First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies

  title={First-in-human, phase I/IIa clinical study of the peptidase potentiated alkylator melflufen administered every three weeks to patients with advanced solid tumor malignancies},
  author={Åke Berglund and Anders Ull{\'e}n and Alla Sergeevua Lisyanskaya and Sergey V. Orlov and Hans Hagberg and Bengt Tholander and Rolf Lewensohn and Peter Nygren and Jack Spira and Johan Harmenberg and Markus Jerling and Carina Alvfors and Magnus Ringbom and Eva K. L. Nordström and Karin S{\"o}derlind and Joachim Gullbo},
  journal={Investigational New Drugs},
SummaryPurpose Melflufen (melphalan flufenamide, previously designated J1) is an optimized and targeted derivative of melphalan, hydrolyzed by aminopeptidases overexpressed in tumor cells resulting in selective release and trapping of melphalan, and enhanced activity in preclinical models. Methods This was a prospective, single-armed, open-label, first-in-human, dose-finding phase I/IIa study in 45 adult patients with advanced and progressive solid tumors without standard treatment options… 

Melflufen for the treatment of multiple myeloma

Melflufen provides a proof-of-concept for the utility of the peptide–drug conjugate platform in relapsed/refractory multiple myeloma and is under discussion with regulatory agencies in the United States and Europe.

Melflufen: A Peptide–Drug Conjugate for the Treatment of Multiple Myeloma

Melflufen, with its novel mechanism of action, has the potential to provide clinically meaningful benefits to patients with relapsed/refractory multiple myeloma, including those with high unmet needs.

Spotlight on Melphalan Flufenamide: An Up-and-Coming Therapy for the Treatment of Myeloma

Melflufen plus dexamethasone as a doublet, and in combination with other novel drugs, has the potential to be beneficial for a broad range of patients with relapsed/refractory multiple myeloma in third- or even in second-line therapy.

OCEAN: a randomized Phase III study of melphalan flufenamide + dexamethasone to treat relapsed refractory multiple myeloma.

The rationale and design of OCEAN (NCT03151811), a randomized, head-to-head, superiority, open-label, global, Phase III study evaluating the efficacy and safety of melphalan flufenamide + dexamethasone versus pomalidomide + DexamethAsone, is described.

Targeting aggressive osteosarcoma with a peptidase-enhanced cytotoxic melphalan flufenamide

Melflufen has shown an anti-proliferative effect in HGOS ex vivo samples and cell lines, including those resistant to methotrexate, etoposide, doxorubicin, and PARP inhibitors, and this sensitivity correlated with high expression of ANPEP.

Melflufen: A Peptide–Drug Conjugate for the Treatment of Multiple Myeloma

Melflufen, with its novel mechanism of action, has the potential to provide clinically meaningful benevolence to patients with relapsed / refractory multiple myeloma, including those with high unmet needs.

In vitro and in vivo anti-leukemic activity of the peptidase-potentiated alkylator melflufen in acute myeloid leukemia

Melflufen demonstrates high and significant preclinical activity in AML and further clinical evaluation seem warranted in this disease, as well as in a patient derived xenograft study.

Melflufen - a peptidase-potentiated alkylating agent in clinical trials.

It is hypothesized that melflufen could provide better efficacy but no more toxicity than what is achieved with melphalan, an assumption so far supported by experiences from hollow fiber and xenograft studies in rodents as well as by clinical data from patients with solid tumors and multiple myeloma.

Melflufen for relapsed and refractory multiple myeloma

Melflufen has potential to fill a gap in the myeloma treatment landscape by providing a new mechanism of action with clinically meaningful efficacy and a favorable safety profile in patients refractory to multiple novel agents.



The systemic administration of intravenous melphalan.

In poor-prognosis patients with non-Hodgkin's lymphoma, Hodgkin's disease, multiple myeloma, or neuroblastoma, high-dose melphalan-containing regimens have yielded both high response rates and improved survival, despite considerable toxicity.

The novel alkylating prodrug J1: diagnosis directed activity profile ex vivo and combination analyses in vitro

The ex vivo profile of J 1 suggests that further evaluation of J1 as the alkylating agent in for example aggressive breast cancer might be of particular interest, preferentially in combination with DNA-topoisomerase II inhibitors like etoposide.

Antitumor efficacy and acute toxicity of the novel dipeptide melphalanyl-p-L-fluorophenylalanine ethyl ester (J1) in vivo

The results indicate that the promising in vitro data from the previous studies of J1 seems translatable into the in vivo situation, and at equal doses of alkylating units J1 was more active in the mouse hollow-fiber model, but showed similar general toxicity.

The novel melphalan prodrug J1 inhibits neuroblastoma growth in vitro and in vivo

The melphalan prodrug J1 is highly active in models of neuroblastoma in vitro and in vivo, encouraging further clinical development in this patient group.

Melphalan and its role in the management of patients with multiple myeloma

Thalidomide, its immunomodulatory derivative lenalidomides and the proteasome inhibitor bortezomib, in combination with oral melphalan in the elderly and with intravenous melphAlan in younger patients, are changing the traditional treatment paradigm of multiple myeloma.

Population pharmacokinetics of melphalan in patients with multiple myeloma undergoing high dose therapy.

Creatinine clearance, fat free mass and haematocrit influence total and unboundmelphalan plasma clearance, andMelphalan exposure is related to melphalan toxicity while the association with efficacy shows promising trends that will be studied further.

Activity of Hydrolytic Enzymes in Tumour Cells is a Determinant for Anti-tumour Efficacy of the Melphalan Containing Prodrug J1

The results show that the activity of the dipeptide mustards is highly dependent on intracellular hydrolysis, which result in rapid intrACEllular release of the alkylating unit in cells with high enzymatic activity.

Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy.

It is predicted that combinations of standard agents, histone deacetylase inhibitors, bromodomain inhibitors, and hypoxia-activated prodrugs will demonstrate efficacy in the treatment of relapsed MM.

The novel alkylating prodrug melflufen (J1) inhibits angiogenesis in vitro and in vivo.