STUDY OBJECTIVES
Primary Objective (Phase Ib portion of Study) To establish a safe dose (ie, number cells/m2)
of ATLCAR.CD30 to infuse after lymphodepletion with bendamustine in adult patients with CD30+
refractory/relapsed Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
To establish a safe dose (ie, number cells/m2) of ATLCAR.CD30 to infuse after lymphodepletion
with bendamustine and fludarabine in pediatric patients with CD30+ refractory/relapsed
Hodgkin lymphoma (HL) and non-Hodgkin lymphoma (NHL).
Primary Objective (Phase II portion of study) To estimate 2 year progression free survival
(PFS) after administration of ATLCAR.CD30 in combined adult/pediatric patients with CD30+
refractory/relapsed HL and NHL
Secondary Objectives
To estimate 2 year overall survival (OS) after administration of CAR.CD30 transduced ATL
following lymphodepletion with bendamustine in adult patients with CD30+ relapsed/refractory
HL and NHL.
To estimate 2 year OS after administration of CAR.CD30 transduced ATL following
lymphodepletion with bendamustine and fludarabine in adult and pediatric patients with CD30+
relapsed/refractory HL and NHL.
To estimate 2 year PFS after administration of ATLCAR.CD30 following lymphodepletion with
bendamustine in adult patients with CD30+ refractory/relapsed HL and NHL.
To estimate 2 year PFS after administration of ATLCAR.CD30 following lymphodepletion with
bendamustine and fludarabine in adult and pediatric patients with CD30+ refractory/relapsed
HL and NHL.
To estimate the objective response rate as defined by the Lugano Classification78 for
CAR.CD30 transduced ATL following lymphodepletion with bendamustine when administered in
adult patients with CD30+ relapsed/refractory HL and NHL.
To estimate the objective response rate as defined by the Lugano Classification78 for
CAR.CD30 transduced ATL following lymphodepletion with bendamustine and fludarabine when
administered in adult and pediatric patients with CD30+ relapsed/refractory HL and NHL.
To estimate duration of response after administration of CAR.CD30 transduced ATL following
lymphodepletion with bendamustine in adult patients with CD30+ relapsed/refractory HL and NHL
To estimate duration of response after administration of CAR.CD30 transduced ATL following
lymphodepletion with bendamustine and fludarabine in adult and pediatric patients with CD30+
relapsed/refractory HL and NHL
To further describe the adverse events associated with CAR.CD30 transduced ATL when
administered in adult and pediatric patients with CD30+ relapsed/refractory HL and NHL.
To evaluate the safety of bendamustine alone or combined with fludarabine as lymphodepleting
agents prior to infusion of CAR.CD30 transduced ATL in adult patients.
To evaluate the safety of bendamustine and fludarabine as lymphodepleting agents prior to
infusion of CAR.CD30 transduced ATLs in pediatric patients.
To measure the survival of ATLCAR.CD30 in vivo when infused after lymphodepletion with
bendamustine.
To measure the survival of ATLCAR.CD30 in vivo when infused after lymphodepletion with
bendamustine and fludarabine.
To measure patient-reported symptom, physical function, and health-related quality of life at
baseline and over time in adult patients treated with CAR.CD30 T cells.
Primary Endpoint (Phase Ib)
Toxicity will be classified and graded according to the National Cancer Institute's Common
Terminology Criteria for Adverse Events (CTCAE, version 4.0) and Cytokine Release Syndrome
(CRS) toxicity will be graded according to the CRS Management Guidelines and CRS Toxicity
Grading Scale
Primary Endpoint (Phase II)
PFS is defined from day of ATLCAR.CD30 infusion to relapse (in patients with a documented
complete response at time of cell infusion) or progression (in patients without complete
response at time of cell infusion), or death as a result of any cause per the Lugano
classification
Secondary Endpoints
Overall survival will be measured from the date of administration of CAR.CD30 transduced ATL
to date of death and will be measured separately in subjects receiving bendamustine alone for
lymphodepletion and those receiving a combination of bendamustine and fludarabine for
lymphodepletion.
Progression free survival is defined from day of ATLCAR.CD30 infusion to relapse (in patients
with a documented complete response at time of cell infusion) or progression (in patients
without complete response at time of cell infusion), or death as a result of any cause per
the Lugano classification78 and will be measured separately in subjects receiving
bendamustine alone for lymphodepletion and those receiving a combination of bendamustine and
fludarabine for lymphodepletion.
The objective response rate will be defined as the rate of complete responses (CR) + partial
responses (PR) as determined by the Lugano classification78 and will be measured separately
in subjects receiving bendamustine alone for lymphodepletion and those receiving a
combination of bendamustine and fludarabine for lymphodepletion.
The duration of response will be defined as time from documentation of tumor response to
disease progression and will be measured separately in subjects receiving bendamustine alone
for lymphodepletion and those receiving a combination of bendamustine and fludarabine for
lymphodepletion.
Toxicity will be classified and graded according to the National Cancer Institute's Common
Terminology Criteria for Adverse Events (CTCAE, version 4.0). S
Persistence of CAR.CD30 T cells in vivo will be determined by quantitative PCR and flow
cytometry in peripheral blood samples and will be measured separately in subjects receiving
bendamustine alone for lymphodepletion and those receiving a combination of bendamustine and
fludarabine for lymphodepletion.
For adult patients: Patient reported symptoms will be measured using selected symptoms from
the NCI PRO-CTCAE. Patient-reported physical function will be measured using the PROMIS
Physical Function Score derived from the PROMIS Physical Function Short Form 20a v1.0.
Patient-reported health-related quality of life will be measured using the PROMIS Global
Health Score derived from the PROMIS Global Health Short Form v1.0-1.1.
OUTLINE
Cell Procurement
Up to 100 mL per collection (up to 3 collections) of peripheral blood will be obtained from
patients for cell procurement. In patients with low (CD3 count as assayed by flow cytometry
less than 200/μl) T-cell count in the peripheral blood, a leukopheresis may be performed to
isolate sufficient T cells. The parameters for pheresis will be 2 blood volumes.
ATLCAR.CD30 Cells Administration
ATLCAR.CD30 cells will be administered as described below 1-14 days (preferably 1-2 days)
after lymphodepletion with bendamustine and fludarabine. ATLCAR.CD30 cells will be given by a
licensed provider (oncology nurse or physician) via intravenous injection over 1-10 minutes
through either a peripheral or a central line. The expected volume will be 1-50cc. Patients
with a partial response or stable disease at 6 weeks may receive a second infusion of
ATLCAR.CD30 if cells are available. Note: Lymphodepletion with bendamustine and fludarabine
will occur for three consecutive days and may be given prior to a second infusion of cells
(if applicable).
Duration of Therapy
Therapy in Lineberger Comprehensive Cancer Center (LCCC) 1532 involves 1-2 infusions of
ATLCAR.CD30 cells. Treatment with one infusion will be administered unless:
- Patient decides to withdraw from study treatment, OR
- General or specific changes in the patient's condition render the patient unacceptable
for further treatment in the judgment of the investigator.
Duration of Follow-up
Patients will be followed for up to 15 years for Replication Competent Retrovirus (RCR)
evaluation or until death, whichever occurs first. Patients removed from study for
unacceptable adverse events will be followed until resolution or stabilization of the adverse
event.
Inclusion Criteria Prior to Cell Procurement
Informed consent explained to, understood by and signed by the subject or legal guardian
for pediatric subjects; subject and/or legal guradian given a copy of informed consent form
for procurement
Ages 3 to 17 years of age for pediatric subjects (weight must be ≥10kg), and for adults
ages ≥18 years of age
Diagnosis of recurrent HL or NHL in subjects who have failed >2 prior treatment regimens.
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 cells). NOTE: CD30+ disease requires documented CD30
expression by immunohistochemistry based on the institutional hematopathology standard.
Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years
old)
Evidence of adequate organ function as defined by:
- Hemoglobin ≥ 8.0 g/dL (transfusion independent for 2 weeks prior to enrollment)
- Total bilirubin ≤ 1.5 × ULN, unless attributed to Gilbert's Syndrome
- AST ≤ 3 × ULN
- Serum creatinine ≤ 1.5 × ULN
- For subjects <18 years old use the following table for serum creatinine requirements:
Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0
≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4
Negative serum pregnancy test in females within 72 hours prior to procurement or
documentation that the subject is post-menopausal or premenarchal.
Women of childbearing potential (WOCBP) should 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.
• Postmenopausal status must be confirmed with documentation of absence of menses for >1
year.
Exclusion Criteria Prior to Cell Procurement
Pregnant or lactating
Tumor in a location where enlargement could cause airway obstruction
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 or negative HIV viral load, negative HTLV1 and 2 antibody, negative
HCV antibody or viral load.
Hepatitis B: 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.
Inclusion Criteria Prior to Lymphodepletion
Informed consent explained to, understood by and signed by the subject or legal guardian
for pediatric subjects; subject and/or legal guradian given a copy of informed consent
form.
CD30+ disease (result can be pending at the time of cell procurement, but must be confirmed
prior to lymphodepletion); Note: CD30+ disease requires documented CD30 expression by
immunohistochemistry based on the institutional hematopathology standard.
Prior to administration of lymphodepletion:
- Absolute neutrophil count (ANC) is > 1.0 × 10^9/L
- Platelet count > 75 × 10^9/L
- For Grade 4 neutropenia, Grade ≥3 febrile neutropenia, or Grade 4 thrombocytopenia,
hold bendamustine until toxicity resolve to Grade ≤2
For WOCBP negative serum pregnancy test within 72 hours prior to lymphodepletion.
Imaging results from within 7 days (30 days in subjects with cutaneous T cell lymphoma)
prior to lymphodepletion. 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).
Karnofsky or Lansky score of >60% (Karnofsky for pediatric subjects ≥16 years old and
Lansky for <16 years old).
Available autologous transduced activated T cells that meet the Certificate of Analysis
(CofA) acceptance criteria.
Women of childbearing potential (WOCBP) should 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.
Exclusion Criteria Prior to Lymphodepletion
Received any investigational agents or received any tumor vaccines within the previous six
weeks prior to cell infusion.
Received anti-CD30 antibody-based therapy within the previous 4 weeks prior to cell
infusion.
Received chemotherapy within the previous 3 weeks prior to lymphodepletion.
Subject has rapidly progressive disease, per treating oncologist's discretion.
Subject is not a good candidate for CAR T cell therapy, per treating oncologist's
discretion.
Pregnant or lactating.
Tumor in a location where enlargement could cause airway obstruction.
Current use of systemic corticosteroids at doses equivalent of ≥10mg prednisone daily or
its equivalent; those receiving <10mg daily may be enrolled at discretion of investigator.
Inhaled steroids are allowed.
For pediatric subjects, physiologic replacement hydrocortisone at doses 6-12 mg/m2/day is
allowed. Equivalently dosed alternative steroids are allowed at discretion of investigator,
though not to exceed 10mg prednisone per day. Inhaled steroids are allowed.
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
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 or negative HIV viral load, negative HTLV1 and 2 antibody, negative
HCV antibody or viral load.
Hepatitis B: Subjects who are positive for Hepatitis B Surface Antigen 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 if the subject has initiated an
anti-HBV prophylaxis regimen prior to lymphodepletion.
Inclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells
Evidence of adequate organ function as defined by:
- Total bilirubin ≤1.5 × ULN, unless attributed to Gilbert's Syndrome
- AST ≤3 × ULN
- Serum creatinine ≤1.5 × ULN
- Pulse oximetry of >90% on room air
- For subjects <18 years old use following table for serum creatinine requirements:
Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0
≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4
Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years
old)
Available autologous transduced activated T cells that meet the Certificate of Analysis
(CofA) acceptance criteria.
Women of childbearing potential (WOCBP) should 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.
Exclusion Criteria Prior to Infusion of ATLCAR.CD30 Cells
Received any investigational agents or received any tumor vaccines within the previous six
weeks prior to cell infusion.
Received anti-CD30 antibody-based therapy within the previous 4 weeks prior to cell
infusion.
Tumor in a location where enlargement could cause airway obstruction.
Subject has rapidly progressive disease, per treating oncologist's discretion.
Subject is not a good candidate for CAR T cell therapy, per treating oncologist's
discretion.
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 For pediatric subjects, physiologic replacement hydrocortisone at
doses 6-12mg/m2/day is allowed. Equivalently dosed alternative steroids are allowed at
discretion of investigator, though not to exceed 10mg prednisone per day. Inhaled steroids
are allowed.
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 or negative HIV viral load, negative HTLV1 and 2 antibody, negative
HCV antibody or viral load.
Hepatitis B: Subjects who are positive for Hepatitis B Surface Antigen 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. These subjects must be receiving
antiviral prophylaxis initiated prior to lymphodepletion.
Eligibility Criteria Prior to Lymphodepletion for Second Infusion (Optional) Note: Subjects
may receive a second infusion without prior lymphodepletion if they meet the eligibility
criteria at the time of infusion, but do not meet the eligibility requirements for adequate
bone marrow function and platelet counts.
Karnofsky or Lansky score of >60% (Karnofsky for ≥16 years old and Lansky for <16 years
old).
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, or 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.
Must not be pregnant or lactating.
Must not have tumor in a location where enlargement could cause airway obstruction.
Subjects must have imaging results confirming active disease from within 30 days prior to
lymphodepletion with the exception of cutaneous lymphoma subjects who do not need to repeat
scans prior to the second cell infusion if the baseline scans showed lymph nodes ≤ 1.5cm at
baseline.
Must not have current use of systemic corticosteroids at doses ≥10 mg prednisone daily or
its equivalent; those receiving <10mg daily may be enrolled at discretion of the
Investigator
Evidence of adequate organ function as defined by:
- ANC>1.0 × 10^9/L
- Platelets >75 × 10^9/L
- Total bilirubin ≤1.5 × ULN, unless attributed to Gilbert's syndrome
- AST ≤3 × ULN
- Serum creatinine ≤1.5 × ULN
- Pulse oximetry of > 90% on room air
- For subjects <18 years old use following table for serum creatinine requirements:
Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0
≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4 ≥16 and <18 ≤1.7 ≤1.4
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.
Subject 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)
Subject is a good candidate for treatment with ATLCAR.CD30 per the investigator's
discretion.
Eligibility Criteria Prior to Second Infusion (Optional)
No evidence of uncontrolled infection or sepsis.
Subject must not have undergone bridging chemotherapy (or other anti-cancer therapies,
which are not mandated by the protocol) prior to the second infusion.
Evidence of adequate organ function as defined by:
- Total bilirubin ≤2 × ULN, unless attributed to Gilbert's syndrome
- AST ≤3 × ULN
- ALT ≤3 × ULN
- Serum creatinine ≤1.5 × ULN
- Pulse oximetry of >90% on room air
- For subjects <18 years old use following table for serum creatinine requirements:
Maximum Serum Creatinine (mg/dL) Age (years) Male Female 3 to <6 ≤0.8 ≤0.8 6 to <10 ≤1.0
≤1.0 10 to <13 ≤1.2 ≤1.2 13 to <16 ≤1.5 ≤1.4
≥16 and <18 ≤1.7 ≤1.4
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 per the investigator's
discretion.
If subjects have had positive hepatitis B core antibody testing at baseline, they must not
have had re-activation of the Hepatitis B virus since baseline testing.
