Acute Myeloid Leukemia, in Relapse, Recurrent Adult Acute Myeloid Leukemia
Conditions
Keywords
Acute Myeloid Leukemia, AML, Relapsed, Refractory, MEN1112, Monoclonal antibody
Brief summary
The purpose of this study is to assess the safety of MEN1112, given as intravenous infusion, in patients with relapsed or refractory AML. Pharmacokinetics, clinical activity and potential immunogenicity of MEN1112 will be evaluated as well.
Detailed description
This trial is designed as an open label, non randomised, dose escalation and cohort expansion, first administration to human study to be conducted in approximately 20 European sites. The study is aiming to identify the Dose Limiting Toxicity (DLT) and Maximum Tolerated Dose (MTD), to assess the pharmacokinetics and to determine the clinical activity and potential immunogenicity of MEN1112, administered as IV infusion for two 21-day cycles. Approximately 100 male and female ≥ 18 years-old patients, with a documented diagnosis of relapsed or refractory AML (not M3 FAB subtype), will be treated in the study, which consists of two steps. Step 1 is the dose escalation phase according to a 3+3 patients cohort design. Incremental mg/Kg doses will be tested. Briefly, MEN1112 doses are to be administered to 3 patients; if no DLT is observed in a cohort of 3 DLT evaluable patients at a given dose level, the next cohort of 3 new patients will be treated with the next higher dose. In case of DLT occurrence by one of the three patients at any dose, the cohort will be expanded to 6 DLT evaluable patients at the same dose level. If two or more patients at a given dose level exhibit DLT, the dose escalation phase will be concluded as the MTD will be identified as one dose level below the one at which ≥ 2 DLT out of 6 treated patients occur. Step 2 is the cohort expansion phase which will include patients treated at the MTD or the maximum dose level judged to be tolerable. In each study Step, patients will be given two induction cycles of MEN1112 followed by a four-week End of Treatment period and a Follow-up period. In Step 1 and Step 2, DLT and MTD will be assessed when MEN1112 is given as a 'one shot' infusion (first group of patients) for all doses as well as a 'ramp up' administration to be infused in 3 days for the first two doses in Cycle 1 (second group of patients). Along the study period, adverse events, changes in hematology/serum biochemistry parameters and bone marrow treatment response will represent the major clinical findings to be monitored on regular basis. The individual experimental clinical phase will last up to 6 months (except for female patients of childbearing potential that will undergo monthly pregnancy test until 6 months from the last study drug administration) encompassing approx. 40 planned visits at site, including Screening,Treatment, End of Treatment, Follow-up period and the End of Study visit.
Interventions
DRUGMEN1112
Intravenous infusion of MEN1112 pro/Kg body weight dose will be administered for two 21-day cycles; MEN1112 dose is administered as' one shot infusion' (first group of patients) and as a dose to be infused in 3 days for the first two doses in Cycle 1 (second group of patients). Two treatment cycles will be followed by a 4-week End of Treatment Period and a Follow-up period. The individual treatment/observation period is six months (except for female patients of childbearing potential that will undergo monthly pregnancy test until 6 months from the last study drug administration).
Sponsors
Menarini Group
Study design
Allocation
NA
Intervention model
SEQUENTIAL
Primary purpose
TREATMENT
Masking
NONE
Intervention model description
The study included ascending doses in the range 0.1 mg/kg to 2.5 mg/kg. According to the Data Safety Review Board, doses to be sequentially tested are 0.1, 0.3, 0.6, 1, 1.7, 2.5 mg/kg single shot and 1.7, 2, and 3 mg/kg ramp up
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Male or female patients aged ≥ 18 years. * Documented definitive diagnosis of AML (according to WHO criteria, 2008) that is relapsed/refractory to standard treatment, for which no standard therapy is available or the patient refuses standard therapy. * WBC count ≤ 10 x 109/L at Visit 1/Day 1; hydroxyurea is allowed to lower WBC count. * Eastern Cooperative Oncology Group (ECOG) performance status of 0 to 2 at Visit1/Day 1. * Life expectancy of at least 2 months. * Adequate renal and hepatic laboratory assessments: Aspartate aminotransferase (AST), alanine aminotransferase (ALT) and alkaline phosphatase (ALP) ≤3.0 × ULN, unless considered due to leukemic organ involvement, Total Bilirubin ≤2.0 × ULN, Serum creatinine ≤2.0 × ULN. * Able to give written informed consent before any study related procedure
Exclusion criteria
* Acute promyelocytic leukaemia (French-American-British M3 classification). * Active central nervous system involvement. * Haematopoietic stem cell transplantation (HSCT) performed within 3 months prior to Screening Visit. * Active infection requiring intravenous antibiotics. * Life-threatening illnesses other than AML, uncontrolled medical conditions or organ system dysfunction which, in the investigator's opinion, could compromise the patient's safety or interfere with the patient's ability to comply with the study activities. * Anti-tumour therapy within 14 days of study Visit 1/Day 1, excluding hydroxyurea. * Prior participation in an investigational study (procedure or device) within 21 days of study Visit 1/Day 1. * Radiotherapy within 28 days prior to study Visit 1/Day 1 or scheduled along the study conduct. * Known history of human immunodeficiency virus (HIV) or active infection with hepatitis C virus (HCV) or hepatitis B virus (HBV). * Other active malignancies. History of malignancy in the last 12 months (except basal cell or squamous cell skin cancer or carcinoma in situ of the cervix or breast or non-melanoma skin cancer).
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Dose Limiting Toxicity (DLT) | over 3 weeks after the first dose | Identification of DLT defined as an adverse event occurring during the first treatment cycle, judged to be related to MEN1112 and meeting any of the following criteria: * Grade 3 non-haematological toxicity lasting more than 7 days * Grade ≥ 4 non-haematological toxicity. |
| Maximum Tolerated Dose (MTD) | over 3 weeks after the first dose | Identification of MTD defined as one dose level below the Maximum Administered Dose (i.e. one dose level below the one at which ≥ 2 DLTs out of 6 treated patients occur). |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| MEN1112 PK Parameter AUC (0-t) | Dose 1- cycle 1 | AUC (0-t) is the area under the serum concentration-time curve from time 0 extrapolated to t time evaluated after the first dose |
| MEN1112 PK Parameter AUC (0-∞) | dose 1 of cycle 1 | AUC (0-∞) is the area under the serum concentration-time curve from time 0 extrapolated to infinite time |
| MEN1112 PK Parameter t1/2 | dose 1 of cycle 1 | t1/2 is the drug elimination half-life It is calculated on the first dose for all cohorts |
| Complete Remission (CR) Rate | 6 months | CR rate at any time point, where CR is defined as: bone marrow blasts \<5%, absence of extramedullary disease, absolute neutrophil count \>1 x 109/L and platelet count \> 100 x 109/L. According to the protocol, the efficacy analysis population includes all patients completing the first treatment cycle and having a post-cycle peripheral blood lab test and bone marrow aspirate. |
| Best Response Rate | 6 months | best observed response at any time point to include Complete Remission (CR is defined as bone marrow blasts \< 5%, absence of extramedullary disease, absolute neutrophil count \> 1 x 109 / L and platelet count \> 100 x 109 / L) Complete Remission with incomplete blood count recovery \[CRi defined as all criteria for CR except residual thrombocytopenia (platelets \<100 x 109/L), and/or neutropenia (absolute neutrophil count \<1 x 109/L)\] Partial remission (PR defined as all haematological criteria for CR with bone marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50%. |
| Overall Survival | 6 months | Overall Survival (OS) is the time from the date of the first drug administration to the date of death from any cause. If the fatal event does not occur during the study, the overall survival time is censored at the date when the patient was last known to be alive. The overall survival (OS) is calculated on 29 patients (72.5%) out of 40 belonging to the efficacy population. Results are reported as mean (and range) days |
| Treatment Emergent Signs and Symptoms (TESSs) | 6 months | Number of patients with Treatment Emergent Signs and Symptoms (TESSs) by CTCAE severity grade \>3 and treatment related causality |
| MEN1112 Pharmacokinetic (PK) Parameter Cmax | end of intravenous infusion | Cmax is the maximum serum drug concentration. For Cohort 1 to 3c (administration as 'one shot' infusion) Cmax is measured at the end of the first intravenous infusion ( 1 to 6 hours; depending on the individual subjects being the infusion frequently interrupted) For Cohort 1.7, 2.0 and 3.0 (dose administration as ramp up, divided in three sub-doses), Cmax is measured at the end of each out of 3 intravenous infusions |
Other
| Measure | Time frame | Description |
|---|---|---|
| Immunogenicity of MEN1112 | 64 days | Incidence of anti-MEN1112 auto-antibodies |
Countries
Belgium, France, Germany, Italy, Spain
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Cohort 1 MEN1112 given as one shot infusion at the dosage of 0.1 mg/kg | 4 |
| Cohort 2 MEN1112 given as one shot infusion at the dosage of 0.3 mg/kg | 7 |
| Cohort 2b MEN1112 given as one shot infusion at the dosage of 0.6 mg/kg | 6 |
| Cohort 3 MEN1112 given as one shot infusion at the dosage of 1.0 mg/kg | 8 |
| Cohort 3b MEN1112 given as one shot infusion at the dosage of 1.7 mg/kg | 26 |
| Cohort 3c MEN1112 given as one shot infusion at the dosage of 2.5 mg/kg | 5 |
| Cohort 1.7 MEN1112 given as ramp-up infusions at the dosage of 1.7 mg/kg | 3 |
| Cohort 2.0 MEN1112 given as ramp-up infusions at the dosage of 2.0 mg/kg | 8 |
| Cohort 3.0 MEN1112 given as ramp-up infusions at the dosage of 3.0 mg/kg | 4 |
| Total | 71 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 | FG002 | FG003 | FG004 | FG005 | FG006 | FG007 | FG008 |
|---|---|---|---|---|---|---|---|---|---|---|
| Overall Study | Adverse Event | 0 | 0 | 1 | 0 | 1 | 1 | 0 | 0 | 0 |
| Overall Study | Dose limiting toxicity (DLT) | 0 | 0 | 0 | 1 | 1 | 1 | 0 | 0 | 1 |
| Overall Study | Lack of Efficacy | 2 | 1 | 2 | 4 | 13 | 2 | 2 | 2 | 1 |
| Overall Study | patient receiving other treatment for AML | 0 | 0 | 1 | 0 | 0 | 0 | 0 | 0 | 0 |
| Overall Study | Physician Decision | 0 | 4 | 2 | 3 | 4 | 0 | 1 | 2 | 0 |
| Overall Study | reason not specified | 1 | 2 | 0 | 0 | 6 | 1 | 0 | 3 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 | 0 | 0 | 1 | 0 | 0 | 1 | 1 |
Baseline characteristics
| Characteristic | Cohort 1 | Cohort 2 | Cohort 2b | Cohort 3 | Cohort 3b | Cohort 3c | Cohort 1.7 | Cohort 2.0 | Cohort 3.0 | Total |
|---|---|---|---|---|---|---|---|---|---|---|
| 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 | 3 Participants | 2 Participants | 1 Participants | 5 Participants | 19 Participants | 5 Participants | 0 Participants | 2 Participants | 2 Participants | 39 Participants |
| Age, Categorical Between 18 and 65 years | 1 Participants | 5 Participants | 5 Participants | 3 Participants | 7 Participants | 0 Participants | 3 Participants | 6 Participants | 2 Participants | 32 Participants |
| Age, Continuous | 69 years | 55.6 years | 53.8 years | 68.6 years | 69.2 years | 77.6 years | 58.3 years | 49.1 years | 56.8 years | 63.6 years |
| Ethnicity (NIH/OMB) Hispanic or Latino | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 8 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 4 Participants | 7 Participants | 6 Participants | 8 Participants | 17 Participants | 5 Participants | 3 Participants | 8 Participants | 4 Participants | 62 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants | 0 Participants | 0 Participants | 0 Participants | 0 Participants | 1 Participants |
| Region of Enrollment Belgium | 4 participants | 0 participants | 2 participants | 1 participants | 6 participants | 0 participants | 2 participants | 2 participants | 1 participants | 18 participants |
| Region of Enrollment France | 0 participants | 0 participants | 0 participants | 1 participants | 2 participants | 0 participants | 0 participants | 0 participants | 3 participants | 6 participants |
| Region of Enrollment Germany | 0 participants | 0 participants | 0 participants | 1 participants | 0 participants | 5 participants | 0 participants | 2 participants | 0 participants | 8 participants |
| Region of Enrollment Italy | 0 participants | 2 participants | 0 participants | 1 participants | 0 participants | 0 participants | 0 participants | 0 participants | 0 participants | 3 participants |
| Region of Enrollment Spain | 0 participants | 5 participants | 4 participants | 4 participants | 18 participants | 0 participants | 1 participants | 4 participants | 0 participants | 36 participants |
| Sex: Female, Male Female | 1 Participants | 2 Participants | 2 Participants | 4 Participants | 12 Participants | 4 Participants | 1 Participants | 4 Participants | 2 Participants | 32 Participants |
| Sex: Female, Male Male | 3 Participants | 5 Participants | 4 Participants | 4 Participants | 14 Participants | 1 Participants | 2 Participants | 4 Participants | 2 Participants | 39 Participants |
| Weight | 82.4 kilo | 62.8 kilo | 67.9 kilo | 69.6 kilo | 74 kilo | 67.7 kilo | 80.6 kilo | 66.6 kilo | 69.6 kilo | 71.1 kilo |
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 | 3 / 4 | 4 / 7 | 5 / 6 | 8 / 8 | 17 / 26 | 4 / 5 | 2 / 3 | 5 / 8 | 3 / 4 |
| other Total, other adverse events | 4 / 4 | 7 / 7 | 6 / 6 | 8 / 8 | 26 / 26 | 5 / 5 | 3 / 3 | 8 / 8 | 4 / 4 |
| serious Total, serious adverse events | 3 / 4 | 5 / 7 | 6 / 6 | 8 / 8 | 25 / 26 | 5 / 5 | 2 / 3 | 8 / 8 | 4 / 4 |
Outcome results
Primary
Dose Limiting Toxicity (DLT)
Identification of DLT defined as an adverse event occurring during the first treatment cycle, judged to be related to MEN1112 and meeting any of the following criteria: * Grade 3 non-haematological toxicity lasting more than 7 days * Grade ≥ 4 non-haematological toxicity.
Time frame: over 3 weeks after the first dose
Population: For 'Single shot' administration: All patients receiving at least 1st \& 2nd drug administration (dose 0.1 and 0.3 mg/kg) or completing first Cycle (doses ≥ 0.6 mg/kg) and safety FU ≥ 6 days post last dose or having experienced a DLT For 'Ramp up'': All patients receiving at least 80% of the scheduled drug administration during 1st Cycle and with a safety FU ≥ 6 days post last dose or having experienced a DLT
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Dose Limiting Toxicity (DLT) | 0 Participants |
| Cohort 2 | Dose Limiting Toxicity (DLT) | 0 Participants |
| Cohort 2b | Dose Limiting Toxicity (DLT) | 1 Participants |
| Cohort 3 | Dose Limiting Toxicity (DLT) | 1 Participants |
| Cohort 3b | Dose Limiting Toxicity (DLT) | 2 Participants |
| Cohort 3c | Dose Limiting Toxicity (DLT) | 2 Participants |
| Cohort 1.7 | Dose Limiting Toxicity (DLT) | 0 Participants |
| Cohort 2.0 | Dose Limiting Toxicity (DLT) | 0 Participants |
| Cohort 3.0 | Dose Limiting Toxicity (DLT) | 1 Participants |
Primary
Maximum Tolerated Dose (MTD)
Identification of MTD defined as one dose level below the Maximum Administered Dose (i.e. one dose level below the one at which ≥ 2 DLTs out of 6 treated patients occur).
Time frame: over 3 weeks after the first dose
Population: All subjects who received at last one dose of study treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cohort 1 | Maximum Tolerated Dose (MTD) | 1.7 mg/kg |
Secondary
Best Response Rate
best observed response at any time point to include Complete Remission (CR is defined as bone marrow blasts \< 5%, absence of extramedullary disease, absolute neutrophil count \> 1 x 109 / L and platelet count \> 100 x 109 / L) Complete Remission with incomplete blood count recovery \[CRi defined as all criteria for CR except residual thrombocytopenia (platelets \<100 x 109/L), and/or neutropenia (absolute neutrophil count \<1 x 109/L)\] Partial remission (PR defined as all haematological criteria for CR with bone marrow blasts 5-25% and decrease of pre-treatment bone marrow blast percentage by at least 50%.
Time frame: 6 months
Population: According to the protocol, the efficacy analysis population includes all patients completing the first treatment cycle and having a post-cycle peripheral blood lab test and bone marrow aspirate.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Best Response Rate | 0 Participants |
| Cohort 2 | Best Response Rate | 0 Participants |
| Cohort 2b | Best Response Rate | 0 Participants |
| Cohort 3 | Best Response Rate | 0 Participants |
| Cohort 3b | Best Response Rate | 0 Participants |
| Cohort 3c | Best Response Rate | 0 Participants |
| Cohort 1.7 | Best Response Rate | 0 Participants |
| Cohort 2.0 | Best Response Rate | 0 Participants |
| Cohort 3.0 | Best Response Rate | 0 Participants |
Secondary
Complete Remission (CR) Rate
CR rate at any time point, where CR is defined as: bone marrow blasts \<5%, absence of extramedullary disease, absolute neutrophil count \>1 x 109/L and platelet count \> 100 x 109/L. According to the protocol, the efficacy analysis population includes all patients completing the first treatment cycle and having a post-cycle peripheral blood lab test and bone marrow aspirate.
Time frame: 6 months
Population: According to the protocol, the efficacy analysis population includes all patients completing the first treatment cycle and having a post-cycle peripheral blood lab test and bone marrow aspirate.
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Cohort 1 | Complete Remission (CR) Rate | 0 Participants |
| Cohort 2 | Complete Remission (CR) Rate | 0 Participants |
| Cohort 2b | Complete Remission (CR) Rate | 0 Participants |
| Cohort 3 | Complete Remission (CR) Rate | 0 Participants |
| Cohort 3b | Complete Remission (CR) Rate | 0 Participants |
| Cohort 3c | Complete Remission (CR) Rate | 0 Participants |
| Cohort 1.7 | Complete Remission (CR) Rate | 0 Participants |
| Cohort 2.0 | Complete Remission (CR) Rate | 0 Participants |
| Cohort 3.0 | Complete Remission (CR) Rate | 0 Participants |
Secondary
MEN1112 Pharmacokinetic (PK) Parameter Cmax
Cmax is the maximum serum drug concentration. For Cohort 1 to 3c (administration as 'one shot' infusion) Cmax is measured at the end of the first intravenous infusion ( 1 to 6 hours; depending on the individual subjects being the infusion frequently interrupted) For Cohort 1.7, 2.0 and 3.0 (dose administration as ramp up, divided in three sub-doses), Cmax is measured at the end of each out of 3 intravenous infusions
Time frame: end of intravenous infusion
Population: patients with reliable PK blood samples available at the end of drug intravenous infusion for Cmax measurement
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 0.22 mcg/mL | Standard Deviation 0.32 |
| Cohort 2 | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 1.86 mcg/mL | Standard Deviation 2.06 |
| Cohort 2b | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 3.29 mcg/mL | Standard Deviation 1.87 |
| Cohort 3 | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 9.29 mcg/mL | Standard Deviation 5.07 |
| Cohort 3b | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 2.67 mcg/mL | Standard Deviation 15.73 |
| Cohort 3c | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 31.59 mcg/mL | Standard Deviation 18.18 |
| Cohort 1.7 | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 2.65 mcg/mL | Standard Deviation 4.49 |
| Cohort 2.0 | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 11.8 mcg/mL | Standard Deviation 2.91 |
| Cohort 3.0 | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 18.57 mcg/mL | Standard Deviation 8.54 |
| Cohort 2.0 (0.1 mg Out of 2.0 mg/kg) | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 0.97 mcg/mL | Standard Deviation 2.18 |
| Cohort 2.0 (0.7 Out of 2.0 mg/kg) | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 7.62 mcg/mL | Standard Deviation 1.59 |
| Cohort 2 (1.2 Out of 2.0 mg) | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 17.53 mcg/mL | Standard Deviation 6.6 |
| Cohort 3.0 (0.2 Out of 3.0 mg/kg) | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 1.26 mcg/mL | Standard Deviation 0.96 |
| Cohort 3.0 (1.0 Out of 3.0 mg/kg) | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 14.83 mcg/mL | Standard Deviation 8.57 |
| Cohort 3.0 (1.8 Out of 3.0 mg/kg) | MEN1112 Pharmacokinetic (PK) Parameter Cmax | 39.73 mcg/mL | Standard Deviation 20.44 |
Secondary
MEN1112 PK Parameter AUC (0-∞)
AUC (0-∞) is the area under the serum concentration-time curve from time 0 extrapolated to infinite time
Time frame: dose 1 of cycle 1
Population: all subjects with Pk concentrations allowing a reliable estimation of AUC (0-∞). NOTE: cohort 1 excluded because of non reliable estimation of AUC (0-∞)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | MEN1112 PK Parameter AUC (0-∞) | 99.89 h*mcg/mL | Standard Error 81.08 |
| Cohort 2 | MEN1112 PK Parameter AUC (0-∞) | 90.55 h*mcg/mL | Standard Error 91.67 |
| Cohort 2b | MEN1112 PK Parameter AUC (0-∞) | 370.69 h*mcg/mL | Standard Error 318.5 |
| Cohort 3 | MEN1112 PK Parameter AUC (0-∞) | 1321.55 h*mcg/mL | Standard Error 800.89 |
| Cohort 3b | MEN1112 PK Parameter AUC (0-∞) | 2220.48 h*mcg/mL | Standard Error 2009.55 |
| Cohort 3c | MEN1112 PK Parameter AUC (0-∞) | 1310.79 h*mcg/mL | Standard Error 1091.61 |
| Cohort 1.7 | MEN1112 PK Parameter AUC (0-∞) | 1516.51 h*mcg/mL | Standard Error 867.13 |
| Cohort 2.0 | MEN1112 PK Parameter AUC (0-∞) | 3894.85 h*mcg/mL | Standard Error 3352.56 |
Secondary
MEN1112 PK Parameter AUC (0-t)
AUC (0-t) is the area under the serum concentration-time curve from time 0 extrapolated to t time evaluated after the first dose
Time frame: Dose 1- cycle 1
Population: population with reliable PK parameters
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | MEN1112 PK Parameter AUC (0-t) | 0.47 h*mcg/mL | Standard Deviation 0.5 |
| Cohort 2 | MEN1112 PK Parameter AUC (0-t) | 79.48 h*mcg/mL | Standard Deviation 80.69 |
| Cohort 2b | MEN1112 PK Parameter AUC (0-t) | 74.11 h*mcg/mL | Standard Deviation 88.45 |
| Cohort 3 | MEN1112 PK Parameter AUC (0-t) | 346.8 h*mcg/mL | Standard Deviation 288.82 |
| Cohort 3b | MEN1112 PK Parameter AUC (0-t) | 891.09 h*mcg/mL | Standard Deviation 642.63 |
| Cohort 3c | MEN1112 PK Parameter AUC (0-t) | 1791.32 h*mcg/mL | Standard Deviation 1525.94 |
| Cohort 1.7 | MEN1112 PK Parameter AUC (0-t) | 62.53 h*mcg/mL | Standard Deviation 87.94 |
| Cohort 2.0 | MEN1112 PK Parameter AUC (0-t) | 200.15 h*mcg/mL | Standard Deviation 79.17 |
| Cohort 3.0 | MEN1112 PK Parameter AUC (0-t) | 940.48 h*mcg/mL | Standard Deviation 686.59 |
| Cohort 2.0 (0.1 mg Out of 2.0 mg/kg) | MEN1112 PK Parameter AUC (0-t) | 5.87 h*mcg/mL | Standard Deviation 10.55 |
| Cohort 2.0 (0.7 Out of 2.0 mg/kg) | MEN1112 PK Parameter AUC (0-t) | 115.1 h*mcg/mL | Standard Deviation 33.66 |
| Cohort 2 (1.2 Out of 2.0 mg) | MEN1112 PK Parameter AUC (0-t) | 843.53 h*mcg/mL | Standard Deviation 518.65 |
| Cohort 3.0 (0.2 Out of 3.0 mg/kg) | MEN1112 PK Parameter AUC (0-t) | 18.67 h*mcg/mL | Standard Deviation 14.63 |
| Cohort 3.0 (1.0 Out of 3.0 mg/kg) | MEN1112 PK Parameter AUC (0-t) | 194.91 h*mcg/mL | Standard Deviation 103.12 |
| Cohort 3.0 (1.8 Out of 3.0 mg/kg) | MEN1112 PK Parameter AUC (0-t) | 2385.21 h*mcg/mL | Standard Deviation 1956.83 |
Secondary
MEN1112 PK Parameter t1/2
t1/2 is the drug elimination half-life It is calculated on the first dose for all cohorts
Time frame: dose 1 of cycle 1
Population: PK population with drug measurment allowing reliable estimation of half-life (cohort 1 excluded since estimation of half-life as well as AUC 0-inf was not reliable)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cohort 1 | MEN1112 PK Parameter t1/2 | 18.63 hour | Standard Deviation 6.47 |
| Cohort 2 | MEN1112 PK Parameter t1/2 | 10.76 hour | Standard Deviation 9.22 |
| Cohort 2b | MEN1112 PK Parameter t1/2 | 21.21 hour | Standard Deviation 15.05 |
| Cohort 3 | MEN1112 PK Parameter t1/2 | 46.49 hour | Standard Deviation 34.25 |
| Cohort 3b | MEN1112 PK Parameter t1/2 | 38.34 hour | Standard Deviation 26.72 |
| Cohort 3c | MEN1112 PK Parameter t1/2 | 46.84 hour | Standard Deviation 35.2 |
| Cohort 1.7 | MEN1112 PK Parameter t1/2 | 72.51 hour | Standard Deviation 46.88 |
| Cohort 2.0 | MEN1112 PK Parameter t1/2 | 61.75 hour | Standard Deviation 30.75 |
Secondary
Overall Survival
Overall Survival (OS) is the time from the date of the first drug administration to the date of death from any cause. If the fatal event does not occur during the study, the overall survival time is censored at the date when the patient was last known to be alive. The overall survival (OS) is calculated on 29 patients (72.5%) out of 40 belonging to the efficacy population. Results are reported as mean (and range) days
Time frame: 6 months
Population: Overall Survival (OS) is the time from the date of the first drug administration to the date of death from any cause. If the fatal event does not occur during the study, the overall survival time is censored at the date when the patient was last known to be alive.~The overall survival (OS) is calculated on 29 patients (72.5%) out of 40 belonging to the efficacy population. OS(measured in days) is reported as mean (and range)
| Arm | Measure | Value (MEAN) |
|---|---|---|
| Cohort 1 | Overall Survival | 33 day |
| Cohort 2 | Overall Survival | 56.5 day |
| Cohort 2b | Overall Survival | 76.8 day |
| Cohort 3 | Overall Survival | 47 day |
| Cohort 3b | Overall Survival | 55.2 day |
| Cohort 3c | Overall Survival | 92 day |
| Cohort 1.7 | Overall Survival | 30 day |
| Cohort 2.0 | Overall Survival | 52.5 day |
| Cohort 3.0 | Overall Survival | 37 day |
Secondary
Treatment Emergent Signs and Symptoms (TESSs)
Number of patients with Treatment Emergent Signs and Symptoms (TESSs) by CTCAE severity grade \>3 and treatment related causality
Time frame: 6 months
Population: All patients who received at least one dose of study treatment by dose cohort
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Cohort 1 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 2 participants |
| Cohort 1 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 3 participants |
| Cohort 2 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 6 participants |
| Cohort 2 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 1 participants |
| Cohort 2b | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 4 participants |
| Cohort 2b | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 6 participants |
| Cohort 3 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 8 participants |
| Cohort 3 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 5 participants |
| Cohort 3b | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 26 participants |
| Cohort 3b | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 11 participants |
| Cohort 3c | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 5 participants |
| Cohort 3c | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 5 participants |
| Cohort 1.7 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 3 participants |
| Cohort 1.7 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 1 participants |
| Cohort 2.0 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 8 participants |
| Cohort 2.0 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 2 participants |
| Cohort 3.0 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with TESSs of CTCAE severity grade > or =3 | 4 participants |
| Cohort 3.0 | Treatment Emergent Signs and Symptoms (TESSs) | Patients with treatment related TESSs of CTCAE severity grade > or =3 | 2 participants |
Other Pre-specified
Immunogenicity of MEN1112
Incidence of anti-MEN1112 auto-antibodies
Time frame: 64 days
Population: Analysis of immunogenicity was not done in any patients participating to the study, since no clinical benefit was detected in any patients under the experimental conditions adopted in the study; the study was terminated