| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| Relapsed or Refractory Light-Chain Amyloidosis |
|
| E.1.1.1 | Medical condition in easily understood language |
| Light-chain amyloidosis, a progressive disease that can cause organ damage resulting from accumulation of amyloid deposits, in patients who have failed at least one other treatment for this indication |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 23.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10083938 |
| E.1.2 | Term | Amyloid light-chain amyloidosis |
| E.1.2 | System Organ Class | 100000004870 |
|
| 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 |
Part A:
•To determine the safety, tolerability, and maximum tolerated dose of ZN d5
•To determine the recommended phase 2 dose of ZN d5
Part B:
•To assess the response to ZN d5 in subjects with RRAL with and without the t(11;14) translocation |
|
| E.2.2 | Secondary objectives of the trial |
Part A:
•To characterize the PK of ZN d5
•To assess the hematologic response to ZN d5 and other efficacy parameters
Part B:
•To assess the duration of response to ZN d5
•To characterize other clinically important aspects of the hematologic response to ZN d5
•To assess the disease progression and survival after 6, 12, and 24 months of treatment with ZN d5
•To characterize the safety and tolerability of ZN-d5
•To characterize the PK of ZN d5
|
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. At least 18 years of age (or the legal age of consent in the jurisdiction in which the study is taking place, whichever is greater) at the time of signing the informed consent.
2.Understands and voluntarily provides written informed consent as described in Section 10.1.1, which includes compliance with the requirements and restrictions listed in the informed consent form (ICF)
and in this protocol.
3.A biopsy-confirmed diagnosis of AL amyloidosis based on one of the
following: histopathology (polarizing light microscopy demonstrating
green birefringent material in congo red-stained tissue specimens
confirmed by immunohistochemistry demonstrating light chain
deposition without the presence of transthyretin), the presence of
characteristic appearance on electron microscopy, or mass spectrometry
typing of amyloid.
4.Requires treatment for AL amyloidosis and has received at least one,
and no more than three, prior lines of therapy as follows:
•Prior therapy can include HSCT or treatment with an alkylating agent,
proteasome inhibitor, immunomodulatory agent, or daratumumab;
•If intolerance to a prior therapy resulted in failure to complete at least
one cycle (or for daily therapeutics, 4 weeks) of treatment because of
AEs, that will not be considered as a prior line of therapy.
5.Measurable disease defined by dFLC ≥20 mg/L.
6.History of organ involvement that included at least one of the following
(current measurable organ disease is not required for enrollment):
a. Renal: albuminuria >0.5 g/day by 24-hour urine collection;
b. Cardiac: mean left ventricular wall thickness on echocardiogram more
than 12 mm in the absence of a history of hypertension or valvular heart
disease, or unexplained low voltage (<0.5 mV) on ECG; or NT-ProBNP
>332 ng/L (or BNP >81 ng/L) in the absence of renal failure;
c. Hepatic: hepatomegaly on PE or ultrasound or alkaline phosphatase
>1.5 x the upper limit of normal (ULN);
d. Gastrointestinal: direct biopsy verification of amyloid deposition and
gastrointestinal symptoms such as gastrointestinal bleeding or diarrhea;
e. Neurologic: symmetrical lower extremity sensorimotor peripheral
neuropathy or autonomic neuropathy including gastric motility disorder,
pseudo-obstruction, or voiding dysfunction unrelated to direct organ
infiltration.
7.Assessment of t(11;14) status by FISH on bone marrow sample.
8.Adequate time since prior therapy before initiation of treatment with
ZN d5 (at least 3 months from HSCT or the shorter of 60 days or 5 halflives
from previous drug or biologic therapy or any investigational
treatment).
9.Eastern Cooperative Oncology Group (ECOG) Performance Status (PS)
score of ≤2.
10.Adequate bone marrow function as follows:
a. Hemoglobin ≥8.0 mg/dL (80 g/L).
b.Absolute neutrophil count ≥1.5 x 109/L.
c.Platelet count ≥50 x 109/L.
11.Adequate organ function as follows:
a.Alanine aminotransferase (ALT) and aspartate aminotransferase (AST)
≤3 x ULN.
b.Alkaline phosphatase ≤5 x ULN.
c.Total bilirubin ≤1.5 x ULN except for subjects with Gilbert syndrome.
d.Serum albumin ≥ 2 g/dL (20 g/L).
Estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2 in Part
A and ≥30 mL/min/1.73 m2 in Part B (according to the Chronic Kidney
Disease-Epidemiology Collaboration equation; Section 11.6 of the
protocol).
12.Willingness and ability to comply with scheduled visits, treatment
plan, laboratory tests, and other study procedures.
13.Women of childbearing potential(defined in Section 11.1.2 in the
Protocol) must have a negative serum pregnancy test within 14 days of
Cycle 1 Day 1 (confirmed with a negative urine pregnancy test prior to
the first dose of ZN-d5 if the serum test was more than 7 days before the
first dose)
14.Women of childbearing potential agree to practice a protocol
specified method of contraception (defined in Section 11.1.3 in the
Protocol) and agree not to harvest and/or donate eggs for the purpose
of fertilization, during the study and for 10 days after the last dose of
ZN-d5
15. Men must agree to use a condom if they engage in intercourse with a
pregnant women during the study and for 10 days after the last dose of
ZN-d5(Section 11.1.5 in the Protocol) |
|
| E.4 | Principal exclusion criteria |
1. Presence of non-AL amyloidosis, including wild type or mutated ATTR
amyloidosis.
2. Diagnosis of multiple myeloma according to the 2014 International
Myeloma Working Group diagnostic criteria (Rajkumar 2014).
3. Mayo2012 Stage IV disease, defined as follows:
a. NT-ProBNP ≥ 1800 ng/L.
b. cTnT ≥ 0.025 ng/mL (0.025 μg/L).
c. dFLC ≥ 180 mg/L (18 mg/dL).
4. Any of the following cardiac conditions:
a. New York Heart Association (NYHA) Class III or IV heart failure
(Table 9).
b. History of sustained ventricular tachycardia or fibrillation, or
ventricular arrhythmias (ventricular tachycardia sustained for over 30
seconds, 1 or more occurrences of non-sustained ventricular tachycardia
of 3 or more consecutive ventricular beats or more than 20 ventricular
pairs per 24 hours) on 24-hour ambulatory ECG monitoring, unless the
subject has an implantable cardioverter defibrillator.
c. Corrected QT interval (QTc) > 500 msec (using Fridericia's correction;
Section 8.5.4) on a 12-lead ECG.
d. Atrial fibrillation with inadequate anti-coagulation (if indicated).
e. Second- or third-degree atrioventricular block (Mobitz type I is
permitted).
f. History of myocardial infarction, coronary stent placement, or coronary
artery bypass grafting within 6 months of enrollment.
g. Left ventricular ejection fraction (LVEF) by echocardiogram < 35%.
h. Supine systolic blood pressure < 90 mm Hg or symptomatic
orthostatic hypotension (decrease in systolic blood pressure upon
standing of > 20 mm Hg in the absence of hypovolemia and despite
medical management).
5. Positive serum antibody tests for hepatitis B surface antigen or
hepatitis C (subjects previously treated for hepatitis B or C who test
positive can be enrolled if negative for active infection according to
applicable viral load and/or antigen testing).
6. Women who are pregnant or intending to become pregnant or who are
breastfeeding or intending to breastfeed, during the study.
7. Concurrent treatment with drugs or consumption of foods that are
strong cytochrome P450 enzyme (CYP) 3A4 inhibitors or strong or
moderate CYP3A4 inducers; such treatments should be discontinued 5
half-lives, or for CYP3A4 inducers 14 days, prior to the first dose of ZNd5.
8. Concurrent treatment with agents used to treat plasma cell disorders
or AL amyloidosis, including experimental agents; such treatments
should be discontinued the shorter of 60 days or 5 half-lives prior to the
first dose of ZN-d5.
9. Prior treatment with ZN-d5, venetoclax, navitoclax, obatoclax or any
other small molecule BCL-2 inhibitor, or known hypersensitivity to ZN-d5
or any of its inactive ingredients.
10. Any concurrent medical condition that would make a potential
subject a poor candidate for this study, including (but not limited to)
uncontrolled serious infection, active malignancy other than nonmelanoma
skin cancer or carcinoma in situ of the cervix, uncontrolled
pulmonary disease, severe diarrhea (Grade 3 or higher), cirrhosis, any
condition likely to require the use of systemic corticosteroids for more
than 1 week during the course of this study, or major surgery within 28
days of enrollment.
11. Any psychiatric illnesses or social situations that would preclude
understanding the informed consent, maintaining study compliance, or
having the ability to tolerate study procedures and/or study therapy.
12. Inability to swallow oral medication, inability, or unwillingness to
comply with the drug administration requirements, or gastrointestinal
procedure that could interfere with the oral absorption or tolerance of
treatment; ZN-d5 may not be administered via a gastronomy tube. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Part A:
•Dose-limiting toxicities
•Incidence and severity of adverse events
Part B:
•HRR: CR, VGPR including subjects with low baseline dFLC, and PR |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Part A:
Through Cycle 1, Day 28
Part B:
Day 28 of each Cycle |
|
| E.5.2 | Secondary end point(s) |
Part A:
•Plasma levels of ZN d5 (and its metabolites, as applicable) and typical
PK parameters by dose
• HRR: CR, VGPR, and PR.
• DOR
• Time to response (CR+VGPR+PR)
• Rate of, duration of, and time to CR, mCR,
• CR+VGPR, and mCR+VGPR
Part B:
• Key secondary endpoint: DOR
• Time to response (CR+VGPR+PR)
• Rate of, duration of, and time to CR, mCR, CR+VGPR, and mCR+VGPR
• Presence of MRD
• Rates of PFS, hematologic PFS, MOD-PFS, and OS after 6, 12, and 24
months
•Incidence and severity of adverse events
•Plasma levels of ZN d5 (and its metabolites, as applicable) and typical
PK parameters |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| Please refer to section "Schedule of Activities" of the Protocol |
|
| 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 | No |
| 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 | Yes |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | Yes |
| E.6.13.1 | Other scope of the trial description |
| Quality of Life, Tolerability, Biomarkers |
|
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
| Estimation of Initial Safety and Tolerability |
|
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
|
| 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
| Information not present in EudraCT |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Information not present in EudraCT |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 24 |
| 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 |
| Israel |
| Japan |
| Korea, Republic of |
| United States |
| Cyprus |
| France |
| Poland |
| Netherlands |
| Germany |
| Greece |
| Italy |
| United Kingdom |
|
| 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
|
The end of study (EOS) is defined as the date of the last visit of the last subject in the study or last scheduled procedure shown in the Schedule of Assessments (Table 3 from the protocol) for the last subject in the trial globally.
The EOS will be declared when all subjects have discontinued from the study or have been followed up for at least 12 cycles after the last subject’s first visit in Part B.
|
|
| 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 | 7 |
| E.8.9.1 | In the Member State concerned days | 16 |
| 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 | 11 |
| E.8.9.2 | In all countries concerned by the trial days | 30 |
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