Doxycycline to Upgrade Organ Response in Light Chain (AL) Amyloidosis Trial

Organ response to anti-plasma cell therapy in AL amyloidosis tends to lags behind hematologic response as chemotherapy may not clear pre-formed organ amyloid. Doxycycline has been shown to have inhibitory effects on amyloid fibril formation as well as de-fibrillogenic effects and shown to be beneficial in in vitro, murine models and other preclinical studies. The investigators will prospectively evaluate the safety and efficacy of doxycycline in AL amyloidosis patients when used in conjunction with anti-plasma cell chemotherapy.

• Doxycycline (Drug), also known as Doxycycline monohydrate: Doxycycline will be continued until one of the following criteria is met: * Patient has completed 1 year of doxycycline therapy * Patient develops any grade 3-4 toxicity related to doxycycline use.

Primary outcomes

• Hematologic Response [1 year]: This measure will record the number of subjects for each grade of response to therapy for subjects with Systematic Disease (hematologic) only. Hematologic response will be determined as follows. Complete response (CR) - Negative serum/urine immunofixation with normal Free Light Chain (FLC) ratio Very Good Partial Response (VGPR)- Difference between involved and uninvolved FLCs (dFLC) < 40 mg/L Partial Response (PR)- dFLC decrease > 50% No Response (NR)- less then PR.

Secondary outcomes

• Amyloid Organ Response [6 months and 1 year]: This measure is the number of subjects (systemic disease only) for each grade of response. Efficacy will be measured in heart, liver, or kidney. Heart N-terminal (NT)-proBNP response >30% and > 300 ng/L decrease in patients with baseline NT-proBNP ≥650 ng/L (Patients with progressively worsening renal function cannot be scored for NT-proBNP progression). Improvement by 2 New York Heart Association (NYHA) classes without an increase in diuretic use or in echocardiographic wall thickness ≥ 2 mm reduction in the interventricular septal thickness by echocardiogram or improvement of ejection fraction by ≥20%. Liver ≥50% decrease in an initially elevated alkaline phosphatase level, or Decrease in liver size by at least 2 cm by ultrasound. Kidney 50% reduction in 24-hour urine protein excretion (at least 0.5 g/day) without worsening of creatinine or creatinine clearance by 25% over baseline. Soft Tissue RECIST criteria will be used.
• Mortality [Baseline, 3 months, 6 months, 1 year]: The number of living subjects will be determined at Baseline, 3 months, 6 months and 1 year
• Patient-reported Health Quality of Life [Baseline, 3, 6, 9 and 12 months]: Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the physical health score. T-scores for this domain range from 16.2 to 67.7. Higher scores indicate poorer physical health.
• Patient-reported Mental Quality of Life [Baseline, 3, 6, 9 and 12 months]: Subjects will complete the Patient Reported Outcomes Measurement Information System Global Health instrument, a 10-item standardized patient-reported outcome measure that provides global ratings of physical function, fatigue, pain, emotional distress to report on common domains of health-related quality of life. The survey comprises a series of 5-response Likert-style questions. For each question, a low score indicates lesser or absent symptom or condition and higher indicates more severe symptom or condition (e.g., 1= None to 5=Very severe). Automated scoring produces a T-score for each domain. This measure reports the mental health score. T-scores for this domain range from 21.2 to 67.6. Higher scores indicate poorer mental health.

Sex: All, ages: 18 Years to any

Inclusion Criteria:

1. Patients with biopsy proven AL amyloidosis.
2. Patients ≥ 18 years of age are eligible.
3. Patient must provide informed consent.
4. All patients must have measurable amyloid organ involvement of a vital organ (eg. heart, liver, kidneys). Localized amyloidosis will also be eligible as long as the amyloid involvement is radiologically measurable.
5. A negative pregnancy test will be required for all women of child bearing potential. Breast feeding is not permitted.
6. Patients who have previously been taking doxycycline will be eligible as long as there is no contraindication to stay on doxycycline 100 mg twice daily (BID) for 1 year in the opinion of the treating physician.
7. Creatinine clearance of >25 ml/min.

Exclusion Criteria:

1. Patients with severe malabsorption syndrome precluding absorption of oral agents will be excluded.
2. Known intolerance or allergic reactions with doxycycline.
3. Previous chemotherapy for AL amyloidosis.

Participant flow

Outcome results

• Hematologic Response (Primary), Count of participants, Participants: Doxycycline (Systemic Disease) 6
• Amyloid Organ Response (Secondary), Count of participants, Participants: Doxycycline (6 Months) 8; Doxycycline (1 Year) 3
• Mortality (Secondary), Count of participants, Participants: Doxycycline (Localized Disease) 6; Doxacycline (Systemic Disease) 25
• Patient-reported Health Quality of Life (Secondary), Mean, score on a scale: Doxycycline (Localized Disease) 46.1 +/- 9.4; Doxacycline (Systemic Disease) 40.9 +/- 0.3
• Patient-reported Mental Quality of Life (Secondary), Mean, score on a scale: Doxycycline (Localized Disease) 52.1 +/- 10.4; Doxacycline (Systemic Disease) 47.9 +/- 0.6

Adverse events

Time frame: 1 year

Serious adverse events by term

Other adverse events by term

78 more terms not shown.

• Results publication: D'Souza A, Szabo A, Flynn KE, Dhakal B, Chhabra S, Pasquini MC, Weihrauch D, Hari PN. Adjuvant doxycycline to enhance anti-amyloid effects: Results from the dual phase 2 trial. EClinicalMedicine. 2020 Jun 5;23:100361. doi: 10.1016/j.eclinm.2020.100361. eCollection 2020 Jun. PMID 32529175

• Study Protocol and Statistical Analysis Plan (PDF, 2016-08-19)
• Informed Consent Form (PDF, 2016-09-14)

• Anita D'Souza, MD, Principal investigator, Medical College of Wisconsin

NIH grants: KL2TR001438, K23HL141445