| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Multiple myeloma (MM) is a relatively rare (114 000 new cases worldwide in 2012, i.e. 0.8% of total cancer cases [Cancer Research UK Incidence Statistics 2016]) blood cancer for which there is no cure. Treatment options rather mitigate symptoms and defer end-stage disease. MM cells have a tendency to clonally evolve which results in development of drug resistance, and patients eventually relapse. |
|
| E.1.1.1 | Medical condition in easily understood language |
| Multiple myeloma is a blood cancer characterized by expansive growth of plasma cells which leads to anemia, bleedings, severe infections, kidney-injuries and other complications and finally to death |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
Primary
Part 1 (Part 1 is completed)
- Estimate the efficacy of MP0250 plus bortezomib+dexamethasone,
based on overall response rate (ORR), in patients with MM who have
received ≥2 lines of therapy, including bortezomib and an
Immunomodulatory Drug (IMiD), and have shown no response to, or
have progressed on the most recent treatment, or within 60 days of the
most recent therapy.
Part 2
- To assess the preliminary efficacy of MP0250 in combination with
bortezomib plus dexamethasone in patients with refractory MM who
have received ≥2 lines of therapy including a proteasome inhibitor
(bortezomib, carfilzomib or both) and an IMiD (thalidomide,
lenalidomide and/or pomalidomide) either alone or in combination and
whose last line of therapy is either a bortezomib-or carfilzomib-based
regimen. |
|
| E.2.2 | Secondary objectives of the trial |
-Determine the safety profile of MP0250 plus bortezomib+dexamethasone
-Characterize the immunogenicity of MP0250
-Estimate the efficacy of MP0250 in combination with bortezomib+dexamethasone in terms of progression free survival (PFS) and duration of response (DOR)
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Participants are eligible to be included in the study only if all of the
following criteria apply:
Type of Participant and Disease Characteristics
1. Patients with MM who have received:
Part 1 (Completed)
- ≥2 lines of therapy (including bortezomib and an IMiD), and
- Have shown no response (i.e. stable disease) to, or
- Have progressed in 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 bortezomibor
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. Measured or calculated creatinine clearance (CrCl) of ≥ 45 mL/min at
Screening based on the Cockcroft and Gault formula:
(140 - Age) x Mass (kg) / (72 x Creatinine mg/dL); multiply result by
0.85 if female
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.
Sex
11. Males and females ≥18 years of age
NOTE: The reliability of sexual abstinence for male and/or female enrollment eligibility needs to be evaluated in relation to the duration of
the clinical study and the preferred and usual lifestyle of the participant.
Periodic abstinence (for example, calendar, ovulation, symptothermal, or
postovulation methods) and withdrawal are not acceptable methods of
contraception.
12. Male Participants: A male participant must agree to use a highly
effective contraception from the Screening visit, during the treatment
period and for at least 3 months after the last dose of study treatment
and refrain from donating sperm during this period.
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:
a. Not a woman of childbearing potential (WOCBP)
OR
b. A WOCBP who agrees to follow the contraceptive guidance from the
Screening visit, during the treatment period and for at least 3 months
after the last dose of study treatment
Informed Consent
14. Capable of giving signed informed consent which includes
compliance with the requirements and restrictions listed in the patient
information sheet (PIS)/informed consent form (ICF) and in this
protocol. |
|
| E.4 | Principal exclusion criteria |
Patients are excluded from the study if any of the following criteria
apply:
Medical Conditions
1. Patients with the following diseases:
- Monoclonal gammopathy of undetermined significance (MGUS) of nonimmunoglobulin (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
Prior/Concomitant Therapy
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.
Prior/Concurrent Clinical Study Experience
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)
Diagnostic Assessments
22. Known infection with human immunodeficiency virus or serologic
status reflecting active hepatitis B or hepatitis C virus infection as
follows:
Eligible:
HIV: Antibody (-)
HBV: HBsAg (-) and anti-HBc (-): anti-HBs (-)/anti-HBc (+); Responding
to approved anti-viral therapy with documented reductions in HBV viral
titers.
HCV: Antibody (-) or Antibody (+); HCV RNA "not detected" (<15
IU/mL); monthly monitoring of HCV RNA recommended
Not Eligible:
HIV: Antibody (+)
HBV: HBsAg (+) and/or anti-HBs (-)/anti-HBc (+); Not receiving or not
responding to anti-viral therapy.
HCV: Antibody (+); HCV RNA detected
Other Exclusions
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 |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part 1
- ORR defined as the proportion of patients achieving a complete response (CR), very good partial response (VGPR), or partial response (PR) during treatment with MP0250 plus bortezomib+dexamethasone determined by the Investigator
(Response subcategories: as defined by the International Myeloma Working Group [IMWG])
Part 2
- The primary efficacy endpoint is ORR defined as the proportion of
patients achieving a complete response (CR), very good partial response
(VGPR), or partial response (PR) during treatment with MP0250 in
combination with bortezomib+dexamethasone as determined by the
Investigator (Response subcategories: as defined by the International
Myeloma Working Group [IMWG]) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| evaluations - on day 1 of each treatment cycle and after 8th cycle of treatment (week 24) |
|
| E.5.2 | Secondary end point(s) |
Type, frequency and severity of adverse events (AEs) based on Common
Terminology Criteria for Adverse Events (CTCAE) version 4.03; changes
from baseline in selected laboratory analytes, vital signs and
electrocardiogram (ECG) findings
Incidence, titer and time-course of anti-drug antibodies (ADAs)
PFS (time from first study treatment until progression or death from
myeloma with deaths from other causes censored) and DOR (duration
from first observation of PR or better until disease progression or death
from myeloma with deaths from other causes censored) |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| evaluations - on day 1 of each treatment cycle and after 8th cycle of treatment (week 24) |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| E.7.1.3.1 | Other trial type description | |
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 3 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 25 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | No |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.7 | Trial has a data monitoring committee | No |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
| EoT Visit will occur between 28 and 35 days after the last study treatment. Patients who discontinue study treatment for reasons other than progression will continue to undergo every 28-day response assessments until they progress, withdraw consent or initiate new antimyeloma therapy. The EoS will occur when the last patient enrolled in Part 2 has completed 8 cycles or discontinued study treatment. Patients will be FU for OS until death, loss to FU or for 2 years after the last dose of MP0250 |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 6 |
| E.8.9.1 | In the Member State concerned days | |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 6 |
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