Determination of the MTD and Encouraging Results in an Ongoing Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and Dexamethasone in Combination for Patients with Relapsed and Relapsed-Refractory Multiple Myeloma (RRMM)

Background: Melphalan is widely used in the treatment of Multiple Myeloma (MM), both as a low dose agent in elderly patients and in myeloablative treatment supported by autologous stem cell transplantation. However, melphalan treatment can be associated with significant toxicities and the development of drug-resistance. Current therapies with novel agents have improved outcomes but alkylators still play a significant role in the treatment of MM. Melflufen (L-melphalanyl-p-L-fluorophenylalanine ethyl ester hydrochloride), is an optimized analogue of melphalan. The mechanism of action is targeted alkylation of tumor cell DNA. Melflufen is highly lipophilic and transport of melflufen into cells is rapid. In the cytoplasm, peptidases that are overexpressed in most malignant cells, will rapidly cleave melflufen releasing hydrophilic melphalan. In vitro, equimolar treatment of tumor cells with melphalan and melflufen results in a 10-20 fold higher intracellular concentration of melphalan after melflufen treatment. In studies of 20 different human cancers in cell culture, including MM, melflufen showed 50- to 100-fold higher cytotoxicity as measured by IC₅₀compared with that of melphalan.

Methods: Melflufen was evaluated in combination with low dose dexamethasone (dex) in a Phase 1/2a study. Patients with RRMM with measurable disease and at least 2 prior lines of therapy were eligible (NCT01897714). Phase 1 followed the standard 3 + 3 modified Fibonacci design with 3 to 6 patients in each cohort, depending on dose limiting toxicity (DLT) observed. 4 dose levels were tested; IV melflufen at 15 mg, 25 mg, 40 mg and 55 mg, given on day 1, with a fixed dose of dex 40 mg PO or IV on days 1, 8 and 15 of each 21 day cycle. An additional 20 patients will be treated at the maximally tolerated dose (MTD) in the Phase 2a part of the study. The primary objective of Phase 1 was to determine the MTD.

Results: As of 25 July 2014, 19 patients have been enrolled into the Phase 1 component of the study. The median time from initial diagnosis to first dose of melflufen was 6.9 years (0.7-15.7). The median number of prior therapies was 4.8 (1-14). All patients to date were relapsed or refractory to both immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) and 13 patients have received melphalan (68%). In total, 57 doses of melflufen have been given (1-12 cycles). No DLTs were observed in the first three dose cohorts (15, 25 and 40 mg). The highest planned dose cohort (55 mg) exceeded the MTD. Two out of 6 patients experienced confirmed DLTs at the time of data cut-off. The DLTs were prolonged and severe thrombocytopenia and neutropenia but proved manageable with appropriate treatment. The most frequent adverse events (AE), all grades, occurring in > 10% of patients, regardless of relationship to study drug include thrombocytopenia (68.4%), anemia (63%), neutropenia (52%), nausea (42%), fatigue (26%), constipation and mucositis (21%), bone fracture, diarrhea, dyspnea, thrush and lymphopenia each in 16% of patients. Treatment-related Grade 3 and 4 AEs have been reported in 73% of patients (N =14); neutropenia (47%), thrombocytopenia (37%), anemia and lymphopenia (10.5%), cutaneous rash, diarrhea, febrile neutropenia, infection and pneumonia each occurred in 2% of patients. Three additional patients are being enrolled on the 40 mg cohort to confirm the MTD.

Sixteen patients were evaluable for response. In the two lower dose cohorts one patient in the 15 mg cohort maintained stable disease (SD) for 12 cycles, there were no responses in the 25 mg cohort as all patients rapidly progressed. In the 40 mg cohort, 2 patients achieved partial response (PR) and one patient has maintained SD for up to 6 cycles, all patients continue on therapy. In the 55 mg cohort 3 of 6 patients were evaluable for response at the time of data cut-off. One has achieved a very good partial response, one PR and the third has maintained SD for 3 cycles of therapy.

Conclusion: Melflufen plus low dose dex appeared in early data to be well tolerated and has activity in this advanced RRMM population. The MTD was exceeded at 55 mg due to myelosuppression, which was expected and manageable and the MTD is currently being confirmed at the 40 mg dose level. Responses have been seen in heavily pre-treated patients including those relapsed and refractory to both IMiDs and PIs. Updated information from both phase 1 and phase 2 will be presented at the time of the conference.