Clinical trial NCT01897714: Safety and Efficacy of Melflufen and Dexamethasone in Relapsed and/or Relapsed-Refractory Multiple Myeloma Patients
Official title: An Open-Label Phase I/IIa Study of the Safety and Efficacy of Melphalan-flufenamide (Melflufen) and Dexamethasone Combination for Patients With Relapsed and/or Relapsed-Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Relapsed and/or Relapsed-refractory Multiple Myeloma
Lead sponsor: Oncopeptides AB
Sponsor class: INDUSTRY
First posted: 2013-07-12
Enrollment: 75
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: SEQUENTIAL
Primary purpose: TREATMENT

Brief summary: The study will explore escalating doses of melflufen in combination with dexamethasone in small groups of patients to find the maximum tolerated dose of melflufen. That dose will then be used to determine the efficacy and safety profile of melflufen in combination with dexamethasone in a larger group of patients.


Eligibility criteria: Inclusion Criteria:

1. Male or female, age 18 years or older
2. Patient has a diagnosis of multiple myeloma with documented relapsed and/or relapsed-refractory disease
3. Patient has measurable disease defined as any of the following:

   1. Serum monoclonal protein ≥ 0.5 g/dL by protein electrophoresis
   2. ≥200 mg of monoclonal protein in the urine on 24-hour electrophoresis
   3. Serum immunoglobulin free light chain ≥10 mg/dL AND abnormal serum immunoglobulin kappa to lambda free light chain ratio
   4. If no monoclonal protein is detected, then ≥ 30% monoclonal bone marrow plasma cells
4. Patient has had at least 2 or more prior lines of therapy including lenalidomide and bortezomib and has demonstrated disease progression on or within 60 days of completion of the last therapy
5. Life expectancy of ≥6 months
6. Patient has an ECOG performance status ≤ 2 (Patients with lower performance status based solely on bone pain secondary to multiple myeloma will be eligible)
7. Females of childbearing potential must have a negative serum or urine pregnancy test prior to patient registration
8. Female patients of child bearing potential and non-vasectomized male patients agree to practice appropriate methods of birth control
9. Ability to understand the purpose and risks of the study and provide signed and dated informed consent and authorization to use protected health information
10. The patient has, or accepts to have, an acceptable infusion device for infusion of melflufen
11. 12 lead ECG with QtcF interval ≤ 470 msec
12. The following laboratory results must be met within 21 days of patient registration:

    * Absolute neutrophil count ≥ 1,000 cells/dL (1.0 x 109/L)
    * Platelet count ≥ 75,000 cells/dL (75 x 109/L)
    * Hemoglobin ≥ 8.0 g/dL
    * Total Bilirubin ≤ 1.5 x upper limit of normal
    * Renal function: Estimated creatinine clearance ≥ 45 ml/min or serum creatinine ≤ 2.5 mg/dL
    * AST (SGOT) and ALT (SGPT) ≤ 3.0 x ULN

Exclusion Criteria:

1. Patient has evidence of mucosal or internal bleeding and/or is platelet transfusion refractory
2. Any medical conditions that, in the Investigator's opinion, would impose excessive risk to the patient or would adversely affect his/her participation in this study
3. Known active infection requiring parenteral or oral anti-infective treatment
4. Other malignancy within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix
5. Other ongoing anti-myeloma therapy. Patients may be receiving concomitant therapy with bisphosphonates and low dose corticosteroids for symptom management and comorbid conditions. Doses of corticosteroid should be stable for at least 7 days prior to patient registration.
6. Pregnant or breast-feeding females
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse follow-up evaluation
8. Known HIV or hepatitis B or C viral infection
9. Patient has concurrent symptomatic amyloidosis or plasma cell leukemia
10. POEMS syndrome
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to start of study treatment. Biologic, novel therapy (including investigational agents in this class) or corticosteroids within 2 weeks prior to patient registration. Patient has side effects of the previous therapy \> grade 1 or previous baseline.
12. Prior peripheral stem cell transplant within 12 weeks of patient registration
13. Radiotherapy within 21 days prior to Cycle 1 Day 1. However, if the radiation portal covered ≤ 5% of the bone marrow reserve, the patient may be enrolled irrespective of the end date of radiotherapy
14. Known intolerance to steroid therapy

Primary outcomes:
measure: Percentage of Patients Who Achieved Best Overall Disease Response
timeFrame: Baseline (Cycle 1 Day 1) and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Overall Response Rate (ORR)
timeFrame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Clinical Benefit Response Rate (CBRR)
timeFrame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Secondary outcomes:
measure: Duration of Disease Response (DOR)
timeFrame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Time to Disease Response in Patients Who Achieved OR and CBR
timeFrame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Time to Disease Progression
timeFrame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Median Progression-Free Survival (PFS)
timeFrame: Baseline and every cycle from Cycle 2 onwards until confirmed disease progression. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Median Overall Survival (OS)
timeFrame: From baseline until death. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Time to First Subsequent Treatment
timeFrame: From baseline until start of first subsequent treatment. Assessed until EOT date of 29 October 2019; up to a maximum of approximately 76 months.
measure: Number of Patients With Treatment Emergent Adverse Events (TEAEs)
timeFrame: From the first dose of study drug up to and including the actual EOT date of 29 October 2019; up to a maximum of approximately 76 months.
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Detroit
country: United States
facility: Karmanos Cancer Center
state: Michigan
city: Chapel Hill
country: United States
facility: Universtity of North Carolina
state: North Carolina
city: Vejle
country: Denmark
facility: Vejle Hospital
city: Turin
country: Italy
facility: Turin Hospital Myeloma Unit
city: Rotterdam
country: Netherlands
facility: Erasmus University Medical Center
city: Gothenburg
country: Sweden
facility: Sahlgrenska Hospital
Study officials:
affiliation: Dana Farber Cancer Institute, Boston MA, USA
name: Paul G Richardson, MD
role: STUDY_DIRECTOR
affiliation: Oncopeptides AB, Stockholm, Sweden
name: Johan Harmenberg, MD
role: STUDY_DIRECTOR
References:
citation: Richardson PG, Bringhen S, Voorhees P, Plesner T, Mellqvist UH, Reeves B, Paba-Prada C, Zubair H, Byrne C, Chauhan D, Anderson K, Nordstrom E, Harmenberg J, Palumbo A, Sonneveld P. Melflufen plus dexamethasone in relapsed and refractory multiple myeloma (O-12-M1): a multicentre, international, open-label, phase 1-2 study. Lancet Haematol. 2020 May;7(5):e395-e407. doi: 10.1016/S2352-3026(20)30044-2. Epub 2020 Mar 23.