This study has been transitioned to CTIS with ID 2023-503438-40-00 check the CTIS register for the current data. Primary: - Part 1 (Dose Escalation): To identify the recommended Phase 2 dose(s) and schedule assessed to be safe for teclistamab - Part…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
SAFETY EVALUATIONS
The safety of teclistamab will be assessed by physical examinations (including
basic neurological assessment or Immune Effector Cell-associated Encephalopathy
[ICE] Tool [Part 3], ECOG performance status, laboratory tests, vital signs,
electrocardiograms, adverse event monitoring, and concomitant medication usage.
The severity of adverse events will be assessed using National Cancer Institute
Common Terminology Criteria for Adverse Events (NCI NCTAE; Version 4.03),
except as follows:
• In Part 1 and Part 2, CRS will be graded according to a CRS revised grading
system. In Part 3, CRS will be graded according to the American Society for
Transplantation and Cellular Therapy (ASTCT) grading system.
• Neurological adverse events will be graded based on NCI CTCAE Version 4.03 in
all Parts of the study. Additionally, in Part 3, an ICE score and ASTCT grade
will also be collected for immune effector cell-associated neurotoxicity
syndrome (ICANS) events.
CRS has been identified as an adverse event of special interest and will
require enhanced reporting and data collection for all Parts of the study.
Neurotoxicity events Grade >=2 have been identified as an adverse event of
special interest for Part 3.
PHARMACOKINETIC AND IMMUNOGENICITY EVALUATIONS
Blood samples will be collected from all subjects for the measurement of serum
teclistamab concentration for pharmacokinetic analyses. Pharmacokinetic
parameters will be determined after the first dose at Cycle 1 and the first
dose at Cycle 3 for Part 1 and Part 2. Exploratory population
pharmacokinetic-based approach may also be applied for the pharmacokinetic
analysis. The detection and characterization of antibodies to teclistamab will
be performed using a validated assay method to enable interpretation of the
anti-drug antibody data. In Part 3, teclistamab serum concentration will be
used in a population pharmacokinetic and exposure-response analysis.
PHARMACODYNAMIC AND BIOMARKER EVALUATIONS
Biomarker assessments will focus on 3 main objectives:
1. evaluate the immune responses indicative of T cell redirection for
potential contributions to teclistamab response;
2. determine the ability of teclistamab to achieve minimal residual disease
(MRD) in subjects who have at least a CR; and
3. determine the clinical benefit of teclistamab in subjects with cytogenetic
modifications or other high- risk molecular subtypes.
4. Samples will be collected to evaluate receptor occupancy (RO) in Part 1
and 2, to quantify the binding of therapeutics to their targets on the cell
surface.
Secondary outcome
Nap
Background summary
Multiple myeloma is a malignant plasma cell disorder characterized by
production of monoclonal proteins (M-proteins) comprised of pathological
immunoglobulins or fragments of such, which have lost their function. The
proliferation of multiple myeloma cells leads to subsequent displacement from
the normal bone marrow niche, while overproduction of M-protein causes
characteristic hallmarks of multiple myeloma such as osteolytic lesions,
increased susceptibility to infections, hypercalcemia, renal insufficiency or
failure, and neurological complications. Despite recent major therapeutic
improvements, the disease recurs and is associated with additional risk factors
(eg, comorbidities or increasing age), thus warranting the need for novel
therapeutic approaches.
In this regard, B cell (B lymphocyte) maturation antigen (BCMA, also known as
CD269 and TNFRSF17) is a 20 kilodalton, type I membrane protein, which is part
of the tumor necrosis receptor family. BCMA is predominantly expressed in
B-lineage cells and selectively induced during plasma cell differentiation
associated with the loss of B cell activating factor receptor (BAFF-R).
Moreover, in multiple myeloma cell lines and patient samples, BCMA is more
stably expressed compared with CD138, a key plasma cell marker, thus making it
an ideal therapeutic target.
Recently, several approaches were developed to redirect T lymphocytes (T cells)
to tumor surface antigens leading to antitumor activity and clinical benefit
for patients. Such approaches include the development of drugs which broke
tumor tolerance by T cell exhaustion checkpoint blockade, including inhibition
of cytotoxic T-lymphocyte-associated antigen-4 and programmed death-1. These
results suggest that redirecting T cells to tumor surface antigens by using
bispecific approaches may be an effective means to harness the immune system to
cause cell death in cancer cells and to create meaningful and long-lasting
clinical responses.
This is a Phase 1/2 study; Phase 1 includes Part 1 and Part 2, and the Phase 2
component is Part 3. This study will enroll subjects with relapsed or
refractory multiple myeloma. Part 3 will enroll subjects in cohorts that differ
by prior therapies. Cohort A and C will enroll first.
• Cohort A will enroll subjects with multiple myeloma who are triple class
exposed (proteasome inhibitor [PI], immunomodulatory drug [IMiD], and an
anti-CD38 monoclonal antibody) and have previously received treatment with >=3
prior lines of therapy.
• Cohort C will enroll subjects who have previously received >=3 prior lines of
therapy that included a PI, an IMiD, an anti-CD38 monoclonal antibody, and an
anti-BCMA treatment (chimeric antigen receptor [CAR]-T cells or an antibody
drug conjugate [ADC]).
Study objective
This study has been transitioned to CTIS with ID 2023-503438-40-00 check the CTIS register for the current data.
Primary: - Part 1 (Dose Escalation): To identify the recommended Phase 2
dose(s) and schedule assessed to be safe for teclistamab - Part 2 (Dose
Expansion): To characterize the safety and tolerability of teclistamab at the
recommended Phase 2 dose(s) (RP2Ds) - Part 3 (Phase 2): To evaluate the
efficacy of teclistamab at the RP2D Secondary: Part 1&2 -To characterize the
pharmacokinetics and pharmacodynamics of teclistamab - To evaluate the
preliminary antitumor activity of teclistamab at the RP2D(s) in Part 2 Part 3 -
To further assess the efficacy of teclistamab at the RP2D - To evaluate MRD at
the RP2D - To further assess the safety and tolerability of teclistamab at the
RP2D
Study design
This is a first-in-human (FIH), Phase 1/2, open-label, multicenter dose
escalation study with dose expansion to identify the RP2D and to evaluate the
safety, tolerability, pharmacokinetics, and anti-myeloma activity of
teclistamab (also known as JNJ-64007957) administered to adult subjects with
relapsed or refractory multiple myeloma. The overall safety of the study drug
will be assessed by the Safety Evaluation Team (SET) in Part 1 and Part 2.
The study will be conducted in 3 parts: dose escalation (Part 1), dose
expansion at proposed RP2Ds (Part 2), and Phase 2 dose expansion in cohorts of
subjects with relapsed or refractory multiple myeloma with unmet medical need
(Part 3).
The study was initiated with a biweekly (ie, every 2 weeks [Q2W]) IV dosing
schedule. A weekly IV dosing schedule was initiated by the sponsor after review
of emerging safety and pharmacokinetic data from the Q2W IV dosing schedule
showed subjects may not have sufficient teclistamab exposure beyond Day 8
following the first dose. A weekly SC dosing schedule was also initiated. Based
on emerging safety and pharmacokinetic data, the SET may propose alternative
dosing; schedules such as monthly dosing or gradual extension of the dosing
interval from weekly to biweekly to monthly may also be explored. Variations on
dosing, including bracketing by weight and fixed dosing, have also been
evaluated in Part 1 1; these subjects will be transitioned to weight-based
dosing following imlememtnation of Amendment
14..
Following Amendment 13, a Part 1 cohort will be added that will receive
teclistamab derived from a new drug substance manufacturing process.
Part 1
Biweekly (Q2W) dosing cohorts:
Dose escalation using IV administration began at the starting dose level of 0.3
µg/kg and the subsequent dose levels were selected based on a statistical model
and using all available data to identify safe and tolerable proposed RP2D(s).
Weekly dosing cohorts:
Dose escalation for both IV and SC administration began at a cleared dose level
approved by the Safety Evaluation Team (SET), and the subsequent dose levels
are being selected based on a statistical model and using all available data to
identify safe and tolerable proposed RP2D(s).
The total number of subjects treated in Part 1 will depend on the number of
dose levels explored and the number of subjects enrolled at each dose level. In
Part 1 the sample size for IV administration is
approximately 100 subjects, with SC dosing enrolling approximately 150
additional subjects. A staggered enrollment strategy will be applied. For each
dose level, a minimum interval of 72 hours after the first dose for the first
subject is required in the accelerated titration phase.
Exploratory cohorts may also be added in Part 1 to investigate administration
of tocilizumab as a pretreatment medication or low-dose dexamethasone given
daily during priming and early in Cycle 1.
Subjects treated with IV administration will be hospitalized for at least 36
hours from the start of any priming doses and the start of the first full dose
of study drug, and at least 24 hours from the start of the second full dose of
study drug. Hospitalization requirements may be modified by the SET based on
all available data, including safety, pharmacokinetics, and pharmacodynamics.
Subjects treated in the initial cohort for SC administration will be
hospitalized for at least 48 hours from the start of any priming injection of
study drug and from the start of the first full injection of study drug, and at
least 24 hours from the start of the second full injection of study drug. The
duration or need for hospitalization after SC administration for further
cohorts will be determined by the SET based on all available data including
safety, pharmacokinetics, and pharmacodynamics.
Part 2
In Part 2 (dose expansion), the proposed RP2D(s) will be further explored and
up to 40 subjects may receive teclistamab at the proposed RP2D(s) determined in
Part 1 to further characterize preliminary antitumor activity and safety in
additional subjects at the relevant dose(s).
Part 3
Enrollment for Part 3 will begin after at least 20 subjects have been treated
with SC teclistamab at 1500 µg/kg for at least 1 cycle. The sponsor may also
determine that additional subjects are required to further evaluate safety and
dose prior to proceeding to Part 3.Cohort B will not enroll.
All Parts
Disease evaluations; including peripheral blood; 24-hour urine collections,
bone marrow samples, and imaging as applicable; will be performed per IMWG.
Disease status will be evaluated according to the IMWG consensus
recommendations for multiple myeloma treatment response criteria.
Subjects will continue to receive study drug until disease progression,
unacceptable toxicity, withdrawal of consent, death, or end of study defined as
2 years after the last subject*s first dose. The sponsor will ensure that
subjects who continue to benefit from treatment with study drug will be able to
continue treatment after the end of the study per local regulations.
Intervention
There are several treatment schedules included in this study; the schedule you
follow depends on when you are enrolled in the study. Your doctor will explain
to you which schedule you are receiving. Treatment is given on what is known
as a *cycle*. The duration of the cycle depends on the treatment schedule. You
may receive the drug via an intravenous infusion (by vein) or via a
subcutaneous injection (under the skin).
Dose Schedules:
- Study drug may be given on a weekly, bi-weekly or monthly schedule.
Subcutaneous dosing will begin on a weekly schedule, but bi-weekly or dosing
may be explored. If you receive study drug on a weekly subcutaneous schedule,
you will be informed if your subcutaneous dosing schedule will change.
- If you are on the weekly IV or SC dose schedule, treatment will be given 3
times in a 21-day cycle. This means that you will receive study drug on Days 1,
8 and 15 of each 21-day cycle.
- If you are on the bi-weekly or monthly IV or SC dose schedule, treatment
will be given 2 times in a 28-day cycle. This means that you will receive study
drug on Days 1 and 15 of each 28-day cycle. Day 15 is not applicable for the
monthly schedule
Hospitalization and Observation Requirements after study drug administration:
Weekly Dose Schedule:
- Cycle 1 Day 1; you will be hospitalized for at least 36 hours (intravenous
infusion) or 48 hours (subcutaneous injection) from the start of the
infusion/injection.
- Cycle 1 Day 8; you will be hospitalized for at least 24 hours from the start
of the infusion/injection.
- For Cycle 1 Day 15 and Cycle 2 Day 1, you will remain at the site for
observation for at least 2 hours (intravenous infusion) or 4 hours
(subcutaneous injection). For subsequent infusions/injections you may be
released from the site after being evaluated by study site staff.
Biweekly/Monthly Dose Schedule
- Cycle 1 Day 1; you will be hospitalized for at least 36 hours (intravenous
infusion) or 48 hours (subcutaneous injection) from the start of the
infusion/injection.
- Cycle 1 Day 15; you will be hospitalized for at least 24 hours from the start
of the infusion/injection.
- For Cycle 2, you will remain at the site for at least 2 hours after the
infusion/injection for observation. For subsequent infusions/injections you may
be released from the site after being evaluated by study site staff
If you have side effects, you may need to be hospitalized after other
infusions/injections.
The duration of hospitalization may change after all available data are
reviewed. You will be informed if the length of hospitalization will change.
Priming Doses
You may receive one or more priming doses before the first full dose of study
drug is given on Cycle 1 Day 1 of the weekly, bi-weekly or monthly schedules
above. Priming doses are given at lower doses (not necessarily the same dose)
and subsequent doses are given at a higher level.
If you receive the study drug intravenously, you will be hospitalized for at
least 36 hours from the start of each priming infusion. This is in addition to
the hospitalization requirements required for Cycle 1 infusions in the dose
schedules above.
If you receive the drug subcutaneously you will be hospitalized for at least 48
hours from the start each priming injection. This is in addition to the
hospitalization requirements required for Cycle 1 injections in the dose
schedules above.
Part 3:
Priming Doses
You will receive 2 priming doses in the week before the first full dose of
study drug is given. Priming doses are given at lower doses than the full
treatment dose to manage side effects (see Risks section below). You will be
hospitalized for at least 48 hours from the start of each priming dose.
Full Doses
After the priming doses are completed, teclistamab will be given 4 times in a
28-day cycle. This means that you will receive study drug on Days 1, 8, 15 and
22 of each 28-day cycle. The number of teclistamab doses you will receive is
unknown as it will depend on how you respond to treatment. You will be
hospitalized for at least 48 hours from the start of the first full dose on
Cycle 1 Day 1. For doses after Cycle 1 Day 1 you may leave the site after being
evaluated by study site staff. If you have side effects, you may need to be
hospitalized after other doses.
The duration of hospitalization may change after all available data are
reviewed. You will be informed if the length of hospitalization will change.
Pre- treatment medications
You will receive pre-treatment medications before each priming dose and before
the first full dose on Cycle 1 Day 1. You will receive pre-treatment
medications before teclistamab doses during other cycles if you have certain
side effects or your investigator thinks it is needed.
Study burden and risks
Multiple myeloma is a malignant plasma cell disorder characterized by
production of monoclonal proteins (M-proteins) comprised of pathological
immunoglobulins or fragments of such, which have lost their function. The
proliferation of multiple myeloma cells leads to subsequent displacement from
the normal bone marrow niche, while overproduction of M-protein causes
characteristic hallmarks of multiple myeloma such as osteolytic lesions,
increased susceptibility to infections, hypercalcemia, renal insufficiency or
failure, and neurological complications. Despite recent major therapeutic
improvements, the disease recurs and is associated with additional risk factors
(eg, comorbidities or increasing age), thus warranting the need for novel
therapeutic approaches.
Antwerpseweg 15-17
Beerse B-2340
BE
Antwerpseweg 15-17
Beerse B-2340
BE
Listed location countries
Age
Inclusion criteria
1. >=18 years of age. 2. Documented diagnosis of multiple myeloma according to
IMWG diagnostic criteria 3. Part 1 and Part 2: Measurable multiple myeloma that
is relapsed or refractory to established therapies with known clinical benefit
in relapsed/refractory multiple myeloma or be intolerant of those established
multiple myeloma therapies, and a candidate for teclistamab treatment in the
opinion of the treating physician. Prior lines of therapy must include a PI an
IMiD and an anti-CD38 monoclonal antibody in any order during the course of
treatment. Subjects who could not tolerate a PI, IMiD or an anti-CD38
monoclonal antibody are allowed. In Part 2 (dose expansion), in addition to
above criteria, multiple myeloma must be measurable per current IMWG published
guidelines by central lab assessment. If central lab assessment is not
available, relevant local measurement must exceed the minimum required level by
at least 25%. Part 3 Measurable disease Cohort A, Cohort C: Multiple myeloma
must be measurable by central laboratory assessment: • Serum monoclonal
paraprotein (M-protein) level >=1.0 g/dL or urine M-protein level >=200 mg/24
hours; or • Light chain multiple myeloma without measurable disease in the
serum or the urine: Serum immunoglobulin free light chain (FLC) >=10 mg/dL and
abnormal serum immunoglobulin kappa lambda FLC ratio. Prior treatment * Cohort
A: Subjects must have 1) received >=3 prior lines of therapy and 2) previously
received a PI, an IMiD, and an anti-CD38 monoclonal antibody. * Cohort C:
received >=3 prior lines of therapy that included a PI, an IMiD, an anti-CD38
monoclonal antibody, and an anti-BCMA treatment (with CAR-T cells or an ADC).
4. Eastern Cooperative Oncology Group (ECOG) Performance Status score of 0 or
1, 5.Pretreatment clinical laboratory values meeting the incl criteria, 6.A
female subject of childbearing potential must have a negative pregnancy test at
screening and prior to the first dose of study drug using a highly sensitive
pregnancy test either serum (β human chorionic gonadotropin [β-hCG]) or urine.,
7. Female subjects of childbearing potential and fertile male subjects who are
sexually active must agree to use a highly effective method of contraception
(<1%/year failure rate). Contraception must begin from the time of signing the
ICF, continue during the study treatment, including during dose interruptions,
and through 6 months and 3 months after the last dose of study drug, for female
and male subjects, respectively. Contraception must be consistent with local
regulations regarding the use of birth control methods for subjects
participating in clinical trials. 8. Subject must sign an informed consent form
(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., 9. Willing
and able to adhere to the prohibitions and restrictions specified in this
protocol.
Exclusion criteria
1. Prior treatment with any BCMA targeted therapy, with the exception of Cohort
C in Part 3. 2.Prior antitumor therapy as follows, before the first dose of
study drug: * Targeted therapy, epigenetic therapy, or treatment with an
investigational drug or used an invasive investigational medical device within
21 days or at least 5 half-lives, whichever is less. * Monoclonal antibody
treatment for multiple myeloma within 21 days. * Cytotoxic therapy within 21
days. * Proteasome inhibitor therapy within 14 days. * Immunomodulatory agent
therapy within 7 days. * Gene modified adoptive cell therapy (eg, chimeric
antigen receptor modified T cells, natural killer [NK] cells) within 3 months.
* Radiotherapy within 14 days or focal radiation within 7 days, 3. Toxicities
from previous anticancer therapies that have not resolved to baseline levels or
to Grade 1 or less except for alopecia or peripheral neuropathy., 4. Received a
cumulative dose of corticosteroids equivalent to >=140 mg of prednisone within
the 14-day period before the first dose of study drug (does not include
pretreatment medication)., 5. Stem cell transplantation: * An allogeneic stem
cell transplant within 6 months. Subjects who received an allogeneic transplant
must be off all immunosuppresive medications for 6 weeks without signs of
graft-versus-host disease. * Received an autologous stem cell transplant <=12
weeks before the first dose of study drug, 6. Known active CNS involvement or
exhibits clinical signs of meningeal involvement of multiple myeloma., 7.
Plasma cell leukemia (>2.0 x 109/L plasma cells by standard differential),
Waldenstro*m*s macroglobulinemia, POEMS syndrome (polyneuropathy, organomegaly,
endocrinopathy, monoclonal protein, and skin changes), or primary amyloid
light-chain amyloidosis., 8. Known to be seropositive for human
immunodeficiency virus or acquired immune deficiency syndrome, 9.Hepatitis B
infection or at risk for hepatitis B virus reactivation as defined according to
the American Society of Clinical Oncology guidelines. Eligibilty will be
determined by the investigator as described in the protocol. In the event the
infection status is unclear, quantitative levels are necessary to determine the
infection status. Active Hepatitis C infection as measured by positive
hepatitis C virus (HCV)-RNA testing, in subjects with positive anti-HCV
antibody or subjects with a history of HCV antibody positivity ., 10. Pulmonary
compromise requiring supplemental oxygen use to maintain adequate oxygenation.,
11. Known allergies, hypersensitivity, or intolerance to the study drug
(teclistamb) or its excipients (refer to Investigator*s Brochure), 12. Any
serious underlying medical condition, such as: * Evidence of serious active
viral, bacterial, or uncontrolled systemic fungal infection * Active autoimmune
disease or a documented history of autoimmune disease with the exception of
vitiligo, type I diabetes, and prior autoimmune thyroiditis that is currently
euthyroid based on clinical symptoms and laboratory testing * Psychiatric
conditions (eg, alcohol or drug abuse), dementia, or altered mental status *
Stroke, seizure e or transient ischemic attack within 6 months of signing ICF.
* Any other 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., 13. Pregnant or breast-feeding, or planning to
become pregnant while enrolled in this study or within 6 months after receiving
the last dose of study drug., 14. Plans to father a child while enrolled in
this study or within 3months after receiving the last dose of study drug., 15.
Major surgery within 2 weeks of the first dose, or will not have fully
recovered from surgery, or has surgery planned during the time the subject is
expected to participate in the study or within 2 weeks after the last dose of
study drug administration. 16. The following cardiac conditions: • New York
Heart Association stage III or IV congestive heart failure • Myocardial
infarction or coronary artery bypass graft (CABG) <=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 17. Myelodysplastic syndrome or active
malignancies (ie, progressing or requiring treatment change in the last 24
months) other than the relapsed/refractory multiple myeloma. The only allowed
exceptions are: • Non-muscle invasive bladder cancer treated within the last 24
months that is considered completely cured. • Skin cancer (non-melanoma or
melanoma) treated within the last 24 months that is considered completely
cured. • Noninvasive cervical cancer treated within the last 24 months that is
considered completely cured. • Localized prostate cancer (N0M0): o With a
Gleason score of 6, treated within the last 24 months or untreated and under
surveillance. o With a Gleason score of 3+4 that has been treated more than 6
months prior to full study screening and considered to have a very low risk of
recurrence, o Or history of localized prostate cancer and receiving androgen
deprivation therapy and considered to have a very low risk of recurrence. •
Breast cancer: o Adequately treated lobular carcinoma in situ or ductal
carcinoma in situ, o Or history of localized breast cancer and receiving
antihormonal agents and considered to have a very low risk of recurrence. •
Malignancy that is considered cured with minimal risk of recurrence. 18. Live,
attenuated vaccine within 4 weeks prior to the first dose of teclistamab.
Design
Recruitment
Medical products/devices used
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 |
|---|---|
| Other | 03145181 |
| EU-CTR | CTIS2023-503438-40-00 |
| EudraCT | EUCTR2016-002122-36-NL |
| CCMO | NL66216.029.18 |