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

Primary Purpose

Multiple Myeloma

Status

Completed

Phase

Phase 2

Locations

International

Study Type

Interventional

Intervention

Melphalan flufenamide (Melflufen)

Dexamethasone

About this trial

This is an interventional treatment trial for Multiple Myeloma focused on measuring relapsed refractory multiple myeloma

Eligibility Criteria

18 Years - undefined (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

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
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

Exclusion Criteria:

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
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

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

melphalan flufenamide (melflufen) + dexamethasone

Arm Description

Melphalan 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.

Outcomes

Primary Outcome Measures

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

Secondary Outcome Measures

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

Duration of Response

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

Overall Survival

Time from start of treatment to death

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.

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.

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.

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).

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.

Full Information

NCT ID

NCT02963493

First Posted

October 18, 2016

Last Updated

November 18, 2022

Sponsor

Oncopeptides AB

Collaborators

Precision For Medicine

1. Study Identification

Unique Protocol Identification Number

NCT02963493

Brief Title

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

Acronym

HORIZON

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

Study Type

Interventional

2. Study Status

Record Verification Date

November 2022

Overall Recruitment Status

Completed

Study Start Date

December 28, 2016 (Actual)

Primary Completion Date

October 22, 2020 (Actual)

Study Completion Date

November 16, 2021 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title

Sponsor

Name of the Sponsor

Oncopeptides AB

Collaborators

Precision For Medicine

4. Oversight

Data Monitoring Committee

Yes

5. Study Description

Brief 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. 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.

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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study

Multiple Myeloma

Keywords

relapsed refractory multiple myeloma

7. Study Design

Primary Purpose

Treatment

Study Phase

Phase 2

Interventional Study Model

Single Group Assignment

Masking

None (Open Label)

Allocation

N/A

Enrollment

157 (Actual)

8. Arms, Groups, and Interventions

Arm Title

melphalan flufenamide (melflufen) + dexamethasone

Arm Type

Experimental

Arm Description

Melphalan 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.

Intervention Type

Drug

Intervention Name(s)

Melphalan flufenamide (Melflufen)

Other Intervention Name(s)

Pepaxto

Intervention Type

Drug

Intervention Name(s)

Dexamethasone

Intervention Description

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

Primary Outcome Measure Information:

Title

Overall Response Rate (ORR)

Description

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.

Secondary Outcome Measure Information:

Title

Progression Free Survival (PFS)

Description

Time Frame

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.

Title

Duration of Response

Description

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

Time Frame

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.

Title

Overall Survival

Description

Time from start of treatment to death

Time Frame

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.

Title

Functional Status and Well-being: EORTC QLQ-C30

Description

Time Frame

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.

Title

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

Description

Time Frame

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.

Title

Clinical Benefit Rate

Description

Time Frame

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.

Title

Time to Response

Description

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).

Time Frame

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

Title

Time to Progression

Description

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.

Time Frame

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.

10. Eligibility

Sex

All

Minimum Age & Unit of Time

18 Years

Accepts Healthy Volunteers

Eligibility Criteria

Inclusion Criteria: 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 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 Exclusion Criteria: 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 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

Overall Study Officials:

First Name & Middle Initial & Last Name & Degree

Johan Harmenberg, MD, PhD

Organizational Affiliation

Oncopeptides AB

Official's Role

Study Chair

Facility Information:

Facility Name

Innovative Clinical Research Institute (ICRI)

City

Whittier

State/Province

California

ZIP/Postal Code

90603

Country

United States

Facility Name

University of Florida

City

Gainesville

State/Province

Florida

ZIP/Postal Code

32610

Country

United States

Facility Name

RUSH

City

Chicago

State/Province

Illinois

ZIP/Postal Code

60612

Country

United States

Facility Name

Dana Farber Cancer Institute

City

Boston

State/Province

Massachusetts

ZIP/Postal Code

02215

Country

United States

Facility Name

Karmanos Cancer Center

City

Detroit

State/Province

Michigan

ZIP/Postal Code

48201

Country

United States

Facility Name

Memorial Sloan Kettering Cancer Center

City

New York

State/Province

New York

ZIP/Postal Code

10065

Country

United States

Facility Name

Hudson Valley Hematology Oncology

City

Poughkeepsie

State/Province

New York

ZIP/Postal Code

10532

Country

United States

Facility Name

UPMC Hillman Cancer Insitute

City

Pittsburgh

State/Province

Pennsylvania

ZIP/Postal Code

15232

Country

United States

Facility Name

Baylor

City

Dallas

State/Province

Texas

ZIP/Postal Code

75246

Country

United States

Facility Name

CHU de Nantes

City

Nantes

ZIP/Postal Code

44000

Country

France

Facility Name

CHU de Poitiers

City

Poitiers

ZIP/Postal Code

86021

Country

France

Facility Name

Universita di Bolognia

City

Bologna

ZIP/Postal Code

40126

Country

Italy

Facility Name

Turin Hospital Myeloma Unit

City

Turin

ZIP/Postal Code

10126

Country

Italy

Facility Name

Hospital Clinic i Provincial de Barcelona

City

Barcelona

ZIP/Postal Code

08036

Country

Spain

Facility Name

Institut Català d'Oncología (ICO) Badalona

City

Barcelona

ZIP/Postal Code

08916

Country

Spain

Facility Name

Hospital Universitario de La Princesa

City

Madrid

ZIP/Postal Code

28006

Country

Spain

Facility Name

Hospital Universitario Fundación Jiménez Díaz

City

Madrid

ZIP/Postal Code

28040

Country

Spain

Facility Name

Clínica Universidad de Navarra

City

Pamplona

ZIP/Postal Code

31008

Country

Spain

Facility Name

Complejo Hospitalario de Salamanca

City

Salamanca

ZIP/Postal Code

37007

Country

Spain

Facility Name

Hospital Universitario Doctor Peset

City

Valencia

ZIP/Postal Code

46017

Country

Spain

12. IPD Sharing Statement

Citations:

PubMed Identifier

33296242

Citation

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.

Results Reference

result

PubMed Identifier

34671975

Citation

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. Erratum In: Br J Haematol. 2022 Aug;198(3):609.

Results Reference

derived

Learn more about this trial

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

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

Multiple Myeloma

About this trial

Eligibility Criteria

Sites / Locations

Arms of the Study

Arm 1

Outcomes

Primary Outcome Measures

Secondary Outcome Measures

Full Information

1. Study Identification

2. Study Status

3. Sponsor/Collaborators

4. Oversight

5. Study Description

6. Conditions and Keywords

7. Study Design

8. Arms, Groups, and Interventions

10. Eligibility

12. IPD Sharing Statement

Learn more about this trial