Part BPrimary:• To determine the anti-tumor activity of NM21 1480 according to RECIST 1.1• To assess the safety and tolerability of NM21 1480 in patients with selected advanced cancers treated at or around the recommended Phase 2 dose (RP2D)• To…
ID
Source
Brief title
Condition
- Miscellaneous and site unspecified neoplasms malignant and unspecified
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
Part B
• BOR (Primary endpoint for Cohort B1-4, 6-7)
• ORR (Primary endpoint for Cohort B5)
• Incidence and severity of TEAEs with specific focus on incidence and severity
of irAEs
• Characterization of exposure-dependent PD markers of target and pathway
engagement. Potential PD markers are included in the below list of exploratory
markers applicable to all Parts A, A-2 and B
Secondary outcome
• Disease Control Rate (DCR)
• DOR
• PFS
• OS
• BOR, DCR, ORR, DOR, PFS as per iRECIST
• PK parameters
o AUCtau
o AUC (0-infinity) (first dose only)
o Cmax
o Cmin
o t*
o Tmax
o *z
o CL
o Vd
• Frequency of specific anti-drug antibodies to NM21 1480
Background summary
NM21-1480 is a protein that binds to 3 molecules called PD-L1, 4-1BB and human
serum.
With this action, NM21-1480 is expected to help the subject's immune system to
fight against cancer.
Study objective
Part B
Primary:
• To determine the anti-tumor activity of NM21 1480 according to RECIST 1.1
• To assess the safety and tolerability of NM21 1480 in patients with selected
advanced cancers treated at or around the recommended Phase 2 dose (RP2D)
• To determine the RP2D
• To determine the safety and efficacy of NM21 1480 in combination with
standard-of-care anti-PD1 therapy in patients with head and neck squamous cell
cancer (Cohort B5)
Secondary:
• To further evaluate the preliminary anti-tumor activity of NM21-1480
• To characterize the PK profile of NM21-1480
• To evaluate the immunogenicity of NM21-1480
Study design
This is a first-in-human (FIH), open label, multi-center, Phase 1/2,
dose-escalation study with dose expansion cohorts in specific tumor types to
evaluate NM21 1480 for safety and immunogenicity, to determine the MTD and
Recommended Phase 2 Dose (RP2D), define the PK, to explore the pharmacodynamics
(PD), and to obtain preliminary evidence of the clinical activity in adult
patients with selected advanced solid tumors.
NM21-1480 is a recombinant protein consisting of 3 stabilized antibody Fv
fragments directed against the molecular targets Programmed death-ligand 1
(PD-L1), 4-1BB, and serum albumin (SA). It is designed for avoidance of
systemic 4-1BB activation and preferential 4-1BB activation in the TME to avoid
the dose-limiting toxicities (DLT) of systemically active 4-1BB agonists.
This is an open-label study and includes an ascending-dose cohort component
(Part A) to be optionally followed by an additional cohort (optional Part A-2)
to further characterize the exposure/PD response relationship of the compound
to support optimal dose range selection for further evaluation in dose
expansion cohorts in specific tumor types in Part B. Depending on Part A data,
Part B may be initiated without the conduct of the optional A2 Cohort. For
patients in all cohorts, the study will consist of 3 periods: Screening (up to
28 days), treatment (until confirmed progression or meeting any other reason
for discontinuation specified by the protocol), and Follow-up (up to 12
weeks).In Part A (and optional Part A-2) of the study, NM21-1480 will be
administered as a single intravenous (IV) infusion approximately every 14 days
for a total of 2 infusions per treatment cycle. A treatment cycle is thus
defined as 28 days (4 weeks). In Part A (and optional Part A-2), response
assessments are done every 8 weeks, thus one assessment cycle is defined as 8
weeks. Any dose level to be studied in Part B (or optionally in Part A-2) will
be below or at the MTD determined upon decision by the Safety Monitoring
Committee (SMC) once all patients enrolled to Part A have completed their
28-day DLT evaluation period. In Part B of the study, NM21-1480 will be
administered as a single IV infusion either approximately every 14 or 21 days,
dependent on the respective dose level. Selection of dose level(s) and
corresponding dosing interval(s) for Part B will be based on Sponsor proposal
and SMC decision after formal conclusion on the Part A 28-day DLT evaluation
period data and resulting determination of the MTD, once all patients enrolled
to Part A have completed their 28-day/end of DLT period assessments. If the
optional Part A-2 of the study is conducted, the SMC may also consider its
resulting data for dose selection for Part B. Any dose level to be selected
for Part B by the SMC must not exceed the MTD determined in Part A. In Part B,
a treatment cycle, dependent on the dosing interval selected by the SMC for a
given dose level (i.e., 2-week or 3-week dosing interval), is thus defined as
28 days (4 weeks) or 42 days (6 weeks), respectively. Response assessments in
Part B will be done every 6 weeks during the first 24 weeks patients are on
treatment and every 8 weeks beyond 24 weeks on treatment.
Intervention
In Part A (and optional Part A-2) of the study, NM21-1480 will be administered
as a single intravenous (IV) infusion approximately every 14 days for a total
of 2 infusions per treatment cycle. A treatment cycle is thus defined as 28
days (4 weeks). In Part A (and optional Part A-2), response assessments are
done every 8 weeks, thus one assessment cycle is defined as 8 weeks. Any dose
level to be studied in Part B (or optionally in Part A-2) will be below or at
the MTD determined upon decision by the Safety Monitoring Committee (SMC) once
all patients enrolled to Part A have completed their 28-day DLT evaluation
period. In Part B of the study, NM21-1480 will be administered as a single IV
infusion either approximately every 14 or 21 days, dependent on the respective
dose level. Selection of dose level(s) and corresponding dosing interval(s) for
Part B will be based on Sponsor proposal and SMC decision after formal
conclusion on the Part A 28-day DLT evaluation period data and resulting
determination of the MTD, once all patients enrolled to Part A have completed
their 28-day/end of DLT period assessments. If the optional Part A-2 of the
study is conducted, the SMC may also consider its resulting data for dose
selection for Part B. Any dose level to be selected for Part B by the SMC must
not exceed the MTD determined in Part A. In Part B, a treatment cycle,
dependent on the dosing interval selected by the SMC for a given dose level
(i.e., 2-week or 3-week dosing interval), is thus defined as 28 days (4 weeks)
or 42 days (6 weeks), respectively. Response assessments in Part B will be
done every 6 weeks during the first 24 weeks patients are on treatment and
every 8 weeks beyond 24 weeks on treatment.
Study burden and risks
NM21-1480 has not yet been tested in humans, and therefore its side effects in
humans are unknown. However, NM21-1480 has been studied in animals, and other
drugs, such as avelumab and atezolizumab (so-called *anti-PD-L1 antibodies*),
are similar to NM21-1480 and have been studied in humans,
Based on human studies with other *PD-L1 antibodies*, serious side effects may
include lung problems (pneumonitis), liver problems (hepatitis), intestinal
problems (colitis), problems in hormone glands (for example thyroid problems or
diabetes), heart, nervous system, and other organs.
More about the side effects and risks from study procedures is listed in
appendix D of the SIS-ICF.
Einsiedlerstrasse 34
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Einsiedlerstrasse 34
Wadenswil CH-8820
CH
Listed location countries
Age
Inclusion criteria
Parts A and A-2 are not conducted in EU/EEA and, therefore, specific
inclusion criteria are not described.
Part B (all cohorts): Patients with locally advanced or metastatic,
non-resectable disease.
• Cohorts B1 and B7
o Patients with NSCLC
• Cohort B2
o Patients with HPV-associated (i.e. HPV+ tumor) SCC of the anus, cervix,
vulva, vagina, penis or oropharynx
• Cohort B4
o Patients with recurrent, persistent or metastatic ovarian, primary peritoneal
or fallopian tumor carcinoma
• Cohort B5
o Patients with head and neck squamous cell cancer
• Cohort B6
o Patients with TNBC according to current ASCO/CAP guidelines that is
measurable according to RECIST1.1 criteria
Part B:
For Cohorts B1, B2, B6 (subgroup with required previous checkpoint inhibitor
therapy) and B7: Last dose of therapy with anti-PD-1 antibody must have been
received at least 2 weeks prior to the administration of the first dose of the
study drug. All cohorts (while not applicable to Cohort B5): Prior
chemotherapy must have been completed at least 4 weeks prior to the
administration of the first dose of study drug. Exceptions: Hormone
replacement therapy.
Exclusion criteria
Key Exclusion Criteria:
Patient previously had known immediate or delayed hypersensitivity reaction or
idiosyncrasy to the excipients of investigational product (IP) or has
experienced >= Grade 3 irAEs with previous checkpoint inhibitor therapy.
Part B:
• Cohort B1 and B7:
o Treatment with PD-1 antibody within 2 weeks.
o Patients who, for the treatment of the current cancer, has received any other
treatment than anti PD 1 and/or chemotherapy prior to initiation of the study
drug or who has not recovered to CTCAE V5.0 Grade 1 or better from the AE due
to anti-PD-1 administered earlier; in addition, patients with any ongoing Grade
1 or higher AE of colitis, hepatitis, nephritis, or pneumonitis considered to
be related to previous anti-PD-1 therapy is exclusionary. However, sensory
neuropathy <=Grade 2, alopecia and endocrine disorder treated with hormone
replacement are acceptable.
• Cohort B2:
o Patients who, for the treatment of the current cancer, has received any
treatment other than anti PD 1 or a platinum-based chemotherapy regimen
recommended as first-line or second-line treatment by current National
Comprehensive Cancer Network (NCCN) treatment guidelines or who has not
recovered to CTCAE V5.0 Grade 1 or better from the AE due first- or second-line
treatment; in addition, patients with any ongoing Grade 1 or higher AE of
colitis, hepatitis, nephritis or pneumonitis considered to be related to
previous anti-PD-1 therapy is exclusionary. However, sensory neuropathy <=Grade
2, alopecia and endocrine disorders treated with hormone replacement are
acceptable.
• Cohort B4:
o Patients who have had prior therapy with anti-PD-1, anti-PD-L, anti-4-1-BB or
anti-CTLA-4 antibodies or any other antibody or drug specifically targeting
T-cell co-stimulation or immune check point pathways.
o Patients who have received prior chemotherapy for any abdominal or pelvic
tumor other than for treatment of ovarian, fallopian tube, or primary
peritoneal cancer within the last 3 years; patients may have received prior
adjuvant chemotherapy and radiotherapy for localized breast cancer, provided
that it was completed more than 2 years prior to consenting to this study, and
the patient remains free of recurrent or metastatic disease and hormonal
therapy has been discontinued; patients who have received prior radiotherapy to
any portion of the abdominal cavity or pelvis or thoracic cavity within the
last 3 years are excluded; prior radiation for localized cancer of the head and
neck or skin is permitted, provided that it was completed more than 3 years
prior to consenting to this study, and the patient remains free of recurrent or
metastatic disease.
• Cohort B5
o Patients who have previously received systemic drug therapy for their disease.
• Cohort B6
o For patients in the subgroup in which previous therapy with a checkpoint
inhibitor is required:
* Treatment with PD-1 antibody within 2 weeks prior to the first dose of study
drug
* Treatment with PD-L1 antibody within 5 half-lives prior to first dose of
study drug
* Patient who has not recovered to CTCAE V5.0 Grade 1 or better from the AE due
to anti-PD-1 or anti-PD-1 antibody administered earlier; in addition, patient
with any ongoing Grade 1 or higher AE of colitis, hepatitis, nephritis, or
pneumonitis considered to be related to previous anti-PD1 or anti-PD-L1 therapy
is exclusionary. However, sensory neuropathy <=Grade 2, alopecia and endocrine
disorder treated with hormone replacement are acceptable
* Previous treatment with anti-CTLA-4 or anti-4-1BB antibody or drug
specifically targeting T cell co-stimulation or immune checkpoint pathways
other than the PD-1/PD-L1 pathway
o For patients in the subgroup in which previous therapy with a checkpoint
inhibitor is prohibited
* Patients who had prior therapy with anti-PD-1, anti-PD-L1, anti-4-1BB or anti
CTLA 4 antibodies or any other antibody or drug specifically targeting T-cell
co-stimulation or immune check point pathways.
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 |
|---|---|
| EudraCT | EUCTR2021-000441-41-NL |
| ClinicalTrials.gov | NCT04442126 |
| CCMO | NL77592.056.21 |