A PK, Safety and Tolerability Study of Peripheral and Central Infusion of Melflufen in RRMM Patients

A Randomized, Two-period, Cross-over, Phase 2 Study, Comparing Pharmacokinetics, and Assessing Safety and Tolerability of Peripheral and Central i.v. Administration of Melphalan Flufenamide (Melflufen) in RRMM Patients

This is a randomized, two-period, cross-over Phase 2 study, comparing PK, and assessing safety and tolerability and efficacy of peripheral and central intravenous administration of melflufen in patients with RRMM. It is an international study, enrolling patients in US and Europe. The study will enroll patients following at least 2 lines of prior therapy.

Inclusion Criteria:

1. Male or female, age 18 years or older

2. Capable of giving signed informed consent as described in Appendix 1 which includes compliance with the requirements and restrictions listed in the informed consent form (ICF) and in this protocol;

3. A prior diagnosis of multiple myeloma (MM) with documented disease progression in need of treatment at time of screening;

4. Measurable disease defined as any of the following:

   • Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
   • ≥ 200 mg/24hr of monoclonal protein in the 24hour urine collection by electrophoresis (UPEP)
   • Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain (FLC) ratio

5. Received at least 2 prior lines of therapy and is refractory to an immunomodulatory drug (IMiD) and a proteasome inhibitor (PI). The definition of refractory includes intolerance to an IMiD/PI after at least two 28-day cycles of therapy, see Appendix 10 and Appendix 8.

6. Adequate peripheral arm veins for repeated intravenous infusions

7. Life expectancy of ≥ 6 months;

8. Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2, see Appendix 6. Patients with ECOG performance status > 2 solely based on bone pain secondary to MM may be eligible following consultation and approval of medical monitor;

9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec, see Appendix 11;

10. Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study treatment administration on Cycle 1 Day 1:

    • Absolute neutrophil count (ANC) ≥ 1,000 cells/mm³ (1.0 x 10⁹/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of study treatment)
    • Platelet count ≥ 75,000 cells/ mm³ (75 x 10⁹/L) (without transfusions during the 10 days prior to initiation of therapy)
    • Hemoglobin ≥ 8.0 g/dL (Red blood cell [RBC] transfusions are permitted)
    • Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), except patients diagnosed with Gilbert's syndrome that have been reviewed and approved by the Medical Monitor
    • Aspartate aminotransferase (AST) serum glutamic-oxaloacetic transaminase (SGOT) and alanine aminotransferase (ALT) serum glutamic-pyruvic transaminase (SGPT) ≤ 3.0 x ULN
    • Renal function: Estimated glomerular filtration rate (eGFR) by Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formula of ≥ 45 mL/min, see Appendix 12.

11. Must have or be willing to have an acceptable central catheter (Port a Cath, peripherally inserted central catheter [PICC] line, or central venous catheter [CVC]) and a PVC;

12. a) Male patients: A male patient is eligible if he agrees to use contraception as detailed in Appendix 4 of this protocol during the treatment period and for at least 3 months after the last dose of study treatment and refrains from donating sperm during this period b) Female patients: A female patient is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies: I. Not a woman of childbearing potential (WOCBP) as defined in Appendix 4 or II. A WOCBP who agrees to follow the contraceptive guidance in Appendix 4 during the treatment period and for at least 28 days after the last dose of study treatment

Exclusion Criteria:

1. Primary refractory disease (i.e. never responded with at least minimal response [MR] to any prior therapy);

2. Evidence of mucosal and/or internal bleeding or platelet transfusion refractory (platelet count fails to increase by > 10,000 cells/mm³ after a transfusion of an appropriate dose of platelets);

3. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participating in this study. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant cardiac conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months);

4. Known active infection that is uncontrolled or has required intravenous systemic therapy within 14 days of randomization. Patients that have required oral anti-infective treatment within 14 days of randomization should be discussed with the Medical Monitor;

5. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance;

6. Pregnant or breast-feeding females;

7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation;

8. Human immunodeficiency virus (HIV) or active hepatitis B or C viral infection;

9. Concurrent known or suspected amyloidosis or plasma cell leukemia;

10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes);

11. Known central nervous system (CNS) or meningeal involvement of myeloma

12. Any of the following treatments, within the specified timeframe

    • Previous cytotoxic therapies, including cytotoxic investigational agents, for MM within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy.
    • The use of live vaccines within 30 days before initiation of therapy.
    • IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy.
    • Other investigational therapies and monoclonal antibodies within 4 weeks of initiation of therapy.
    • Prednisone up to but no more than 10 mg orally q.d. or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy.

    Other washout times may be considered following consultation with the medical monitor.

13. Residual side effects to previous therapy > Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted);

14. Prior stem cell transplant (autologous and/or allogenic) within 6 months of initiation of therapy;

15. Prior allogeneic stem cell transplantation with active graft-versus-host-disease;

16. Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy);

17. Known intolerance to the required dose and schedule of steroid therapy, as determined by the investigator;

18. Known hypersensitivity reaction to melphalan, melflufen or its excipients

19. Prior treatment with melflufen