AzTrials
AzTrials

Multiple MyelomaPhase 2HORIZONNCT02963493

A Study of Melphalan Flufenamide (Melflufen) Plus Dexamethasone in Patients With Relapsed or Refractory Multiple Myeloma

A Phase 2 study testing Melphalan flufenamide (Melflufen) and Dexamethasone in people with Multiple Myeloma, run by Oncopeptides AB at 20 sites in 4 countries.

Completed

Finished. The study has ended and is not enrolling. Results may be posted on the official record.

Official record
Search all trials

Trial summary

This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. Read more about this study

Who is it for?
Ages 18 years and older
Conditions the study is for
Multiple Myeloma
What is being tested?
Melphalan flufenamide (Melflufen) and Dexamethasone
Could I receive a placebo?
No, everyone receives an active treatment
How many people
157 participants
Where
20 sitesin 4 countries
Study dates
28 Dec 2016to 16 Nov 2021
Phase
Phase 2
Are there results?
Yes, posted in the registrySummary in the doctors' view

Key requirements

Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.

  • Ages 18 years and older
  • All sexes
  • No healthy volunteers
  • Adult, Older adult

Who may be able to join

  • Male or female, age 18 years or older
  • A prior diagnosis of multiple myeloma with documented disease progression
  • Measurable disease based on either of a) serum monoclonal protein by protein electrophoresis (SPEP), b) monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP), and/or c) serum immunoglobulin free light chain combined with abnormal serum immunoglobulin kappa to lambda free light chain ratio
  • A minimum of 2 prior lines of therapy including an IMiD and a PI and is refractory to pomalidomide and/or daratumumab
  • Life expectancy of ≥ 6 months
  • Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
Show all 11Show fewer
  • Female of child bearing potential (FCBP) and non-vasectomized male agree to practice appropriate methods of birth control
  • Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
  • 12-lead ECG with QTc interval within defined limit
  • Acceptable laboratory results during screening and prior to first study drug administration of the following parameters: absolute neutrophil count (ANC), platelet count, hemoglobin, total bilirubin, aspartate transaminase (AST/SGOT) and alanine transaminase (ALT/SGPT), renal function based on estimated creatinine clearance
  • Must have, or accept to have, an acceptable central catheter for infusion of melflufen

Who cannot join

  • Evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
  • 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
  • Known active infection requiring parenteral or oral anti-infective treatment within defined period
  • Primary refractory disease
  • Other malignancy diagnosed or requiring treatment within the defined period with specific exceptions
  • Pregnant or breast-feeding females
Show all 16Show fewer
  • Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
  • Known HIV or active hepatitis B or C viral infection
  • Concurrent symptomatic amyloidosis or plasma cell leukemia
  • POEMS syndrome [plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein (M-protein) and skin changes]
  • Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within defined values prior to start of study treatment
  • Residual side effects to previous therapy over specific grade prior to initiation of therapy
  • Prior autologous or allogeneic stem cell transplant within defined period of initiation of therapy
  • Prior allogeneic stem cell transplant with active graft-versus-host- disease (GVHD).
  • Prior major surgical procedure or radiation therapy within specified period of the first dose of study treatment (with defined exception).
  • Known intolerance to steroid therapy

Trial locations and contacts

20 sites in 4 countries.

20 sites in 4 countries

United States9 sites
  • Dana Farber Cancer Institute

    Boston, Massachusetts, 02215

  • RUSH

    Chicago, Illinois, 60612

  • Baylor

    Dallas, Texas, 75246

  • Karmanos Cancer Center

    Detroit, Michigan, 48201

  • University of Florida

    Gainesville, Florida, 32610

  • Memorial Sloan Kettering Cancer Center

    New York, New York, 10065

  • UPMC Hillman Cancer Insitute

    Pittsburgh, Pennsylvania, 15232

  • Hudson Valley Hematology Oncology

    Poughkeepsie, New York, 10532

  • Innovative Clinical Research Institute (ICRI)

    Whittier, California, 90603

Other trials in United States

Spain7 sites
  • Hospital Clinic i Provincial de Barcelona

    Barcelona, 08036

  • Institut Català d'Oncología (ICO) Badalona

    Barcelona, 08916

  • Hospital Universitario de La Princesa

    Madrid, 28006

  • Hospital Universitario Fundación Jiménez Díaz

    Madrid, 28040

  • Clínica Universidad de Navarra

    Pamplona, 31008

  • Complejo Hospitalario de Salamanca

    Salamanca, 37007

  • Hospital Universitario Doctor Peset

    Valencia, 46017

Other trials in Spain

France2 sites
  • CHU de Nantes

    Nantes, 44000

  • CHU de Poitiers

    Poitiers, 86021

Other trials in France

Italy2 sites
  • Universita di Bolognia

    Bologna, 40126

  • Turin Hospital Myeloma Unit

    Turin, 10126

Other trials in Italy

About this study

Official title: A Single Arm, Open-Label, Phase 2 Study of Melflufen in Combination With Dexamethasone in Patients With Relapsed Refractory Multiple Myeloma Who Are Refractory to Pomalidomide and/or an Anti-CD38 Monoclonal Antibody

This study will evaluate melflufen in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma in whose disease is refractory to pomalidomide and/or an anti-CD38 monoclonal antibody. All patients in the study will be treated with melflufen on Day 1 and dexamethasone on Days 1, 8, 15 and 22 of each 28-day cycle.

Read the detailed description

Melphalan flufenamide (melflufen) is a peptide-drug conjugate that rapidly delivers an alkylating payload into tumor cells. Peptidases are expressed in several cancers, including solid tumors and hematologic malignancies. Melphalan flufenamide is rapidly taken up by myeloma cells due to its high lipophilicity. Once inside the myeloma cell, the activity of melphalan flufenamide is determined by its immediate cleavage by peptidases into hydrophilic alkylator payloads that are entrapped. Melphalan flufenamide is 50-fold more potent than melphalan in myeloma cells in vitro due to increased intracellular alkylator concentration. It rapidly induces irreversible DNA damage leading to apoptosis of myeloma cells. Melphalan flufenamide displays cytotoxic activity against myeloma cell lines resistant to other treatments, including alkylators, in vitro. Melphalan flufenamide also has demonstrated inhibition of angiogenesis and DNA damage with a lack of functional DNA repair in preclinical studies.

Being tested
Melphalan flufenamide (Melflufen), Dexamethasone
Keywords
relapsed refractory multiple myeloma
Medical subject headings
Multiple Myeloma

What participants receive

What participants receive. In a randomised study each person is assigned to one group by chance.

  • Melphalan flufenamide (Melflufen)Drug

    Also called Pepaxto

  • DexamethasoneDrug

    IV dexamethasone may be substituted for oral dexamethasone in the US. Oral only in Europe.

Study groups in NCT02963493
Study groupRoleWhat they receive
melphalan flufenamide (melflufen) + dexamethasoneExperimentalMelphalan flufenamide (melflufen) 40 mg Day 1 and dexamethasone 40 mg (20 mg for patients 75 years or older) on Days 1, 8, 15 and 22 of each 28-day cycle.
Receives: Drug: Melphalan flufenamide (Melflufen); Drug: Dexamethasone

What is being measured

The primary outcome is the main question the study is designed to answer.

  1. Overall Response Rate (ORR)

    The overall response rate (ORR) will be estimated as the percentage of patients who achieve sCR, CR, VGPR, or PR as their best response as assessed by the investigator. Response assessed by IMWG (International myeloma working group) criteria sCR-stringent complete response: CR plus Normal FLC (free light chain) ratio and absence of clonal cells in BM CR-complete response: Negative immunofixation in serum/urine; Disappearance of soft tissue plasmacytomas; <5% plasma cells in BM; If only FLC disease, normal FLC ratio (0.26-1.65) VGPR-very good partial response: Serum/urine M-protein detectable by immunofixation but not electrophoresis or ≥90% reduction in serum M-protein and urine M-protein <100 mg/24 h; If only FLC disease, >90% decrease in the difference between involved and uninvolved FLC levels PR-partial response: 50% reduction of serum M-protein and soft tissue plasmacytomas, ≥90% reduction in urinary M-protein or to <200 mg/24 h; other special cases if M-protein unmeasurable

    Measured: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest time to response in study recorded as 15.3 months. Longest time on treatment 35 months.

Secondary outcomes (8)
  1. Progression Free Survival (PFS)

    Time from start of treatment to either progression or death, whichever comes first as assessed by the investigator using IMWG criteria. Progression of disease is defined by an increase of 25% from the lowest response for either of Serum M-component (absolute increase of ≥ 0.5 g/dL) or Urine M-component (absolute increase of ≥200 mg/ 24h); In patients without measurable M-protein a 25% increase in the difference between involved and uninvolved FLC (free light chain) levels (absolute increase must be >10 mg/dL); If unmeasurable FLC levels, a 25% increase in bone marrow plasma cell percentage (absolute percentage must be >10%); New bone or soft tissue plasmacytomas or definite increase in existing ones; Development of hypercalcemia (corrected serum calcium >11.5 mg/dL) that can be attributed solely to the plasma cell proliferative disorder

    Measured: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest follow-up time for PFS recorded as 37.2 months at study end.

  2. Duration of Response

    Time from first response to progression based on investigator assessment. See definitions of response and progression in ORR and PFS outcomes.

    Measured: From date of response until the date of first documented progression or date of death from any cause, whichever came first. Longest time of response recorded as 36.2 months at study end.

  3. Overall Survival

    Time from start of treatment to death

    Measured: From date of first dose of study medication until the date of death from any cause, assessed up to 24 months after study drug discontinuation.

  4. Functional Status and Well-being: EORTC QLQ-C30

    Change from baseline in Patient Reported Outcome questionnaire EORTC QLQ-C30. The EORTC QLQ-C30 includes 30 items resulting in 5 functional scales, 1 Global Health Status scale, 3 symptom scales, and 6 single items. The recall period is 1 week (the past week). The scales are transformed to a 0 (worst) to 100 (best) scale. The QLQ-C30 summary score is calculated as the mean of the combined 13 QLQ-C30 scale and item scores (excluding global QoL and financial impact), with a higher score indicating a better HRQoL. If at least 50% of the items from the scale had been answered, the missing items were assumed to have values equal to the average of those items which were present for that respondent.

    Measured: To be assessed prior to dosing at Cycle 1, 2, 4, 6, 8, and End of Treatment. 23 patients were ongoing for QoL assessments at data cutoff. QoL was added in Protocol Amendment 4 beginning in Oct. 2018.

  5. Functional Status and Well-being: EQ-5D-3L

    Change from baseline in Patient Reported Outcome questionnaire EQ-5D-3L. The EQ-5D-3L questionnaire converts 5 dimensions: Mobility, Self-Care, Usual Activities, Pain/Discomfort, and Anxiety/Depression of patient-reported, current-day health status into a "health utility" score. For the EQ-5D-3L questionnaire, each dimension is scored on an ordinal scale with 3 available levels of response and scores ranging from 1 to 3, "no problems," "some problems," and "extreme problems," respectively. The EQ VAS scores rates "health today" with anchors ranging from 0 (worst imaginable health state) to 100 (best imaginable health state). No imputation of missing items or composite scores were done. The scores for the 5 dimensions are used to compute a single utility score ranging from zero (0.0) to 1 (1.0) representing the general health status of the individual.

    Measured: To be assessed prior to dosing at Cycle 1, 2, 4, 6, 8, and End of Treatment. 23 patients were ongoing for QoL assessments at data cutoff. QoL was added in Protocol Amendment 4 beginning in Oct. 2018.

  6. Clinical Benefit Rate

    The clinical benefit rate (CBR) will be estimated as the percentage of patients who achieve sCR, CR, VGPR, PR, or MR as their best response as assessed by the investigator. See Primary Outcome (ORR) for definitions of response categories.

    Measured: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest time on study treatment recorded as 35.0 months at study end.

  7. Time to Response

    Duration from start of treatment to the first occurrence of a confirmed response of PR or better as assessed by the investigator. See definitions of response in Primary Outcome (ORR).

    Measured: From start of treatment to first confirmed response. Longest time to response in study recorded as 15.3 months.

  8. Time to Progression

    Duration from start of treatment to first evidence of disease progression as assessed by the investigator. See definitions of response and progression in ORR and PFS outcomes.

    Measured: From start of treatment to first evidence of disease progression or date of death from any cause, whichever came first. Longest time to progression recorded was 37.2 months at study end.

Timeline

From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.

  1. First posted15 Nov 2016 (estimated)
  2. Study start28 Dec 2016
  3. Primary completion22 Oct 2020
  4. Study completion16 Nov 2021

Resources

More details

For doctors and researchers: how the study is designed, who runs it, and its registry IDs.

Study design
Study type
Interventional
Phase
Phase 2
Primary purpose
Treatment
Allocation
Not applicable
Intervention model
Single group
Masking
None (open label)
Enrolment
157 participants (actual)
IDs, dates and publications
ClinicalTrials.gov ID
NCT02963493
Sponsor's protocol ID
OP-106
Acronym
HORIZON
Status last verified
Nov 2022
First submitted
18 Oct 2016
Last updated
22 Nov 2022
Data monitoring committee
Yes

Publications

  • Richardson PG, Oriol A, Larocca A, Blade J, Cavo M, Rodriguez-Otero P, Leleu X, Nadeem O, Hiemenz JW, Hassoun H, Touzeau C, Alegre A, Paner A, Maisel C, Mazumder A, Raptis A, Moreb JS, Anderson KC, Laubach JP, Thuresson S, Thuresson M, Byrne C, Harmenberg J, Bakker NA, Mateos MV; HORIZON (OP-106) Investigators. Melflufen and Dexamethasone in Heavily Pretreated Relapsed and Refractory Multiple Myeloma. J Clin Oncol. 2021 Mar 1;39(7):757-767. doi: 10.1200/JCO.20.02259. Epub 2020 Dec 9.

    PubMed 33296242
  • Sonneveld P, Richardson PG, Ludwig H, Dimopoulos MA, Schjesvold FH, Hajek R, Abdulhaq H, Thuresson M, Norin S, Bakker NA, Mateos MV. Benefit Versus Risk Assessment of Melflufen and Dexamethasone in Relapsed/Refractory Multiple Myeloma: Analyses From Longer Follow-up of the OCEAN and HORIZON Studies. Clin Lymphoma Myeloma Leuk. 2023 Sep;23(9):687-696. doi: 10.1016/j.clml.2023.05.004. Epub 2023 May 6.

    PubMed 37355418
  • Larocca A, Leleu X, Touzeau C, Blade J, Paner A, Mateos MV, Cavo M, Maisel C, Alegre A, Oriol A, Raptis A, Rodriguez-Otero P, Mazumder A, Laubach J, Nadeem O, Sandberg A, Orre M, Torrang A, Bakker NA, Richardson PG. Patient-reported outcomes in relapsed/refractory multiple myeloma treated with melflufen plus dexamethasone: analyses from the Phase II HORIZON study. Br J Haematol. 2022 Feb;196(3):639-648. doi: 10.1111/bjh.17887. Epub 2021 Oct 21.

    PubMed 34671975

Questions about this trial

What is this clinical trial studying?

A Phase 2 study testing Melphalan flufenamide (Melflufen) and Dexamethasone in people with Multiple Myeloma, run by Oncopeptides AB at 20 sites in 4 countries.

The full registered description is in the About this study section and the official record.

Who may be eligible to take part?

The sponsor lists 11 inclusion and 16 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.

Is this clinical trial currently recruiting?

The record says: finished, as of the sponsor's last update on 22 Nov 2022. Status can change between updates, so confirm with the study contact before making plans.

Where is the study taking place?

The record lists 20 sites in United States, Spain, France, Italy. Whether a site is taking part right now should be confirmed with that site. See every site.

What are the possible benefits and risks?

They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.

What does this phase mean?

Phase 2 studies give the treatment to a larger group to see whether it has the intended effect and to keep checking safety.

Not every study follows the same path, and some studies (observational studies, device studies) have no phase.

Are results available for this study?

Yes. Results are posted in the registry (first posted 1 Feb 2022). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.

How can a doctor refer a patient or contact the research team?

The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.

What does the primary outcome measure?

Overall Response Rate (ORR) (time frame: Patients were followed until documented progression, unacceptable toxicity, patient/physician decision to withdraw or date of death, whichever came first. Longest time to response in study recorded as 15.3 months. Longest time on treatment 35 months.). It is what the study was designed to measure, not a finding.

Where can I read the original study information?

On the ClinicalTrials.gov record for NCT02963493, which also lists 3 linked publications.

Does a listing mean the treatment is approved or proven to work?

No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.

How often is this information updated?

AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 22 Nov 2022.

Free account

Log in to keep searching

You’ve used your 3 free searches. AzTrials is free: log in or create a free account to keep searching clinical trials and save the ones you want to follow.

Create a free accountLog in