AL AmyloidosisPhase 1NCT03000660
Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
A Phase 1 study testing Venetoclax and Dexamethasone in people with AL Amyloidosis, run by Tufts Medical Center at 1 site in United States.
Trial summary
This is a study to determine the safety, tolerability and maximum tolerated dose of Venetoclax (ABT-199) and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients. Read more about this study
- Who is it for?
- Ages 18 years and older
- Conditions the study is for
- AL Amyloidosis
- What is being tested?
- Venetoclax and Dexamethasone
- Type of treatment
- Pill or oral medicine
- Could I receive a placebo?
- No, everyone receives an active treatment
- How many people
- 3 participants
- Where
- 1 siteUnited States
- Study dates
- Jan 2017to 10 Oct 2019
- Phase
- Phase 1
- Are there results?
- None posted in the registry
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 years and older
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- Histologic diagnosis of AL amyloidosis, confirmed by positive Congo red stained biopsy, with evidence of measurable clonal disease according that requires active treatment
- Eastern Cooperative Oncology Group (ECOG) status of 0 to 2
- Relapsed or refractory after at least 1 prior therapy for AL amyloidosis and, in the investigator's opinion, require further treatment. Participants with a history of autologous stem cell transplantation must have adequate blood counts independent of growth factor support and have recovered from any transplant-related toxicities and be at least 100 days post-autologous transplant.
- Less than 30% plasma cells in the bone marrow biopsy and no bone lesions or hypercalcemia.
- The pre-screening test of CD138+ patient marrow plasma cells must show that the patient's CD138+ plasma cells have an apoptosis ratio of Venetoclax treated over untreated cells of greater than 1.4.
- Objective, measurable organ involvement. Skin purpura, carpal tunnel syndrome, or the presence of vascular amyloid on a bone marrow biopsy alone are not sufficient to meet criteria for "symptomatic organ involvement". Patients may have any of the following amyloid-related organ involvement as defined below:
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- Renal: albuminuria higher than 0.5 g/day in a 24-hour urine collection.
- Cardiac: involvement is defined as the presence of a 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 electrocardiogram; or an NT-proBNP > 332 ng/L in CKD 1 or 2 patients or a BNP > 100ng/L in those who are CKD3.
- Hepatic: hepatomegaly on physical examination with alkaline phosphatase > 1.5 X the upper limit of normal (ULN).
- Autonomic or peripheral neuropathy: based on clinical history, autonomic dysfunction with orthostasis, symptoms of nausea or dysgeusia, gastric atony by gastric emptying scan, diarrhea or constipation, or abnormal sensory and/or motor findings on neurologic examination.
- AL Amyloidosis Cardiac Risk stage I, II or IIIa disease. Staging system defined by: NT-proBNP cut off of < 332 pg/mL and troponin I cut-off of < 0.10 ng/mL as thresholds for stages I, II and III; NT-proBNP < 8500 for stage IIIa.
- Stage I, both under threshold;
- Stage II, either troponin or NT-proBNP [but not both] over threshold;
- Stage III, both over threshold;
- Stage IIIa, both over threshold but NT-proBNP < 8500 pg/ml.
- Clinical laboratory values as specified below before the first dose of study drug:
- Echocardiographic ejection fraction > 45% within 28 days before the first dose of study drug.
- Within the 3 days of the first dose of study drug: i. Platelet count > 75 x 109/L; ii. Neutrophil count > 1.0 x 109/L; iii. Total bilirubin < 2 x ULN; iv. Alkaline phosphatase < 5 x ULN; v. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) < 3 x ULN; vi. eGFR > 30 mL/min/1.73 m2
- Female patients who are postmenopausal for at least 1 year before the screening visit, OR are surgically sterile, OR, if they are of childbearing potential, agree to practice 2 effective methods of contraception, at the same time, from the time of signing the informed consent through 30 days after the last dose of study drug, or agree to completely abstain from heterosexual intercourse.
- Male patients, even if surgically sterilized (ie, status post vasectomy), who agree to practice effective barrier contraception during the entire study treatment period and through 30 days after the last dose of study drug, OR agree to completely abstain from heterosexual intercourse.
- Voluntary written consent must be given before performance of any study-related procedure not part of standard medical care with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care.
Who cannot join
- Treatment with any investigational products within 28 days before the first dose of study drug.
- Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational.
- Failure to have fully recovered (ie, > Grade 1 toxicity) from the effects of prior chemotherapy regardless of the interval since last treatment.
- Active fungal infection requiring continued therapy.
- Cardiac system:
- QTc > 470 milliseconds (msec) on a 12 lead ECG obtained during the Screening period. If a machine reading is above this value, the ECG should be reviewed by a qualified reader and confirmed on a subsequent ECG.
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- AL Amyloidosis Risk Stage IIIb disease. Stage IIIb is defined by NT-proBNP > 8500 pg/mL and troponin I > 0.10 ng/mL.
- New York Heart Association (NYHA) classification III or IV.
- Enzyme-documented myocardial infarction within 6 months before enrollment.
- Chronic atrial fibrillation.
- Grade 2 or 3 atrioventricular (AV) block (Mobitz, Type I permitted).
- Supine systolic blood pressure < 90 mmHg, or symptomatic orthostatic hypotension, or a decrease in systolic blood pressure on standing of > 20 mm Hg in spite of being treated for orthostatic hypotension.
- History of a bleeding diathesis or currently receiving treatment with warfarin. Patients are allowed to take aspirin.
- GI system:
- Severe diarrhea (= Grade 3) not controllable with medication (such as octreotide) or requires administration of total parenteral nutrition.
- Known GI disease or GI procedure that could interfere with the oral absorption or tolerance of study drug, including difficulty swallowing.
- Neurologic/ Social system:
- Patients with > Grade 2 peripheral neuropathy or painful peripheral neuropathy on clinical examination will be excluded.
- Previous or ongoing psychiatric illness.
- Social situations that would limit compliance with study requirements.
- Systemic infections:
- Known to be human immunodeficiency virus (HIV)-positive.
- Known to be hepatitis B surface antigen-positive or has known active hepatitis C infection.
- Uncontrolled infection requiring systemic antibiotics.
- Clinically overt multiple myeloma (bone marrow plasma cells > 30%) and bone lesions or hypercalcemia.
- Patients with non-AL amyloidosis.
- Presence of uncontrolled autoimmune hemolytic anemia or thrombocytopenia, or of active malignancy with the exception of non-melanoma skin cancer, cervical cancer, treated early-stage prostate cancer provided that prostate-specific antigen is within normal limit, or any completely resected carcinoma in situ.
- Female patients who are lactating or pregnant.
- Major surgery within 14 days before the first dose of study drug.
- Patients who are taking and are required to take any of the following agents that are CYP3A inhibitors: Amiodarone, Erythromycin, Fluconazole, Itraconazole, Ketoconazole, Miconazole, Diltiazem, Verapamil, Amprenavir, Fosamprenavir, Clarithromycin, Telithromycin, Nefazodone, Atazanavir, Darunavir, Indinavir, Lopinavir, Nelfinavir, Ritonavir, Saquinavir, Tipranavir.
Trial locations and contacts
1 site in 1 country.
About this study
Official title: A Phase I Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
This is a study to determine the safety, tolerability and maximum tolerated dose of Venetoclax (ABT-199) and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients.
Read the detailed description
The study is being conducted to determine the safety, tolerability and maximum tolerated dose of Venetoclax and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients. AL amyloidosis is a disease involving cells called plasma cells that make antibodies as part of your immune system. These cells are not functioning the way they are supposed to and they start to produce abnormal fragments of antibodies that are toxic to your body and can form amyloid. The antibody fragments are called "light chains." They can cause damage to organs, especially the kidneys, heart, skin, liver, and lungs.
Researchers are looking for ways to stop the light chains from being formed to treat the disease. Under some circumstances, patients will receive chemotherapy drugs in order to manage the disease. However, researchers do not know what the best treatment is for relapsed AL amyloidosis, so the researchers are testing new drugs or new combinations of drugs to see what will work best with the least side effects.
The researchers want to find out if Venetoclax (ABT-199) in addition to dexamethasone will reduce or eliminate AL amyloidosis plasma cells. In this study, varying doses of Venetoclax will be given to determine the maximum tolerated and safe dose for further study. The researchers may also gain a better understanding of whether Venetoclax and dexamethasone can counter the plasma cell disease that causes AL amyloidosis.
- Conditions
- AL Amyloidosis
- Being tested
- Venetoclax, Dexamethasone
- Keywords
- Amyloidosis, AL Amyloidosis, Amyloid Light Chain Amylodosis, ABT-199, Venetoclax
- Medical subject headings
- Immunoglobulin Light-chain Amyloidosis, Amyloidosis
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
VenetoclaxDrug
Also called ABT-199
Venetoclax at one of four escalating doses
DexamethasoneDrug
Also called Ozurdex, Maxidex, Baycadron
Dexamethasone 20mg by mouth on days 1, 8, 15, and 22 of each cycle.
| Study group | Role | What they receive |
|---|---|---|
| Venetoclax and Dexamethasone | Experimental | Venetoclax will be given at one of four escalating doses (100 mg/day, 200 mg/day, 400 mg/day, or 800 mg/day) by mouth on each day of the cycle. Dexamethasone will be given at 20mg by mouth on days 1, 8, 15, and 22 of each cycle. Receives: Drug: Venetoclax; Drug: Dexamethasone |
What is being measured
The primary outcome is the main question the study is designed to answer.
Participants with treatment related adverse events using NCI CTCAE version 4.03.
Dose limiting toxicity will be based on hematologic and non-hematologic adverse events that are considered by the investigator to be possibly related to Venetoclax include any Grade 4 thrombocytopenia lasting more than 7 days, any Grade 4 neutropenia lasting more than 7 days, any Grade 3 or higher nonhematologic toxicity, a delay of more than 2 weeks in the initiation of Cycle 2 of treatment because of a lack of adequate recovery of Venetoclax-related hematological or nonhematologic toxicities, and any other Venetoclax-related nonhematologic toxicities Grade 2 or greater than, in the opinion of the investigator, requires discontinuation of therapy with Venetoclax. Also, events of concern that may be related to Venetoclax therapy will include worsening neuropathy, ventricular or atrial arrhythmia with hemodynamic instability, fluid retention that does not resolve with 3 or 4 days of intravenous diuretic therapy and bedrest, symptomatic congestive heart failure, and hypotension.
Measured: Up to 8 months after beginning study drug
Secondary outcomes (3)
Hematologic response based on serum free light chain (FLC) response criteria.
Complete response is normalization of FLC levels and ratio with negative immunofixation studies of serum and urine. Very good partial response is reduction of the difference between the involved and uninvolved FLC to less than 40mg/L. Partial response is reduction of the difference between involved and uninvolved FLC of greater than 50% baseline. No response or stable disease is none of the above.
Measured: Up to 8 months after beginning study drug
Proportion of subjects with progression-free survival
Hematologic progression will be evaluated every 12 weeks until the subject progresses. From CR any detectable monoclonal protein or abnormal free light chain ratio (light chain must double). From PR, 50% increase in serum M-protein of > 0.5 g/dl or 50% increase in urine M-protein to > 200 mg/day (a visible peak must be present), or free light chain increase of 50% to > 100 mg/L
Measured: Until disease progression up to three (3) years
Overall survival of subjects
Subjects will be followed until death after they have come off study
Measured: From time of end of treatment to death for up to three (3) years
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted22 Dec 2016 (estimated)
- Study startJan 2017
- Primary completionOct 2019
- Study completion10 Oct 2019
Why it stopped: partial clinical hold per FDA
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Other trials for AL AmyloidosisStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase 1
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Enrolment
- 3 participants (actual)
Sponsor and investigators
- Lead sponsor
- Tufts Medical Center
- Sponsor type
- University, hospital or other
- Responsible party
- Sponsor
- Investigators
- Raymond Comenzo, MD, Principal investigator, Tufts Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT03000660
- Sponsor's protocol ID
- AbbVie ABT-199
- Status last verified
- Aug 2020
- First submitted
- 12 Dec 2016
- Last updated
- 21 Aug 2020
- Results posted
- No
- Data monitoring committee
- No
- FDA-regulated drug
- Yes
- Individual data sharing
- No
Study at a glance
From the registry record, last updated by the sponsor on 21 Aug 2020. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Phase I Trial of Venetoclax (ABT-199) and Dexamethasone for Relapsed or Refractory Systemic AL Amyloidosis
- ClinicalTrials.gov ID
- NCT03000660
- Acronym / sponsor ID
- AbbVie ABT-199
- Conditions
- AL Amyloidosis
- Keywords
- Amyloidosis, AL Amyloidosis, Amyloid Light Chain Amylodosis, ABT-199, Venetoclax
- Phase
- Phase 1
- Study type
- Interventional
- Recruitment status
- TerminatedReason stopped: partial clinical hold per FDA
- Enrolment
- 3 participants (actual)
- Lead sponsor
- Tufts Medical CenterUniversity, hospital or other
- Study start
- Jan 2017
- Primary completion
- Oct 2019 (actual)
- Study completion
- 10 Oct 2019 (actual)
- First posted
- 22 Dec 2016 (estimated)
- Results
- Not posted in the source record
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
This is a study to determine the safety, tolerability and maximum tolerated dose of Venetoclax (ABT-199) and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients.
Detailed description
The study is being conducted to determine the safety, tolerability and maximum tolerated dose of Venetoclax and dexamethasone in relapsed or refractory amyloid light chain (AL) amyloidosis patients. AL amyloidosis is a disease involving cells called plasma cells that make antibodies as part of your immune system. These cells are not functioning the way they are supposed to and they start to produce abnormal fragments of antibodies that are toxic to your body and can form amyloid. The antibody fragments are called "light chains." They can cause damage to organs, especially the kidneys, heart, skin, liver, and lungs.
Researchers are looking for ways to stop the light chains from being formed to treat the disease. Under some circumstances, patients will receive chemotherapy drugs in order to manage the disease. However, researchers do not know what the best treatment is for relapsed AL amyloidosis, so the researchers are testing new drugs or new combinations of drugs to see what will work best with the least side effects.
The researchers want to find out if Venetoclax (ABT-199) in addition to dexamethasone will reduce or eliminate AL amyloidosis plasma cells. In this study, varying doses of Venetoclax will be given to determine the maximum tolerated and safe dose for further study. The researchers may also gain a better understanding of whether Venetoclax and dexamethasone can counter the plasma cell disease that causes AL amyloidosis.
Study design
- Primary purpose
- Treatment
- Allocation
- Not applicable
- Intervention model
- Single group
- Masking
- None (open label)
- Number of arms
- 1
| Arm | Type | Receives |
|---|---|---|
| Venetoclax and Dexamethasone | Experimental | Drug: Venetoclax, Drug: DexamethasoneVenetoclax will be given at one of four escalating doses (100 mg/day, 200 mg/day, 400 mg/day, or 800 mg/day) by mouth on each day of the cycle. Dexamethasone will be given at 20mg by mouth on days 1, 8, 15, and 22 of each cycle. |
Who may qualify
- Ages
- 18 years and older
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (21 listed)
- Histologic diagnosis of AL amyloidosis, confirmed by positive Congo red stained biopsy, with evidence of measurable clonal disease according that requires active treatment
- Eastern Cooperative Oncology Group (ECOG) status of 0 to 2
- Relapsed or refractory after at least 1 prior therapy for AL amyloidosis and, in the investigator's opinion, require further treatment. Participants with a history of autologous stem cell transplantation must have adequate blood counts independent of growth factor support and have recovered from any transplant-related toxicities and be at least 100 days post-autologous transplant.
- Less than 30% plasma cells in the bone marrow biopsy and no bone lesions or hypercalcemia.
- The pre-screening test of CD138+ patient marrow plasma cells must show that the patient's CD138+ plasma cells have an apoptosis ratio of Venetoclax treated over untreated cells of greater than 1.4.
Key exclusion criteria (30 listed)
- Treatment with any investigational products within 28 days before the first dose of study drug.
- Requirement for other concomitant chemotherapy, immunotherapy, radiotherapy, or any ancillary therapy considered to be investigational.
- Failure to have fully recovered (ie, > Grade 1 toxicity) from the effects of prior chemotherapy regardless of the interval since last treatment.
- Active fungal infection requiring continued therapy.
- Cardiac system:
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| VenetoclaxAlso: ABT-199Venetoclax at one of four escalating doses | Drug | Venetoclax and Dexamethasone |
| DexamethasoneAlso: Ozurdex, Maxidex, BaycadronDexamethasone 20mg by mouth on days 1, 8, 15, and 22 of each cycle. | Drug | Venetoclax and Dexamethasone |
Primary outcome
Participants with treatment related adverse events using NCI CTCAE version 4.03.
Time frame: Up to 8 months after beginning study drug
Dose limiting toxicity will be based on hematologic and non-hematologic adverse events that are considered by the investigator to be possibly related to Venetoclax include any Grade 4 thrombocytopenia lasting more than 7 days, any Grade 4 neutropenia lasting more than 7 days, any Grade 3 or higher nonhematologic toxicity, a delay of more than 2 weeks in the initiation of Cycle 2 of treatment because of a lack of adequate recovery of Venetoclax-related hematological or nonhematologic toxicities, and any other Venetoclax-related nonhematologic toxicities Grade 2 or greater than, in the opinion of the investigator, requires discontinuation of therapy with Venetoclax. Also, events of concern that may be related to Venetoclax therapy will include worsening neuropathy, ventricular or atrial arrhythmia with hemodynamic instability, fluid retention that does not resolve with 3 or 4 days of intravenous diuretic therapy and bedrest, symptomatic congestive heart failure, and hypotension.
3 secondary outcomes
Hematologic response based on serum free light chain (FLC) response criteria.
Time frame: Up to 8 months after beginning study drug
Proportion of subjects with progression-free survival
Time frame: Until disease progression up to three (3) years
Overall survival of subjects
Time frame: From time of end of treatment to death for up to three (3) years
Results and safety
The study was stopped early (reason given: partial clinical hold per FDA). Results are not available in the source record.
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 21 Aug 2020.
- Individual participant dataSharing planned: No
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Raymond Comenzo, MD principal investigator
Tufts Medical Center
1 site in 1 country: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A Phase 1 study testing Venetoclax and Dexamethasone in people with AL Amyloidosis, run by Tufts Medical Center at 1 site in United States.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 21 inclusion and 30 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: stopped early, as of the sponsor's last update on 21 Aug 2020. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 1 site in United States. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
What does this phase mean?
Phase 1 studies test a treatment in a small group of people for the first time or in a new way, mainly to check safety and find the right dose.
Not every study follows the same path, and some studies (observational studies, device studies) have no phase.
Are results available for this study?
The study was stopped early (reason given: partial clinical hold per FDA). Results are not available in the source record.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Participants with treatment related adverse events using NCI CTCAE version 4.03. (time frame: Up to 8 months after beginning study drug). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 21 Aug 2020.