Clinical trial NCT03481556: Study of Melphalan Flufenamide (Melflufen) + Dex With Bortezomib or Daratumumab in Patients With RRMM
Official title: An Open-Label Phase 1/2a Study of the Safety and Efficacy of Melflufen and Dexamethasone in Combination With Either Bortezomib or Daratumumab in Patients With Relapsed or Relapsed-Refractory Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: TERMINATED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma
Lead sponsor: Oncopeptides AB
Sponsor class: INDUSTRY
First posted: 2018-03-29
Enrollment: 56
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NON_RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This is an open-label Phase 1/2a study which will enroll patients that have relapsed or relapsed-refractory multiple myeloma to combination regimens of melflufen with currently approved agents. Patients will receive either melflufen+dexamethasone+bortezomib or melflufen+dexamethasone+daratumumab.


Eligibility criteria: Inclusion Criteria:

1. Male or female, age 18 years or older
2. A prior diagnosis of multiple myeloma with documented disease progression in need of treatment at time of screening
3. One to four prior lines of therapy
4. Measurable disease defined as any of the following:

   * Serum monoclonal protein ≥ 0.5 g/dL by serum protein electrophoresis (SPEP)
   * ≥ 200 mg/24 hours of monoclonal protein in the urine on 24-hour urine electrophoresis (UPEP)
   * Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
5. Life expectancy of ≥ 6 months
6. ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to multiple myeloma may be eligible following consultation and approval of the medical monitor)
7. Patient is a female of childbearing potential (FCBP)\* with a negative serum or urine pregnancy test prior to initiation of therapy and agrees to practice appropriate methods of birth control, or the patient is male and agrees to practice appropriate methods of birth control
8. Ability to understand the purpose and risks of the study and provide signed and dated informed consent
9. 12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec
10. Adequate organ function with the following laboratory results during screening (within 21 days) and immediately before study drug administration on Cycle 1 Day 1:

    * Absolute neutrophil count (ANC) ≥ 1,000 cells/mm3 (1.0 x 109/L) (Growth factors cannot be used within 10 days (14 days for pegfilgrastim) prior to initiation of therapy)
    * Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without required transfusions during the 10 days prior to initiation of therapy)
    * Hemoglobin ≥ 8.0 g/dl (red blood cell (RBC) transfusions are permitted)
    * Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or patients diagnosed with Gilbert's syndrome, that have been reviewed and approved by the medical monitor
    * AST/SGOT and ALT/SGPT ≤ 3.0 x ULN
    * Renal function: Estimated creatinine clearance by Cockcroft-Gault formula ≥ 45 mL/min and serum creatinine ≤ 2 mg/dL
11. Must have, or be willing to have an acceptable central catheter. (Port a cath, peripherally inserted central catheter \[PICC\] line, or central venous catheter)

    Regimen A
12. Must be intolerant or refractory to a prior IMiD; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose.

    Regimen B
13. Must have had a prior IMiD and a proteasome inhibitor (PI); alone or in combination and must be refractory or intolerant to an IMiD, PI or both.

    * (FCBP) is any sexually mature female who: 1) has not undergone a hysterectomy or bilateral oophorectomy or 2) has not been naturally postmenopausal (not having menstrual cycles due to cancer therapy does not rule out childbearing potential) for at least 24 consecutive months.

Exclusion Criteria:

1. Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy)
2. Evidence of mucosal or internal bleeding and/or are platelet transfusion refractory (i.e. platelet count fails to increase by \> 10,000 cells/mm3 after transfusion of an appropriate dose of platelets)
3. 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. Examples of such conditions are: a significant history of cardiovascular disease (e.g., myocardial infarction, significant conduction system abnormalities, uncontrolled hypertension, ≥ Grade 3 thromboembolic event in the last 6 months)
4. Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy
5. Other malignancy diagnosed or requiring treatment within the past 3 years with the exception of adequately treated basal cell carcinoma, squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance
6. Pregnant or breast-feeding females
7. Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
8. Known human immunodeficiency virus or active hepatitis B or C viral infection
9. Concurrent symptomatic amyloidosis or plasma cell leukemia
10. POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
11. Previous cytotoxic therapies, including cytotoxic investigational agents, for multiple myeloma within 3 weeks (6 weeks for nitrosoureas) prior to initiation of therapy. The use of live vaccines within 30 days before initiation of therapy. IMiDs, PIs and or corticosteroids within 2 weeks prior to initiation of therapy. Other investigational therapies and monoclonal antibodies (mAb) within 4 weeks of initiation of therapy Prednisone up to but no more than 10 mg orally once daily (q.d.) or its equivalent for symptom management of comorbid conditions is permitted but dose should be stable for at least 7 days prior to initiation of therapy
12. Residual side effects to previous therapy \> Grade 1 prior to initiation of therapy (Alopecia any grade and/or neuropathy Grade 1 without pain are permitted)
13. Prior peripheral stem cell transplant within 12 weeks of initiation of therapy
14. Prior allogeneic stem cell transplantation with active graft-versus-host- disease
15. Prior major surgical procedure or radiation therapy within 4 weeks of initiation of therapy (this does not include limited course of radiation used for management of bone pain within 7 days of initiation of therapy)
16. Known intolerance to the required dose and schedule of steroid therapy as determined by the investigator
17. Prior treatment with melflufen

    Regimen A
18. Refractory to a PI in the last line of therapy prior to enrollment in this trial; refractory defined as failure to respond (MR or better) or progression while on therapy or within 60 days of last dose
19. History of allergic reaction/hypersensitivity attributed to compounds containing boron, mannitol, polysorbate 80 or sodium citrate dihydrate

    Regimen B
20. Prior exposure to an antiCD-38 mAb
21. Chronic obstructive pulmonary disease (COPD) with a Forced Expiratory Volume in 1 second (FEV1) less than 50% of predicted normal
22. Moderate or severe persistent asthma within the past 2 years, or currently has uncontrolled asthma of any classification
23. ≥ Grade 3 conduction system abnormalities unless patient has a pacemaker
24. Active hepatitis B (defined as HBsAg+) or those at risk for reactivation (HBsAg-, Anti- HBs+, Anti-HBc+)

    * Patients with prior hepatitis B vaccine are permitted (defined as HBsAg-, Anti-HBs+, Anti-HBc-)

      * Non-active hepatitis B (HBsAg-, Anti-HBs+, Anti-HBc+) may only be enrolled after approval of the sponsor and consideration of risk of reactivation (additional screening and monitoring for reactivation of Hepatitis B and consultation with a liver disease specialist may be required)

Primary outcomes:
measure: Phase 1: Number of Participants Who Experienced a Dose Limiting Toxicity (DLT)
timeFrame: Cycle 1: Day 1 to Day 28
measure: Phase 2: Overall Response Rate (ORR)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
Secondary outcomes:
measure: Best Response (BR)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Duration of Response (DOR)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Time to Response (TTR)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Progression-Free Survival (PFS)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Overall Survival (OS)
timeFrame: Up to 24 months following confirmed disease progression, or initiation of subsequent therapy (a maximum of 198.9 weeks)
measure: Duration of Clinical Benefit (DOCB)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Time to Progression (TTP)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Clinical Benefit Rate (≥ Minimal Response)
timeFrame: Until disease progression, death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Time to Next Treatment (TTNT)
timeFrame: Until death or initiation of subsequent therapy (a maximum of 194.3 weeks)
measure: Number of Participants Who Experienced a Treatment-emergent Adverse Event (TEAE)
timeFrame: Cycle 1 Day 1 up to a maximum of 198.9 weeks
Other outcomes:
Locations:
city: Boston
country: United States
facility: Dana Farber Cancer Institute
state: Massachusetts
city: Columbus
country: United States
facility: The Ohio State University
state: Ohio
city: Brno
country: Czechia
facility: Fakultní nemocnice Brno
city: Hradec Králové
country: Czechia
facility: Fakultní nemocnice Hradec Králové
city: Ostrava
country: Czechia
facility: Fakultní nemocnice Ostrava
city: Praha
country: Czechia
facility: Všeobecná fakultní nemocnice
city: Brest
country: France
facility: Hôpital Morvan
city: Le Mans
country: France
facility: Centre Jean Bernard - Clinique Victor Hugo
city: Nantes
country: France
facility: Hôpital privé du Confluent
city: Pierre-Bénite
country: France
facility: Centre Hospitalier Lyon Sud
city: Villejuif
country: France
facility: Centre Hospitalier Universitaire Institut Gustave Roussy
city: Badalona
country: Spain
facility: Hospital Universitai Germans Trias i Pujol
city: Barcelona
country: Spain
facility: Hospital de la Santa Creu i Sant Pau
city: Madrid
country: Spain
facility: Hospital Universitario 12 de Octubre
city: Salamanca
country: Spain
facility: Complejo Hospitalario de Salamanca
city: Santander
country: Spain
facility: Hospital Universitario Marques de Valdecilla
Study officials:
References: