Advanced Solid Tumor, Colorectal Cancer, Fallopian Tube Cancer, Head and Neck Squamous Cell Carcinoma, Non-small Cell Lung Cancer, Ovarian Carcinoma, Peritoneal Carcinoma, Squamous Cell Carcinoma, Triple Negative Breast Cancer
Conditions
Keywords
Carcinoma, Neoplasms
Brief summary
This is a first-in-human, open-label, multi-center, Phase 1/2, dose-escalation study with expansion cohorts to evaluate NM21-1480 for safety and immunogenicity, to determine the maximal tolerated dose and recommended Phase 2 dose, define the pharmacokinetics, to explore the pharmacodynamics, and to obtain preliminary evidence of the clinical activity in adult patients with selected advanced solid tumors.
Interventions
BIOLOGICALNM21-1480
Trispecific anti-PD-L1/anti-4-1BB/anti-Human Serum Albumin (HSA) single-chain Fv fusion protein
Sponsors
Numab Therapeutics AG
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
Part A * Patients with any previously treated solid tumor-type other than hepatocellular carcinoma or intrahepatic cholangiocarcinoma that is advanced, or recurrent and progressing since last anti-tumor therapy, and for which no alternative, standard therapy exists. * Prior chemotherapy, radiation therapy or immunotherapy must have been completed at least 4 weeks prior to the administration of the first dose of study drug, and patient has recovered Part B: * Patients with Non-small Cell Lung Cancer (NSCLC) or other protocol specified solid tumors with locally advanced or metastatic, non-resectable disease, which has progressed despite treatment with first-line standard of-care treatment, or first- and second-line treatment, dependent on expansion cohort. * Prior therapy must have been completed 2-4 weeks prior to the administration of the first dose of study drug as specified per protocol according to type of prior therapy
Exclusion criteria
* Patient previously had known immediate or delayed hypersensitivity reaction or idiosyncrasy to the excipients * Part A: Treatment with any PD-1, or Cytotoxic T-Lymphocyte Associated Protein (CTLA)-4 directed antibody, or with any other immunotherapy within 4 weeks prior to initiation of the study drug. * Part A: Use of other biological investigational drugs (drugs not marketed for any indication), including use of investigational drugs targeting CD137/4-1BB within at least 5 half-lives (or within 8 weeks, whatever is longer) prior to the administration of the first dose of study drug. * Part B: As defined per protocol for each expansion cohort, has not been treated with specified first/second-line standard-of-care therapies biological drugs (marketed or investigational) for treatment of the current cancer, or has not adequately recovered from AEs that occurred with prior therapy. * Patient has an active autoimmune disease or a documented history of autoimmune disease.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | From baseline to up to 12 weeks post last dose, up to 48 weeks. | Frequency and severity of adverse events |
| Maximum Tolerated Dose (MTD) of NM21-1480 | Cycle 1 (28 days). | To determine the MTD of NM21-1480 based on Part A. Note, No MTD was identified across all dose levels tested and a technical MTD was defined by the SMC as 800 mg following Part A, which was updated to 1400 mg by the SMC after completion of Part A-2. |
| Determination of Phase 2 Dose of NM21-1480 | From baseline to up to 12 weeks post last dose, up to 48 weeks. | To determine the recommended Phase 2 dose of NM21-1480 for Part B of the study |
| To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | From baseline to up to 12 weeks post last dose, up to 48 weeks. | For best overall response (BOR) and objective response rate (ORR), patients in the Efficacy Analysis Set (EAS) who did not have sufficient on-study tumor assessments to characterize response were included in the denominator when calculating BOR percent and ORR and were thus treated as non-responders. |
Secondary
| Measure | Time frame |
|---|---|
| Assessment of the Elimination Half-life (t½) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Clearance (CL) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| To Determine the Anti-tumor Activity (Duration of Response) of NM21-1480 According to RECIST 1.1 | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| To Determine the Anti-tumor Activity (Time-to-response) of NM21-1480 According to RECIST 1.1 | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Volume of Distribution (Vd) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
| Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | From baseline to up to 12 weeks post last dose, up to 48 weeks. |
Countries
Spain, Taiwan, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Part A Dose Level 1NM21-1480-Q2W0.15mg Flat dose level; 0.15mg(Dose Level 1) | 1 |
| Part A Dose Level 2NM21-1480-Q2W1.5mg Flat dose level; 1.5mg(Dose Level 2) | 1 |
| Part A Dose Level 3NM21-1480-Q2W 8mg Flat dose level; 8mg(Dose Level 3) | 3 |
| Part A Dose Level 4NM21-1480-Q2W24mg Flat dose level; 24mg(Dose Level 4) | 3 |
| Part A Dose Level 5NM21-1480-Q2W80mg Flat dose level; 80mg(Dose Level 5) | 6 |
| Part A Dose Level 6NM21-1480-Q2W240mg Flat dose level; 240mg(Dose Level 6) | 3 |
| Part A Dose Level 7NM21-1480-Q2W800mg Flat dose level; mg800(Dose Level 7) | 9 |
| Part A2 NM21-1480-Q2W This part of the study consisted of a 1400mgflat dose across one cohort. | 5 |
| Part B NM21-1480-Q2W This part of the study consisted of a 800mgflat dose across three cohorts. | 21 |
| Total | 52 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Death | 1 | 0 | 0 | 1 | 2 | 2 | 4 | 1 | 5 |
| Overall Study | Lost to Follow-up | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 | 2 |
| Overall Study | Other | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 0 | 1 |
| Overall Study | Progressive Disease | 0 | 1 | 3 | 0 | 3 | 0 | 0 | 0 | 0 |
| Overall Study | Study Terminated by Sponsor | 0 | 0 | 0 | 0 | 0 | 1 | 4 | 2 | 10 |
| Overall Study | Withdrawal by Subject | 0 | 0 | 0 | 2 | 1 | 0 | 1 | 1 | 3 |
Baseline characteristics
| Characteristic | Total | Part A Dose Level 2NM21-1480-Q2W1.5mg | Part A Dose Level 3NM21-1480-Q2W 8mg | Part A Dose Level 1NM21-1480-Q2W0.15mg | Part A Dose Level 4NM21-1480-Q2W24mg | Part A Dose Level 5NM21-1480-Q2W80mg | Part A Dose Level 6NM21-1480-Q2W240mg | Part A Dose Level 7NM21-1480-Q2W800mg | Part A2 NM21-1480-Q2W | Part B NM21-1480-Q2W |
|---|---|---|---|---|---|---|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 23 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 3 Participants | 1 Participants | 2 Participants | 2 Participants | 12 Participants |
| Age, Categorical Between 18 and 65 years | 29 Participants | 0 Participants | 2 Participants | 1 Participants | 2 Participants | 3 Participants | 2 Participants | 7 Participants | 3 Participants | 9 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 51 Participants | 1 Participants | 3 Participants | 1 Participants | 3 Participants | 6 Participants | 3 Participants | 9 Participants | 5 Participants | 20 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 3 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 2 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 4 Participants | 0 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 44 Participants | 0 Participants | 3 Participants | 0 Participants | 2 Participants | 5 Participants | 3 Participants | 6 Participants | 5 Participants | 20 Participants |
| Sex: Female, Male Female | 20 Participants | 1 Participants | 2 Participants | 0 Participants | 2 Participants | 2 Participants | 1 Participants | 3 Participants | 1 Participants | 8 Participants |
| Sex: Female, Male Male | 32 Participants | 0 Participants | 1 Participants | 1 Participants | 1 Participants | 4 Participants | 2 Participants | 6 Participants | 4 Participants | 13 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk | EG003 affected / at risk | EG004 affected / at risk | EG005 affected / at risk | EG006 affected / at risk | EG007 affected / at risk | EG008 affected / at risk |
|---|---|---|---|---|---|---|---|---|---|
| deaths Total, all-cause mortality | 0 / 1 | 0 / 1 | 0 / 3 | 0 / 3 | 0 / 6 | 0 / 3 | 0 / 9 | 0 / 5 | 1 / 21 |
| other Total, other adverse events | 1 / 1 | 1 / 1 | 3 / 3 | 3 / 3 | 5 / 6 | 3 / 3 | 9 / 9 | 5 / 5 | 16 / 21 |
| serious Total, serious adverse events | 0 / 1 | 1 / 1 | 1 / 3 | 1 / 3 | 2 / 6 | 1 / 3 | 4 / 9 | 3 / 5 | 6 / 21 |
Outcome results
Primary
Determination of Phase 2 Dose of NM21-1480
To determine the recommended Phase 2 dose of NM21-1480 for Part B of the study
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | Determination of Phase 2 Dose of NM21-1480 | 800 mg |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | Determination of Phase 2 Dose of NM21-1480 | 800 mg |
Primary
Maximum Tolerated Dose (MTD) of NM21-1480
To determine the MTD of NM21-1480 based on Part A. Note, No MTD was identified across all dose levels tested and a technical MTD was defined by the SMC as 800 mg following Part A, which was updated to 1400 mg by the SMC after completion of Part A-2.
Time frame: Cycle 1 (28 days).
Population: MTD of NM21-1480 based on Part A and part A2. No MTD was identified across all dose levels tested and a technical MTD was defined by the SMC as 800 mg following Part A, which was updated to 1400 mg by the SMC after completion of Part A-2.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Maximum Tolerated Dose (MTD) of NM21-1480 | 800 mg |
| Part A2 NM32-1480-Q2W | Maximum Tolerated Dose (MTD) of NM21-1480 | 1400 mg |
Primary
Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0
Frequency and severity of adverse events
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Participant with any TREA
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 1 participants |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 1 participants |
| Part A Dose Level 3 NM21-1490-Q2W 8mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 3 participants |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 3 participants |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 5 participants |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 3 participants |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 9 participants |
| Part A2 NM32-1480-Q2W | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 5 participants |
| Part B NM32-1480-Q2W | Number of Participants With Treatment-related Adverse Events as Assessed by CTCAE v5.0 | 16 participants |
Primary
To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1
For best overall response (BOR) and objective response rate (ORR), patients in the Efficacy Analysis Set (EAS) who did not have sufficient on-study tumor assessments to characterize response were included in the denominator when calculating BOR percent and ORR and were thus treated as non-responders.
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: The ORR for each given group (dose level, cohort, or arm) in the EAS are summarized according to RECIST 1.1 (and according to iRECIST), accompanied by a 2-sided exact 95% Clopper-Pearson confidence interval (CI).
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part A Dose Level 3 NM21-1490-Q2W 8mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 1 Participants |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part A2 NM32-1480-Q2W | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
| Part B NM32-1480-Q2W | To Determine the Anti-tumor Activity (Best Overall Response) of NM21-1480 According to RECIST 1.1 | 0 Participants |
Secondary
Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: AUCtau determined at C1 for all dose levels with the exception of Part A Dose Level 1, Part A Dose Level 2 and Part A Dose Level 3. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | 803200 h*ng/mL | Standard Deviation 340000 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | 2662000 h*ng/mL | Standard Deviation 1022000 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | 9648000 h*ng/mL | Standard Deviation 6863000 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | 32420000 h*ng/mL | Standard Deviation 3342000 |
| Part A2 NM32-1480-Q2W | Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | 69890000 h*ng/mL | Standard Deviation 3413000 |
| Part B NM32-1480-Q2W | Assessment of the Area Under Serum Concentration-time Curve Over Dosing Interval (AUCtau) | 36810000 h*ng/mL | Standard Deviation 11890000 |
Secondary
Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity])
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: AUC0-t determined at C1 for all dose levels with the exception of Part A Dose Level 1 and Part A Dose Level 2. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 3 NM21-1490-Q2W 8mg | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 81570 h*ng/mL | Standard Deviation 59740 |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 802200 h*ng/mL | Standard Deviation 339000 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 2602000 h*ng/mL | Standard Deviation 1177000 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 9442000 h*ng/mL | Standard Deviation 6364000 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 32630000 h*ng/mL | Standard Deviation 3717000 |
| Part A2 NM32-1480-Q2W | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 57570000 h*ng/mL | Standard Deviation 12480000 |
| Part B NM32-1480-Q2W | Assessment of the Area Under the Serum Concentration-time Curve Extrapolated From the Last Quantifiable Concentration to Infinity Quantifiable Concentration to Infinity (AUC[0-infinity]) | 39560000 h*ng/mL | Standard Deviation 12150000 |
Secondary
Assessment of the Clearance (CL)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Assessment of the clearance (CL) determined at C1 for all dose levels with the exception of Part A Dose Levels 1, 2 and 3. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Clearance (CL) | 0.03037 L/h | Standard Deviation 0.01332 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Clearance (CL) | 0.03034 L/h | Standard Deviation 0.01764 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Clearance (CL) | 0.02257 L/h | Standard Deviation 0.01329 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Clearance (CL) | 0.01717 L/h | Standard Deviation 0.002606 |
| Part A2 NM32-1480-Q2W | Assessment of the Clearance (CL) | 0.01218 L/h | Standard Deviation 0.002768 |
| Part B NM32-1480-Q2W | Assessment of the Clearance (CL) | 0.01596 L/h | Standard Deviation 0.004527 |
Secondary
Assessment of the Elimination Half-life (t½)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Assessment of the elimination half-life (t½) determined at C1 for all dose levels with the exception of Part A Dose Level 1, Part A Dose Level 2 and Part A Dose Level 3. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL. No descriptive statistics determined when fewer than three individual PK parameters are available.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Elimination Half-life (t½) | 102.824 h | Standard Deviation 28.41 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Elimination Half-life (t½) | 165.179 h | Standard Deviation 90.7037 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Elimination Half-life (t½) | 230.048 h | Standard Deviation 80.2781 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Elimination Half-life (t½) | 203.241 h | Standard Deviation 36.4457 |
| Part A2 NM32-1480-Q2W | Assessment of the Elimination Half-life (t½) | 272.095 h | Standard Deviation 116.9242 |
| Part B NM32-1480-Q2W | Assessment of the Elimination Half-life (t½) | 253.230 h | Standard Deviation 56.1072 |
Secondary
Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: A patient is considered positive if they are positive at any scheduled or unscheduled post-baseline assessment.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 1 Participants |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 1 Participants |
| Part A Dose Level 3 NM21-1490-Q2W 8mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 2 Participants |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 3 Participants |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 5 Participants |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 3 Participants |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 6 Participants |
| Part A2 NM32-1480-Q2W | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 1 Participants |
| Part B NM32-1480-Q2W | Assessment of the Frequency of Specific Anti-drug Antibodies to NM21-1480 | 14 Participants |
Secondary
Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Cmax determined at C1 for all dose levels with the exception of Part A Dose Level 1 which has been noted as NA ,for which was BLQ. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | NA ng/mL | — |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 184.3 ng/mL | Standard Deviation 184.3 |
| Part A Dose Level 3 NM21-1490-Q2W 8mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 1604 ng/mL | Standard Deviation 1101 |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 6334 ng/mL | Standard Deviation 2331 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 19800 ng/mL | Standard Deviation 5576 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 66890 ng/mL | Standard Deviation 43340 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 204700 ng/mL | Standard Deviation 32070 |
| Part A2 NM32-1480-Q2W | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 420300 ng/mL | Standard Deviation 12040 |
| Part B NM32-1480-Q2W | Assessment of the Maximum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmax) | 258500 ng/mL | Standard Deviation 65390 |
Secondary
Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Lambda z determined at C1 for all dose levels with the exception of Part A Dose Level 1,2 and 3. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL. The constant Lambda z and its derived parameters meet one of the following conditions: the adjusted regression coefficient is less than 0.8 or the AUC%extrap exceeds 20%.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | 0.007163 1/h | Standard Deviation 0.0023 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | 0.005417 1/h | Standard Deviation 0.00294 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | 0.003352 1/h | Standard Deviation 0.00146 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | 0.003522 1/h | Standard Deviation 0.0007292 |
| Part A2 NM32-1480-Q2W | Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | 0.002923 1/h | Standard Deviation 0.001239 |
| Part B NM32-1480-Q2W | Assessment of the Terminal Phase (Apparent Elimination) Rate Constant (λz) | 0.002840 1/h | Standard Deviation 0.0006234 |
Secondary
Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Cmin determined at C1 for all dose levels with the exception of Part A Dose Level 1 which has been noted as NA ,for which was BLQ. Note: Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | NA ng/mL | — |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 0 ng/mL | Standard Deviation 0 |
| Part A Dose Level 3 NM21-1490-Q2W 8mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 201.7 ng/mL | Standard Deviation 227.5 |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 658.2 ng/mL | Standard Deviation 451.7 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 4203 ng/mL | Standard Deviation 1340 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 15880 ng/mL | Standard Deviation 14540 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 48670 ng/mL | Standard Deviation 17090 |
| Part A2 NM32-1480-Q2W | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 166000 ng/mL | Standard Deviation 41730 |
| Part B NM32-1480-Q2W | Assessment of the the Minimum Observed Serum Concentration Determined by Direct Inspection of the Concentration Versus Time Data (Cmin) | 54270 ng/mL | Standard Deviation 22000 |
Secondary
Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Tmax determined at C1 for all dose levels with the exception of Part A Dose Level 1 and Part A Dose Level 2. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Part A Dose Level 1 NM21-1490-Q2W 0.15mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | NA h |
| Part A Dose Level 2 NM21-1490-Q2W 1.5mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 1 h |
| Part A Dose Level 3 NM21-1490-Q2W 8mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 26.533 h |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 6.407 h |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 5.778 h |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 2.340 h |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 8.720 h |
| Part A2 NM32-1480-Q2W | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 3.13 h |
| Part B NM32-1480-Q2W | Assessment of the Time From Dosing at Which Cmax is Apparent Determined by Direct Inspection of the Concentration Versus Time Data (Tmax) | 1.587 h |
Secondary
Assessment of the Volume of Distribution (Vd)
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Assessment of the volume of distribution (Vd) determined at C1 for all dose levels with the exception of Part A Dose Level 1,2 and 3. Lower limit of quantification (LLOQ) of NM21-1480 = 5 ng/mL.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | Assessment of the Volume of Distribution (Vd) | 4.155 L | Standard Deviation 0.9071 |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | Assessment of the Volume of Distribution (Vd) | 5.882 L | Standard Deviation 2.263 |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | Assessment of the Volume of Distribution (Vd) | 6.674 L | Standard Deviation 3.379 |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | Assessment of the Volume of Distribution (Vd) | 4.952 L | Standard Deviation 0.6848 |
| Part A2 NM32-1480-Q2W | Assessment of the Volume of Distribution (Vd) | 4.454 L | Standard Deviation 0.9507 |
| Part B NM32-1480-Q2W | Assessment of the Volume of Distribution (Vd) | 5.930 L | Standard Deviation 2.472 |
Secondary
To Determine the Anti-tumor Activity (Duration of Response) of NM21-1480 According to RECIST 1.1
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Where blank the duration of response was not evaluable.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | To Determine the Anti-tumor Activity (Duration of Response) of NM21-1480 According to RECIST 1.1 | 1.84 Months |
Secondary
To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: Progression-Free Survival (PFS) is defined as the time from the start of study treatment until the earliest documented date of disease progression or death.~\[1\] Q1, Median and Q3 are Kaplan-Meier estimates and the 2-sided 95% confidence interval for median is calculated using the Brookmeyer-Crowley method.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Part A Dose Level 3 NM21-1490-Q2W 8mg | To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | 1.84 Months |
| Part A Dose Level 4 NM21-1490-Q2W 24mg | To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | 5.49 Months |
| Part A Dose Level 5 NM21-1490-Q2W 80mg | To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | 1.81 Months |
| Part A Dose Level 6 NM21-1490-Q2W 240mg | To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | 7.28 Months |
| Part A Dose Level 7 NM21-1490-Q2W 800mg | To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | 2.86 Months |
| Part B NM32-1480-Q2W | To Determine the Anti-tumor Activity (Progression-free Survival) of NM21-1480 According to RECIST 1.1 | 1.41 Months |
Secondary
To Determine the Anti-tumor Activity (Time-to-response) of NM21-1480 According to RECIST 1.1
Time frame: From baseline to up to 12 weeks post last dose, up to 48 weeks.
Population: One patient at dose level 4 exhibited a PR (Partial Response).
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Part A Dose Level 4 NM21-1490-Q2W 24mg | To Determine the Anti-tumor Activity (Time-to-response) of NM21-1480 According to RECIST 1.1 | 110 Days |