| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis |
| Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis |
| Relapsed or Refractory Systemic Light Chain (AL) Amyloidosis |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
To determine whether dexamethasone plus Ixazomib improves hematologic response (PR + VGPR + CR) versus a physician’s choice of a chemotherapy regimen as selected from the list of offered treatment options in patients diagnosed with
relapsed or refractory AL amyloidosis.
To determine whether dexamethasone plus Ixazomib improves 2-year vital organ (that is, heart or kidney) deterioration and mortality rate versus a physician’s choice of a chemotherapy regimen as selected from the list of offered treatment options in
patients diagnosed with relapsed or refractory AL amyloidosis. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to end-stage renal disease (ESRD) with the need for maintenance dialysis or renal transplantation. |
|
| E.2.2 | Secondary objectives of the trial |
Key secondary objectives:
To determine OS
To determine the complete hematologic response rate
The protocol provides details of further secondary objectives. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Male or female patients 18 years or older.
2. Biopsy-proven diagnosis of AL amyloidosis according to the following standard criteria:
a. Histochemical diagnosis of amyloidosis, as based on tissue specimens with Congo
red staining with exhibition of an apple-green birefringence
b. If clinical and laboratory parameters insufficient to establish AL amyloidosis or in
cases of doubt, amyloid typing may be necessary (see Section 15.1)
3. Measurable disease as defined by serum differential free light chain concentration
(dFLC, difference between amyloid forming [involved] and nonamyloid forming
[uninvolved] free light chain [FLC]) ≥ 50 mg/L).
4. Objective, measurable major (cardiac or renal ) organ amyloid involvement as defined as follows (amyloid involvement of at least 1 required):
a. Cardiac involvement is defined as the presence of a mean left ventricular wall
thickness on echocardiogram greater than 12 mm in the absence of
other potential causes of left ventricular hypertrophy (controlled hypertension is allowed) with a non cardiiac biopsy showing amyloid, or a positive cardiac biopsy in the presence of clinical or laboratory evidence of involvement. If there is isolated cardiac involvement, then typing of amyloid deposits is recommended.
b. Renal involvement is defined as proteinuria (predominantly albumin) > 0.5 g/day in
a 24- hour urine collection
Note: Amyloid involvement of other organ systems is allowed, but not required.
5. Must be relapsed or refractory after 1 or 2 prior therapies.
For this protocol, relapsed is defined as PD documented more than 60 days after last
dose; refractory is defined as documented absence of hematologic response or
hematologic progression on or within 60 days after last dose of prior therapy.
a. Patient must not have been previously treated with proteasome inhibitors. (The sponsor reserves the right to open the study to proteasome inhibitor-exposed patients in the future, at some time point after the first IA. In that case, the patient may not be refractory to proteasome inhibitor therapy.)
b. Given that the physician may select from an offered list of regimens to treat a
specific patient, the patient may be refractory to an agent/s listed within the list of offered treatment choices
c. Must have recovered (ie, ≤ Grade 1 toxicity or patient’s baseline status) from the reversible effects of prior therapy
d. If a patient has received a transplant as his/her first-line therapy, he/she must be
at least 3 months posttransplantation and recovered from the side effects of the
stem cell transplant
6. Patient must meet criteria for 1 of the following AL Amyloidosis Risk Stages (as defined
by NT-proBNP cut off of < 332 pg/mL and troponin T cut-off of 0.035 ng/mL as
thresholds):
a. Stage 1: both NT-proBNP and troponin T under threshold
b. Stage 2: either NT-proBNP or troponin T [but not both] over threshold;
c. Stage 3: both NT-proBNP and troponin T over threshold (but NT-proBNP
< 8000 pg/mL)
7. ECOG Performance Status ≤ 2
8. Clinical laboratory values:
a. Absolute neutrophil count ≥ 1000/μL
b. Platelet count ≥75,000/μL
c. Total bilirubin ≤ 1.5 x ULN except for patient with Gilber't syndrome as defined by > 80% unconjugated bilirubin and total bilirubin <= 6 mg/dL
d. Alkaline phosphatase ≤ 5 x ULN,
e. ALT or AST ≤3 x ULN
f. Calculated creatinine clearance ≥ 30 mL/min
9. Female patients who:
a. If they are of childbearing potential, agree to practice 2 effective methods of
contraception, at the same time, from the time of signing the informed consent
through 90 days after the last dose of study treatment, AND
b. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
c.Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
Male patients, even if surgically sterilized (ie, status post vasectomy), who:
a. Agree to practice effective barrier contraception during the entire study treatment period and through 90 days after the last dose of study drug, AND
b. Must also adhere to the guidelines of any treatment-specific pregnancy prevention program, if applicable, OR
c. Agree to practice true abstinence when this is line with the preferred and usual lifestyle of the subject. (Periodic abstinence [eg, calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are not acceptable methods of contraception.)
10. Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
|
|
| E.4 | Principal exclusion criteria |
Prospective patients will be excluded from this study if they meet ANY of the following
criteria:
1. Amyloidosis due to mutations of the transthyretin gene or presence of other
non-AL amyloidosis.
2. Female patients who are lactating, breastfeeding, or pregnant.
3. Medically documented cardiac syncope, uncompensated NYHA Class 3 or 4 congestive heart failure (Section 15.6), myocardial infarction within the previous 6 months, unstable angina pectoris, clinically significant repetitive ventricular arrhythmias despite antiarrhythmic treatment, or severe orthostatic hypotension or clinically important autonomic disease.
4. Clinically overt multiple myeloma,, according to the IMGW criteria with at least 1 of the following:
a. Bone lesions
b. Hypercalcemia, defined as a calcium of > 11 mg/dL
5. Inability to swallow oral medication, inability or unwillingness to comply with the drug administration requirements, or GI procedure that could interfere with the oral
absorption or tolerance of treatment.
6. Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational or which would be considered as a treatment of AL amyloidosis. However, patients may be on chronic steroids (maximum dose 20 mg/day prednisone or equivalent [Section 15.7]) if they are being given for
disorders other than amyloidosis (eg, adrenal insufficiency, rheumatoid arthritis, etc.).
7. Comorbid systemic illnesses or other severe concurrent disease which, in the judgment of the investigator, would make the patient inappropriate for entry into this study or interfere significantly with the proper assessment of safety and toxicity of the prescribed regimens.
8. Ongoing or active infection, known HIV positive, active hepatitis B or C infection.
9. Psychiatric illness/social situations that would limit compliance with study requirements.
10. Known allergy to boron, MLN9708, any of the study treatments, their analogues, or
excipients.
11. Systemic treatment with strong CYP3A inducers (rifampin, rifapentine, rifabutin, carbamazepine, phenytoin, phenbarbital), or use of Ginkgo biloba ot St. John's wort within 14 days before the first dose of study treatment.
12. Diagnosed or treated for another malignancy within 3 years before study enrollment or previously diagnosed with another malignancy and have any evidence of residual disease. Patients with nonmelanoma skin cancer or carcinoma in situ of any type are not excluded if they have undergone complete resection. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Overall hematologic (CR + VGPR + PR) response rate based on central laboratory results and the 2010 International Society of Amyloidosis (ISA) Consensus Criteria as evaluated by an Adjudication Committee (AC)
2-year vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney deterioration is defined as progression to end-stage renal disease (ESRD) with the
need for maintenance dialysis or renal transplantation. Vital organ deterioration will be evaluated by an AC. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Timepoints are also assessed at screening
Serum M-protein/FLC: D1 until PD, EOT; every 6wks during PFS
Urine M-protein: C1D1, as clinically indicated, EOT; every 12wks during PFS
IgG/immunofixation: PD, EOT, as clinically indicated
Skeletal survey: as clinically indicated
Bone marrow: as clinically indicated, confirm CR
Total protein: D1/C3, D1/QC3 until PD, EOT, every 12wks in fu
Cardiac Markers: D1/ C2, D1/C3, D1/QC3 until PD, EOT, every 6wks in fu
ECG: D1/C2, EOT
ECHO: D1/C3, D1/QC3 until PD, EOT, every 12wks in fu
NYHA: D1/C2, D1/C3, D1 of subsequent cycles until PD, EOT, every 12wks in fu
Serum albumin/calculated creatinine CL/eGFR: D1/C3, D1/QC3 until PD, EOT, every 12wks in fu
CT/MRI/Alkaline phosphatase/ALT: D1/C3, QC3 until PD, EoT, every 12wks in fu |
|
| E.5.2 | Secondary end point(s) |
The key secondary endpoints are:
Complete hematologic response rate (CR) according to central laboratory results and ISA criteria as evaluated by an AC
OS, measured as the time from randomization to the date of death
Other secondary endpoints are:
PFS, defined as the time from the date of randomization to the date of first
documentation of disease progression (hematologic PD or major organ progression [specifically involvement of heart or kidney] whichever occurs first) according to central laboratory results and ISA criteria as evaluated by an AC, or death due to any cause, whichever occurs first
Hematologic disease PFS, defined as the time from the date of randomization to the
date of first documented hematologic disease progression according to central
laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, whichever occurs first
Time to vital organ (that is, heart or kidney) deterioration and mortality rate. Cardiac deterioration is defined as the need for hospitalization for heart failure. Kidney
deterioration is defined as progression to ESRD with the need for maintenance
dialysis or renal transplantation.
Best response in the vital organs allowed at study entry (heart and kidney) according
to central laboratory results and International Society of Amyloidosis criteria as evaluated by an AC.
Vital organ PFS, defined as the time from the date of randomization to the date of
first documentation of progression of vital organ (that is, heart or kidney) according
to central laboratory results and ISA criteria, as evaluated by an AC, or death due to any cause, whichever occurs first
Duration of hematologic response, measured as the time from the date of first
documentation of hematologic response to the date of first documented hematologic
disease progression, respectively according to central laboratory results and ISA
criteria as determined by an AC
Adverse events (AEs), serious adverse events (SAEs), and assessments of clinical
laboratory values
TTF, defined as the time from the date of randomization to the date of first
documented treatment failure. Treatment failure is defined as : 1) death due to any
cause; 2) hematologic progression or major organ progression according to central laboratory results and ISA criteria as evaluated by an AC; 3) clinically morbid organ disease requiring additional therapy; or 4) withdrawn for any reason
Time to subsequent anticancer treatment, defined as the time from the date of randomization to the start date of subsequent anticancer treatment
QOL from patient-reported outcomes instruments (changes from baseline in health status based on SF-36 v2 survey, the FACT/GOG-Ntx, and a symptom scale
questionnaire
Collection of Health Utilization (HU) related to the disease and the therapy in both treatment arms and the EQ-5D questionnaire data.
Plasma concentration-time data to contribute to future population PK analysis
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
OS-every 12wks in follow-up
PFS-every 6wks in follow-up
AEs-first dose until 30 days after last dose
SAEs-informed consent until 30 days after last dose
PK-C1/D1 (1h & 4h post dose), C1/D14, C2/pre-dose, C2/D14; C3 to C10 (predose)
As well as the timepoints provided, all the below are assessed at screening.
ECOG-D1 all cycles, EOT, every 6wks in follow-up
SF36v2-D1/C1, D1 QC3 until PD, EOT, every 6wks in follow-up
FACT/GOG-Ntx/Symptom Scale-D1 all cycles, EOT, every 6wks in follow-up
EQ5D-D1 all cycles, EOT, every 6wks in follow-up
Serum free light chains-D1/C2, D1/C3, D1 subsequent cycles until PD, EOT, every 6wks in follow-up
AL Amyloidosis Symptoms-D1 all cycles, EOT, every 6wks in follow-up
A full list of procedures is presented in the Schedule of Events. |
|
| 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 | No |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| 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) | No |
| E.7.3 | Therapeutic confirmatory (Phase III) | Yes |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | Yes |
| E.8.1.1 | Randomised | Yes |
| 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) | Yes |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 2 |
| 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 | 31 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Australia |
| Brazil |
| Canada |
| China |
| Denmark |
| France |
| Germany |
| Greece |
| Israel |
| Italy |
| Japan |
| Korea, Republic of |
| Netherlands |
| Turkey |
| Ukraine |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| 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
|
The duration of the study will be approximately 112 month (ie 9.3 years), including 84 months fo renrollinment and 28 months of follow-up after the last patient is enrolled. All patients included in the analysis for the second primary endpoint will have the opportunity to be followed for a minimum of 2 years.
The final analysis of the clinicalstudy report will be conducted after the required number of OS events is reached and estimated at approximately 112 months. |
Studiet var ca 112 måneder (9,3 år) inklusiv 84 måneder til indrullering og 28 måneders opfølgning. All patienter som indgår i analysen vedrørende anden primære endepunkt wil have mulighed for at blive flugt i minimum 2 år.
Den endelige analyse af den kliniske forsøgsrapport vil blive udført efter det nødvendige antal af OS events er nået, hvilket skønnes at tage ca 112 måneder. |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 9 |
| E.8.9.1 | In the Member State concerned months | 4 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 9 |
| E.8.9.2 | In all countries concerned by the trial months | 4 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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