Clinical trial NCT03136653: A Phase 2 Trial of MP0250 Plus Bortezomib + Dexamethasone in Patients With Multiple Myeloma
Official title: A Phase 2 Open-label, Single-arm, Multicenter Trial of MP0250 Plus Bortezomib + Dexamethasone in Patients With Refractory and Relapsed Multiple Myeloma
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE1
PHASE2
Conditions: Multiple Myeloma in Relapse
Keywords: DARPin
MP0250
VEGF
HGF
RRMM
Lead sponsor: Molecular Partners AG
Sponsor class: INDUSTRY
First posted: 2017-05-02
Enrollment: 33
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to assess the efficacy, safety, tolerability, pharmacokinetics (PK), immunogenicity and efficacy of MP0250 in combination with bortezomib + dexamethasone in patients with refractory and relapsed multiple myeloma (RRMM).

MP0250 is a multi-DARPin® drug candidate with three specificities, able to simultaneously neutralize the activities of vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) and also to bind to human serum albumin (HSA) to give an increased plasma half-life and potentially enhanced tumor penetration.


Eligibility criteria: Inclusion Criteria:

1. Patients with MM who have received:

   * Part 1 ≥2 lines of therapy (including bortezomib and an IMiD) and have shown no response (i.e. stable disease) to, have progressed on the most recent treatment or have progressed within 60 days of the most recent therapy
   * Part 2 ≥2 lines of prior therapy that included a proteasome inhibitor (bortezomib, carfilzomib or both) and an IMiD (thalidomide, lenalidomide and/or pomalidomide) either alone or in combination and a response no better than SD lasting at least 4 months on a bortezomib- or carfilzomib-based regimen as last line of therapy or progression on treatment or within 60 days of stopping a bortezomib- or carfilzomib-based regimen as last line of therapy. Note: For transplant-eligible patients enrolled to Part 1 or Part 2, induction plus conditioning chemotherapy/ASCT +/- maintenance therapy constitute one regimen.
2. Presence of a measurable disease with at least one of the following criteria:

   * Serum M protein ≥0.5 g/dL, or
   * Urine M protein ≥200 mg/24 h, or
   * Involved serum free light chain (FLC) levels \>100 mg/L and abnormal kappa/lambda (κ/λ) ratio in patients without detectable serum or urine M protein, or
   * For patients with immunoglobulin A (IgA) myeloma whose disease can only be reliably measured by quantitative immunoglobulin measurement, a serum IgA level ≥0.5g/dL.
3. Eastern Cooperative Oncology Group (ECOG) performance status (0 to 1)
4. Life expectancy \>3 months
5. Adequate hepatic function at Screening, with aspartate aminotransferase (AST) and alanine aminotransferase (ALT) \<3x ULN and total bilirubin \<2 x upper limit of normal (ULN). For patients with Gilbert's syndrome (Gilbert-Meulengracht syndrome), higher bilirubin of 5 x ULN is acceptable
6. Absolute neutrophil count (ANC) ≥1000/mm3 at Screening. Screening ANC must be independent of growth factor support for ≥1 week
7. Hemoglobin ≥8.0 g/dL at Screening. Use of erythropoietic stimulating factors and red blood cell (RBC) transfusions per institutional guidelines is allowed, however most recent RBC transfusion must not have been done within 7 days prior to obtaining screening hemoglobin
8. Platelet count ≥50 000/mm3 at Screening. Patients must not have received platelet transfusions for at least 1 week prior to obtaining the screening platelet count
9. Calculated or measured creatinine clearance (CrCl) of ≥ 45 mL/min at Screening based on the Cockcroft and Gault formula
10. Serum albumin concentration ≥ 25 g/L. Note: Patients with lower levels of serum albumin at baseline may receive albumin supplementation to comply with this criterion
11. Males and females ≥18 years of age
12. Male Participants: A male participant must agree to use a highly effective contraception
13. Female Participants: A female participant is eligible to participate if she is not pregnant, not breastfeeding, and at least one of the following conditions applies:

    1. Not a woman of childbearing potential (WOCBP) OR
    2. A WOCBP who agrees to follow contraceptive guidance from the Screening visit, during the treatment period and for at least 3 months after the last dose of study treatment
14. Capable of giving signed informed consent

Exclusion Criteria:

1. Patients with the following diseases:

   * Monoclonal gammopathy of undetermined significance (MGUS) of non- immunoglobulin (Ig)M and IgM subtypes,
   * Light chain MGUS,
   * Solitary plasmacytoma (alone or with minimal marrow involvement),
   * Systemic Ig light chain amyloidosis,
   * Waldenstrom's Macroglobulinemia,
   * Myelodysplastic syndrome,
   * Plasma cell leukemia defined as a plasma cell count \>2000/mm3
   * Polyneuropathy, organomegaly endocrinopathy, monoclonal protein, and skin changes (POEMS) syndrome
2. Peripheral neuropathy Grade 2 or higher at Screening or patients with a history of Grade 3/4 neuropathy or Grade 2 with pain
3. Prior or concurrent malignancy, except for: Adequately treated basal cell or squamous cell skin cancer, carcinoma in-situ of the cervix or breast or very low and low risk prostate cancer in active surveillance or any other cancer from which the patient has been disease-free for \>5 years
4. Active congestive heart failure (New York Heart Association \[NYHA\] Class III to IV), symptomatic cardiac ischemia, or conduction abnormalities uncontrolled by conventional intervention. Myocardial infarction within 6 months prior to screening
5. Uncontrolled hypertension (defined as systolic blood pressure (SBP) \>150 mm Hg diastolic blood pressure (DBP) \>100 mm Hg despite antihypertensive medication)
6. Stroke, or transient ischemic attack within 6 months of Screening, clinically significant bleeding and vascular disease
7. Abdominal fistula, gastrointestinal perforation, or intra-abdominal abscess within the past 6 months
8. Significant concurrent, uncontrolled medical condition including, but not limited to, severe wound healing complication, renal (except related to MM), hepatic, hematological except MM, gastrointestinal, endocrine, pulmonary, neurological, cerebral or psychiatric disease
9. Acute active infection requiring systemic antibiotics, antiviral (except antiviral therapy directed at hepatitis B) or antifungal agents within 14 days prior to screening
10. Clinical signs of or documented leptomeningeal or cerebral involvement of MM
11. Treatment with ixazomib as last line of therapy in Part 2
12. Therapy with approved or investigational anticancer therapeutics within 21 days (or in the case of nitrosureas, within 6 weeks) prior to treatment (except anti-myeloma treatment with a carfilzomib- or bortezomib-based regimen in Part 2) Note: Patients must have recovered from pre-existing, treatment-related adverse events to Grade 1 or lower
13. Autologous stem cell transplantation (ASCT) within 12 weeks before the date of enrollment
14. Prior allogeneic stem cell transplantation with active graft-versus-host-disease
15. Major surgery within 21 days prior to Screening
16. Immunotherapy within 21 days prior to Screening
17. Newly initiated therapy with bisphosphonate or RANKL (within two months prior to Screening). Patients on stable regimen with bisphosphonate or receptor activator of nuclear kappa-B ligand (RANKL)-inhibitor therapy over 2 months can continue these treatments at the same dose. No new therapy with bisphosphonate/RANKL inhibitor is allowed during the study
18. Radiation therapy within 2 months of Cycle 1, Day 1 is not permitted Except for local low-dose, palliative radiation to bone lesions for pain control.
19. Patients who have received treatment with any non-marketed product within 21 days prior to treatment start
20. Current participation in any other interventional clinical study
21. Patients known or suspected of not being able to comply with a study protocol (e.g. due to alcoholism, drug dependency or psychological disorder)
22. Known infection with human immunodeficiency virus or serologic status reflecting active hepatitis B or hepatitis C virus infection as follows:

    * Not receiving or not responding to anti-viral therapy.
    * HCV RNA detected
23. Patients with contraindication to dexamethasone or bortezomib according to the applicable local product label
24. Known hypersensitivity to components of the investigational product, for example, histidine buffer or the Tween diluent

Primary outcomes:
measure: Part 1: Overall Response Rate (ORR)
timeFrame: 24 months
measure: Part 2: ORR
timeFrame: 24 months
Secondary outcomes:
measure: Number of Participants Who Experienced One or More Treatment-Emergent Adverse Events
timeFrame: 24 months
measure: Number of Participants who Experienced One or More Treatment-Emergent SAEs
timeFrame: 24 months
measure: Number of Participants Who Experienced One or More Common Terminology Criteria for Adverse Events (CTCAE) Grade ≥ 3 Adverse Events
timeFrame: 24 months
measure: Number of Participants with a Clinical Significant Change from Baseline in Laboratory Results
timeFrame: 24 months
measure: Number of Participants with a Clinically Significant Change from Baseline in Vital Signs
timeFrame: 24 months
measure: Number of Participants with a Clinically Significant Change from Baseline in Electrocardiogram (ECG) Results
timeFrame: 24 months
measure: Number of Participants with a Positive Anti-drug Antibody (ADA) Result
timeFrame: 24 months
measure: Titer of Anti-drug Antibodies (ADA)
timeFrame: 24 months
measure: Time Course of Anti-drug Antibodies
timeFrame: 24 months
measure: Duration of Response (DOR)
timeFrame: 24 months
measure: Progression Free Survival (PFS)
timeFrame: 24 months
Other outcomes:
Locations:
city: Wien
country: Austria
facility: Hanusch Krankenhaus Wiener Gebietskrankenkasse
state: Vienna
city: Salzburg
country: Austria
facility: Landeskliniken Salzburg Saint Johanns-Spital
city: Brno
country: Czechia
facility: Fakultní Nemocnice Brno
state: Jihormoravsky Krav
city: Ostrava - Poruba
country: Czechia
facility: Fakultní Nemocnice Ostrava
state: Severomoravsky KRAJ
city: Odense C
country: Denmark
facility: Odense University Hospital
city: Vejle
country: Denmark
facility: Vejle Sygehus
city: Hamburg-Altona
country: Germany
facility: Asklepios Klinik Altona
state: Hamburg
city: Dresden
country: Germany
facility: Universitätsklinikum Dresden
state: Sachsen
city: Essen
country: Germany
facility: Universitaetsklinikum Essen
city: Heidelberg
country: Germany
facility: Universitätsklinikum Heidelberg
city: Leipzig
country: Germany
facility: Universitätsklinikum Leipzig
city: Münster
country: Germany
facility: Universitätsklinikum Münster
city: Würzburg
country: Germany
facility: Universitätsklinikum Würzburg
city: Bari
country: Italy
facility: Azienda Ospedaliera Policlinico di Bari
city: Bologna
country: Italy
facility: Azienda Ospedaliero Universitaria di Bologna Policlinico Sant'Orsola-Malpighi
city: Reggio Emilia
country: Italy
facility: Arcispedale Santa Maria Nuova
city: Roma
country: Italy
facility: Fondazione Policlinico Universitario Agostino Gemelli
city: Torino
country: Italy
facility: Azienda Ospedaliera Città della Salute e della Scienza di Torino
city: Chorzów
country: Poland
facility: Samodzielny Publiczny Zakład Opieki Zdrowotnej Zespół Szpitali Miejskich
state: Slaskie
city: Gdańsk
country: Poland
facility: Uniwersyteckie Centrum Kliniczne
city: Kraków
country: Poland
facility: Szpital Uniwersytecki w Krakowie
city: Lublin
country: Poland
facility: Centrum Onkologii Ziemi Lubelskiej
city: Opole
country: Poland
facility: Szpital Wojewódzki w Opolu
city: Warszawa
country: Poland
facility: Instytut Hematologii i Transfuzjologii
Study officials:
References: