| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| AL amyloidosis |
| Amiloidosi AL |
|
| E.1.1.1 | Medical condition in easily understood language |
| AL amyloidosis |
| Amiloidosi AL |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | PT |
| E.1.2 | Classification code | 10002022 |
| E.1.2 | Term | Amyloidosis |
| E.1.2 | System Organ Class | 10021428 - Immune system disorders |
|
| 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 assess the rate good quality (i.e. CR+VGPR) hematologic response at the completion of 6 cycles of Daratumumab plus pomalidomide in patients with R/R AL amyloidosis not in VGPR or better after any previous therapy. |
| Valutare la risposta ematologica (CR + VGPR) al completamento di 6 cicli di Daratumumab più pomalidomide in pazienti con amiloidosi ALricaduti o refrattari,che non hanno raggiunto VGPR o risposta migliore dopo una precedente linea di terapia |
|
| E.2.2 | Secondary objectives of the trial |
To determine safety and tolerability of Daratumumab plus pomalidomide (type, frequency, severity, drug discontinuation for toxicity or intolerance, dose modification/delay and relationship of adverse events to study treatment).
To assess in all patients
• Overall Hematologic Response Rate
• The Overall Hematologic Response Rate including PR at the completion of 6 cycles;
• The duration of hematologic response;
• The rate of organ response and organ improvement, according to standard criteria;
• The time to hematologic and organ response;
• The hematologic disease progression free survival (PFS) and 1-year PFS;
• The overall survival (OS) and 1-year OS;
• MRD negativity rate according to next generation flow cytometry.
To assess quality of life (QoL) using EQ5D-5L. |
Determinare la sicurezza e la tollerabilità di Daratumumab più pomalidomide.
Valutare in tutti i pazienti, in base alla storia della malattia
• Tasso di risposta ematologica generale (CR + VGPR + PR) al termine del 1 ° e del 3 ° ciclo;
• La percentuale di risposta ematologica complessiva comprendente PR al completamento di 6 cicli;
• La durata della risposta ematologica;
• Il tasso di risposta d'organo e il miglioramento d'organo, secondo criteri standard;
• Il tempo di risposta ematologica e d'organo;
• La sopravvivenza libera da progressione della malattia ematologica (PFS) e PFS a 1 anno;
• La sopravvivenza globale (OS) e la sopravvivenza a 1 anno;
• percentuale di pazienti che ottengono una negatività alla valutazione della malattia minima residua midollare secondo il protocollo di citometria (MRD by next generation flow).
Valutare la qualità della vita (QoL) usando il questionario EQ5D-5L. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Histologic diagnosis of AL amyloidosis;
2. Patients should have received at least one line (and no more than 3 lines) with an alkylating agentand/or a PIn and dexamethasone and not be in VGPR or CR at the time of inclusion (patients who
did not reach VGPR or patients in VGPR or better but with an hematological relapse can be included);
3. Measurable hematologic disease: difference between involved and uninvolved FLC > 20 mg/L with an abnormal ¿/¿ ratio;
4. Symptomatic organ involvement (heart, kidney, liver/GI tract, peripheral nervous system) (See attachment 1);
5. Wash-out period of at least 4 weeks from previous antitumor therapy or any investigational treatment or 5 half-lives from previous antibodies, whichever is longer. Treatment from previous therapy should be in accordance to the local clinical practice in which a 4 weeks period is required for the evaluation of response;
6. Adequate bone marrow function prior to 1st drug intake (C1D1), without transfusion or growth factor support within 5 days prior to 1st drug intake, defined as:
- Absolute neutrophils = 1000/mm3,
- Platelets = 50000/mm3,
- Hemoglobin = 9.0 g/dL,
7. Adequate organ function defined as:
- Serum SGOT/AST or SGPT/ALT < 3.0 X Upper Limit of the normal range (ULN),
- Serum total bilirubin level <1.5 x ULN, unless for subjects with Gilbert’s syndrome where the direct bilirubin should then be =2.0 x ULN.
8. Female patients who are postmenopausal for at least 1 year before the screening visit, or are surgically sterile, or if they are of childbearing potential, agree to practice effective methods of contraception from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from intercourse (serum pregnancy test has to be performed for all women of childbearing potential at the beginning of each cycle during the study. In addition, a pregnancy test may be done at any time during the study at the discretion of the investigator if a subject miss a period or has unusual menstrual bleeding);
9. 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. |
Diagnosi istologica di amiloidosi AL;
I pazienti devono aver ricevuto almeno una linea di terapia (e non più di 3 linee) con un agente alchilante e/o un inibitore del proteasoma e desametasone e non essere in VGPR o CR al momento dell'inclusione nel presente studio (pazienti che non hanno raggiunto VGPR o pazienti in VGPR o risposta migliore, ma con una ricaduta ematologica, possono essere inclusi);
Malattia ematologica misurabile;
Coinvolgimento di organi sintomatici (cuore, reni, fegato / tratto GI, sistema nervoso periferico);
Donne in post-menopausa da almeno 1 anno prima della visita di screening, o chirurgicamente sterili, o, se potenzialmente fertili, accettano di applicare metodi contraccettivi efficaci dal momento della firma del consenso informato a 30 giorni dall'ultima dose del farmaco in studio. |
|
| E.4 | Principal exclusion criteria |
1. Presence of non-AL amyloidosis;
2. AL amyloidosis with isolated soft tissue involvement;
3. Bone marrow plasma cells >30% and clinically symptomatic multiple myeloma with lytic bone lesions;
4. NT-proBNP > 8500 ng/L and hs-troponin I >100 ng/L (cardiac stage IIIb patients);
5. Repetitive ventricular arrhythmias on 24h Holter ECG despite anti-arrhythmic treatment, except if a pacemaker has been implanted;
6. Chronic atrial fibrillation with uncontrolled heart rate;
7. Supine systolic blood pressure <100 mmHg;
8. Subject is a woman who is pregnant, or breast-feeding, or planning to become pregnant;
9. Subjects with known chronic obstructive pulmonary disease or persistent asthma ;
10. Previous anti-CD38 or pomalidomide therapy;
11. Presence of other active malignancy with the exception of non-melanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate specific antigen is within normal
limit, or any completely resected carcinoma in situ;
12. Subjects with known/underlying medical conditions that, in the investigator’s opinion would make the administration of the study drug hazardous (ie: uncontrolled diabetes or uncontrolled coronary
artery disease);
13. Subject is:
o (Known to be) seropositive for human immunodeficiency virus (HIV)
o seropositive for hepatitis B (defined by a positive test for hepatitis B surface antigen [HBsAg]). Subjects with resolved infection (ie, subjects who are HBsAg negative but positive for antibodies to hepatitis B core antigen [anti-HBc] and/or antibodies to hepatitis B surface antigen [anti-HBs]) must be screened using real-time polymerase chain reaction (PCR) measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive will be excluded. EXCEPTION: Subjects with serologic findings suggestive of HBV vaccination (anti-HBs positivity as the only serologic marker) AND a known history of prior HBV vaccination, do not need to be tested for HBV DNA by PCR.
o (Known to be) seropositive for hepatitis C (except in the setting of a sustained virologic response [SVR], defined as aviremia at least 12 weeks after completion of antiviral therapy). |
Presenza di amiloidosi non AL;
Amiloidosi AL con coinvolgimento isolato dei tessuti molli;
Plasmacellule> 30% e mieloma multiplo clinicamente sintomatico con lesioni ossee litiche;
NT-proBNP> 8500 ng/L e hs-troponina I>100 ng/L (pazienti in stadio IIIb cardiaco);
Aritmie ventricolari ripetute verificate tramite Holter delle 24H ore, nonostante il trattamento antiaritmico;
Pressione sanguigna sistolica supina <100 mmHg;
Donnegravide, in allattamento, o che stanno pianificando una gravidanza;
Soggetti con malattia polmonare ostruttiva cronica nota o asma persistente;
Precedente terapia con farmaci anti-CD38 o pomalidomide;
Presenza di altri tumori maligni attivi, ad eccezione del carcinoma cutaneo non melanoma, del cancro cervicale, del cancro alla prostata in stadio precoce, a condizione che l'antigene prostatico specifico sia entro i limiti, o qualsiasi carcinoma completamente resecato in situ;
Positività nota per HIV o epatite B or C attiva. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
|
| 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 | No |
| 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) | 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 | No |
| 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.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | No |
| 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 | Information not present in EudraCT |
| 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
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 3 |
| E.8.9.1 | In the Member State concerned months | 0 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 3 |
| E.8.9.2 | In all countries concerned by the trial months | 0 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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