Description:
This is a research study to determine the safety and tolerability of ATLCAR.CD30 for treating
relapsed/refractory Peripheral T Cell Lymphoma. Blood samples will be collected from study
participants and the immune T cells will be separated. T cells will be genetically modified
in a laboratory at UNC-Chapel Hill to enable them to produce CD30 antibody. The modified T
cells, called ATLCAR.CD30, will be able to target and attach to lymphoma cancer cells that
carry the CD30 antigen. Once they are attached, the T cells will attack and destroy the
lymphoma cancer cells. To prepare the body for the ATLCAR.CD30 cells, participants will
complete lymphodepletion with two chemotherapy agents. Lymphodepletion will happen over three
days prior to ATLCAR.CD30 infusion. If participants respond to this treatment, and there are
sufficient unused ATLCAR.CD 30 cells, they may be eligible to receive a second infusion. The
second infusion will be given after a second lymphodepletion chemotherapy. Most of the clinic
visits in this research will last between 1-8 hours.
Participants will be followed closely for 4 consecutive weeks after ATLCAR.CD30 infusion(s).
Other follow-up visits will happen on Weeks 6 and 8, and continue every 3 months for the
first year after infusion. Long-term follow up will continue annually for up to 15 years
after the last ATLCAR.CD30 infusion.
There are risks associated in participating in this research study. Risks of treatment
include pain, fever, nausea, vomiting, and neurotoxicity. Other risks are associated with
study procedures, such as biopsies, imaging, infusion, and breach of confidentiality.
Title
- Brief Title: CD30 CAR for Relapsed/Refractory CD30+ T Cell Lymphoma
- Official Title: Phase II Study of the Administration of T Lymphocytes Expressing the CD30 Chimeric Antigen Receptor (CAR) for Relapsed/Refractory CD30+ Peripheral T Cell Lymphoma
Clinical Trial IDs
- ORG STUDY ID:
LCCC1904-ATL
- NCT ID:
NCT04083495
Conditions
- Peripheral T Cell Lymphoma
Interventions
Drug | Synonyms | Arms |
---|
ATLCAR.CD30 T cells | | ATLCAR.CD30 cells |
Bendamustine | Bendeka | ATLCAR.CD30 cells |
Fludarabine | | ATLCAR.CD30 cells |
Cyclophosphamide | | ATLCAR.CD30 cells |
Purpose
This is a research study to determine the safety and tolerability of ATLCAR.CD30 for treating
relapsed/refractory Peripheral T Cell Lymphoma. Blood samples will be collected from study
participants and the immune T cells will be separated. T cells will be genetically modified
in a laboratory at UNC-Chapel Hill to enable them to produce CD30 antibody. The modified T
cells, called ATLCAR.CD30, will be able to target and attach to lymphoma cancer cells that
carry the CD30 antigen. Once they are attached, the T cells will attack and destroy the
lymphoma cancer cells. To prepare the body for the ATLCAR.CD30 cells, participants will
complete lymphodepletion with two chemotherapy agents. Lymphodepletion will happen over three
days prior to ATLCAR.CD30 infusion. If participants respond to this treatment, and there are
sufficient unused ATLCAR.CD 30 cells, they may be eligible to receive a second infusion. The
second infusion will be given after a second lymphodepletion chemotherapy. Most of the clinic
visits in this research will last between 1-8 hours.
Participants will be followed closely for 4 consecutive weeks after ATLCAR.CD30 infusion(s).
Other follow-up visits will happen on Weeks 6 and 8, and continue every 3 months for the
first year after infusion. Long-term follow up will continue annually for up to 15 years
after the last ATLCAR.CD30 infusion.
There are risks associated in participating in this research study. Risks of treatment
include pain, fever, nausea, vomiting, and neurotoxicity. Other risks are associated with
study procedures, such as biopsies, imaging, infusion, and breach of confidentiality.
Detailed Description
This multicenter, open-label phase II study will determine the efficacy and safety of
autologous activated T lymphocytes (ATLs) expressing the chimeric antigen receptor specific
for CD30 (ATLCAR.CD30) administered in two sequential infusions in subjects with
relapsed/refractory CD30+ PTCL. Up to 20 subjects will receive 2 infusions of 2 × 108
cells/m2 of ATL product expressing the CAR.CD30. Subjects will have cells procured to
manufacture the ATLCAR.CD30 cells and during the time period required to manufacture the
product the subjects will be able to receive standard of care bridging therapy to be
determined by their primary local oncologist. Prior to receiving the first cell infusion,
subjects will undergo lymphodepletion with fludarabine and bendamustine. Any subject with
prior hypersensitivity reaction to bendamustine will be considered for an alternative
lymphodepletion regimen. Subjects will have their disease assessed at week 8 by either CT
chest, abdomen and pelvis or PET/CT. Subjects who have stable disease (SD), partial response
(PR) or complete response (CR) without subsequent progressive disease and meet the
eligibility criteria for a second infusion, will receive lymphodepletion followed by a second
infusion. The lymphodepletion for the second infusion will consist of cyclophosphamide and
fludarabine.
OUTLINE
Cell Procurement Up to 300 mL of peripheral blood (in up to 3 collections) will be obtained
from subjects for cell procurement. Additionally, leukapheresis may be performed to isolate
sufficient cells in subjects with a low absolute lymphocyte count or who had inadequate
peripheral blood collection. The parameters for apheresis will be up to 2 blood volumes.
Bridging Chemotherapy Subjects will be allowed to receive additional standard of care therapy
(e.g., chemotherapy or radiation therapy) to stabilize their disease if the treating
physician feels it is in the subject's best interests.
Lymphodepleting Chemotherapy Prior to the initial cellular product administration subjects
will receive a lymphodepleting regimen of bendamustine 70 mg/m^2/day administered IV over 1
hour followed by an IV dose over 30 minutes of fludarabine 30 mg/m^2/day administered over 3
consecutive days. These agents will be administered per institutional guidelines. Prophylaxis
(e.g., hydration, antiemetics, etc.) needed prior to fludarabine and bendamustine
chemotherapy will be provided per institutional guidelines 2-14 days prior to the initial
cell product administration. Subjects who have previously had hypersensitivity to
bendamustine may receive a lymphodepletion regimen of cyclophosphamide 300 mg/m^2 IV and
fludarabine 30 mg/m^2 each as a daily infusion for 3 days per institutional guidelines 2-14
days prior to the initial cell product administration.
Two to 14 days prior to the second infusion, subjects will receive a lymphodepletion regimen
of cyclophosphamide 300 mg/m^2 IV and fludarabine 30 mg/m^2 each as a daily infusion for 3
days per institutional guidelines. Subjects whose absolute neutrophil count and/or platelet
count takes >/= 3 months (from the first day of lymphodepletion prior to the initial cellular
product administration) to recover to levels required to meet eligibility for lymphodepletion
(ANC >/= 1.0 x 10^9/L and platelet count >/= 50 x 10^9/L) prior to the second infusion will
receive a 25% dose reduction in cyclophosphamide and fludarabine lymphodepletion for the
second round of lymphodepletion.
ATLCAR.CD30 Cell Administration The cellular product consisting of ATLCAR.CD30 cells will be
administered by a licensed healthcare provider (oncology nurse or physician) via intravenous
injection over 5 - 10 minutes through either a peripheral or a central line. The volume of
infusion will depend upon the concentration of the cells when frozen and the size of the
subject. The expected volume will be 1 - 50 mL. Post lymphodepletion, subjects who meet
eligibility criteria for cellular therapy will receive ATLCAR.CD30 cells within 2 - 14 days
after completing the lymphodepleting chemotherapy regimen. The recommended phase 2 dose
(RP2D) determined in the phase 1 study of ATLCAR.CD30 will be administered to subjects (2 ×
108 CAR-T/m2).
If a subject only has enough ATLCAR.CD30 cells product for one infusion, they will still be
able to receive one infusion of cells and will not have a 2nd lymphodepletion or infusion of
cells. These subjects will be replaced for the purposes of efficacy determination.
Trial Arms
Name | Type | Description | Interventions |
---|
ATLCAR.CD30 cells | Experimental | The cellular product consisting of ATLCAR.CD30 cells will be administered via intravenous injection over 5 - 10 minutes through either a peripheral or a central line. The volume of infusion will depend upon the concentration of the cells when frozen and the size of the subject. Administration to eligible subjects will occur within 2 - 14 days after completing the lymphodepleting chemotherapy regimen | - ATLCAR.CD30 T cells
- Bendamustine
- Fludarabine
- Cyclophosphamide
|
Eligibility Criteria
Inclusion Criteria for the Study
1. Written informed consent and HIPAA authorization for release of personal health
information explained to, understood by and signed by the subject or legally
authorized representative.
2. Age ≥ 18 years at the time of consent.
3. Karnofsky score of >60%
4. Histological or cytological evidence/confirmation of CD30+ peripheral T-cell lymphoma
per the 2017 World Health Organization Classification of Haematopoietic and Lymphoid
Tissues.
5. CD30+ disease determined by biopsy after the subject's most recent anti-CD30 therapy
prior to ATLCAR.CD30 (result can be pending at the time of cell procurement, but must
be confirmed prior to treatment with the first infusion of ATLCAR.CD30 cells). NOTE:
CD30+ disease requires documented CD30 expression by immunohistochemistry based on the
institutional hematopathology standard.
6. Subjects must have received at least two prior lines of therapy for their lymphoma. If
transplant is given as a preplanned consolidation in first remission, it will not be
counted as a second line of therapy.
7. Subjects relapsed after autologous stem cell transplant are eligible for this study.
8. Subjects relapsed after allogeneic stem cell transplantation are eligible provided the
patient is ≥180 days from transplant, not on immunosuppresive therapy to treat/prevent
graft-versus-host disease, and has no evidence of active graft-versus-host disease.
9. Female subjects of childbearing potential must have a negative serum pregnancy test
within 72 hours prior to cell procurement. Note: Females are considered of
childbearing potential unless they are surgically sterile (have undergone a
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
naturally postmenopausal for at least 12 consecutive months. Documentation of
postmenopausal status must be provided.
10. Female subjects of childbearing potential must be willing to abstain from heterosexual
activity or to use 2 forms of effective methods of contraception from the time of
informed consent until 6 months after study treatment discontinuation. The two
contraception methods can be comprised of two barrier methods, or a barrier method
plus a hormonal method or an intrauterine device that meets <1% failure rate for
protection from pregnancy in the product label. Women of childbearing potential will
also be instructed to tell their male partners to use a condom.
11. Subject is willing and able to comply with study procedures based on the judgement of
the investigator or protocol designee.
Exclusion Criteria for the Study
1. Subject is pregnant or lactating (Note: Breast milk cannot be stored for future use
while the mother is being treated on study).
2. Subject has a known additional malignancy that is active and/or progressive requiring
treatment; exceptions include basal cell or squamous cell skin cancer, in situ
cervical or bladder cancer, or other cancer for which the subject has been
disease-free for at least five years.
3. Subjects diagnosed with cutaneous T-cell lymphoma including mycosis fungoides, Sézary
syndrome, or any other variant of cutaneous T-cell lymphoma.
4. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its
equivalent; those receiving <10 mg daily may be enrolled at discretion of
investigator. Inhaled steroids are allowed.
5. Active infection with HIV, HTLV, HCV (tests can be pending at the time of cell
procurement; only those samples confirming lack of active infection will be used to
generate transduced cells). Note: To meet eligibility subjects are required to be
negative for HIV antibody, negative for HTLV1 and 2 antibody or PCR negative for HTLV1
and 2, negative for HCV antibody or HCV viral load.
6. Subjects who are positive for hepatitis B surface antigen (can be pending at the time
of cell procurement; only those samples confirming lack of active infection will be
used to generate transduced cells) are excluded. Subjects who are hepatitis B surface
antigen negative but hepatitis B core antibody positive must have their hepatitis B
viral load checked. These subjects will be excluded if their viral load is positive at
baseline. Subjects who are core antibody positive and viral load negative at baseline
will be considered eligible.
Eligibility Criteria Prior to Cell Procurement
1. Informed consent to undergo cell procurement understood by and signed by the subject
or legally authorized representative; subject and/or legally authorized representative
given a copy of informed consent form for cell procurement.
2. Subject has life expectancy ≥ 6 weeks.
3. Subject has evidence of adequate organ function as defined by:
- Hemoglobin ≥8.0 g/dL (transfusion independent for 2 weeks prior to procurement)
- Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's Syndrome
- AST ≤ 3 × ULN
- ALT < 3 x ULN
- Creatinine ≤ 2 × ULN
- Pulse oximetry of >90% on room air
4. Imaging results from within 90 days prior to procurement to assess presence of active
disease.
5. Negative serum pregnancy test within 72 hours prior to procurement or documentation
that the subject is post-menopausal. Post-menopausal status must be confirmed with
documentation of absence of menses for >1 year, or documentation of surgical menopause
(have undergone a hysterectomy, bilateral tubal ligation, or bilateral oophorectomy)
or they are naturally postmenopausal for at least 12 consecutive months.
Eligibility Criteria Prior to Lymphodepletion #1
1. Written informed consent explained to, understood by and signed by the subject or
legally authorized representative; subject and/or legally authorized representative
given a copy of informed consent form.
2. Imaging results from within 10 days prior to lymphodepletion. Imaging must occur at
least 3 weeks after most recent therapy (used as baseline measure for documentation of
progression before the lymphodepletion) to document measurable or assessable disease.
3. Subject must demonstrate adequate organ function prior to lymphodepletion as defined
below. All tests must be obtained within 72 hours prior to lymphodepletion:
- Absolute neutrophil count ≥ 1.0 × 10^9/L
- Platelet count ≥ 50 × 10^9/L
- Total bilirubin < 2 x ULN unless attributed to Gilbert's syndrome
- AST ≤ 5 x ULN
- ALT ≤ 5 x ULN
- Creatinine ≤ 3 x ULN
- Pulse Oximetry of >90% on room air
4. Subject must have available autologous transduced activated T cells product at a dose
of 2x10^8 cells/m^2 and meets the Certificate of Analysis acceptance criteria.
5. No major surgery within 28 days prior to lymphodepletion.
6. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for
female participants of childbearing potential. Note: Females are considered of
childbearing potential unless they are surgically sterile (have undergone a
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
naturally postmenopausal for at least 12 consecutive months.
7. Subject has not received any investigational agents or any tumor vaccines within the
previous six weeks prior to lymphodepletion.
8. Subject has not received anti-CD30 antibody-based therapy within the previous 4 weeks
prior to lymphodepletion.
9. Subject has not received chemotherapy within the previous 3 weeks prior to
lymphodepletion.
10. Subject does not have rapidly progressive disease, per treating oncologist's
discretion.
11. Subject is a good candidate for CAR T cell therapy, per treating oncologist's
discretion.
12. Subjects on strong inhibitors of CYP1A2 (e.g., fluvoxamine, ciprofloxacin) as these
may increase plasma concentrations of bendamustine, and decrease plasma concentrations
of its metabolites. See http://medicine.iupui.edu/clinpharm/ddis/ for an updated list
of strong inhibitors of CYP1A2. (This applies to subjects who receive bendamustine for
lymphodepletion (required) up through 72 hours after the last dose of bendamustine.)
13. Subject is not taking a prohibited or contraindicated medication prior to
lymphodepletion.
14. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its
equivalent; those receiving <10 mg daily may be enrolled at discretion of
investigator. Inhaled steroids are allowed.
Eligibility Criteria Prior to Cell Product Administration #1
1. Subject has no evidence of uncontrolled infection or sepsis.
2. Negative serum pregnancy within 7 days of cell product administration for females of
childbearing potential (does not need to be repeated if pre-lymphodepletion pregnancy
test is within window). Note: Females are considered of childbearing potential unless
they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation,
or bilateral oopherectomy) or they are naturally postmenopausal for at least 12
consecutive months.
3. Evidence of adequate organ function as defined by:
- Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome
- AST ≤ 5 × ULN
- ALT ≤ 5 × ULN
- Creatinine ≤ 3 × ULN
- Pulse Oximetry of >90% on room air
4. Subject has no clinical indication of rapidly progressing disease in the opinion of
the clinical investigator.
5. Subject is a good candidate for treatment with ATLCAR.CD30 cell product per the
clinical investigator's discretion.
Eligibility Criteria Prior to Lymphodepletion #2
1. Imaging results from within 21 days prior to lymphodepletion to confirm that the
subject has derived clinical benefit from the initial infusion as assessed by the
investigator (stable disease or better after the first ATLCAR.CD30 infusion without
subsequent progressive disease).
2. Subjects who experienced Grade 4 CRS or Grade 4 ICANS as a result of the initial
ATLCAR.CD30 infusion are only eligible for a second round of lymphodepletion and
infusion if they have partial response or better to the initial ATLCAR.CD30 infusion.
3. Subject must demonstrate adequate organ function prior to lymphodepletion as defined
below. All tests must be obtained within 24 hours prior to lymphodepletion:
- Absolute neutrophil count ≥ 1.0 × 10^9/L
- Platelet count ≥ 50 × 10^9/L
- Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome
- AST ≤ 5 × ULN
- ALT ≤ 5 × ULN
- Creatinine ≤ 3 × ULN
- Pulse Oximetry of >90% on room air
4. Subject must have available autologous transduced activated T cells product at a dose
of 2x10^8 cells/m^2 and meets the Certificate of Analysis acceptance criteria.
5. Negative serum pregnancy test within 72 hours prior to lymphodepleting therapy for
female participants of childbearing potential. Note: Females are considered of
childbearing potential unless they are surgically sterile (have undergone a
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy) or they are
naturally postmenopausal for at least 12 consecutive months.
6. Subject does not have evidence of uncontrolled infection or sepsis.
7. Subject is not receiving a prohibited medication at time of starting lymphodepletion
up through 72 hours after the last dose of cyclophosphamide.
8. Subject is a good candidate for CAR T cell therapy, per treating oncologist's
discretion.
9. Current use of systemic corticosteroids at doses ≥10 mg prednisone daily or its
equivalent; those receiving <10 mg daily may be enrolled at discretion of
investigator. Inhaled steroids are allowed.
Eligibility Criteria Prior to Cell Product Administration #2
1. Subject has no evidence of uncontrolled infection or sepsis.
2. Negative serum pregnancy within 7 days of cell product administration for females of
childbearing potential (does not need to be repeated if pre-lymphodepletion pregnancy
test is within window). Note: Females are considered of childbearing potential unless
they are surgically sterile (have undergone a hysterectomy, bilateral tubal ligation,
or bilateral oophorectomy) or they are naturally postmenopausal for at least 12
consecutive months.
3. Evidence of adequate organ function as defined by:
- Total bilirubin ≤ 2 × ULN, unless attributed to Gilbert's syndrome
- AST ≤ 5 × ULN
- ALT ≤ 5 × ULN
- Creatinine ≤ 3 × ULN
- Pulse Oximetry of >90% on room air
4. Subject has no clinical indication of rapidly progressing disease in the opinion of
the clinical investigator.
5. Subject is a good candidate for treatment with ATLCAR.CD30 cell product per the
clinical investigator's discretion.
Maximum Eligible Age: | 99 Years |
Minimum Eligible Age: | 18 Years |
Eligible Gender: | All |
Healthy Volunteers: | No |
Primary Outcome Measures
Measure: | Progression free survival (PFS) after administration of the ATLCAR.CD30 in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma |
Time Frame: | 8 weeks |
Safety Issue: | |
Description: | PFS is defined from day of initial lymphodepletion administration of the first ATLCAR.CD30 product infusion to the date of disease progression per the Revised Lugano Criteria or death as a result of any cause. Subjects who do not meet criteria for progression by the analysis data cut-off date will be censored at their last evaluable disease assessment date. |
Secondary Outcome Measures
Measure: | Best overall response rate (BOR) mediated by the ATLCAR.CD30 product administered in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma |
Time Frame: | 2 years |
Safety Issue: | |
Description: | The best overall response rate (BOR) will be defined as the best response recorded from the first administration of the ATLCAR.CD30 product to the date of disease progression per the Revised Lugano Criteria or death as a result of any cause. |
Measure: | Objective response rate (ORR) mediated by the first infusion of the ATLCAR.CD30 product administered in patients with relapsed/refractory CD30+ peripheral T cell lymphoma. |
Time Frame: | 8 weeks |
Safety Issue: | |
Description: | The objective response rate (ORR) will be defined as the rate of complete responses (CR) + partial responses (PR) by 8 weeks from the date of first lymphodepletion prior to the first administration of the ATLCAR.CD30 product per the Revised Lugano Criteria. |
Measure: | Responses improved by the second infusion of the ATLCAR.CD30 product administered in subjects with either partial response or stable disease following the first infusion of ATLCAR.CD30 |
Time Frame: | 8 weeks |
Safety Issue: | |
Description: | The percentage of subjects who have an improvement in their response after the second administration of ATLCAR.CD30 product will be defined at 8 weeks after the second administration of the ATLCAR.CD30 product per the Revised Lugano Criteria. Subjects entering the second infusion in a complete response will be reported as continued CR (CCR) but will not be included in percentage of improved responses after the second infusion. |
Measure: | Incidence of Dose Limiting Toxicity (DLT) (safety and tolerability) when administering two sequential infusions of the ATLCAR.CD30 product in subjects with relapsed/refractory CD30+ peripheral T cell lymphoma |
Time Frame: | 8 weeks |
Safety Issue: | |
Description: | DLT defined as ≥ Grade 3 cytokine release syndrome (CRS), Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS), or any other ≥ Grade 3 non-hematologic toxicity, including allergic reactions to T cell infusions. Toxicity will be classified and graded according to the National Cancer Institute's Common Terminology Criteria for Adverse Events (CTCAE), version 5.0. CRS toxicity will be graded according to CRS Grading Criteria and Management Guidelines Version 3.0 (March 14, 2019). ICANS toxicity will be graded according to the ICANS Grading Criteria for Management of Immune Effector Cell-Associated Neurotoxicity Syndrome (ICANS) for CAR T-Cell Therapy. |
Measure: | Overall survival (OS) after administration of the ATLCAR.CD30 administered to subjects with relapsed/refractory CD30+ peripheral T cell lymphoma |
Time Frame: | 15 years |
Safety Issue: | |
Description: | Overall survival is defined from day of initial lymphodepletion for the first administration ATLCAR.CD30 product to date of death. |
Measure: | Comparison of the expansion and persistence of ATLCAR.CD30 in peripheral blood when infused after a single infusion of ATLCAR.CD30 cells and after two infusions with ATLCAR.CD30 cells |
Time Frame: | 1 year |
Safety Issue: | |
Description: | Persistence and expansion of ATLCAR.CD30 in peripheral blood after a single infusion and after two infusions will be determined by quantitative polymerase chain reaction (PCR) and flow cytometry in sample of peripheral blood. Feasibility is defined as ability of subjects to receive 2 sequential infusions taking into account manufacturing and any other limiting factors to receiving a second infusion of ATLCAR.CD30 |
Details
Phase: | Phase 2 |
Primary Purpose: | Interventional |
Overall Status: | Recruiting |
Lead Sponsor: | UNC Lineberger Comprehensive Cancer Center |
Trial Keywords
- lymphoma
- CD30
- peripheral T cell lymphoma
Last Updated
August 24, 2021