Relapsed or Refractory Light-Chain Amyloidosis MedDRA version: 23.0 Level: LLT Classification code 10083938 Term: Amyloid light-chain amyloidosis System Organ Class: 100000004870
Conditions
Interventions
Product Name: ZN-d5
Pharmaceutical Form: Tablet
Current Sponsor code: ZN-d5
Other descriptive name: KP-2541
Concentration unit: mg milligram(s)
Concentration type: equal
Concentration number: 25-
Pro
Sponsors
K-Group Alpha, Inc., a wholly owned subsidiary of Zentalis Pharmaceuticals, Inc.
Eligibility
Sex/Gender
All
Inclusion criteria
Inclusion criteria: English 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 10.1.2, which includes compliance with the requirements and restrictions listed in the 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 (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 aspirate. 8. At least 3 months from HSCT or the shorter of 30 days or 5 halflives from previous drug or biologic therapy or any investigational treatment prior to Cycle 1 Day 1. 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 (0.08 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 in subjects with Gilbert syndrome. d.Serum albumin = 2 g/dL (20 g/L). e.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 CKD-EPI 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 pregna
Exclusion criteria
Exclusion criteria: 1. Presence of non-AL amyloidosis, including wild type or mutated transthyretin amyloidosis (ATTR). 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 at Screening (Table 7). 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 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. 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. 9. 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), 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. 10. Any psychiatric illnesses or social situation that would preclude understanding the informed consent, maintaining study compliance, or having the ability to tolerate study procedures and/or study therapy. 11. 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 gastrostomy tube.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Main Objective: 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;Secondary Objective: 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 ;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 ;Timepoint(s) of evaluation of this end point: Part A: Through Cycle 1, Day 28 Part B: Day 28 of each Cycle | — |
Secondary
| Measure | Time frame |
|---|---|
| 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;Timepoint(s) of evaluation of this end point: Please refer to section "Schedule of Activities" of the Protocol | — |
Countries
Australia, Cyprus, France, Germany, Greece, Israel, Italy, Korea, Republic of, Netherlands, Poland, United States
Contacts
Public ContactRegulatory Affairs
K-Group Alpha, Inc
Outcome results
None listed