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

Inclusion Criteria:

1. Age 18 - 75 years
2. Histologically proven carcinoma,
3. Documented advanced or metastatic disease not suitable for complete surgical resection
4. Measurable or evaluable lesions according to RECIST v1.1 criteria
5. ECOG performance status 0 - 1
6. 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)
7. 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).
8. Adequate renal function as evidenced by:

   * serum creatinine: \< 150µmol/l
   * calculated creatinine clearance \> 50ml/min. (recommendation: to be calculated according to the MDRD formula)
9. Total bilirubin \< 1.0 x upper normal limit (UNL)
10. Normal ECG or ECG without any clinically significant findings
11. Regular follow-up feasible. A registered patient must be treated and followed at the participating center.
12. Able to understand and sign an informed consent
13. No contraindication to any study drugs
14. 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:

1. Active central nervous system metastases (indicated by clinical symptoms, cerebral edema, steroid requirement, or progressive disease)
2. Bone-only disease
3. Clinically significant gastrointestinal (GI) disorder including hepatic disorders, bleeding, inflammation, GI obstruction, or diarrhea \> grade 1
4. Patients refractory to irinotecan (i.e. prior exposure to irinotecan-based therapy with progressive disease as best response)
5. Known Dose Limiting Toxicity (DLT) responses to irinotecan
6. Patients known to be homozygous for UGT1A1 \*28
7. 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
8. Prior exposure to MM-398
9. Known hypersensitivity to any of the components of MM-398, or other liposomal products
10. 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
11. Chronic inflammatory bowel disease and/or bowel obstruction
12. 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
13. 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
14. 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
15. Received radiation therapy in the last 14 days
16. Major surgery or traumatic injury within the last 28 days
17. 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
18. 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.
19. Concomitant administrations use with St John Worth, or CYP3A4 inducing anticonvulsants (phenytoin, Phenobarbital, carbamazepine), ketoconazole, itraconazole, troleandomycin, erythromycin, diltiazem and verapamil
20. Concomitant administration of live attenuated virus vaccine such as yellow fever vaccine
21. Known dihydropyrimidine dehydrogenase (DPD) deficiency
22. Known active hepatitis B or C and/or active or chronic human immunodeficiency virus (HIV)