This study has been transitioned to CTIS with ID 2023-504581-29-00 check the CTIS register for the current data. Primary* Part 1 (Dose Escalation): To characterize the safety of JNJ-64407564 and recommend thePhase 2 dose(s) and schedule* Part 2 (…
ID
Source
Brief title
Condition
- Haematopoietic neoplasms (excl leukaemias and lymphomas)
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
* Part 1 (Dose Escalation): Frequency and type of dose-limiting toxicity (DLT),
and frequency and severity of adverse events, serious adverse
events, and laboratory abnormalities
* Part 2 (Dose Expansion): Frequency and severity of adverse events, serious
adverse events, and laboratory abnormalities
* Part 3: Overall Response Rate (partial response or better) as defined by the
IMWG criteria based on review by the Independent Review Committee.
Secondary outcome
For part 1 and 2:
- Pharmacokinetic parameters and pharmacodynamic markers including, but not
limited to, depletion of GPRC5D expressing cells, systemic cytokine
concentrations, and markers of T cell activation
- Presence of anti-JNJ-64407564 antibodies
- Assess the overall response rate (ORR) (at least a partial response [PR] or
better), clinical benefit rate (CBR), duration of and time to response
(DOR and TTR), and progression-free survival (PFS), as defined by the
International Myeloma Working Group (IMWG) response criteria
For part 3:
- duration of response
- Very Good Partial Response or better/Complete Response or better/stringend
Complete Response as defined by IMWG response criteria
- Time To response
- Progression free survival
- Overall survival
- MRD-negative status
- Occurrence and severity of adverse events, serious adverse events, and
laboratory values
- Pharmacokinetic parameters in a population PK analysis
- Presence and activity of anti-talquetamab antibodies
- Change from baseline in overall HRQoL, symptoms, and functioning
- Overall response rate in patients with high-risk molecular features
Background summary
A Phase 1/2, First-in-Human, Open-Label, Dose Escalation Study of JNJ-64407564,
a Humanized DuoBody® Antibody, in Subjects with Relapsed or Refractory Multiple
Myeloma
Multiple myeloma is a malignant plasma cell disorder characterized by
osteolytic lesions, increased susceptibility to infections, and renal failure,
and is the third most common hematological malignancy.
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.
Despite these therapeutic achievements, the disease recurs and is associated
with additional risk factors such as comorbidities or increasing age. Thus,
multiple myeloma remains an incurable malignancy and an unmet medical need with
significant morbidity and mortality warranting the need for novel therapeutic
approaches.
G protein-coupled receptor family C group 5-member D (GPRC5D) is an orphan
receptor whose ligand and signaling mechanisms are yet to be identified. Levels
of GPRC5D expression in patients with multiple myeloma correlated well with
plasma cell burden and genetic aberrations such as retinoblastoma (Rb)-1
deletion. This expression of GPRC5D on the plasma-cell lineage designates it as
a potential target for T lymphocyte (T cell)-mediated therapy to treat plasma
cell disorders like multiple myeloma.
This is the first time in human (FIH) study of the humanized immunoglobulin G4
proline, alanine, alanine (IgG4 PAA) bispecific DuoBody® antibody,
JNJ-64407564, which was developed to evaluate the therapeutic potential of
targeting GPRC5D for T cell redirection. The antibody binds to the CD3 receptor
complex on T cells and to GPRC5D on plasma cells. It is hypothesized that by
inducing enhanced T cell mediated cytotoxicity through recruitment of
CD3-expressing T cells to the GPRC5D-expressing cells, treatment with
JNJ-64407564 will be an effective therapy for patients with multiple myeloma.
Study objective
This study has been transitioned to CTIS with ID 2023-504581-29-00 check the CTIS register for the current data.
Primary
* Part 1 (Dose Escalation): To characterize the safety of JNJ-64407564 and
recommend thePhase 2 dose(s) and schedule
* Part 2 (Dose Expansion): To further characterize the safety of JNJ-64407564
at the recommended Phase 2 dose(s) (RP2Ds)
* Part 3 (Phase 2): To evaluate the efficacy of talquetamab at the RP2D
Secondary (part 1 and 2)
- To characterize the pharmacokinetics and pharmacodynamics of JNJ-64407564
- To assess the immunogenicity of JNJ-64407564
- To evaluate the preliminary antitumor activity of JNJ-64407564 at the RP2D(s)
in Part 2
Secondary (part 3)
- To further assess the efficacy of talquetamab at the RP2D
- To evaluate MRD at the RP2D
- To further assess the safety and tolerability of talquetamab at the RP2D
- To characterize the PK of talquetamab at the RP2D
- To assess the immunogenicity of talquetamab
- To assess PROs after treatment with talquetamab
- To evaluate the efficacy of talquetamab in high risk molecular subgroups
Study design
This is a FIH, Phase 1/2, open-label, multicenter study of JNJ-64407564
administered to adult subjects with relapsed or refractory multiple myeloma.
The study will be conducted in 3 parts: dose escalation (Part 1), dose
expansion (Part 2), efficacy (part 3). The overall aim of the study is to
evaluate the safety of JNJ-64407564 and to evaluate preliminary antitumor
activity. Safety will be monitored by the SET.
Part 1 (dose escalation) will begin at the minimum anticipated biologic effect
level (MABEL)-based starting dose. Subsequent dose levels will be selected
based on a statistical model and using all available data to identify one or
more putative RP2D(s), defined as the dose(s) and schedule(s) of JNJ-64407564
for characterization in Part 2. The study was initiated with a biweekly dosing
schedule. A weekly dosing schedule is being initiated by the sponsor after
review of emerging safety and pharmacokinetic data from the biweekly dosing
schedule that showed subjects may not have sufficient JNJ-64407564 exposure
beyond Day 8 following the first dose. The maximum sample size is approximately
85 subjects, but the
actual number of subjects treated will depend on the number of dose levels
explored and the number of subjects enrolled at each dose level.
Biweekly dosing cohort: Dose escalation began at the starting dose level of 0.5
µg/kg and the subsequent dose levels were selected based on a statistical model
and using all available data to identify safe and tolerable putative RP2D(s).
Weekly dosing cohort: Dose escalation will begin at a starting dose level that
has already been determined to be safe for biweekly dosing during the
accelerated phase of dose escalation, and the subsequent dose levels will be
selected based on a statistical model and using all available data to identify
safe and tolerable putative RP2D(s).
Addition 1 APRIL 2019:
With amendement 8 a twice-weekly cohort is introduced:
The first dose will start at a level that has been determined to be safe in the
weekly cohort escalation.
JNJ-64407564 will be administered at day 1, 4, 8, 11, 15 and 18 in a 21-day
cycle.
A minimum interval of 48 (subcutane administration) or 36 hour (IV
administration) after the first and second subject*s first dose will be
required. The sponsor will operationalize enrollment such that this 48/36-hour
period is maintained across the sites. Initial dose(s) will be administered in
the hospital setting to allow for continuous safety monitoring and
pharmacokinetic assessments; subsequent doses will be administered in an
outpatient setting.
In Part 2 (dose expansion), subjects will be treated at the putative RP2D(s)
for JNJ-64407564 determined in Part 1. Approximately 20 subjects may be treated
at each of the putative RP2D(s) to further characterize safety and preliminary
antitumor activity.
Disease status will be evaluated according to the International Myeloma Working
Group (IMWG) consensus recommendations for multiple myeloma treatment response
criteria. Subjects will continue to receive study drug until disease
progression, unacceptable toxicity, withdrawal of consent, otherwise deemed
necessary by the investigator or the sponsor, or end of study. The end of study
is defined as the
last study assessment for the last subject on study.
Addition 08OCT2020:
Enrollment for Part 3 will begin after approximately 20 subjects have been
treated with SC talquetamab at 405 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.
Addition 15Jul2021:
Cohort C will be added to part 3 of the study. Patients will receive biweekly
Talquetamab at 800 µg/kg SC. Amendement INT-13 will allow patients to switch
from a weekly 400 µg/kg SC dosing schedule to a biweekly 800 µg/kg SC dosing
schedule in Part 3 of the study, when a subject has had a response of CR or
better for a minimum of 6 months and if approved by the sponsor.
Addition 02Feb2023:
Total number of patients updated to 718. Update in exclusion criteria 3.
Intervention
Biweekly dosing: The study was initiated using a biweekly dosing schedule in
which JNJ-64407564 will be administered on Days 1 and 15 in each 28-day cycle.
Dose escalation began at the MABEL-based starting dose of 0.5 µg/kg. Review of
the preliminary biweekly pharmacokinetic data indicated that weekly dosing
should also be explored.
Weekly dosing: Weekly dosing will begin using the weekly dosing schedule.
JNJ-64407564 will be administered on Days 1, 8, and 15 in each 21-day cycle.
Dose escalation will begin at a dose level that has been determined to be safe
during dose escalation for biweekly dosing.
A priming dose schedule may be considered to mitigate drug-related toxicities
such as cytokine release syndrome (CRS) after one case (ie, first incidence) of
a Grade >=2 CRS event occurs. This decision will be determined by the SET. The
first priming dose will be chosen based on emerging data.
Addition 1 APRIL 2019:
With amendement 8 a twice-weekly cohort is introduced:
The first dose will start at a level that has been determined to be safe in the
weekly cohort escalation.
JNJ-64407564 will be administered at day 1, 4, 8, 11, 15 and 18 in a 21-day
cycle.
Adidition 08 OCTOBER 2020:
For part 1 and 2: there is a possibility for a monthly dosing regimen.
For part 3: a weekly SC dosing regimen will be followed. Talquetamab will be
administered on days 1, 8, 15 en 22 in every 28-day cycle
Addition 18Dec2020:
Introduction of a second GPRC5DxCD3 concentration of 90 mg/mL (Liquid in Vial)
in addition to the current concentration of 10 mg/mL (Frozen Liquid in Vial).
Addition 15Jul2021:
Cohort C will be added to part 3 of the study. Patients will receive biweekly
Talquetamab at 800 µg/kg SC. Amendement INT-13 will allow patients to switch
from a weekly 400 µg/kg SC dosing schedule to a biweekly 800 µg/kg SC dosing
schedule in Part 3 of the study, when a subject has had a response of CR or
better for a minimum of 6 months and if approved by the sponsor.
Study burden and risks
This is the first study of JNJ-64407564; as such, only preliminary information
is available regarding toxicities associated with JNJ-64407564 in humans. The
potential safety risks of JNJ-64407564 are based on:
1) results of nonclinical studies;
2) mechanism of action;
3) route of administration, and
4) results from the 3 subjects treated with JNJ-64407564 to date (see Section
1.8).
A risk assessment could not be conducted in the cynomolgus monkey due to poor
cross-reactivity with JNJ-64407564. In the pivotal 1-month GLP toxicity study
to characterize the potential hazard with the surrogate molecule, JNJ-64024701,
no adverse findings were noted up to 30 mg/kg (total of 4 weekly doses). In
summary, some noteworthy findings included non-adverse, transient depletion in
total lymphocytes, consistent with the drug*s pharmacological action, and
minimal increase in globulins and unstained cells toward the end of the study
(Day 23 to 28). The confined harmacological and toxicological activity with the
surrogate molecule, at doses considered supra-physiological, points to very
limited target distribution in normal tissues/monkey. Taken together, the
findings with the surrogate molecule should be considered in light of the
technical limitations: the surrogate molecule does not fully represent the
study drug, JNJ-64407564, and a healthy monkey potentially carries a lower
target burden than a patient with multiple myeloma. Additionally, by
stimulating the endogenous immune system there is the potential for toxic
effects on other tissues or organs. As such, special attention should be given
to both immunological / immunogenicity-related toxicities.
The therapeutic benefit of the study drug has also not been determined in
humans. Based on preclinical studies targeting GPRC5D, JNJ-64407564 has shown
efficacy in depleting multiple myeloma cells in an in vitro cytotoxicity assay
and significantly inhibited and regressed tumor growth in xenograft rodent
models in vivo. These results indicate that JNJ-64407564 may affect clinical
outcomes for patients with relapsed or refractory multiple myeloma.
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 initial diagnosis of multiple myeloma according to IMWG diagnostic
criteria (attachment 8 of the protocol)
3. Part 1: Subjects with measurable multiple myeloma who have progressed on, or
could not tolerate, all available established therapies.
Part 2: Subjects with multiple myeloma measurable by central laboratory
assessment who have progressed on, or could not tolerate, all available
established therapies. If central laboratory assessments are not available,
relevant local laboratory measurements must exceed the minimum required level
by at least 25%.
Part 3: Measurable disease: Cohort A, Cohort B, and Cohort C: Multiple myeloma
must be measurable by central laboratory assessment. If central laboratory
assessments are not available, relevant local laboratory
measurements must exceed the minimum required level by at least 25%. Cohort A
and Cohort C: have previously received >=3 prior lines of therapy that included
at least one PI, one IMiD, and an anti-CD38 monoclonal antibody, and have not
been exposed to T cell redirection therapies such as CAR-T or bispecific
antibodies. Cohort B: have previously received >=3 prior lines of therapy that
included at least one PI, one IMiD, and an anti-CD38 monoclonal antibody, and
have been exposed to T cell redirection therapies such as CAR-T or bispecific
antibodies.
4.Eastern Cooperative Oncology Group (ECOG) performance status score, of 0 or 1
for part 1 and 2 and 0-3 for part 3
5. Pretreatment clinical laboratory values meeting the predefined criteria,
during the Screening Phase (see table on pg 120 of protocol)
6. Women of childbearing potential (WOCBP) 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.
(a woman is considered of childbearing potential (WOCBP) ie, fertile, following
menarche and until becoming post-menopausal unless permanently
sterile. Permanent sterilization methods include hysterectomy, bilateral
salpingectomy and bilateral oophorectomy.),
7.Women:
Women must be (as defined in Attachment 16) either one of the following:
a) Not of childbearing potential
b) Of childbearing potential and
- Practicing true abstinence OR
- Have a sole partner who is vasectomized OR
- Practicing at least 1 highy effective user-independent method of
contraception (see Attachment 16)
Subject must agree to continue to above from the time of signing the informed
consent form (ICF), while receiving study drug, and until 100 days after the
last dose of study drug. Women of childbearing potential must agree to
pregnancy testing (serum or urine) within 100 days after the last study drug
administration.
Men
Men must wear a condom (with or without spermicidal foam/gel/cream/suppository)
when engaging in any activity that allows for passage of ejaculate to another
person, during the study and for 100 days after the last dose of study drug.
His female partner, if of childbearing potential, must also be practicing a
highly effective methdod of contraception (see Attachment 16).
If the male subject is vasectomized, he still must wear a condom (with or
without spermicidal foam/gel/cream/suppository) but his female partner is not
required to use contraception.
8. 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 and
able 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.
10. Women and men must agree to not donate eggs (ova, oocytes) or sperm,
respectively, during the study and for 100 days after the last dose of study
drug.
11. Subject must agree to not donate blood or blood components during the study
and for 100 days after the last dose of study drug.
Exclusion criteria
1. 1. Prior Grade 3 or higher CRS related to any T cell redirection (eg, CD-3
redirection technology or CAR-T cell therapy) or any prior GPRC5D targeting
therapy.
2. Prior antitumor therapy as follows, prior to the first dose of study drug:,
• Gene modified adoptive cell therapy (eg, chimeric antigen receptor modified
T cells, natural killer [NK] cells) within 3 months.
• Targeted therapy, epigenetic therapy, or treatment with an, investigational
drug or 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.
• Radiotherapy within 14 days. However, if palliative focal radiation is used,
the subject is eligible irrespective of, the end date of radiotherapy.,
• Part 3 only:
o Cohort A and cohort C: exposed to a CAR-T or T cell redirection therapy at
any time.
o Cohort B: T cell redirection therapy within 3 months
3. Participants who received or plan to receive any live, attenuated
vaccine within 4 weeks prior to the first dose, during treatment, or
within 4 weeks of the last dose of talquetamab. Non-live or nonreplicating
vaccines approved or authorized for emergency use (eg,COVID-19) by local health
authorities are allowed.
4. Toxicities from previous anticancer therapies should have resolved to,
baseline levels or to Grade 1 or less except for alopecia or peripheral,
neuropathy.,
5. Received a cumulative dose of corticosteroids equivalent to >=140 mg of
prednisone within the 14-day period before the first dose of study, drug.,
6. Received either of the following:
-An allogenic stem cell transplant within 6 months before first dose of study
drug. Subjects who received an allogeneic transplant must be off all
immunosuppressive medications for 6 weeks without signs of GVHD.:
-An autologous stem cell transplant <=12 weeks before first dose of study drug,
7.Central nervous system (CNS) involvement or clinical signs of meningeal
involvement of multiple myeloma. If either is suspected, negative whole brain
magnetic resonance imaging (MRI) and lumbar cytology are required. ,
8. Plasma cell leukemia (>2.0 x 10 to the 9th/L plasma cells by standard,
differential), Waldenström's macroglobulinemia, POEMS syndrome,
(polyneuropathy, organomegaly, endocrinopathy, monoclonal protein, [M-protein],
and skin changes), or primary amyloid light chain (AL) amyloidosis.,
9. Known to be seropositive for human immunodeficiency virus or, acquired
immune deficiency syndrome.,
10. Hepatitis B infection as defined according to the American Society of,
Clinical Oncology guidelines. 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 HCV-RNA testing., Subjects with a
history of Hepatitis C virus antibody positivity must, undergo HCV-RNA
testing.,
11. Pulmonary compromise requiring supplemental oxygen use to, maintain
adequate oxygenation.,
12. Known allergies, hypersensitivity, or intolerance to talquetamab or, its
excipients.,
13. 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, •
Psychiatric conditions (eg, alcohol or drug abuse), severe dementia, or
altered, mental status, • 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.,
14. Pregnant, breast-feeding, or planning to become pregnant while, enrolled in
this study or within 100 days after the last dose of study, drug.,
15. Plans to father a child while enrolled in this study or within 100 days,
after the last dose of study drug.,
16. 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.
Any potential subject who meets any of the following criteria will be excluded
from participating in Part 3:
17. Stroke or seizure within 6 months prior to signing the ICF.
18. The following cardiac conditions:
o New York Heart Association Stage III or IV congestive heart failure
o Myocardial infarction or coronary artery bypass graft (CABG) <=6 months prior
to enrollment
o History of clinically significant ventricular arrhythmia or unexplained
syncope, not believed to be vasovagal in nature or due to dehydration
o History of severe non-ischemic cardiomyopathy.
19. Active malignancies (ie, progressing or requiring treatment change in the
last 24 months) other than the disease being treated under study.
(Note: subjects with planned, surgical procedures to be conducted under local
anesthesia may, participate.), NOTE: Investigators should ensure that all study
inclusion/exclusion, criteria have been met at screening and prior to the first
dose of study, drug. If a subject's clinical status changes (including any
available, laboratory results or receipt of additional medical records) after,
screening but before the first dose of study drug is given such that he or, she
no longer meets all eligibility criteria, supportive treatment may be,
administered according to local standards of care, if necessary, so that,
eligibility criteria may be met and laboratory test(s) may be repeated, once,
to determine if the subject qualifies for the study. If, inclusion/exclusion
criteria are not met after further evaluation, the subject should be excluded
from participation in the study.
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 |
|---|---|
| EU-CTR | CTIS2023-504581-29-00 |
| EudraCT | EUCTR2017-002400-26-NL |
| ClinicalTrials.gov | NCT03399799 |
| CCMO | NL67205.029.18 |