Clinical trials

APG-2575 (varying doses) + pomalidomide and dexamethasone (Pd)

What is the drug in question?
Approximately 50% of patients with AL amyloidosis have a chromosomal (genetic) change involving part of chromosome 11 swapping with part of chromosome 14, referred to as “t(11;14)”. BCL-2 inhibitors target this mutation and can cause cell death of the plasma cells that make the amyloid. APG-2575 is a novel BCL-2 inhibitor.

In this study, APG-2575 is combined with pomalidomide, an immunomodulatory drug which has been used extensively in myeloma, and appears to be effective and well tolerated in AL amyloidosis too. Dexamethasone, a steroid, is also combined with APG-2575 and pomalidomide, to hopefully enhance the effect of the drug.
During the study, patients will be assigned different doses of APG-2575 to determine the highest dose that is the best tolerated.

Who is eligible for the trial?
Any patient with relapsed AL amyloidosis with organ involvement (eg. heart and/or kidneys), or a patient who has not achieved an excellent response to their first 3 cycles of front-line chemotherapy.

Does every patient receive the actual trial drug?
Yes, all patients receive APG-2575, pomalidomide and dexamethasone

How is the drug administered?
This is an all oral, tablet treatment

How long does the trial go for?
Patients will continue to receive treatment until disease progression, unacceptable toxicity, or withdrawal of consent.

Key inclusion criteria:
Systemic AL (not ATTR) amyloidosis, involving the heart, as proven by

1. ≥ 18 years of age.
2. Histochemical diagnosis based on detection by polarizing microscopy of green birefringent material in Congo red-stained tissue specimens, the type must have been confirmed unequivocally.
3. Symptomatic organ involvement.
4. At least one prior line of systemic therapy for AL. Patients who do not achieve at least a PR to frontline therapy in 3 months are eligible.
5. All MM/AL patients should have measurable disease as defined by at least ONE of the following:
   • Serum monoclonal protein 1.0 g/dl or more by protein electrophoresis.
   • >200 mg of monoclonal protein in the urine on 24-hour electrophoresis.
   • If both serum and urine monoclonal proteins are non-measurable:
   • Serum differential FLC concentration (dFLC) > 5 mg/dL; OR serum FLC of 7.5 mg/dL provided the κ/λ FLC ratio is abnormal
6. Eastern Cooperative Oncology Group (ECOG) ≤ 2.
7. Life expectancy ≥ 6 months.
8. Adequate hematologic function defined as:
   • ANC ≥1.0 x 109/L independent of growth factor support within 7 days of the first dose with study drug.
   • Haemoglobin ≥8 g/dL without transfusion or growth factor support within 7 days of the first dose of study drug.
   • Platelet count ≥ 100 x 109/L or ≥ 50 x 109/L if bone marrow involvement independent of transfusion support
9. Adequate hepatic and renal function defined as:
   • AST and ALT < 3 x upper limit of normal
   • Creatinine ≤3 mg/dL and CrCL ≥25 ml/min using the Cockcroft-Gault formula
   • Bilirubin< 1.5 x ULN (except if considered secondary to Gilbert’s syndrome and primarily indirect bilirubinemia)
10. PT/INR ≤2 x ULN and PTT (or aPTT) ≤2 x ULN.
11. Female subjects who are of non-reproductive potential. Female subjects of childbearing potential must have a negative serum pregnancy test upon study entry.
12. Male and female subjects who agree to use highly effective methods of birth control during the period of therapy and for 90 days after the last dose of study drug.
13. Ability to cooperate to complete neurological examinations if required

Key exclusion criteria:

1. AL amyloidosis patients who have not been treated with any systemic therapy
2. AL amyloidosis clinically overt multiple myeloma i.e. original CRAB criteria. Extent of marrow plasmacytosis is not prohibitive.
3. Subject has received antineoplastic therapy within 2 weeks before the date of initiating study treatment.
4. Subjects planning to undergo a stem cell transplant prior to progression of disease on this study, i.e., these subjects should not be enrolled in order to reduce disease burden prior to transplant.
5. Subject has peripheral neuropathy ≥grade 3 except caused by AL amyloidosis.
6. Active cardiovascular disease, such as uncontrolled arrhythmia (including Frederica corrected QT interval (QTc ≥470 msec) or Class 3 or 4 congestive heart failure as defined by the New York Heart Association Functional Classification; or a history of myocardial infarction or unstable angina.
7. Major surgical procedure within ≤14 days prior to initiating study treatment, or anticipation of the need for major surgery during the course of the study treatment, radiotherapy ≤14 days prior to initiating study treatment, systemic treatment within 14 days before the first dose of APG2575.
8. Recent infection requiring systemic treatment that was completed ≤14 days before the first dose of study drug.
9. Subject has any concurrent or recent malignancy ≤ 1 year prior to registration with the exception of: basal or squamous cell skin cancer, any carcinoma in situ.

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