Primary objective: To evaluate the efficacy of JNJ-68284528 (Phase 2)Secondary objectives:# To characterize the safety of JNJ-68284528 (Phase 2)# To characterize the pharmacokinetics and pharmacodynamics of JNJ-68284528# To assess the immunogenicity…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Overall Response Rate (at least a partial response or better) as defined by the
International Myeloma Working Group response criteria (Phase 2).
Secondary outcome
# Incidence and severity of adverse events
# Pharmacokinetic and pharmacodynamic markers including but not limited
depletion of BCMA expressing cells, circulating soluble BCMA, systemic cytokine
concentrations, and markers of CAR-T cells, T cell expansion (proliferation),
and persistence via monitoring CAR-T positive cell counts and CAR transgene
level
# Presence of anti-JNJ-68284528 antibodies
# Very good partial response (VGPR) / complete response (CR) / stringent
complete response (sCR) rate, minimal residual disease (MRD) negative rate as
defined by the IMWG response criteria, clinical benefit rate (CBR; CBR = ORR
(sCR + CR + VGPR + PR) + MR (minimal response))), duration of and time to
response, progression-free survival, overall survival
# Change in HRQoL (symptoms, functioning, and wellbeing) using the European
Organization for Research and Treatment of Cancer QLQ-C30, EuroQoL Five
Dimension Questionnaire (EQ-5D-5L), Patient Global Impression of Change (PGIC),
Patient Global Impression of Severity (PGIS), and single items from EORTC
QLQ-MY20
Background summary
Multiple myeloma is characterized by the production of monoclonal
immunoglobulin (Ig) proteins or protein fragments (M proteins) that have lost
their function. The proliferation of multiple myeloma cells leads to subsequent
displacement of normal bone marrow hematopoietic precursors and overproduction
of M-proteins. Hallmarks of multiple myeloma include osteolytic lesions,
anemia, increased susceptibility to infections, hypercalcemia, renal
insufficiency or failure, and neurological complications. Treatment options for
multiple myeloma have substantially improved over time and vary depending on
the aggressiveness of the disease, underlying prognostic factors, physical
condition of the patient, and existing co-morbidities. Therapeutic options
include agents such as proteasome inhibitors (PIs), immunomodulatory drugs
(IMiDs), monoclonal antibodies, and stem cell transplantation. Despite these
therapeutic achievements, the disease recurs and remains incurable. Thus, there
is a need for novel therapeutic approaches when the disease is resistant to
available therapy.
Chimeric antigen receptor T (CAR-T) cell therapy uses modified autologous T
cells that are activated in a MHC-independent manner upon binding to their
target. This results in lysis of the targeted cells. Data published on research
with CAR-T cell-based immunotherapy suggest that administering BCMA-directed
CAR-T immunotherapy may be an effective means to treat multiple myeloma. The
current investigational agent, JNJ-68284528, consists of autologous CAR-T cells
designed to treat subjects with relapsed or refractory multiple myeloma. The
target antigen is BCMA. The novel design features dual targeting domains on
BCMA, enabling tight binding of JNJ-68284528 to the BCMA-expressing cells. BCMA
is a cell surface antigen highly expressed on cells of the B cell lineage.
Comparative studies show a lack of BCMA in most normal tissues and absence of
expression on CD34-positive hematopoietic stem cells. This selective expression
and the biological importance for the proliferation and survival of myeloma
cells makes BCMA a promising target for CAR-T based immunotherapy. Results in
74 subjects from the Legend-2 study indicate an ORR of 87,8% with a CR rate of
64,9%. The observed response rates and the reversible adverse events for most
subjects, support further investigation of this approach in the current study.
Study objective
Primary objective: To evaluate the efficacy of JNJ-68284528 (Phase 2)
Secondary objectives:
# To characterize the safety of JNJ-68284528 (Phase 2)
# To characterize the pharmacokinetics and pharmacodynamics of JNJ-68284528
# To assess the immunogenicity of JNJ-68284528
# To further characterize the efficacy of JNJ-68284528
# To compare the patient-reported outcomes (PRO) after treatment to subject*s
reported health state prior to treatment and to assess the sustained benefit of
subject*s perceived health-related quality of life (HRQoL) (Phase 2)
Study design
Phase 1b-2, open-label, multicenter study of JNJ-68284528, a Chimeric Antigen
Receptor T cell (CAR-T) therapy directed against BCMA. In The Netherlands only
the phase 2 part will be conducted.
During the Screening Phase, all subjects will provide written consent for study
participation and will be screened for study eligibility within 28 days prior
to apheresis. Safety criteria, as defined in the protocol, must be met prior to
starting apheresis. Eligible subjects will undergo apheresis for collection of
peripheral blood mononuclear cells (PBMC). Study enrollment is defined at the
day of apheresis. JNJ-68284528 will be generated from T-cells selected from the
apheresis.
Bridging therapy will be allowed when clinically indicated, with the permission
of the sponsor. Bridging therapy must be a short-term treatment which
previously generated at least a response of stable disease for the subject.
After meeting safety criteria for treatment, subjects will be administered a
conditioning regimen of IV cyclophosphamide 300 mg/m^2 and fludarabine 30
mg/m^2 daily for 3 days. JNJ-68284528 will be administered at a pre-determined
targeted dose of CAR-positive viable T cells/kg. Hospitalization and local stay
requirements for subsequent subjects will be based on recommendations by the
Safety Evaluation Team.
Safety evaluations will include a review of adverse events, laboratory test
results, vital sign measurements, physical examination findings, and assessment
of Eastern Cooperative Oncology Group (ECOG) performance status grade during
the post-infusion period (day 1 to day 100). Disease status will be evaluated
according to the IMWG consensus recommendations for multiple myeloma treatment
response criteria and will continue during the post-treatment period (day 101
up to study completion). Response will be determined using a validated computer
algorithm. Follow up of subjects for disease progression and survival will
continue during the follow-up period. All study evaluations will be conducted
according to the Time and Events Schedules in the protocol.
The primary analysis will be conducted approximately 6 months after the last
subject receives their initial dose of JNJ-68284528. Subjects will be followed
for survival after the clinical cutoff for the primary CSR. Study
completion/end of the study will be defined as no later than 2 years after the
last subject has received their initial dose of JNJ-68284528. However, the
sponsor will monitor subjects treated with JNJ-68284528 for 15 years for
complications of lentiviral integration, including second primary malignancies
on a long-term follow-up study.
Intervention
Treatment with JNJ-68284528, an autologous Chimeric Antigen Receptor T cell
therapy that targets B cell maturation antigen, with the possibility to receive
retreatment with JNJ-68284528 within the same dose range if all criteria to be
eligible for retreatment are met and approved by the sponsor. JNJ-68284528 will
be administered in one intravenous infusion and the actual dose for study
treatment administration will be based on the subject*s weight at apheresis.
Study burden and risks
The (potential) burden and risks associated with participation are extensively
described in the patient information sheet of the Informed Consent Form. This
includes side effects such as cytokine release syndrome, tumor lysis syndrome,
neurological problems, effects on blood cells (i.e. detected by laboratory
assessment of clinical chemistry and hematology samples), risk of infection,
risk of new cancer and other possible side effects from study tests and medical
treatment. There is an expected benefit for the subject in reduction of disease
burden and improved quality of life. This might not be the case for all
subjects.
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Graaf Engelbertlaan 75
Breda 4837 DS
NL
Listed location countries
Age
Inclusion criteria
1. 18 years of age.
2. Documented diagnosis of multiple myeloma according to IMWG diagnostic
criteria.
3. Measurable disease at Screening as defined by any of the following:
- Serum monoclonal paraprotein (M-protein) level greater than or equal to 1.0
g/dL or urine M-protein level greater than or equal to 200 mg/24 hours or
- Light chain multiple myeloma without measurable disease in the serum or the
urine: Serum immunoglobulin free light chain greater than or equal to 10 mg/dL
and abnormal serum immunoglobulin kappa lambda free light chain ratio.
4. Received at least 3 prior multiple myeloma treatment regimens or are double
refractory to an IMiD and PI (refractory multiple myeloma as defined by IMWG
consensus criteria). Note: induction with or without hematopoietic stem cell
transplant and with or without maintenance therapy is considered a single
regimen. Undergone at least 1 complete cycle of treatment for each regimen,
unless PD was the best response to the regimen.
5. Received as part of previous therapy a PI, an IMiD, and an anti-CD38
antibody (prior exposure can be from different monotherapy or combination
regimens).
6. Subject must have documented evidence of progressive disease based on
investigator*s determination of response by the IMWG criteria on or within 12
months of their last regimen. Confirmation may be from either central or local
testing. Also, subjects with documented evidence of progressive disease (as
above) within the previous 6 months and who are refractory or non-responsive to
their most recent line of treatment afterwards are eligible.
7. ECOG Performance Status grade of 0 or 1.
8. Clinical laboratory values as specified in the protocol.
9. Women of childbearing potential must have a negative pregnancy test at
screening and prior to the first dose of cyclophosphamide and fludarabine using
a highly sensitive serum pregnancy test (β human chorionic gonadotropin [β-
hCG]).
10. When a woman is of childbearing potential the following is required:
-Subject must agree to practice a highly effective method of contraception
(failure rate of <1% per year when used consistently and correctly) and agree
to remain on a highly effective method of contraception from the time of
signing the informed consent form (ICF) until at least 100 days after receiving
a JNJ-68284528 infusion.
In addition to the highly effective method of contraception a man:
-Who is sexually active with a woman of childbearing potential must agree to
use a barrier method of contraception (eg, condom with spermicidal
foam/gel/film/cream/suppository) from the time of signing the ICF until at
least 100 days after receiving a JNJ-68284528 infusion.
- Who is sexually active with a woman who is pregnant must use a condom.
Women and men must agree not to donate eggs (ova, oocytes) or sperm,
respectively, during the study and for 100 days after the last dose of study
treatment.
11. Subject must sign an ICF indicating that he or she understands the purpose
of and procedures required for the study and is willing to participate in the
study. Consent is to be obtained prior to the initiation of any study-related
tests or procedures that are not part of standard-of-care for the subject*s
disease.
12. Willing and able to adhere to the prohibitions and restrictions specified
in this protocol.
Exclusion criteria
1. Prior treatment with CAR-T therapy directed at any target.
2. Any therapy that is targeted to BCMA.
3. Diagnosed or treated for invasive malignancy other than multiple myeloma,
except:
-Malignancy treated with curative intent and with no known active disease
present for greater than or equal to 2 years before enrollment or
-Adequately treated non-melanoma skin cancer without evidence of disease.
4. Prior antitumor therapy as follows, prior to apheresis:
-Targeted therapy, epigenetic therapy, or treatment with an investigational
drug or used an invasive investigational medical device within 14 days or at
least 5 half lives, whichever is less.
-Monoclonal antibody treatment for multiple myeloma within 21 days.
-Cytotoxic therapy within 14 days.
-Proteasome inhibitor therapy within 14 days.
-Immunomodulatory agent therapy within 7 days.
-Radiotherapy within 14 days. However, if the radiation portal covered less
than or equal to 5% of the bone marrow reserve, the subject is eligible
irrespective of the end date of radiotherapy.
5. Toxicity from previous anticancer therapy must resolve to baseline levels or
to Grade 1 or less except for alopecia or peripheral neuropathy.
6. The following cardiac conditions:
-New York Heart Association (NYHA) stage III or IV congestive heart failure.
-Myocardial infarction or coronary artery bypass graft (CABG) less than or
equal to 6 months prior to enrollment.
-History of clinically significant ventricular arrhythmia or unexplained
syncope, not believed to be vasovagal in nature or due to dehydration.
-History of severe non-ischemic cardiomyopathy.
-Impaired cardiac function (LVEF <45%) as assessed by echocardiogram or
multiple-gated acquisition (MUGA) scan (performed less than or equal to 8 weeks
of apheresis).
7. Received a cumulative dose of corticosteroids equivalent to >=70 mg of
prednisone within the 7 days prior to apheresis.
8. Received either of the following:
-An allogenic stem cell transplant within 6 months before apheresis. Subjects
who received an allogeneic transplant must be off all immunosuppressive
medications for 6 weeks without signs of graft-versus-host disease (GVHD).
-An autologous stem cell transplant less than or equal to 12 weeks before
apheresis.
9. Known active, or prior history of central nervous system (CNS) involvement
or exhibits clinical signs of meningeal involvement of multiple myeloma.
10. Stroke or seizure within 6 months of signing ICF.
11. Plasma cell leukemia at the time of screening (>2,0 x 10^9/L plasma cells
by standard differential), Waldenström*s macroglobulinemia, POEMS syndrome
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, and skin
changes), or primary AL amyloidosis.
12. Seropositive for human immunodeficiency virus (HIV).
13. Vaccinated with live, attenuated vaccine within 4 weeks prior to apheresis.
14. Hepatitis B infection as defined in the protocol. In the event the
infection status is unclear, quantitative levels are necessary to determine the
infection status.
15. Hepatitis C infection defined as (anti-hepatitis C virus [HCV] antibody
positive or HCV-RNA positive) or known to have a history of hepatitis C. For
subjects with known history of HCV infection, confirmation of sustained
virologic response [SVR] is required for study eligibility, defined as >=24
weeks after completion of antiviral therapy.
16. Supplemental oxygen use to maintain adequate oxygenation.
17. Known life threatening allergies, hypersensitivity, or intolerance to
JNJ-68284528 or its excipients, including DMSO.
18. Serious underlying medical condition, such as:
-Evidence of serious active viral, bacterial, or uncontrolled systemic fungal
infection.
-Active autoimmune disease or a history of autoimmune disease within 3 years.
-Overt clinical evidence of dementia or altered mental status.
19. Any issue that would impair the ability of the subject to receive or
tolerate the planned treatment at the investigational site, to understand
informed consent or any condition for which, in the opinion of the
investigator, participation would not be in the best interest of the subject
(eg, compromise the well-being) or that could prevent, limit, or confound the
protocol-specified assessments.
20. Pregnant or breast-feeding, or planning to become pregnant while enrolled
in this study or within 100 days after receiving study treatment.
21. Plans to father a child while enrolled in this study or within 100 days
after receiving study treatment.
22. Major surgery within 2 weeks prior to apheresis, or has surgery planned
during the study or within 2 weeks after study treatment administration. (Note:
subjects with planned surgical procedures to be conducted under local
anesthesia may participate.)
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 | EUCTR2018-000121-32-NL |
| ClinicalTrials.gov | NCT03548207 |
| CCMO | NL69092.000.19 |