Overview

Study of CAR-T Cells Expressing CD30 and CCR4 for r/r CD30+ HL and CTCL

Status:
Recruiting
Trial end date:
2041-09-30
Target enrollment:
0
Participant gender:
All
Summary
The body has different ways of fighting infection and disease. No single way is perfect for fighting cancer. This research study combines two different ways of fighting disease: antibodies and T cells. Antibodies are proteins that protect the body from disease caused by bacteria or toxic substances. Antibodies work by binding bacteria or substances, which stops them from growing and causing bad effects. T cells, also called T lymphocytes, are special infection-fighting blood cells that can kill other cells, including tumor cells or cells that are infected with bacteria or viruses. Both antibodies and T cells have been used to treat patients with cancers. They both have shown promise, but neither alone has been sufficient to treat cancer. This study will combine both T cells and antibodies in order to create a more effective treatment called Autologous T Lymphocyte Chimeric Antigen Receptor cells targeted against the CD30 antigen (ATLCAR.CD30). Another treatment being tested includes the Autologous T Lymphocyte Chimeric Antigen Receptor cells targeted against the CD30 antigen with CCR4 (ATLCAR.CD30.CCR4) to help the cells move to regions in the patient's body where the cancer is present. Participants in this study will receive either ATLCAR.CD30.CCR4 cells alone or will receive ATLCAR.CD30.CCR4 cells combined with ATLCAR.CD30 cells. Previous studies have shown that a new gene can be put into T cells that will increase their ability to recognize and kill cancer cells. The new gene that is put in the T cells in this study makes an antibody called anti-CD30. This antibody sticks to lymphoma cells because of a substance on the outside of the cells called CD30. Anti-CD30 antibodies have been used to treat people with lymphoma but have not been strong enough to cure most patients. For this study, the anti-CD30 antibody has been changed so instead of floating free in the blood it is now joined to the T cells. When an antibody is joined to a T cell in this way it is called a chimeric receptor. These CD30 chimeric (combination) receptor-activated T cells (ATLCAR.CD30) can kill some of the tumor, but they do not last very long in the body and so their chances of fighting the cancer are unknown. Researchers are working to identify ways to improve the ability of ATLCAR.CD30 to destroy tumor cells. T cells naturally produce a protein called CCR4 which functions as a navigation system directing T cells toward tumor cells specifically. In this study, researchers will also genetically modify ATLCAR.CD30 cells to produce more CCR4 proteins and they will be called ATLCAR.CD30.CCR4. The study team believes that the ATLCAR.CD30.CCR4 cells will be guided directly toward the tumor cells based on their navigation system. In addition, the study team believes the majority of ATLCAR.CD30 cells will also be guided directly toward tumor cells when given together with ATLCAR.CD30.CCR4, increasing their anti-cancer fighting ability. This is the first time ATLCAR>CD30.CCR4 cells or combination of ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells are used to treat lymphoma. The purpose of this study to determine the following: - What is the safe dose of ATLCAR.CD30.CCR4 cells to give to patients - What is the safe dose of the combination of ATLCAR.CD30 and ATLCAR.CD30.CCR4 cells to give to patients
Phase:
Phase 1
Accepts Healthy Volunteers?
No
Details
Lead Sponsor:
UNC Lineberger Comprehensive Cancer Center
Treatments:
Bendamustine Hydrochloride
Fludarabine
Fludarabine phosphate
Criteria
Inclusion Criteria

- Unless otherwise noted, subjects must meet all of the following criteria to
participate in this study:

- Written informed consent and HIPAA authorization for release of personal health
information. Subjects or their Legally Authorized Representative must sign a consent
to undergo cell procurement. Written informed consent to enroll in the CAR T-cell
therapy trial must be obtained prior to lymphodepletion.

- Adults ≥18 years of age.

- Subjects must have one of the following diagnoses by WHO criteria:

- Classic Hodgkin Lymphoma

- Mycosis fungoides

- Sezary syndrome

- Primary cutaneous CD30 positive T cell lymphoproliferative disorder including
lymphomatoid papulosis or primary cutaneous anaplastic large cell lymphoma

- B-cell lymphoma, unclassifiable, with features intermediate between DLBCL and
classic Hodgkin Lymphoma (Grey Zone Lymphoma)

- Diagnosis of recurrent lymphoma in subjects who have failed ≥2 prior treatment
regimens.

- These prior treatment regimens must include brentuximab vedotin.

- If the subject has Hodgkin Lymphoma, the subject must have either failed autologous
transplant or must not be eligible for autologous transplant.

- If the subject has grey zone lymphoma, the subject must have failed an anthracycline
containing regimen unless the subject was not previously a candidate for anthracycline

- Subjects relapsed after autologous or allogeneic stem cell transplant are eligible for
this study.

- CD30+ disease (result can be pending at the time of cell procurement, but must be
confirmed prior to treatment with ATLCAR.CD30.CCR4 and ATLCAR.CD30 cells); NOTE: CD30+
disease requires documented CD30 expression by immunohistochemistry based on the
institutional hematopathology standard.

- Karnofsky score of > 60%

- For Subjects in the Expansion Cohort: Willing to undergo biopsy following the cell
infusion. A biopsy may be required (i.e., considered mandatory) in subjects receiving
both cellular products if the Investigator determines the tumor site is easily
accessible (e.g., palpable tumor). If the Investigator feels that the biopsy would be
difficult to obtain or poses a high degree of risk to the subject, it may be deferred.

- Women of childbearing potential (WOCBP) must be willing to use 2 methods of birth
control or be surgically sterile, or abstain from heterosexual activity for the course
of the study, and for 6 months after the study is concluded. WOCBP are those who have
not been surgically sterilized or have not been free from menses for > 1 year. The two
birth control methods can be composed of: two barrier methods or a barrier method plus
a hormonal method to prevent pregnancy. WOCBP subjects will also be instructed to tell
their male partners to use a condom.

Exclusion Criteria

- Subjects meeting any of the following exclusion criteria will not be able to
participate in this study:

- Pregnant or lactating.

- Tumor in a location where enlargement could cause airway obstruction.

- Current use of systemic corticosteroids at doses ≥10mg prednisone daily or its
equivalent; those receiving <10mg daily may be enrolled at discretion of the
Investigator.

- Active infection with HIV, HTLV, HCV (can be pending at the time of cell procurement;
only those samples confirming lack of active infection will be used to generate
transduced cells) defined as not being well controlled on therapy. Subjects are
required to have negative HIV antibody, negative HTLV1 and 2 antibody, and negative
HCV antibody or viral load.

- Active infection with HBV. Subjects are required to have a negative Hepatitis B
surface Antigen. In addition, subjects must either have core antibody negative HBV
(results can be pending at the time of cell procurement) OR if a subject is Hepatitis
B core antibody positive they 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.

- 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 three years.

- A history of intolerance to fludarabine. Subjects with an intolerance to bendamustine
may be allowed to enroll at the discretion of the clinical investigator if he/she
thinks that the subject is a candidate for lymphodepletion with cyclophosphamide and
fludarabine.

- Subject is not a good candidate for treatment with ATLCAR.CD30.CCR4 with and without
ATLCAR.CD30 per Investigator's discretion.

Eligibility criteria to be met prior to procurement

Evidence of adequate organ function as defined by:

The following is required prior to procurement:

- Hgb ≥ 8.0g/dL (transfusion independent for 2 weeks prior to enrollment)

- Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome
may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated
bilirubin is <1.5× ULN

- AST ≤ 3 times ULN

- Serum creatinine ≤1.5 times ULN.

- Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault

- Pulse oximetry of >90% on room air

- Imaging results from within 120 days prior to procurement to assess presence of active
disease (no tumor imaging is required prior to procurement for participants with
active cutaneous lymphoma).

- 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 involving bilateral oophorectomy.

- Subject has no clinical indication of rapidly progressing disease in opinion of
treating physician.

- Subject has adequate cardiac function, defined as:

- No ECG evidence of acute ischemia

- No ECG evidence of active, clinically significant conduction system abnormalities

- Prior to study entry, any ECG abnormality at screening not felt to put the
subject at risk has to be documented by the Investigator as not medically
significant

- No uncontrolled angina or severe ventricular arrhythmias

- No clinically significant pericardial disease

- No history of myocardial infarction within the last 6 months prior to infusion

- No Class 3 or higher New York Heart Association Congestive Heart Failure

Eligibility criteria to be met prior to lymphodepletion

- Presence of active disease. Imaging results from within 7 days prior to
lymphodepletion to confirm presence of active disease. Subjects who have received
bridging chemotherapy must have imaging performed at least 3 weeks after most recent
therapy (imaging does not need to be repeated if it is within 7 days prior to
lymphodepletion).

Evidence of adequate organ function as defined by:

The following are required prior to lymphodepletion:

- Adequate bone marrow function (ANC>1000 cells/mm3 and platelets >75,000/mm3). Subjects
cannot have received platelet transfusion within 7 days of lymphodepletion.

- Bilirubin ≤1.5 times the upper limit of normal (ULN). Subjects with Gilbert's syndrome
may be enrolled despite a total bilirubin level >1.5 mg/dL if their conjugated
bilirubin is <1.5× ULN)

- AST ≤ 3 times ULN

- Serum creatinine ≤1.5 times ULN.

- Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault

- Pulse oximetry of > 90% on room air

- Negative serum pregnancy test within 72 hours prior to lymphodepletion 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 involving bilateral oophorectomy.

- Subjects must have autologous transduced activated T-cells that meet the Certificate
of Analysis (CofA) acceptance criteria.

- Has not received any investigational agents or received any tumor vaccines within the
previous six weeks prior to lymphodepletion.

- Has not received anti-CD30 antibody-based therapy within the previous 4 weeks prior to
lymphodepletion.

- Has not received chemotherapy or radiation therapy within the previous 3 weeks prior
to lymphodepletion.

Subjects cannot be 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).

- Subjects who are HBV core antibody positive and HBV viral load negative prior to
lymphodepletion must have initiated anti-HBV prophylaxis prior to lymphodepletion.

- Subject has no clinical indication of rapidly progressing disease in the opinion of
the treating physician.

- Subject is a good candidate for treatment with ATLCAR.CD30.CCR4 with and without
ATLCAR.CD30 per the investigator's discretion.

Eligibility criteria to be met prior to cell infusion after lymphodepletion

- No evidence of uncontrolled infection or sepsis.

Evidence of adequate organ function as defined by:

1. Bilirubin ≤2 times the upper limit of normal (ULN) unless attributed to Gilbert's
syndrome

2. AST ≤3 times ULN

3. ALT ≤3 times ULN

4. Creatinine Clearance (CrCl) >60mL/min per Cockcroft and Gault

5. Pulse oximetry of >90% on room air

- Subject has no clinical indication of rapidly progressing disease in the opinion
of the treating physician.

- Subject is a good candidate for treatment with ATLCAR.CD30.CCR4 with and without
ATLCAR.CD30 per the investigator's discretion.