Primary Objective, Part A: To assess the safety of a single escalating dose and multiple dose regimen of CTX130 in subjects with unresectable or metastatic ccRCCPrimary Objective, Part B (Cohort Expansion): To assess the efficacy of CTX130 in…
ID
Source
Brief title
Condition
- Renal and urinary tract neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Parts A1, A3 (Single Dose Escalation): Incidence of adverse events (AEs),
defined asdose-limiting toxicities (DLTs).
Parts A2, A4 (Multiple Dose Regimen): Incidence of AEs after multiple doses of
CTX130.
Part B (cohort expansion): ORR, defined as the proportion of subjects who have
achieved a best overall response of complete response (CR) or partial response
(PR) according to RECIST v1.1, as assessed by an Independent Review Committee
(IRC).
Secondary outcome
• To further characterize the efficacy of CTX130 over time
• To further assess the safety of CTX130, and to describe and assess adverse
events (AEs) of interest, including cytokine release syndrome (CRS), tumor
lysis syndrome and Graft versus Host Disease (GvHD)
• To characterize pharmacokinetics (PK) (expansion and persistence) of CTX130
in blood
Background summary
Investigational Product Description:
CTX130 is a CD70-directed T cell immunotherapy comprised of allogeneic T cells
that are genetically modified ex vivo using CRISPR-Cas9 (clustered regularly
interspaced short palindromic repeats/CRISPR associated protein 9) gene editing
components (single-guide ribonucleic acids [sgRNAs] and Cas9 nuclease). The
modifications include targeted disruption of the T cell receptor alpha constant
(TRAC), beta 2-microglobulin (B2M), and CD70 loci and the insertion of an
anti-CD70 chimeric antigen receptor (CAR) transgene into the TRAC locus via an
adeno associated virus (AAV) expression cassette. The CAR is composed of an
anti CD70 single-chain variable fragment derived from a previously
characterized anti CD70 hybridoma IF6, the CD8 transmembrane domain, a 4-1BB
costimulatory domain, and a CD3* signaling domain.
Study rationale:
The study will be divided into 2 parts: Part A (dose escalation), which
includes Parts A1 through A4, followed by Part B (cohort expansion). Parts A1
and A3 will evaluate the safety of a single escalating dose of CTX130 (with the
option of additional doses of CTX130 following relapse, stable disease [SD], or
disease progression with clinical benefit). Part A2 and A4 will evaluate the
safety of a multiple dose schedule for CTX130. Part B will assess the safety
and efficacy of the recommended dosing regimen for CTX130 in cohort expansion.
CAR T cell therapies are adoptive T cell therapeutics (ACTs) used to treat
human malignancies. Currently approved ACTs are autologous and require
patient-specific cell collection and manufacturing, which has led to
reintroduction of residual contaminating tumor cells. Also, low response rates
in patients with chronic lymphocytic leukemia (CLL) and lack of responses in
patients with B-cell acute lymphoblastic leukemia (ALL) treated with autologous
CAR T cell therapy have been partially attributed to the exhausted T cell
phenotype. Finally, collection, shipment, manufacturing, and shipment back to
the patient*s treating physician is time-consuming and, as a result, some
patients have experienced disease progression or death while awaiting
treatment. An allogeneic off-the-shelf CAR T cell product could provide
benefits such as immediate availability and chemotherapy-naïve T cells from
healthy donors, thus a more consistent product relative to autologous CAR T
cell therapies.
CRISPR-Cas9 engineering employs a recombinant AAV vector to insert an anti-CD70
CAR expression cassette into the TRAC locus, disrupting expression of the T
cell receptor (TCR), which is intended to minimize the probability of graft vs
host disease (GvHD). Expression of B2M, a component of major histocompatibility
(MHC) class I molecules, is also targeted for disruption, which is intended to
minimize the host*s MHC mediated immune rejection of the allogeneic T cell
product, thus improving persistence of CTX130. This first-in-human trial in
subjects with unresectable or metastatic clear cell renal cell carcinoma
(ccRCC) will evaluate the safety and efficacy of this CRISPR Cas9 modified
allogeneic CAR T cell approach.
CTX130, a CD70-directed genetically modified allogeneic T cell immunotherapy,
is manufactured from the cells of healthy donors; therefore, the resultant
manufactured cells are intended to provide each subject with a consistent final
product of reliable quality. Furthermore, the manufacturing of CTX130, through
precise delivery and insertion of the CAR at the TRAC site using AAV and
homology-directed repair, does not present the risks associated with random
insertion of lentiviral and retroviral vectors.
Finally, CD70 is the membrane-bound ligand of the CD27 receptor, which belongs
to the tumor necrosis factor receptor superfamily. It is commonly expressed at
elevated levels in multiple carcinomas and lymphomas, and it is a diagnostic
biomarker for ccRCC. The tightly controlled normal tissue expression in humans
is mostly limited to transient surface expression in blood and lymphoid
tissues, specifically activated peripheral T and B lymphocytes, scattered T
cells in tonsils, skin and intestine, germinal B cell centers, thymic
epithelial cells, and natural killer cells. Based on studies in knockout animal
models, CD70/CD27 does not seem to be essential for the development and
function of the immune system in mice. Therefore, the above characteristics of
CD70 render CTX130 a promising therapy for CD70-positive malignancies.
Study objective
Primary Objective, Part A: To assess the safety of a single escalating dose and
multiple dose regimen of CTX130 in subjects with unresectable or metastatic
ccRCC
Primary Objective, Part B (Cohort Expansion): To assess the efficacy of CTX130
in subjects with unresectable or metastatic ccRCC, as measured by objective
response rate (ORR) according to Response Evaluation Criteria in Solid Tumors
version 1.1 (RECIST v1.1)
Secondary Objectives (Parts A and B)
1. To further characterize the efficacy of CTX130 over time
2. To further assess the safety of CTX130, and to describe and assess adverse
events of special interest, including cytokine release syndrome (CRS), tumor
lysis syndrome and GvHD
3. To characterize pharmacokinetics (expansion and persistence) of CTX130 in
blood
Study design
This is an open-label, multicenter, Phase 1 study evaluating the safety and
efficacy of CTX130 in subjects with unresectable or metastatic RCC with clear
cell differentiation. The study will be divided into 2 parts: Part A (dose
escalation), which includes Part A1 through A4, followed by Part B (cohort
expansion).
Each part of the study will consist of 3 main stages:
Stage 1 - Screening to determine eligibility for treatment (up to 14 days)
Stage 2 - Treatment (Stage 2A and Stage 2B); see Table S1 in protocol synopsis
for treatment in each part of the study
Stage 3 - Follow-up (5 years after last CTX130 infusion)
Subjects* clinical eligibility must be reconfirmed according to the
protocol-specified criteria prior to the initiation of daratumumab
administration (subjects in Parts A3 and A4 only), prior to lymphodepleting
(LD) chemotherapy (all subjects), and prior to CTX130 infusion (all subjects).
During the post-CTX130 infusion period, subjects will be monitored for acute
toxicities (Days 1-28), including CRS, immune effector cell-associated
neurotoxicity syndrome (ICANS), GvHD, and other adverse events (AEs). Toxicity
management guidelines are provided in the study protocol. During Part A,
subjects will be hospitalized for the first 7 days following each CTX130
infusion, or longer if required by local regulation or site practice. In Part A
and Part B, subjects must remain within proximity of the investigative site
(i.e., 1-hour transit time) for 28 days after each CTX130 infusion.
After the acute toxicity observation period, subjects will be subsequently
followed for up to 5 years after last CTX130 infusion with physical exams,
regular laboratory and imaging assessments, and AE assessments. After
completion of this study, subjects will be asked to participate in a separate
long-term follow-up study for an additional 10 years to assess long-term safety
and survival.
Dose escalation in Part A will be performed using a standard 3+3 design in
which 3 to 6 subjects will be enrolled at each dose level depending on the
occurrence of dose limiting toxicities (DLTs), as defined in the protocol. The
DLT evaluation period will begin with the initial CTX130 infusion and last for
28 days.
Part A1: In DL1, subjects will be treated in a staggered manner such that a
subject will only receive
CTX130 once the previous subject has completed the DLT evaluation period (i.e.,
staggered by 28
days). If the occurrence of a DLT in >=2 of 3 subjects at DL1 has resulted in
dose de-escalation, dosing
of all subjects at DL -1 will also be staggered by 28 days. If no DLT occurs at
DL1, dose escalation
will progress to DL2, and dosing between each subject will be staggered by 14
days. If no DLT occurs
at the first 2 dose levels (DL1 and DL2), dosing will be staggered by 7 days
between each subject at
subsequent dose levels (DL3 and DL4).
Part A2: Enrollment into a Part A2 dose level may begin at a dose level that
has been deemed safe by
the SRC in Part A1. Each subject will receive a total of up to 3 doses of
CTX130: 1 dose administered
every 8 weeks (1 dose per cycle in Cycles 1-3).
Part A3: Dosing of CTX130 at any dose level in Part A3 will not begin unless
the dose level has been
deemed safe by the SRC in Part A1. Dose escalation/de-escalation is allowed
according to the 3+3
design (see Section 4.3). Sentinel dosing will be implemented for the starting
dose level, i.e., the first
subject will complete the DLT evaluation period before the second and third
subjects are dosed. The
second and third subjects may be dosed concurrently. In subsequent dose levels
or expansion of the
same dose level, cohorts of up to 3 subjects may be enrolled and dosed
concurrently.
Part A4: Enrollment into a Part A4 dose level may begin if that dose level has
been deemed safe by
the SRC in Part A3. Each subject will receive a total of up to 3 doses of
CTX130: 1 dose administered
every 8 weeks (1 dose per cycle in Cycles 1-3). Dosing of subjects may occur
concurrently.
Subjects must receive CTX130 to be evaluated for DLT, as defined in the
protocol. If a subject discontinues the study any time prior to the initial
CTX130 infusion, the subject will be deemed nonevaluable for DLT and will be
replaced. If a DLT evaluable subject (i.e., a subject that has been
administered CTX130) has signs or symptoms of a potential DLT, the DLT
evaluation period will be extended according to the protocol-defined window to
allow for improvement or resolution before a DLT is declared.
The SRC will review available data when the DLT observation period ends for the
last subject treated in each dose level. The SRC will be responsible for making
dose escalation decisions based on review of all available safety data.
Throughout dose escalation, for cases in which a dose had been cleared and dose
escalation is permitted, the sponsor in consultation with the SRC may
alternatively decide to enroll an additional 6 subjects at the current dose
level. Based on ongoing assessment of benefit and risk, the SRC may stop dose
escalation before a maximum tolerated dose (MTD) is determined.
The sponsor will declare the recommended Part B dose (RPBD)with a preferred
dosing schedule for cohort expansion at or below the MTD (if determined). At
least 6 subjects will be administered CTX130 before an RPBD is declared.
Toxicities will be graded and documented according to National Cancer Institute
Common Terminology Criteria for Adverse Events version 5.0 (CTCAE v5.0), except
for CRS (American Society for Transplantation and Cellular Therapy criteria),
neurotoxicity ICANS criteria and CTCAE v5.0), and GvHD (Mount Sinai Acute GvHD
International Consortium criteria).
Intervention
Subjects will receive an intravenous (IV) infusion of CTX130 following
lymphodepleting (LD) chemotherapy.
Study burden and risks
The completed nonclinical studies adequately demonstrate the safety of CTX130
and support the first-in human (FIH) clinical studies in subjects with
advanced, relapsed, or refractory renal cell carcinoma.
Please refer to the complete risk benefit analysis document.
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Age
Inclusion criteria
1. >=18 years of age and body weight >=42 kg.
2. Able to understand and comply with protocol-required study procedures and
voluntarily sign a written informed consent document.
3. Diagnosed with unresectable or metastatic RCC with clear cell
differentiation:
• Have previous exposure to both a CPI and a VEGF inhibitor and documented
progression after adequate exposure for favorable risk by International
Metastatic RCC Database Consortium criteria or a lack of response and/or
progression after adequate exposure for intermediate and poor risk
characteristics.
• Have a previously pathologically confirmed diagnosis of RCC with clear cell
differentiation.
• Availability of tumor tissues.
• Have measurable disease as assessed by the investigator/site radiologist per
RECIST v1.1. Target lesions situated in a previously irradiated area are
considered measurable if progression has been demonstrated in such lesions.
• Have at least 1 nontarget lesion that is suitable for biopsies.
4. Karnofsky performance status >=80% as assessed during the screening period.
5. Meets protocol-specified criteria to undergo daratumumab administration
(Parts A3 and A4 only), LD chemotherapy and CAR T cell infusion.
6. Adequate organ function:
• Renal: Creatinine clearance >=50 mL/min.
• Liver:
* Aspartate aminotransferase and alanine aminotransferase < 3 x upper limit of
normal (ULN)
* Total bilirubin <2 x ULN (for Gilbert*s syndrome: total bilirubin < 3 mg/dL
and normal conjugated bilirubin)
* Albumin >90% of lower limit of normal.
• Cardiac: Hemodynamically stable and left ventricular ejection fraction >=45%
by echocardiogram.
• Pulmonary: Oxygen saturation level on room air >92% per pulse oximetry.
• Hematologic: Platelet count >100,000/mm^3, absolute neutrophil count
>1500/mm^3, and hemoglobin >9 g/dL without prior blood cell transfusion before
screening.
• Coagulation: Activated partial thromboplastin time or partial thromboplastin
time <=1.5 x ULN.
7. Female subjects of childbearing potential (postmenarcheal, has an intact
uterus and at least 1 ovary, and is less than 1 year postmenopausal) must agree
to use a highly effective method of contraception (as specified in the
protocol) from enrollment through at least 12 months after last CTX130
infusion.
8. Male subjects must agree to use acceptable effective method of contraception
(as specified in the protocol) from enrollment through at least 12 months after
last CTX130 infusion.
Exclusion criteria
1. Prior treatment with any anti-CD70 targeting agents.
2. Prior treatment with any CAR T cells or any other modified T or natural
killer cells.
3. Known contraindications to daratumumab (Parts A3 and A4 only) any LD
chemotherapy agent(s) or any of the excipients of CTX130 product.
4. Subjects with central nervous system (CNS) manifestation of their malignancy
as evidenced by positive screening MRI or past history.
5. History or presence of clinically relevant CNS pathology such as seizure,
stroke, severe brain injury, cerebellar disease, history of posterior
reversible encephalopathy syndrome with prior therapy, or another condition
that in opinion of the investigator may increase CAR T cell-related toxicities.
6. Ongoing, clinically significant pleural effusion, or ascites or any
pericardial effusion, or a history of
pleural effusion or ascites in the last 2 months.
7. Unstable angina, clinically significant arrhythmia per investigator*s
judgement, or myocardial infarction within 6 months prior to screening.
8. Diabetes mellitus with a current hemoglobin A1c level of >7.0%.
9. Ongoing bacterial, viral, or fungal infection, requiring systemic
anti-infectives.
10. Positive for presence of human immunodeficiency virus type 1 or 2, or
active hepatitis B virus or hepatitis C virus infection. Subjects with prior
history of hepatitis B or C infection who have documented undetectable viral
load (by quantitative polymerase chain reaction or nucleic acid testing) are
permitted.
11. Previous or concurrent malignancy, except those treated with curative
approach not requiring systemic therapy and have been in remission for >12
months, or any other localized malignancy that has a low risk of developing
into metastatic disease, per investigator*s judgement.
12. Primary immunodeficiency disorder or active autoimmune disease requiring
steroids and/or any other immunosuppressive therapy.
13. Prior solid organ transplantation or bone marrow transplant.
14. Use of systemic antitumor therapy or investigational agent, including
radiotherapy, within 14 days prior to enrollment. Use of physiological doses of
steroids (e.g. <=10mg/day prednisone or equivalent) will be permitted for
subjects previously on steroids if clinically indicated.
15. Received live vaccines or herbal medicines as part of traditional Chinese
medicine or non-over-the-counter herbal remedies within 28 days prior to
enrollment.
16. Diagnosis of significant psychiatric disorder that could seriously impede
the subject*s ability to participate in the study.
17. Pregnant or breastfeeding females.
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 | EUCTR2019-004513-14-NL |
| ClinicalTrials.gov | NCT04438083 |
| CCMO | NL74278.000.20 |