor, the genes from those cells are studied to find the parts that make the
attack possible. White blood cells are then taken from the person s body, and the gene
transfer occurs in a laboratory. A type of virus is used to transfer the genes that make
those white blood cells able to attack the mutation in the tumor. The gene transfer therapy
is the return of those white blood cells back to the person.
Objective:
To see if gene transfer therapy of white blood cells can shrink tumors.
Eligibility:
People with certain metastatic cancer for which standard treatments have not worked.
Design:
Participants may complete screening under another protocol. Screening includes:
- Getting tumor cells from a previous procedure
- Medical history
- Physical exam
- Scans
- Blood, urine, heart, and lung tests
The study has 8 stages:
1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is
removed by a needle in one arm. A machine removes white blood cells. The rest of the
blood is returned by a needle in the other arm.
2. Care at home over approximately 12 weeks.
3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
4. Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in
the chest to administer drugs.
5. Patients on Arm 2 of the study will receive the first dose of pembrolizumab while in the
hospital. Three additional doses will be given after the cell infusion 3 weeks apart.
6. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells
live longer.
7. Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and
urine tests.
8. Participants will take an antibiotic and maybe an antiviral for at least 6 months after
treatment. They will have repeat screening tests at visits every few months for the
first year, every 6 months for the second year, then as determined.
...
Title
- Brief Title: Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in People With Metastatic Cancer
- Official Title: A Phase II Study Using the Administration of Autologous T-Cells Genetically Engineered to Express T-Cell Receptors Reactive Against Neoantigens in People With Metastatic Cancer
Clinical Trial IDs
- ORG STUDY ID:
180049
- SECONDARY ID:
18-C-0049
- NCT ID:
NCT03412877
Conditions
- Endocrine Tumors
- Non-Small Cell Lung Cancer
- Ovarian Cancer
- Breast Cancer
- Gastrointestinal/Genitourinary Cancer
- Neuroendocrine Tumors
Interventions
Drug | Synonyms | Arms |
---|
Cyclophosphamide | | 1/iTCR |
Fludarabine | | 1/iTCR |
Aldesleukin | | 1/iTCR |
Individual Patient TCR-Transduced PBL | | 1/iTCR |
Pembrolizumab (KEYTRUDA ) | | 2/iTCR + Pembro |
Purpose
Background:
A person s tumor is studied for mutations. When cells are found that can attack the mutation
in a person s tumor, the genes from those cells are studied to find the parts that make the
attack possible. White blood cells are then taken from the person s body, and the gene
transfer occurs in a laboratory. A type of virus is used to transfer the genes that make
those white blood cells able to attack the mutation in the tumor. The gene transfer therapy
is the return of those white blood cells back to the person.
Objective:
To see if gene transfer therapy of white blood cells can shrink tumors.
Eligibility:
People with certain metastatic cancer for which standard treatments have not worked.
Design:
Participants may complete screening under another protocol. Screening includes:
- Getting tumor cells from a previous procedure
- Medical history
- Physical exam
- Scans
- Blood, urine, heart, and lung tests
The study has 8 stages:
1. Screening tests repeated over 1-2 weeks. Participants will have leukapheresis: Blood is
removed by a needle in one arm. A machine removes white blood cells. The rest of the
blood is returned by a needle in the other arm.
2. Care at home over approximately 12 weeks.
3. Stopping therapy for 4-6 weeks while their cells are changed in a lab.
4. Hospital stay approximately 3-4 weeks for treatment. An IV catheter will be placed in
the chest to administer drugs.
5. Patients on Arm 2 of the study will receive the first dose of pembrolizumab while in the
hospital. Three additional doses will be given after the cell infusion 3 weeks apart.
6. Receiving changed cells by catheter. Then getting a drug over 1-5 days to help the cells
live longer.
7. Recover in the hospital for 1-2 weeks. Participants will get drugs and have blood and
urine tests.
8. Participants will take an antibiotic and maybe an antiviral for at least 6 months after
treatment. They will have repeat screening tests at visits every few months for the
first year, every 6 months for the second year, then as determined.
...
Detailed Description
Background:
- The administration of autologous tumor-infiltrating lymphocytes (TIL) can mediate
complete, durable regressions in 20-25% of participants with metastatic melanoma. Recent
studies have shown that these TIL predominantly recognize unique mutated neoantigens
expressed by the cancer not shared by other melanomas.
- Administration of bulk autologous TIL to participants with a variety of other solid
cancers, including cancers of the gastrointestinal tract and genitourinary tract, have
little if any therapeutic impact.
- Recent studies in the National Cancer Institute Surgery Branch, (NCI-SB), have shown
that TIL from non-melanoma solid cancers can also contain T-cells reactive against
non-shared unique mutated or oncoviral neoantigens expressed in the cancer. The
frequency of these T-cells is very low (often < 0.1%) and it is thus difficult to
isolate and grow mutation reactive T-cells to levels required for effective therapy.
- In a single patient with chemo-refractory metastatic cholangiocarcinoma we were able to
grow a relatively pure population of neoantigen reactive TIL and administration of these
cells mediated a near-complete regression of all metastatic disease now lasting 2.5
years.
- We have developed approaches to identify these rare neoantigen reactive T-cells from
common non-melanoma cancers, to isolate their T-cell receptors (TCR), and to genetically
engineer autologous peripheral blood lymphocytes (PBL) to express these TCRs with high
efficiency. The neoantigen TCR gene-modified cells can recognize and destroy the
autologous cancer in vitro.
- In addition to reactivity to neoantigens derived from nonsynonymous mutations, T-cells
can recognize human papilloma virus (HPV) epitopes in participants with HPV- induced
cancers. The TCR from these reactive cells can be isolated and retrovirally-transduced
into autologous PBL with high efficiency.
- With these techniques, we have isolated a number of TCRs selectively recognizing shared
mutated oncogenes (e.g., KRAS, TP53) or shared oncoviral proteins (e.g. HPV) in the
context of several major histocompatibility complexes (MHC-I and MHC-II).
- This clinical protocol will treat participants with refractory solid cancers using the
adoptive transfer of autologous PBL transduced with genes encoding TCRs that recognize
unique mutated or oncoviral neoantigens expressed by the cancer.
Objectives:
-Primary objective:
--Determine the rate of objective response (using RECIST v1.1 criteria) of participants with
solid cancers who receive pembrolizumab plus autologous PBL (Arm 2) that have been transduced
with genes encoding T-cell receptors that recognize mutated or oncoviral neoantigens in the
autologous cancer
Eligibility:
-Participants must be/have:
- Age greater than or equal to 18 years and less than or equal to 70 years
- Metastatic solid cancer with at least one lesion that can be measured, that falls into
one of four cohorts: (1) gastrointestinal and genitourinary cancers; (2) breast,
ovarian, and other solid cancers; (3) non-small cell lung cancer (NSCLC); and, (4)
endocrine tumors including neuroendocrine tumors.
- Evaluable solid cancer that has recurred following standard chemotherapy or standard
systemic therapy
- Normal basic laboratory values.
- No allergies or hypersensitivity to high-dose aldesleukin administration
- No concurrent major medical illnesses or any form of immunodeficiency.
Design:
- Participants will have already undergone resection or biopsy to obtain tumor for
generation of autologous TIL cultures. This will have been conducted under the NCI-SB
cell harvest protocol 03-C-0277 (Cell Harvest and Preparation for Surgery Branch
Adoptive Cell Therapy Protocols).
- Exomic sequencing, and often RNA-Seq will be performed to identify the mutations
expressed in the patient s cancer. Multiple autologous TIL cultures will be grown and
tested for reactivity against mutations from the autologous tumor using assays we have
developed that involve the exposure of autologous antigen-presenting cells to long
peptides containing the mutation or tandem mini-genes encoding the mutation.
- T-cell cultures with reactivity against mutations will be identified and the individual
T- cell receptors that recognize the mutation will be synthesized and used to create a
retrovirus for transduction of the TCR into the patient s autologous PBL.
- Participants that present with tumors expressing oncoviral neoantigens will be treated
with autologous PBLs retrovirally transduced with TCR(s) targeting the oncoviral
neoantigen.
- Participants that present with tumors expressing mutated shared oncogenes (e.g., KRAS,
TP53) or oncoviral proteins (e.g., HPV) that also express the appropriate restriction
element may be treated with autologous PBLs retrovirally transduced with TCR(s)
previously isolated in the Surgery Branch targeting the shared mutated antigen. These
participants will be administered a cell infusion product of TCRs targeting mutated
shared oncogenes (e.g., KRAS, TP53) or oncoviral proteins (e.g., HPV). Their cell
infusion product will not include PBL transduced with unique (i.e., non-shared) TCR(s).
- Participants will be enrolled into one of four cohorts: (1) metastatic gastrointestinal
and genitourinary cancers; (2) metastatic breast, ovarian, and other solid cancers; (3)
metastatic non-small cell lung cancer (NSCLC); and, (4) metastatic endocrine tumors
including neuroendocrine tumors. Autologous PBL transduced with TCR(s) targeting
neoantigens (mutated shared oncogenes e.g., TP53, KRAS, individual non-synonymous
mutations , or oncoviral proteins) will then be expanded to large numbers using our
standard rapid expansion protocol.
- Participants enrolled on Arm 1 and Arm 2 will receive a non-myeloablative,
lymphodepleting preparative regimen consisting of cyclophosphamide and fludarabine
followed by the infusion of autologous transduced PBL and high-dose aldesleukin. At the
discretion of the Principal Investigator (PI), participants enrolled in Cohort 3 (NSCLC)
may receive low-dose aldesleukin.
- Participants enrolled on Arm 2 will receive pembrolizumab prior to cell administration
and three additional doses every three weeks following the cell infusion. Participants
who have experienced major organ toxicity due to previous treatment with pembrolizumab
(or equivalent PD-1/PD-L1 blockade) will be enrolled on Arm 1.
- Clinical and immunologic response will be evaluated about 4-6 weeks after cell infusion
and periodically thereafter.
- It is anticipated that approximately one participant per month may enroll on the trial
for each of the four histologic cohorts for Arm 2. There will be a limit of 15
participants per cohort enrolled on Arm 1 (60 participants for Arm 1), and accrual of up
to 4 x 50 = 200 total evaluable participants on Arm 2. It is expected that once full
manufacturing capability is reached, the accrual may be completed in approximately 4-5
years. In order to allow for a small number of inevaluable participants, the accrual
ceiling will be set to 270.
Trial Arms
Name | Type | Description | Interventions |
---|
1/iTCR | Experimental | Non-myeloablative lymphocyte depleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCR-Transduced PBL + high or low-dose aldesleukin | - Cyclophosphamide
- Fludarabine
- Aldesleukin
- Individual Patient TCR-Transduced PBL
|
2/iTCR + Pembro | Experimental | Non-myeloablative, lymphodepleting preparative regimen of cyclophosphamide and fludarabine + Individual Patient TCRTransduced PBL + high- or low-dose aldesleukin + pembrolizumab prior to cell administration and 3 additional doses every 3 weeksfollowing cell infusion | - Cyclophosphamide
- Fludarabine
- Aldesleukin
- Individual Patient TCR-Transduced PBL
- Pembrolizumab (KEYTRUDA )
|
Eligibility Criteria
- INCLUSION CRITERIA:
- Metastatic, solid cancer that can be measured, that falls into one of four cohorts:
(1) gastrointestinal and genitourinary cancers; (2) breast, ovarian, and other solid
cancers; (3) non-small cell lung cancer (NSCLC); and, (4) endocrine tumors including
neuroendocrine tumors.
Note: NSCLC includes but is not limited to squamous cell carcinoma, adenosquamous
carcinoma, or adenocarcinomas.
- Confirmation of diagnosis of cancer by the NCI Laboratory of Pathology.
- Refractory to approved standard systemic therapy. Specifically:
- Participants with metastatic colorectal cancer must have received oxaliplatin or
irinotecan.
- Participants with breast and ovarian cancer must be refractory to both first- and
second- line treatments.
- Participants with NSCLC must have received at least one platinum-based
chemotherapy regimen and at least one FDA-approved targeted treatment (when
appropriate).
- Participants with 3 or fewer brain metastases that are < 1 cm in diameter and
asymptomatic are eligible. Lesions that have been treated with stereotactic
radiosurgery must be clinically stable for one month after treatment for the
participant to be eligible. Participants with surgically resected brain metastases are
eligible.
- Age greater than or equal to 18 years and less than or equal to 70 years.
- Clinical performance status of ECOG 0 or 1.
- Participants of both genders must be willing to practice birth control from the time
of enrollment on this study and for four months after treatment.
- Women of child-bearing potential must be willing to undergo a pregnancy test prior to
the start of treatment because of the potentially dangerous effects of the treatment
on the fetus.
- Serology:
- Seronegative for HIV antibody. (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Participants who are HIV
seropositive may have decreased immune-competence and thus 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 participant must be tested for the
presence of antigen by RT-PCR and be HCV RNA negative.
- Hematology:
- ANC > 1000/mm^3 without the support of filgrastim
- WBC greater than or equal to 2500/mm^3
- Platelet count greater than or equal to 80,000/mm^3
- Hemoglobin > 8.0 g/dl. Subjects may be transfused to reach this cut-off.
- Chemistry:
- Serum ALT/AST less than or equal to 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 participants with
Gilbert's Syndrome, who must have a total bilirubin less than or equal to 3.0
mg/dl.
- Participants must have completed any prior systemic therapy at the time of enrollment.
Note: Participants may have undergone minor surgical procedures or limited field
radiotherapy within the four weeks prior to enrollment, as long as related major organ
toxicities have recovered to grade 1 or less.
- For Cohort 3: More than two weeks must have elapsed since any prior palliation for
major bronchial occlusion or bleeding at the time the patient receives the preparative
regimen, and patient s toxicities must have recovered to a grade 1 or less.
- Ability of subject to understand and the willingness to sign a written informed
consent document.
- Willing to sign a durable power of attorney.
- Subjects must be co-enrolled on protocol 03-C-0277.
EXCLUSION CRITERIA:
- Women of child-bearing potential who are pregnant or breastfeeding because of the
potentially dangerous effects of the treatment on the fetus or infant.
- Concurrent systemic steroid therapy.
- Active systemic infections requiring anti-infective treatment, coagulation disorders,
or any other active or uncompensated major medical illnesses.
For Cohort 3: Any major bronchial occlusion or bleeding not amenable to palliation.
- Any form of primary immunodeficiency (such as Severe Combined Immunodeficiency Disease
and AIDS).
- For Arm 2: History of major organ autoimmune disease.
Note: Participants with a history of major organ autoimmune disease may be enrolled on Arm
1 if all other eligibility criteria are met.
-For Arm 2: Grade 3 or 4 major organ irAEs following treatment with anti-PD-1/PD-L1,
including but not limited to myocarditis and pneumonitis.
Note: Participants with grade 3 or 4 major organ irAEs may be enrolled on Arm 1 if all
other eligibility criteria are met.
- Concurrent opportunistic infections (The experimental treatment being evaluated in
this protocol depends on an intact immune system. Participants who have decreased
immune-competence may be less responsive to the experimental treatment and more
susceptible to its toxicities.)
- History of severe immediate hypersensitivity reaction to cyclophosphamide,
fludarabine, or aldesleukin.
- For Cohorts 1, 2, or 4: Clinically significant participant history which in the
judgment of the Principal Investigator (PI) would compromise the participants ability
to tolerate high-dose aldesleukin.
Note: At the discretion of the PI, participants enrolled in Cohort 3 may receive low-dose
aldesleukin.
- History of coronary revascularization or ischemic symptoms.
- For select participants with a clinical history prompting cardiac evaluation: last
known LVEF less than or equal to 45%.
- For select participants with a clinical history prompting pulmonary evaluation: known
FEV1 less than or equal to 50% predicted.
- Participants who are receiving any other investigational agents.
Maximum Eligible Age: | 70 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Response rate |
Time Frame: | 6 and 12 weeks after cell infusion, then every 3 months x3, then every 6 months x 2 years, then per PI discretion |
Safety Issue: | |
Description: | Percentage of patients who receive pembrolizumab as part of the treatment regimen that have a clinical response to treatment (objective tumor regression) |
Secondary Outcome Measures
Measure: | Safety and tolerance |
Time Frame: | 6 weeks ( 2 weeks) following administration of the cell product or 30 days following the last dose of pembrolizumab |
Safety Issue: | |
Description: | Using standard CTCAE 5.0 |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Suspended |
Lead Sponsor: | National Cancer Institute (NCI) |
Trial Keywords
- Gene Therapy
- Immunotherapy
- Cell Therapy
- Adoptive Cell Therapy
Last Updated
January 29, 2021