Phase 1:To identify the recommended Phase 2 dose (RP2D) of JCAR017 in pediatric subjects withCD19+ r/r B-ALL.Phase 2:To evaluate the following efficacy endpoints of the JCAR017 RP2D identified in Phase 1, in the following three diseasecohorts:•…
ID
Source
Brief title
JCAR017-BCM-004
TRANSCEND PEDALL
Condition
- Lymphomas non-Hodgkin's B-cell
- Leukaemias
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Phase 1
Recommended Phase 2 dose (RP2D). Identify pharmacokinetic (PK), and number of
subjects experiencing a dose-limiting toxicity (DLT).
Phase 2 - Cohort 1
(relapsed/refractory [r/r] B-cell acute lymphoblastic leukemia [B-ALL]):
Overall response rate (ORR). Percentage of subjects achieving a confirmed
complete response (CR) or complete response with incomplete blood count
recovery (CRi)
Phase 2 - Cohort 2
(MRD+ BALL): Minimal residual disease (MRD) negative (MRD-) rate.
Percentage of subjects achieving a confirmed MRD negative rate
Phase 2 - Cohort 3
(r/r B-cell non-Hodgkin lymphoma [BNHL]): Overall response rate (ORR).
Percentage of subjects achieving CR or partial response (PR)
Secondary outcome
1. Safety - Type, frequency, and severity of adverse events (AEs), including
serious adverse events (SAEs) and laboratory abnormalities
2. Feasibility of manufacturing JCAR017 (Phase 1 only) - Percentage of JCAR017
product generated successfully
3. Overall response rate (ORR) in the non-selected dose from Phase 1 -
Percentage of subjects achieving a confirmed CR or Cri
4. Duration of response (DOR) - Time from first response until progressive
disease (PD), disease relapse, or death from any cause, whichever occurs first
5. Relapse-free survival (RFS) - Time from first response to documentation of
PD, disease relapse, or death due to any cause, whichever occurs first
6. Best overall response (BOR)
7. Event-free survival (EFS) - Time from JCAR017 infusion to PD, disease
relapse, start of a new anticancer therapy, or death from any cause, whichever
occurs first
8. Overall survival (OS) - Time from JCAR017 infusion to time of death due to
any cause
9. MRD response rate (non-selected RP2D cohort in Phase 1 and Cohort 1 in Phase
2 only) - Percentage of subjects achieving a CR or CRi and a negative MRD bone
marrow
10. Rate of hematopoietic stem cell transplant (HSCT) after response to JCAR017
infusion - Percentage of subjects who achieve a response after JCAR017 infusion
and then proceed to HSCT
11. Pharmacokinetics (PK) - Maximum concentration (Cmax), time to peak
concentration (Tmax), area under the curve (AUC), including maximum expansion
and duration of persistence of JCAR017
Background summary
CD19 as a Therapeutic Target
CD19 is a 95 kDa glycoprotein present on B-cells from early development until
differentiation into plasma cells. It is a member of the immunoglobulin
superfamily and functions as a positive regulator of the B-cell receptor by
lowering the signaling threshold for B-cell activation. CD19 is an attractive
therapeutic target because it is expressed by most B-cell malignancies,
including BNHL. Importantly, the CD19 antigen is not expressed on hematopoietic
stem cells or on any normal tissue apart from those of the B-cell lineage.
Additionally, CD19 is not shed in the circulation, which limits off-target
adverse effects.
CD19-Targeted Chimeric Antigen Receptors
CD19-specific CARs are generated by the fusion of a single chain variable
fragment (scFv), derived from an anti-CD19 monoclonal antibody (mAb), to an
intracellular signaling domain. Expression of the CD19-directed CAR in
autologous T cells is achieved by ex vivo transduction
using a recombinant retroviral or lentiviral vector. The CAR is expressed on
the T cell surface and redirects the transfected T cells to CD19-expressing
lymphoma cells, leading to CD19- specific tumor cell recognition, lysis,
cytokine secretion, and T cell proliferation. In clinical studies,
CD19-targeted CARs have demonstrated encouraging activity in adult and
pediatric subjects with r/r B-ALL and B-NHL.
CD19 CAR T cell therapy is an effective adoptive cell treatment and has the
potential to overcome chemo-refractory B-cell leukemia and lymphoma, as
demonstrated in the ELIANA clinical study and recent approval of Kymriah in the
US.
JCAR017 Investigational Drug Product
The final JCAR017 investigational drug product being evaluated in this study
includes two
individually formulated CD4+CAR+ and CD8+ CAR+ --- T cell suspensions in media
containing dimethyl sulfoxide (DMSO) that are thawed and infused separately.
JCAR017 is
administered by IV infusion.
The CD19-specific CAR and truncated human epidermal growth factor receptor
(EGFRt) are introduced into autologous CD8+ and CD4+ T cells ex vivo using a
replication-incompetent,self-inactivating lentiviral vector. The CD19-specific
CAR includes an scFv binding domain
derived from a murine CD19-specific monoclonal antibody (mAb; FMC63) and 4-1BB
and CD3* chain signaling domains. The EGFRt protein is expressed as a separate
cell surface protein for purposes of cell tracking.
Refer to the Investigator*s Brochure (IB) for detailed information concerning
the available pharmacology, toxicology, drug metabolism, clinical studies, and
adverse event (AE) profile of the investigational product (IP).
Study objective
Phase 1:
To identify the recommended Phase 2 dose (RP2D) of JCAR017 in pediatric
subjects with
CD19+ r/r B-ALL.
Phase 2:
To evaluate the following efficacy endpoints of the JCAR017 RP2D identified in
Phase 1, in the following three disease
cohorts:
• Cohort 1 (r/r B-ALL): Overall response rate (ORR) defined as proportion of
subjects with
complete response (CR) or complete response with incomplete blood count recovery
(CRi) on Day 28 that must be confirmed on Day 56
• Cohort 2 (MRD [minimal residual disease] positive [MRD+] B-ALL): MRD negative
rate defined as proportion of subjects with a negative MRD (MRD-) response on
Day 28
that must be confirmed on Day 56
• Cohort 3 (r/r B-NHL [DLBCL, BL, or PMBCL]): ORR defined as proportion of
subjects
with a CR or partial response (PR) on Day 28
Study design
This is a Phase 1/2, open-label, single arm, multicohort study incorporating
the mTPI-2 dose escalation design in Phase 1 and a Simon*s Optimal two-stage
design in Phase 2 to evaluate the safety and efficacy of JCAR017 in pediatric
subjects with CD19+ r/r B-ALL and B-NHL--.
Phase 1
Up to 5 dose levels of JCAR017 will be evaluated.
Enrollment will commence in pediatric subjects with r/r B-ALL at Dose Level 1
(DL1) of 0.05x106 chimeric antigen receptor (CAR)+ T cells/kg (maximum DL1 of
5x106 JCAR017 CAR+ T cells [non-weight adjusted]). If this dose is confirmed
to be safe and tolerable, additional subjects will be enrolled at higher
dose(s) up to 0.75 x106 CAR+ T cells/kg (maximum of 75x106 JCAR017 CAR+ T cells
[non-weight adjusted]) with the aim to identify the RP2D. Dose
escalation/de-escalation will follow a modified toxicity probability interval
(mTPI-2) algorithm with a target dose limiting toxicity (DLT) rate of 30% and
an equivalence interval of 25% to 35%. A dose level will be considered unsafe,
with no additional pediatric subjects enrolled at that dose level, if it has an
estimated 95% or more probability of exceeding the target DLT rate of 30% (ie,
P (DLT > 30%|data) > 95%) with at least 3 pediatric subjects treated at that
dose level. For a dose level to be declared safe per the mTPI-2 algorithm, at
least 3 DLT-evaluable pediatric subjects must have completed the DLT period and
the level estimated to be safe.
Once the RP2D for JCAR017 has been selected, additional subjects will be
enrolled until at least 10 pediatric subjects are treated at the identified
RP2D. The final number of pediatric subjects enrolled and treated, will depend
on the number of dose levels tested and the number of DLTs observed within each
dose level.
A Safety Review Committee (SRC) will convene regularly during Phase 1 to review
DLTs) and recommend a Phase 2 dose based on an integrated assessment of the
safety, pharmacokinetic (PK) data and preliminary efficacy information from at
least 10 pediatric subjects treated at the RP2D. Analysis of the JCAR017
manufactured product may also be considered.
Phase 2
Up to 71 primary endpoint evaluable pediatric subjects (< 18 years of age) will
be treated at the RP2D in one of the 3 cohorts listed below. The sample size
for Cohorts 1 and 2 is calculated according to Simon*s Optimal two-stage design
and based on the primary endpoints of ORR (Cohorts 1 and 3) and MRD negative
rate (Cohort 2).
The 10 or more pediatric subjects treated at the RP2D in Phase 1 will form part
of the sample size (ie, Cohort 1 and Cohort 2). Therefore, the protocol
intends to treat 81 primary endpoint evaluable pediatric subjects in Phase 2,
if warranted by the evaluation of results at the completion of the first stage
of the study in each cohort. 8.
• Cohort 1: 48 r/r B-ALL evaluable pediatric subjects (13 subjects in Stage 1
and 35 subjects in Stage 2)
• Cohort 2 : 23 MRD+ B-ALL evaluable pediatric subjects (9 subjects in Stage 1
and 14 subjects in Stage 2)
• Cohort 3: 10 r/r B-NHL (DLBCL, BL, or PMBCL) evaluable pediatric subjects
(due to the very low incidence rate and therefore expected low subject accrual,
there is no formal sample size for this arm).
Celgene may elect to explore the identified RP2D in up to 20 additional B-ALL
subjects between 18 and 25 years of age in an optional cohort in Phase 2, if it
is determined that the risk-benefit profile is such that exploration is
warranted after consultation with the SRC.
Intervention
Following enrollment in the study, an unstimulated leukapheresis collection
will be performed
on each subject to obtain a sufficient quantity of peripheral blood mononuclear
cells (PBMCs)
for the production of the JCAR017 investigational product (IP).
Subjects will receive 3 days of fludarabine intravenously (IV) (30 mg/m2) and
cyclophosphamide
IV (300 mg/m2) for LD chemotherapy. Two to 7 days after completion of LD
chemotherapy,
JCAR017 will be administered by IV infusion as a single dose on Day 1. The
final JCAR017
drug product consists of two individually formulated CD4+ CAR+ and CD8+ CAR+
frozen T
cell suspensions administered in a 1:1 ratio in a formulation containing
dimethyl sulfoxide
(DMSO).
In Phase 1, up to 5 dose levels of JCAR017 will be evaluated. The first dose
level will be 0.05x106 CAR+ T cells/kg (maximum dose of 5x106 JCAR017 CAR+ T
cells [non-weight adjusted]). The declared RP2D will be applied in Phase 2.
JCAR017 dosing will be capped at 100kg for all dose levels.
Study burden and risks
Participation in the study will involve risks from the study procedures, from
treatment with lymphodepleting chemotherapy and from treatment with JCAR017.
The two most significant side effects that have been observed to occur with
genetically modified T cells in previous studies are cytokine release syndrome
(CRS) and neurologic toxicity.
Participation in the study also means additional time from participants (up to
24 hospital visits), additional or longer hospital stays, additional tests and
instructions to be followed.
Although, the risks are significant for the participating subjects, they are
acceptable when balanced against the anticipated efficacy of JCAR017 in this
disease population provided that there is meticulous clinical management.
JCAR017 offers substantial potential clinical activity to the patients. Current
clinical (in clinical studies, CD19-targeted CARs) have demonstrated
encouraging activity in adult and pediatric subjects with R/R B-cell acute
lymphoblastic leukemia (ALL) and B-cell NHL. The remission rate for subjects
treated with JCAR017 significantly improved compared to historical data.
Therefore, JCAR017 may provide an opportunity to increase the rates and
duration of remissions thereby potentially extending survival for a population
with historically dismal clinical outcomes. Currently available treatments have
limited activity.
Despite recent advances in the treatment of B-cell malignancies, many patients
relapse or have refractory disease and remain incurable with current treatment
options. Novel therapies are therefore urgently needed.
In conclusion, the current benefit-risk profile for JCAR017 after
administration of the lymphodepleting chemotherapy is considered acceptable in
the proposed clinical study given the potential for a durable remission, the
overall manageable safety profile, and the
plan for risk mitigation of potential safety concerns associated with JCAR017
administration, including routine trial safety surveillance practices.
Morris Avenue 86 -
Summit NJ 07901
US
Morris Avenue 86 -
Summit NJ 07901
US
Listed location countries
Age
Inclusion criteria
1. Phase 1: Subject < 18 years of age and weighs >= 6 kg at the time of signing
the informed consent form (ICF)/informed assent form (IAF). Phase 2: Subject <=
25 years of age and weighs >= 6 kg at the time of signing the ICF/IAF
2. Subject (when applicable, parental/legal representative) must understand and
voluntarily provide permission to the ICF/IAF prior to conducting any
study-related assessments/procedures.
3. Subject is willing and able to adhere to the study visit schedule and other
protocol requirements.
4. Investigator considers the subject is appropriate for adoptive T cell
therapy.
5. Evidence of CD19 expression via flow cytometry (peripheral blood or bone
marrow) or immunohistochemistry (bone marrow biopsy)
6. Subject has a Karnofsky score of >= 50 (subjects >= 16 years of age) or a
Lansky score >= 50 (subjects < 16 years of age).
7. Diagnosis of B-cell ALL or B-cell NHL as defined below: Phase 1:
- Phase 1: Subjects with r/r B-ALL, defined as morphological evidence of
disease in BM (5% or greater lymphoblast by morphology) and either of the
following: First or greater marrow relapse, or, Any marrow relapse after
allogeneic HSCT, or, Primary refractory defined as not achieving a CR or a CRi
after 2 or more separate induction regimens (or chemo-refractory as not
achieving CR/CRi after 1 cycle of standard chemotherapy for relapsed leukemia),
or, Ineligible for allogeneic HSCT. -
Phase 2: Subjects with one of the following:, Cohort 1: r/r B-ALL, defined as
morphological evidence of disease in BM (5% or greater lymphoblast by
morphology) and either:, First or greater marrow relapse, or, Any marrow
relapse after allogeneic HSCT, or, Primary refractory defined as not achieving
a CR or a CRi after 2 or more separate induction regimens (or chemo-refractory
as not achieving CR/CRi after 1 cycle of standard chemotherapy for relapsed
leukemia), or, Ineligible for allogeneic HSCT.
Cohort 2: MRD+ B-ALL, defined as: less as 5% lymphoblasts by morphology with,
MRD detected by a validated assay at a frequency of 1 x10-4 or greater in BM
cells. Subjects eligible for enrollment in Cohort 2 are those with MRD
positive morphologic CR2 after re-induction when these subjects had previously
experienced an early relapse (< 36 months) after first-line chemotherapy.
Subjects who are in MRD+ morphologic CR3 and later, regardless of time to
relapse in earlier lines, are also eligible. Subjects who are in morphologic
relapse at screening (r/r B-ALL) and become MRD+ after bridging chemotherapy
are also eligible for treatment in Cohort 2.
Cohort 3: r/r B-NHL (DLBCL, BL or PMBCL), defined as Measurable disease after 1
or more lines of chemotherapy and/or having failed HSCT or being ineligible for
HSCT. Note: B-NHL subjects with secondary CNS lymphoma involvement are eligible
however subject selection must consider clinical risk factors for severe
neurological AEs and alternative treatment options. Subjects should only be
enrolled if the Investigator considers the potential benefit outweighs the risk
for the subject.
8. Subjects with Philadelphia chromosome positive ALL are eligible if they are
intolerant to or have failed one or more lines of tyrosine-kinase inhibitor
(TKI) therapy or if TKI therapy is contraindicated.
9. Adequate organ function, defined as: Adequate BM function to receive LD
chemotherapy as assessed by the Investigator. Subject with adequate renal
function, which is defined as Subjects that do not meet the criteria but who
have a creatinine clearance or radioisotope glomerular filtration rate (GFR) of
more than 70 mL/min/1.73 m2 are eligible. Alanine aminotransferase (ALT) <= 5 x
upper limit of normal (ULN) and total bilirubin less than 2.0 mg/dL (or less
than 3.0 mg/dL for subjects with Gilbert*s syndrome or, leukemic/lymphomatous
infiltration of the liver)., Adequate pulmonary function, defined as <= Grade 1
dyspnea according to Common Toxicity Criteria for Adverse Events (CTCAE) and
oxygen saturation (SaO2) >= 92% on room air., Adequate cardiac function, defined
as left ventricular ejection fraction (LVEF) >= 40% as assessed by
echocardiogram (ECHO) or multi-gated acquisition scan (MUGA) within 4 weeks
prior to leukapheresis.
10. Adequate vascular access for leukapheresis procedure.
11. Subjects must agree to not donate blood, organs, sperm or semen, and egg
cells for usage in other individuals for at least 1 year following LD
chemotherapy. There are insufficient exposure data to provide any
recommendation concerning the duration of refraining from tissue donation
following treatment with JCAR017. Therefore, subjects treated with JCAR017
should not donate blood, organs, tissues and cells for transplantation.
See protocol for more inclusion criteria
Exclusion criteria
1. Subject has any significant medical condition, laboratory abnormality, or
psychiatric illness that would prevent the subject from participating in the
study., 2. Subject has any condition including the presence of laboratory
abnormalities, which places the subject at unacceptable risk if he/she were to
participate in the study., 3. Subject has any condition that confounds the
ability to interpret data from the study., 4. Subject with a history of another
primary malignancy that has not been in remission for at least 2 years prior to
enrollment., 5. Subjects who have received previous CD19-targeted therapy must
have CD19-positive disease confirmed since completing the prior CD19-targeted
therapy., 6. Prior CAR T cell or other genetically-modified T cell therapy., 7.
Subject with a previous history of or active hepatitis B, hepatitis C, or human
immunodeficiency virus (HIV) infection., 8. Subjects with uncontrolled systemic
fungal, bacterial, viral or other infection (including tuberculosis) despite
appropriate antibiotics or other treatment at the time of leukapheresis or
JCAR017 infusion., 9. Subject has presence of acute or chronic
graft-versus-host disease (GVHD)., 10. Subject with active autoimmune disease
requiring immunosuppressive therapy., 11. Subject has cardiac disorders (CTCAE
version 4.03 Grade 3 or 4) within the past 6 months., 12. Subject with a
concomitant genetic syndrome, with the exception of Down*s syndrome., 13.
Subject with active CNS disease and significant neurological deterioration.
Subjects with CNS-2 or CNS-3 involvement are eligible provided they are
asymptomatic and do not have significant neurological deterioration and, in the
opinion of the study investigaton --- 14. Subject with a history or presence of
clinically relevant CNS pathology --- 15. Subject is pregnant or nursing., 16.
Subject has used the following:, Therapeutic doses of corticosteroids (defined
as > 0.4 mg [maximum]) within 7 days prior to leukapheresis or 72 hours prior
to JCAR017 infusion. Physiologic replacement, topical, and inhaled steroids are
permitted., Low-dose chemotherapy (eg, vincristine, rituximab, cyclophosphamide
<= 300 mg/m2) given after leukapheresis to maintain disease control must be
stopped >= 7 days prior to LD chemotherapy. Cytotoxic chemotherapeutic agents
that are not considered lymphotoxic (see below) within 1 week prior to
leukapheresis. Oral anticancer agents --- are allowed if at least 3 half-lives
have elapsed prior to leukapheresis. Lymphotoxic chemotherapeutic agents (eg,
cyclophosphamide, ifosfamide, bendamustine) within 2 weeks prior to
leukapheresis., Experimental agents within 4 weeks prior to leukapheresis
unless no response or PD is documented on the experimental therapy and at least
3 half-lives have elapsed prior to leukapheresis., Immunosuppressive therapies
within 4 weeks prior to leukapheresis and JCAR017 infusion (eg, calcineurin
inhibitors, methotrexate or other chemotherapeutics, mycophenolate, rapamycin,
thalidomide, immunosuppressive antibodies such as antitumor necrosis factor
[TNF], anti-IL-6, or anti-IL-6R)., Donor lymphocyte infusions (DLI) within 6
weeks prior to JCAR017 infusion., Radiation within 6 weeks prior to
leukapheresis. Subjects must have PD in irradiated lesions or have additional
non-irradiated lesions to be eligible. Radiation to a single lesion, if
additional non-irradiated, measurable lesions are present, is allowed up to 2,
weeks prior to leukapheresis., Allogeneic HSCT within 90 days prior to
leukapheresis. 17. Tumor invasion of venous or arterial vessels (B-NHL subjects
only)
18. Deep Venous Thrombosis (DVT) or Pulmonary Embolism (PE) within3 months
prior to leukapheresis. Subjects with DVT or PE that occurred longer than 3
months prior to leukapheresis, who still require ongoing therapeutic levels of
anti-coagulation therapy, are also excluded. 19. Existence of CD19-negative
clone(s) of leukemia cells.
Design
Recruitment
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2018-001246-34-NL |
| ClinicalTrials.gov | NCT03743246;U1111-1220-3324 |
| CCMO | NL66379.000.18 |