A Dose Escalation Study of MM-398 Plus Irinotecan in Patients With Unresectable Advanced Cancer

Study Overview
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Brief Summary
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MM-398 (also known as PEP02) is nanoliposomal encapsulated irinotecan: the liposomal formulation is designed to extend plasma circulation and to increase accumulation in the tumor through the enhanced permeability and retention (EPR) effect. This study introduces a new concept of combining free and nanoliposomal drugs.

Detailed Description
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This is a dose-finding and therapeutic exploratory phase Ib multi-center, open label study of MM-398 plus irinotecan in two different settings: Group A : patients with unresectable advanced non-colorectal cancer who should receive only MM-398 and irinotecan Group B : patients with unresectable metastatic colorectal cancer who should receive MM-398 and irinotecan combined with leucovorin, 5-fluorouracil and bevacizumab. These groups will be enrolling in parallel. Pharmacokinetic and biomarker sampling will also be performed. There are three periods to this study : Screening period (up to -28d): patients undergo screening assessments to determine the eligibility for the study MM-398 treatment period (C1D1 until safety evaluation/progression): patients receive treatment every 2 weeks and undergo biopsies and other required assessments. The treatment period is divided into a maximum of 3 dose levels Follow up period: patients will be followed-up 30 days after their last dose of MM-398 for final safety assessments, and every 2 months thereafter for overall survival follow-up

Official Title
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A Phase Ib Dose Escalation Study of MM-398 Plus Irinotecan in Patients With Unresectable Advanced Cancer - DOUBLIRI

Conditions
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Unresectable Advanced Cancer

Intervention / Treatment
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* Drug: MM-398
* Drug: Irinotecan
* Drug: Leucovorin (LV)
* Drug: 5-fluorouracile (5-FU)
* Drug: bevacizumab
* Drug: MM-398


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Age 18 - 75 years Histologically proven carcinoma, Documented advanced or metastatic disease not suitable for complete surgical resection Measurable or evaluable lesions according to RECIST v1.1 criteria ECOG performance status 0 - 1 Adequate Bone marrow reserves as evidenced by: Absolute Neutrophil Count (ANC) ≥1.5 x 109/L without the use of hematopoietic growth factors platelets ≥ 100 x 109/L hemoglobin > 9 g/dL (may be transfused to maintain or exceed this level) International Normalized Ratio (INR) ≤1.5; aPTT<1.5 x upper normal limit (UNL); EXEMPTION: patients on full anticoagulation therapy due to Venous Thromboembolism (VTE) must have an in-range INR (usually between 2 and 3). Adequate renal function as evidenced by: serum creatinine: < 150µmol/l calculated creatinine clearance > 50ml/min. (recommendation: to be calculated according to the MDRD formula) Total bilirubin < 1.0 x upper normal limit (UNL) Normal ECG or ECG without any clinically significant findings Regular follow-up feasible. A registered patient must be treated and followed at the participating center. Able to understand and sign an informed consent No contraindication to any study drugs Registration in a national health care system (CMU included for France). NB.: prior exposure to irinotecan is allowed, except for irinotecan-refractory patients (i.e. exclusion criteria) Exclusion Criteria: Active central nervous system metastases (indicated by clinical symptoms, cerebral edema, steroid requirement, or progressive disease) Bone-only disease Clinically significant gastrointestinal (GI) disorder including hepatic disorders, bleeding, inflammation, GI obstruction, or diarrhea > grade 1 Patients refractory to irinotecan (i.e. prior exposure to irinotecan-based therapy with progressive disease as best response) Known Dose Limiting Toxicity (DLT) responses to irinotecan Patients known to be homozygous for UGT1A1 *28 History of any second malignancy in the last 3 years; patients with prior history of in-situ cancer or basal or squamous cell skin cancer are eligible. Patients with a history of other malignancies are eligible if they have been continuously disease-free for at least 3 years Prior exposure to MM-398 Known hypersensitivity to any of the components of MM-398, or other liposomal products Concurrent illnesses that would be a relative contraindication to trial participation such as active cardiac or liver disease Severe arterial thromboembolic events (myocardial infarction, unstable angina pectoris, stroke) less than 6 months before inclusion NYHA Class III or IV congestive heart failure, ventricular arrhythmias Chronic inflammatory bowel disease and/or bowel obstruction Active infection or an unexplained fever >38.5°C during screening visits or on the first scheduled day of dosing (at the discretion of the investigator, patients with tumor fever may be enrolled), which in the investigator's opinion might compromise the patient's participation in the trial or affect the study outcome Prior chemotherapy administered within 3 weeks, or within a time interval less than at least 5 half-lives of the agent, whichever is longer, prior to the first scheduled day of dosing in this study Uncontrolled hypertension (defined as persistent systolic blood pressure >150 mmHg and/or diastolic blood pressure >100 mmHg), or history of hypertensive crisis, or hypertensive encephalopathy Received radiation therapy in the last 14 days Major surgery or traumatic injury within the last 28 days Any other medical or social condition deemed by the Investigator to be likely to interfere with a patient's ability to sign informed consent, cooperate and participate in the study, or interfere with the interpretation of the results including tutelage and guardianship Pregnant or breast feeding; females of child-bearing potential must test negative for pregnancy at the time of enrollment based on a urine or serum pregnancy test. Both male and female patients of reproductive potential must agree to use a reliable method of birth control, during the study and for 6 months following the last dose of study drug. Concomitant administrations use with St John Worth, or CYP3A4 inducing anticonvulsants (phenytoin, Phenobarbital, carbamazepine), ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and verapamil Concomitant administration of live attenuated virus vaccine such as yellow fever vaccine Known dihydropyrimidine dehydrogenase (DPD) deficiency Known active hepatitis B or C and/or active or chronic human immunodeficiency virus (HIV)

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 75 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: Single Group Assignment
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: GROUP A / GROUP B (two differents cohorts)<br>GROUP A (Patients with unresectable advanced non-colorectal cancer ) - irinotecan + MM-398 dose escalation (3-18 patients) Level 1 : initial DOUBLIRI dose 60/90 (0-3 patients) MM-398 : 60mg/m² Irinotecan (CPT-11) : 90mg/m² Level 2: DOUBLIRI dose 80/90 (9 - 18 patients) MM-398 : 80mg/m² CPT-11: 90mg/m² Level 3A: DOUBLIRI dose 60/120 (12-18 patients) MM-398 : 60mg/m² CPT-11: 120mg/m² Level 3B: DOUBLIRI dose : 80/120 (12-18 patients) MM-398 : 80mg/m² CPT-11 : 120 mg/m² GROUP B (Patients with unresectable metastatic colorectal cancer)- LV/5FU-bevacizumab+irinotecan+MM-398 dose Escalation (3-18 patients) same level as group A + LV/5FU - bevacizumab regimen : Bevacizumab : 5mg/kg(day (d) 1) Leucovorin (LV) : 400mg/m² (d1) 5-fluorouracile infusion (5 FU) :2400mg/m² (d1,2) | Drug: MM-398<br>* unresectable Advanced non-colorectal cancer<br>* Other names: GROUP A;Drug: Irinotecan<br>* unresectable metastatic colorectal cancer<br>* Other names: GROUP A;Drug: Leucovorin (LV)<br>* unresectable metastatic colorectal cancer<br>* Other names: GROUPE B;Drug: 5-fluorouracile (5-FU)<br>* unresectable metastatic colorectal cancer<br>* Other names: GROUPE B;Drug: bevacizumab<br>* unresectable metastatic colorectal cancer<br>* Other names: GROUPE B;Drug: MM-398<br>* unresectable metastatic colorectal cancer<br>* Other names: GROUPE B;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adverse Event (AE) |  | Assessed from study inclusion to 30 days after last dose | 
| Dose Limiting Toxicities (DLT) |  | DLTs will be evaluated during 28-day period following the first dose of study treatment | 
| Maximal tolerated dose (MTD) |  | after the last patient in each cohort up to 28 months | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Response Rate (RR) |  | tumor responses will be evaluated every 8 weeks after start treatment up to 29 months | 
| Best overall Response (BOR) |  | BOR is the best response recorded from the inclusion until treatment failure up to 28 months | 
| Overall survival (OS) |  | assessed from the date of inclusion to the date of patient death, due to any cause or to the last date the patient was known to be alive, up to 29 months | 
| Progression free survival (PFS) |  | PFS is the time from the date of inclusion to the date of progressive disease or death up to 29 months | 
| Pharmacokinetic of MM-398 plus irinotecan combination therapy | to determine the levels of MM-398/irinotecan, SN-38 and SN-38G | cycle 1 Day 1 (1 cycle every 2 weeks) at Hour (H) 0, H+1, H+2.5, H+4.5, H+6.5, H+26.5, Day 3, Day 8, Day 15 and 30 days after the last dose of treatment | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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cancer, GERCOR, unresectable, MM-398, CPT-11, colorectal, non colorectal