A PK Study of Melphalan During Treatment With Melphalan Flufenamide (Melflufen) and Dex in RRMM Pat With Impaired Renal Function
Study Details
Study Description
Brief Summary
This is a multicenter, PK study of Melphalan during treatment with Melflufen and Dexamethasone in patients with RRMM and impaired renal function. Received 2 - 4 prior lines of therapy and a renal function (creatinine clearance by Cockcroft-Gault formula) between ≥30 mL/min to <45 mL/min in Cohort 1,and ≥15 mL/min to <30 mL/min in Cohort 2.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 2 |
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| Experimental: Single arm Cohort 1A Melphalan flufenamide 40 mg iv Day 1 of each 28 day cycle Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle. If > 75 years of age 20 mg. Cohort 1B Melphalan flufenamide 30 mg iv Day 1 of each 28 day cycle Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle. If > 75 years of age 20 mg. Cohort 2A Melphalan flufenamide 20 mg iv Day 1 of each 28 day cycle Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle. If > 75 years of age 20 mg. Cohort 2B Melphalan flufenamide 30 mg iv Day 1 of each 28 day cycle Dexamethasone 40 mg po Day 1,8, 15 and 22 of each 28 day cycle. If > 75 years of age 20 mg. |
Drug: Melphalan flufenamide (melflufen)
intravenous infusion
Drug: Dexamethasone
oral tablets
|
Outcome Measures
Primary Outcome Measures
- Pharmakokinetics tmax [Cycle 1 and 2 - three measurements post infusion. At Day 1 of each cycle (28 days cycles)]
Primary objective is to evaluate the relationship between renal function and the PK. Several PK parameters will be assessed. • Time of maximum observed concentration (tmax)
- Pharmakokinetics Cmax [Cycle 1 and 2 - three measurements post infusion. At Day 1 of each cycle (28 days cycles)]
• Maximum observed concentration (Cmax)
- Pharmakokinetics AUC0-t [Cycle 1 and 2 - three measurements post infusion. At Day 1 of each cycle (28 days cycles)]
• Area under the concentration versus time curve between 0h and end of drug infusion (AUC0-t)
- Pharmakokinetics AUCinf [Cycle 1 and 2 - three measurements post infusion. At Day 1 of each cycle (28 days cycles)]
• Area under the concentration versus time curve from 0h to infinity (AUCinf)
- Pharmakokinetics t1/2 [Cycle 1 and 2 - three measurements post infusion. At Day 1 of each cycle (28 days cycles)]
• Elimination phase half-life (t½)
- Pharmakokinetics CL [Cycle 1 and 2 - three measurements post infusion. At Day 1 of each cycle (28 days cycles)]
• Clearance (CL) parameters for melphalan during treatment with melflufen
- Incidence of Treatment Emergent Adverse Events (Safety and Tolerability) [From screening to 30 days after last dose]
Primary objective is to assess the safety and tolerability of melflufen in patients with moderate renal impairment
Secondary Outcome Measures
- ORR [From initiation of therapy until disease progression. For an average patient this is achieved within 6 months.]
To assess the best tumor response as well as overall response rate
- PFS [From initiation of therapy until disease progression or initiation of new therapy. For an average patient thius is reached after 6 month.]
To assess progression free survival
- DOR [From confirmed response until disease progression. For an average patient this last for approximatel 8-9 months.]
To assess duration of response (DOR) in patients with ≥ PR (stringent complete response (sCR), complete response (CR), very good partial response (VGPR), PR) as best response
- CBR [During treatment, for an average patient this is approximately 6 months]
To assess clinical benefit rate (CBR) and duration of clinical benefit (i.e., proportion of patients with ≥ MR) as best response
- TTR [From initiation of therapy until documented disease response. For an average patient this is achieved within 6 months.]
To assess time to response (TTR) in patients with a PR or better
Eligibility Criteria
Criteria
Inclusion Criteria:
-
Male or female, age 18 years or older
-
A prior diagnosis of MM with documented disease progression
-
2 - 4 prior lines of therapy
-
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)
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Serum free light chain (SFLC) ≥ 10 mg/dL AND abnormal serum kappa to lambda free light chain ratio
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Life expectancy of ≥ 6 months
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ECOG performance status ≤ 2. (Patients with lower performance status based solely on bone pain secondary to MM may be eligible following consultation and approval of the medical monitor)
-
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
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Ability to understand the purpose and risks of the study and provide signed and dated informed consent.
-
12-lead Electrocardiogram (ECG) with QT interval calculated by Fridericia Formula (QTcF) interval of ≤ 470 msec
-
Renal function: Estimated eGFR by CKD-EPI formula between ≥30 mL/min to <45 mL/min at screening and at Cycle 1 Day 1 for cohort 1A and 1B, between ≥15 mL/min to < 30 mL/min for cohort 2A and 2B.
-
The following laboratory results must be met during screening 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 study therapy)
-
Platelet count ≥ 75,000 cells/mm3 (75 x 109/L) (without transfusions during the 10 days prior to initiation of study therapy)
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Hemoglobin ≥ 8.0 g/dL (red blood cell [RBC] transfusions are permitted)
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Total Bilirubin ≤ 1.5 x upper limit of normal (ULN), or higher in patients diagnosed with Gilberts syndrome that have been reviewed and approved by the medical monitor.
-
AST/SGOT and ALT/SGPT ≤ 3.0 x ULN.
- Must have, or be willing to have, an acceptable central catheter. (Port a cath, peripherally inserted central catheter [PICC] line, or central venous catheter)
- (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:
-
Primary refractory disease (i.e. never responded with ≥ MR to any prior therapy)
-
Evidence of mucosal or internal bleeding and/or platelet transfusion refractory (platelet count fails to increase by > 10,000 cells/mm3 [10.0 x 109/L] after a transfusion of an appropriate dose of platelets)
-
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),
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Known active infection requiring parenteral or oral anti-infective treatment within 14 days of initiation of therapy.
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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.
-
Pregnant or breast-feeding females
-
Serious psychiatric illness, active alcoholism, or drug addiction that may hinder or confuse compliance or follow-up evaluation
-
Known human immunodeficiency virus or active hepatitis B or C viral infection
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Concurrent symptomatic amyloidosis or plasma cell leukemia
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POEMS syndrome (plasma cell dyscrasia with polyneuropathy, organomegaly, endocrinopathy, monoclonal protein and skin changes)
-
Previous cytotoxic therapies, including cytotoxic investigational agents, for MM 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 corticosteroids within 14 days prior to initiation of study therapy. Other investigational therapies and monoclonal antibodies within 4 weeks of initiation of study therapy. Prednisone up to but no more than 10 mg orally 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 study therapy. Plasmapheresis is not permitted within 14 days of initiation of therapy.
-
Residual side effects to previous therapy > Grade 1 prior to enrollment (Alopecia any grade and/or neuropathy Grade 2 without pain are permitted)
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Prior peripheral stem cell transplant within 12 weeks of initiation of study therapy
-
Prior allogeneic stem cell transplantation with active graft-versus-host-disease.
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Prior major surgical procedure or radiation therapy within 4 weeks of the initiation of study therapy (this does not include limited course of radiation used for management of bone pain to be completed within 7 days of initiation of study therapy).
-
Known intolerance to steroid therapy
-
Prior renal transplant
-
Currently in need of renal dialysis
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | University Hospital Brno, Clinic of Internal Medicine - Hematology and Oncology | Brno | Czechia | ||
| 2 | University Hospital Olomouc, Clinic of Hemato-Oncology | Olomouc | Czechia | ||
| 3 | General University Hospital in Prague, 1st Internal Clinic - Clinic of Hematology | Praha | Czechia | ||
| 4 | General Hospital of Athens "Evangelismos" | Athens | Greece | ||
| 5 | General Hospital of Athens Alexandra, Therapeutic Clinic | Athens | Greece | ||
| 6 | University General Hospital of Patras | Patra | Greece | ||
| 7 | Nasz Lekarz Medical Outpatient Clinics Slawomir Jeka | Toruń | Torun | Poland | |
| 8 | Maria Sklodowska-Curie Institute of Oncology, Branch in Gliwice, Department of Bone Marrow Transplantation and Hematologic Oncology | Gliwice | Poland | ||
| 9 | Independent Public Healthcare Facility Municipal Hospitals, Department of Hematology | Katowice | Poland | ||
| 10 | Independent Public Teaching Hospital No.1 in Lublin, Department of Hematooncology, Bone Marrow Transplantation and Chemotherapy | Lublin | Poland |
Sponsors and Collaborators
- Oncopeptides AB
Investigators
None specified.Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- OP-107