A Trial of Doxycycline vs. Standard Supportive Therapy in Newly-diagnosed Cardiac AL Amyloidosis Patients Undergoing Bortezomib-based Therapy

This is an interventional treatment trial for Cardiac AL Amyloidosis Read More

INCLUSION CRITERIA

1. Age ≥ 18.
2. Newly-diagnosed AL amyloidosis.

3. Confirmed diagnoses of AL amyloidosis by the following:

   1. histochemical diagnoses of AL amyloidosis determined by polarizing light microscopy of green birefringent material in Congo red stained issue specimens OR characteristic electron microscopy appearance AND
   2. confirmatory electron microscopy immunohistochemistry OR mass spectroscopy of AL amyloidosis. Confirmation of amyloid type can be omitted in patients with a clear-cut clinical evidence of AL amyloidosis (e.g. cardiac and renal involvement, soft tissue involvement) in the presence of a monoclonal component.

4. Cardiac involvement as defined by ALL of the following:

   1. Either an endomyocardial biopsy consistent with AL amyloidosis OR an echocardiogram demonstrating a mean left ventricular wall thickness in diastole >12 mm in the absence of other causes (e.g., severe hypertension, aortic stenosis) which would adequately explain the degree of wall thickening .
   2. Cardiac stage II disease: either cTnT > 0.035 ng/mL (or in place of cTnT the cTnI > 0.10 ng/mL or hs-cTnT >77 ng/L) or simultaneous NT-proBNP >332 ng/L OR patients with cardiac stage IIIa: both cTnT > 0.035 ng/mL (or in place of cTnT the cTnI > 0.10 ng/mL or hs-cTnT >77 ng/L) and simultaneous NT-proBNP >332 ng/L and NT-proBNP ≤8500 ng/L.
5. Planned bortezomib-based therapy.
6. Total bilirubin <1.5 × upper reference limit (url), patients with Gilbert disease who have a total bilirubin, predominantly unconjugated >1.5 × url without any other liver function test abnormalities are still eligible.
7. Alkaline phosphatase <5 × url.
8. Alanine aminotransferase <3 × url.
9. Systolic blood pressure 90-180 mmHg.

10. Women of childbearing potential (WOCBP) must have a negative serum pregnancy test within 14 days prior to the first administration of study drug and perform a pregnancy test every 4 weeks to rule out pregnancy, they must agree to use highly effective physician-approved contraception 30 days prior to the first study drug administration.

    Highly-effective contraceptive methods with a Pearl Index lower than 1 are: Oral hormonal contraception ('pill') (as far as its efficacy is not expected to be impaired during the trial, e.g. with IMPs that cause vomiting and diarrhoea or interfere with hormone metabolism, adequate safety cannot be assumed), Dermal hormonal contraception (e.g. contraceptive patch), Vaginal hormonal contraception (NuvaRing®), Long-acting injectable contraceptives, Tubal ligation (female sterilisation), Double barrier methods. This means that the following are not regarded as safe: condom plus spermicide, simple barrier methods (vaginal pessaries, condom, female condoms), copper spirals, the rhythm method, basal temperature method, and the withdrawal method (coitus interruptus).

    The following duration of highly effective contraception is necessary: Bortezomib: during and until 3 months after the end of therapy, Melphalan: during and 6 months after the end of therapy, Cyclophosphamide: during and 12 months after the end of therapy

11. Males must be surgically sterile or must agree to use highly effective physician approved contraception from 30 days prior to the first study drug administration to 90 days following the last study drug administration.
12. Ability to understand and willingness to sign an informed consent form prior to initiation of any study procedures.
13. Patient was assessed to determine ineligibility for ASCT. Patients who are eligible for high-dose chemotherapy and ASCT but decline the procedure, can be enrolled in the study.

EXCLUSION CRITERIA

1. Non-AL amyloidosis.
2. Stage IIIb (NT-proBNP >8500 ng/L and cTnI >0.1 ng/mL, or cTnT >0.035 ng/mL, or hs-cTnT >77 ng/L.
3. Previous treatment for AL amyloidosis.
4. Clinically overt multiple myeloma with lytic bone lesions.
5. Symptomatic orthostatic hypotension that in the medical judgment of the Investigator would interfere with subject's ability to safely receive treatment or complete study assessments.
6. Patients with uncontrolled infection or active malignancy with the exception of adequately treated basal cell or squamous cell skin cancer, in situ cervical cancer, adequately treated Stage I cancer from which the patient is currently in complete remission, or any other cancer from which the patient has been disease-free for 5 years.
7. Known HIV positive.
8. Pregnant or nursing women.
9. Known hypersensitivity to doxycycline, bortezomib, boron, or mannitol.
10. Treatment with drugs potentially affecting doxycycline absorption.
11. Significant acute gastrointestinal symptoms.
12. Active peptic ulceration and/or esophageal reflux disease.
13. Patients with serious medical or psychiatric illness likely to interfere with participation in this clinical study.
14. Contraindication to bortezomib based therapy