MEN1309 I.v. Infusion in Pts With CD205-positive Metastatic Solid Tumors and Relapsed or Refractory NHL Ph I Study

Study Overview
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Brief Summary
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The purpose of this clinical trial is to identify the highest dose of MEN1309 drug with acceptable safety profile and that can be used in patients affected by CD205-positive solid tumors and Non-Hodgkin Lymphoma

Detailed Description
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This clinical trial will investigate the safety and activity of MEN1309 in patients with CD205-positive metastatic solid tumors and Non-Hodgkin Lymphoma who have tried other types of treatment for cancer without adequate response (or the cancer came back). CD205 is a protein present in certain types of cancer. This is a Phase I study, which means that it is designed to look at several dose levels of a study drug in small groups of patients to find the dose that is well-tolerated and suitable to be administered in subsequent clinical trials in patients. The clinical trial is also looking at the effectiveness of the study drug. This is the first time the study drug will be given in humans. The clinical trial consists of two sequential parts: Part 1 involves patients with CD205-positive metastatic solid tumors and the main purpose of this part of the clinical trial is to determine the highest dose of the study drug that can be used safely in these type of cancers. Part 2 involves patients with CD205-positive Non-Hodgkin Lymphoma and will test doses of MEN1309 which have demonstrated to be adequately tolerated in patients with solid tumors. Patients participating to the clinical trial will take the study drug as intravenous infusion once every 3 weeks. The clinical trial includes four periods: a pre-screening period (to check if tumor is positive for CD205), a screening period (to check whether the participation to the clinical trial is right for patient), a treatment period (when patient receives the study drug), and a follow-up period (to check the health status of the patient after stopping study treatment).

Official Title
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Open-Label, Multicenter, Phase I Dose Escalation Study of MEN1309, a CD205 Antibody-Drug Conjugate,in Patients With CD205-Positive Metastatic Solid Tumors and Non-Hodgkin Lymphoma

Conditions
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Metastatic Solid Tumors, Relapsed/Refractory Non-Hodgkin Lymphoma

Intervention / Treatment
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* Drug: MEN1309


Participation Criteria
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Eligibility Criteria
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Main Inclusion Criteria: Male or female patients aged ≥ 18 years. Patients with: confirmed diagnosis of advanced or metastatic solid tumor and diagnosis of multiple relapsed or refractory NHL; progressive after last treatment received; availability of archived tumor material, either as a block or slides; measurable or evaluable disease by Response Evaluation Criteria in solid tumors guideline (RECIST v1.1) and by Cheson Criteria (The Lugano Classification, 2014) in NHL. Eastern Cooperative Oncology Group (ECOG) performance status (PS) of 0 to 2. Neutrophil count ≥ 1,500/µL; platelets ≥ 100,000/µL; haemoglobin ≥ 9 g/dL. Adequate renal and hepatic laboratory assessments. Life expectancy of at least 2 months. Woman of childbearing potential (WOCBP) who agrees to use highly effective contraception (see Appendix I). Main Exclusion Criteria: Central nervous system involvement (excluding treated stable cerebral metastasis, not requiring therapy to control symptoms in the last 60 days). Pregnant or breastfeeding women. Life-threatening illnesses other than solid tumors and NHL, uncontrolled medical conditions or organ system dysfunction which, in the Investigator's opinion, could compromise the patient's safety, or put the study outcomes at risk. Less than 2 previous cancer treatments, including high dose chemotherapy and ASCT, for NHL unless patient refuses standard therapy and/or is not eligible for ASCT. Have significant, uncontrolled, or active cardiovascular disease.

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Intervention Model: Sequential Assignment
Interventional Model Description: Cohort1 0.05mg/kg STEP 1 Solid Tumors Cohort2 0.10mg/kg STEP 1 Solid Tumors Cohort3 0.20mg/kg STEP 1 Solid Tumors Cohort4 0.40mg/kg STEP 1 Solid Tumors Cohort5 0.80mg/kg STEP 1 Solid Tumors Cohort6 1.60mg/kg STEP 1 Solid Tumors Cohort7 2.40mg/kg STEP 1 Solid Tumors Cohort8 3.36mg/kg STEP 1 Solid Tumors + GCSF Cohort7b 2.40mg/kg STEP 1 Solid Tumors +GCSF Cohort7c 2.00mg/kg STEP 1 Solid Tumors +GCSF Cohort5 0.80mg/kg STEP 2 NHL
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: MEN1309 (Step 1-Solid Tumors)/(Step 2-NHL)<br>Step1: Accelerated Titration Design with 1 single pt per cohort and double dose level per cohort until grade ≥ 2 drug related toxicity. Then, study reverts to 3+3 design. Any cohort in which 1 pt experiences a DLT (along ATD or 3+3) will be expanded up to 6 pts. Step2: MTD defined in Step 1, 3 MEN1309 dose levels will be tested (MTD-2, MTD-1, and MTD), with 6 pts per each dose level. A further MTD-3 level will be explored if 2 DLTs occur at the MTD-2 dose level. | Drug: MEN1309<br>* MEN1309 solution for intravenous infusion once every 3 weeks<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Maximum-Tolerated Dose (MTD) | Defined as the highest dose level at which no more than 1 of 6 patients experiences a DLT during the DLT assessment window. | 21-day period after the first dose | 
| Dose-Limiting Toxicity (DLT) | Adverse drug reactions (ADRs) that will be assessed during Cycle 1: any grade ≥ 3 cardiac toxicity, new segmental wall-motion abnormalities, or cardiac troponin I or T elevation of grade 3 or higher; any grade ≥ 3 elevations in total bilirubin, hepatic transaminases, or ALP levels; in patients with baseline grade 2 hepatic transaminase or ALP levels, an elevation to ≥ 10 x ULN is considered a DLT; any grade 3 non-haematologic toxicity lasting > 7 days, (excluding diarrhea/nausea for which no adequate and optimal therapy has been implemented and alopecia); any grade 3 vomiting lasting > 3 days despite adequate and optimal therapy; any grade ≥ 4 non-haematologic toxicity; any grade 4 thrombocytopenia or anemia; any grade 4 neutropenia lasting > 7 days or febrile neutropenia; any treatment delay of > 2 weeks because of delayed recovery from toxicity related to MEN1309 (except for alopecia). | 21-day period after the first dose | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Overall Survival | Timeframe between the first study drug administration and death from any cause. | Through study completion, from August 28, 2017 to January 8, 2020 (2 years and 4 months) | 
| Progression Free Survival | The Number of days between the first study administration to the date of first documented disease progression. | Through study completion, from August 28, 2017 to January 8, 2020 (2 years and 4 months) | 
| Preliminary Tumor Activity (RR) | Preliminary tumor activity (RR) Response Rate. RECIST v 1.1 assessment was performed using CT or MRI scan of the chest and abdomen (including adrenal glands). For the baseline assessment, CT or MRI scan were to be performed no more than 6 weeks (4+2 weeks) before the treatment start. Follow-up assessment were performed every other cycle starting from cycle 3 until the End of Study Visit. | From Day1Visit1 to End of the treatment (At Baseline no more than 6 weeks before treatment and then every cycle starting from cycle 3 until End of Study) | 
| Preliminary Antitumor Activity (DCR) | Preliminary Antitumor Activity (DCR) Disease control Rate. RECIST v 1.1 assessment was performed using CT or MRI scan of the chest and abdomen (including adrenal glands). For the baseline assessment, CT or MRI scan were to be performed no more than 6 weeks (4+2 weeks) before the treatment start. Follow-up assessment were performed every other cycle starting from cycle 3 until the End of Study Visit. | From Day1Visit1 to End of the treatment (At Baseline no more than 6 weeks before treatment and then every cycle starting from cycle 3 until End of Study) | 
| Preliminary Antitumor Activity (DOR) | Prliminary Antitumor Activity. Measure of the Duration of response. RECIST v 1.1 assessment was performed using CT or MRI scan of the chest and abdomen (including adrenal glands). For the baseline assessment, CT or MRI scan were to be performed no more than 6 weeks (4+2 weeks) before the treatment start. Follow-up assessment were performed every other cycle starting from cycle 3 until the End of Study Visit. | From Day1Visit1 to End of the treatment (At Baseline no more than 6 weeks before treatment and then every cycle starting from cycle 3 until End of Study) | 
| MEN1309 PK Parameter Cmax | Cmax is the maximum drug concentration | Cycle 1 | 
| MEN1309 PK Parameter Ctrough | MEN1309 PK parameter Ctrough (Predose concentration) | Pre-infusion Cycle 2 | 
| MEN1309 Pharmacokinetic (PK) Parameter t1/2 | MEN1309 Pharmacokinetic (PK) parameter t1/2 (terminal serum half-life) | Cycle 1 | 
| MEN1309 Pharmacokinetic (PK) Parameter AUC | MEN1309 Pharmacokinetic (PK) parameter AUC (area under curve) | Cycle 1 | 
| MEN1309 (PK) Parameter CL | Systemic clearance of MEN1309 Pharmacokinetic | Cycle 1 | 
| MEN1309 Pharmacokinetic (PK) Parameter Vd | volume of distribution based on the terminal phase | Cycle 1 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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NHL, Solid Tumors, Non-Hodgkin Lymphoma, MEN1309, CD205, Relapsed, Refractory, R-R NHL, ADC, Antibody-Drug Coniugate, Metastatic Tumors