Trial Title:
Venetoclax, Daratumumab, and Dexamethasone for Systemic Light-Chain Amyloidosis With Translocation (11;14) (ALTITUDE)
NCT ID:
NCT05486481
Condition:
AL Amyloidosis
Light Chain (AL) Amyloidosis
Systemic Light Chain Disease
Conditions: Official terms:
Immunoglobulin Light-chain Amyloidosis
Amyloidosis
Dexamethasone
Venetoclax
Daratumumab
Immunoglobulins
Immunoglobulins, Intravenous
Antibodies
Antibodies, Monoclonal
Immunoglobulin Heavy Chains
Conditions: Keywords:
Translocation
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
Non-Randomized
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
Venetoclax
Description:
Given orally (PO)
Arm group label:
Phase I (venetoclax, dexamethasone, daratumumab)
Arm group label:
Phase II (venetoclax, dexamethasone, daratumumab)
Other name:
Venclexta
Intervention type:
Drug
Intervention name:
Dexamethasone
Description:
Given PO
Arm group label:
Phase I (venetoclax, dexamethasone, daratumumab)
Arm group label:
Phase II (venetoclax, dexamethasone, daratumumab)
Other name:
Ozurdex
Intervention type:
Drug
Intervention name:
Daratumumab
Description:
Given Subcutaneously (SC)
Arm group label:
Phase I (venetoclax, dexamethasone, daratumumab)
Arm group label:
Phase II (venetoclax, dexamethasone, daratumumab)
Other name:
Darzalex
Other name:
Daratumumab SC
Intervention type:
Device
Intervention name:
Cyclin D1 gene (CCDN1) /immunoglobulin heavy chain (IGH) fluorescence in situ hybridization (FISH) assay
Description:
Lab test
Arm group label:
Phase I (venetoclax, dexamethasone, daratumumab)
Arm group label:
Phase II (venetoclax, dexamethasone, daratumumab)
Summary:
This phase I/II trial tests the safety, side effects, and best dose of venetoclax,
daratumumab, and dexamethasone for the treatment of systemic light-chain amyloidosis in
patients with a deoxyribonucleic acid (DNA) abnormality called a translocation involving
chromosomes 11 and 14, or "t(11;14)". Venetoclax works by attaching to a protein called
Bcl-2, in order to kill cancer cells. Daratumumab works by binding to a target on the
surface of cancer cells called Cluster of differentiation 38 (CD38). When daratumumab
binds to CD38, it enables the immune system to find the cancer cell and kill it.
Dexamethasone is a type of drug called a corticosteroid. A corticosteroid is a drug made
of artificial steroid hormones, that are used to treat symptoms such as inflammation
(swelling and irritation to a part of the body). The combination of these medications may
more effectively treat patients with systemic light-chain amyloidosis and t(11;14).
Detailed description:
PRIMARY OBJECTIVES:
I. To determine the maximum-tolerated dose (MTD)/ the recommended phase 2 dose (RP2D) of
venetoclax (VEN) with or without daratumumab subcutaneous (DARA SC) and dexamethasone
(DEX), in previously treated light chain (AL) amyloidosis (PTAL) participants with
t(11;14). (Phase I).
II. To evaluate the efficacy of the combination VEN/DARA SC and DEX as measured by
Complete Hematologic Response (CHR rate) in PTAL participants with t(11;14). (Phase II)
SECONDARY OBJECTIVES:
I. To evaluate the safety and tolerability of VEN/DARA SC, and DEX in the treatment of
PTAL participants with t(11;14). (Phase I) II. To evaluate the efficacy of VEN/DARA SC
and DEX in the treatment of PTAL participants with t(11;14) as measured by overall
hematologic response rate (ORR), progression free survival (PFS), overall survival (OS),
organ response rate (orRR), major organ deterioration PFS (MOD-PFS), time to complete
response (TTCR), duration of response (DOR), and time to new treatment (TTNT). To
evaluate safety of VEN/DARA SC and DEX in the treatment of PTAL participants with
t(11;14). (Phase II) IV. To evaluate the death rate, therapy-related death rate,
infection rate, and cardiac event rate, in the VEN/DARA SC and DEX arm and the DARA SC
and DEX arm. (Phase II).
EXPLORATORY OBJECTIVES:
I. To evaluate the feasibility of performing M protein detection by MALDI TOF mass
spectrometry on the EXENT® system on serum and urine participant-samples collected by
each site during the first 6 months of the study.
II. To evaluate the agreement between MALDI TOF mass spectrometry results by the EXENT®
system and standard serologic and urine measures of disease after the enrollment for both
phase 1 and 2 has been complete.
III. To evaluate the complete response (CR) rate, ORR, PFS, MOD-PFS, OS, OrRR, TTCR, TTNT
and DOR separated by participants who are minimal residual disease (MRD) negative versus
positive by EXENT®.
IV. To evaluate the CR rate, overall hematologic response rate (ORR), progression-free
survival (PFS), major organ deterioration PFS (MOD-PFS), overall survival (OS), organ
response rate (OrRR), time to complete response (TTCR), time to next treatment (TTNT) and
duration of response (DOR) and relationship to light-chain glycosylation patterns over
time by EXENT®.
OUTLINE: This is a phase I, dose-escalation study of venetoclax followed by a phase II
study. If dose level 3 (VEN/DARA SC and DEX) is not the recommended phase 2 doses/maximum
tolerated dose in phase 1, the study will not open to phase 2.
PHASE I: All participants receive venetoclax orally (PO) once daily (QD) on days 1-28 of
each cycle. Depending on dose-level assignment, participants may also receive
dexamethasone PO on days 1, 8, 15, and 22 of each cycle with or without daratumumab SC on
days 1, 8, 15, and 22 of cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles
thereafter. Cycles repeat every 28 days for up to 2 years in the absence of disease
progression or unacceptable toxicity.
PHASE II: Participants receive venetoclax PO QD on days 1-28 of each cycle, dexamethasone
PO on days 1, 8, 15, and 22 of each cycle, and daratumumab SC on days 1, 8, 15, and 22 of
cycles 1-2, days 1 and 15 of cycles 3-6, then on day 1 of cycles thereafter. Cycles
repeat every 28 days for up to 2 years in the absence of disease progression or
unacceptable toxicity.
After completion of study treatment, participants are followed up at 30 days and then
every 3 months until the last participant on the study completes 2 years of treatment.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age >= 18 years
2. Histopathological diagnosis of amyloidosis based on detection by
immunohistochemistry (IHC) and polarizing light microscopy of green bi-refringent
material in Congo red-stained tissue specimens (in an organ other than bone marrow)
or characteristic electron microscopy appearance.
*Considerations for specific populations where other types of amyloidosis may be
encountered:
**For male subjects 70 years of age or older who have cardiac involvement only, and
patients of African descent (black subjects), mass spectrometry typing of AL amyloid
in a tissue biopsy is recommended to rule out other types of amyloidosis such as
age-related amyloidosis or hereditary amyloidosis (ATTR mutation)
3. Presence of t(11;14) on bone marrow plasma cells (BMPC) by fluorescence in-situ
hybridization (FISH), performed at the University of California San Francisco (UCSF)
cytogenetics laboratory
4. >= 1 prior line of therapy for the treatment of systemic AL amyloidosis.
*Note: Induction with only autologous stem cell transplant is considered 1 line of
therapy. Steroid monotherapy treatment will not be counted as 1 prior line of
therapy per National Comprehensive Cancer Network (NCCN) guidelines. Patients are
not required to having progressed from the prior line of therapy
5. No prior CD38-directed antibody treatment OR If the patient previously received
CD38-directed antibody treatment, the patient achieved >= partial response (PR) and
did not progress while on CD38-directed antibody therapy. Progression on
CD38-directed antibody treatment will be defined as progressive disease while on
therapy or within 60 days of last dose.
* Note: If the patient's last prior treatment included daratumumab and the patient
relapsed (and does not meet the exclusion criteria as outlined in exclusion
criterion #1) after cessation of treatment, a 3-month wash-out from CD38 antibody
treatment is required. No washout period for DARA is deemed necessary when patients
are already on DARA-based treatment and the treatment regimen needs to be stopped
due to hematologic very good partial response (VGPR) or PR (suboptimal response) or
non-DARA-related toxicity.
6. Measurable disease of light chain amyloidosis as defined by at least ONE of the
following:
1. Serum M-protein >= 0.5 g/dL by protein electrophoresis (routine serum protein
electrophoresis and immunofixation (IFE) performed at a local laboratory),
2. Serum free light chain >= 40mg/L with an abnormal kappa:lambda ratio or
3. The difference between involved and uninvolved free light chains (dFLC) >= 20
mg/L.
7. One or more organs impacted by AL amyloidosis according to consensus guidelines.
8. Eastern Cooperative Oncology Group (ECOG) performance status =< 2.
9. Pretreatment clinical laboratory values meeting the following criteria during the
Screening Phase (within 1 day of C1D1):
1. Absolute neutrophil count >= 1.0 × 10^9/L without growth factor support for 7
days (14 days if pegfilgrastim).
2. Hemoglobin level >= 8.0 g/dL (>= 5 mmol/L).
3. Platelet count >= 100 × 10^9/L without transfusion for 14 days.
4. Alanine aminotransferase level (ALT) =< 2.5 times the upper limit of normal
(ULN).
5. Aspartate aminotransferase (AST) =< 2.5 times the ULN.
6. Total bilirubin level =< 3 × ULN except for subjects with Gilbert syndrome, in
which case direct bilirubin =< 2 × ULN.
7. Creatinine clearance of ≥ 30 mL/min based upon Cockcroft-Gault formula
calculation or a 24-hour urine collection.
10. Patients must have completed other systemic therapy >= 14 days or investigational
drug/vaccine >= 28 days prior to treatment, focal radiation therapy >= 14 days,
surgery (other than biopsies) >= 21 days prior to treatment, and any autologous stem
cell transplant (ASCT) >= 100 days prior to start of treatment.
11. Patients must not have received any medications or supplements which have been known
to have some anti-amyloidogenic effect (such as: doxycycline; curcumin; prednisone;
dexamethasone; epigallocatechin gallate) within 14 days prior to start of treatment.
12. Women of childbearing potential must commit to either abstain continuously from
heterosexual sexual intercourse (if this is the preferred and usual lifestyle of the
subject) or to use 2 methods of reliable birth control simultaneously. This includes
one highly effective form of contraception (tubal ligation, intrauterine device,
hormonal [birth control pills, injections, hormonal patches, vaginal rings or
implants] or partner's vasectomy) and one additional effective contraceptive method
(male latex or synthetic condom, diaphragm, or cervical cap). Contraception must
begin 4 weeks prior to treatment and continue for 30 days after discontinuation of
venetoclax or 3 months after discontinuation of DARA SC, whichever is longer.
Reliable contraception is indicated even where there has been a history of
infertility, unless due to hysterectomy or bilateral oophorectomy.
13. During the study and for 30 days after stopping VEN or 3 months after receiving the
last dose of DARA SC, whichever is longer, a woman must agree not to donate eggs
(ova, oocytes) for the purposes of assisted reproduction.
14. A man who is sexually active with a woman of childbearing potential and has not had
a vasectomy must agree to use a barrier method of birth control; e.g., either condom
with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap
(diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository
during and up to 30 days after discontinuation of VEN or 3 months after
discontinuation DARA SC, whichever is longer. All men must also not donate sperm
during the study and for 30 days after discontinuation of VEN or 3 months after
discontinuation of DARA SC, whichever is longer.
15. Patients must have documentation of yearly flu vaccination and a pneumococcus
vaccination. Note: If the patient is due for 2 doses of pneumococcus vaccination,
patients must have documentation of having received one dose of vaccine. Live
attenuated vaccines are not allowed
16. Ability to understand a written informed consent document, and the willingness to
sign it.
Exclusion Criteria:
1. Any prior hematologic progression to CD38 antibody therapy (regardless of presence
of a response) while on treatment or within 90 days of the last dose. Hematologic
progression is defined as any ONE of the following:
1. From CR, any detectable monoclonal protein or abnormal free light chain ratio
(the absolute concentration of the light chains must double)
2. From PR, 50% increase in serum M protein to >0.5 g/dl or 50% increase in urine
M protein to 4200 mg/day (a visible peak must be present)
3. Free light chain increase of 50% to >100 mg/l
2. Prior exposure to BCL-2 inhibitors.
3. Intolerance to anti-CD38 antibody therapy, monoclonal antibodies, or hyaluronidase
4. Previous or current diagnosis of multiple myeloma by International Myeloma Working
Group (IMWG) criteria, including the presence of lytic bone disease, plasmacytomas,
>= 60% plasma cells in the bone marrow, or hypercalcemia.
5. Systemic AL amyloidosis from a lymphoma.
6. Any form of non-AL amyloidosis, including wild type or mutated (ATTR) amyloidosis.
7. Evidence of significant cardiovascular conditions as specified below:
1. Troponin I >0.1 ng/ml and B-type natriuretic peptide (BNP) >700 pg/ml (cardiac
stage 3B)
2. Left ventricular ejection fraction (LVEF) <40%
3. New York Heart Association (NYHA) classification IIIB or IV heart failure
4. Heart failure that in the opinion of the investigator is on the basis of
ischemic heart disease (e.g. prior myocardial infarction with documented
history of cardiac enzyme elevation and electrocardiogram [ECG] changes) or
uncorrected valvular disease and not primarily due to AL amyloid cardiomyopathy
5. Inpatient admission to a hospital for unstable angina or myocardial infarction
within the last 6 months prior to first dose or percutaneous cardiac
intervention with recent stent within 6 months or coronary artery bypass
grafting within 6 months
6. For patients with congestive heart failure, cardiovascular-related
hospitalizations within 4 weeks prior to Cycle 1 Day 1.
7. Patients with a history of sustained ventricular tachycardia or aborted
ventricular fibrillation or with a history of atrioventricular nodal or
sinoatrial (SA) nodal dysfunction for which a pacemaker/implantable
cardioverter-defibrillator (ICD) is indicated but not placed. Note: Patients
who do have a pacemaker/ICD are allowed on study.
8. Screening 12-lead ECG showing a baseline QT interval as corrected by
Fridericia's formula (QTcF) >500 msec. Note: Patients who have a pacemaker may
be included regardless of calculated QTc interval.
9. Supine systolic blood pressure <90 mm Hg, or symptomatic orthostatic
hypotension, defined as a decrease in systolic blood pressure upon standing of
>20 mmHg despite medical management (e.g., midodrine, fludrocortisones) in the
absence of volume depletion.
8. Planned stem cell transplant. Note: Stem cell collection is permitted. Timing should
be discussed with sponsor-investigator.
9. History of malignancy (other than AL amyloidosis) within 3 years before the date of
study enrollment. Note: Exceptions are squamous and basal cell carcinomas of the
skin, carcinoma in situ of the cervix or breast, or other non-invasive lesion that
in the opinion of the investigator, with concurrence with the sponsor's medical
monitor, is considered cured with minimal risk of recurrence within 3 years).
10. For patients with known or suspected COPD, chronic obstructive pulmonary disease
(COPD) with a forced expiratory volume in 1 second (FEV1) < 50% of predicted normal
are excluded. Note: FEV1 testing is required only for patients known or suspected of
having COPD and patients must be excluded if FEV1 is < 50% of predicted normal.
11. Moderate or severe persistent asthma within the past 2 years, or currently has
uncontrolled asthma of any classification. Note: Patients who currently have
controlled intermittent asthma or controlled mild persistent asthma are allowed to
participate.
12. Participant meets one of the following criteria:
1. Known history of human immunodeficiency virus (HIV).
2. Seropositive for hepatitis B (defined by a positive test for hepatitis B
surface antigen (HBsAg)). Note: Patients with resolved infection (i.e.,
patients who are HBsAg negative with antibodies to total hepatitis B core
antigen (anti-HBc) with or without the presence of hepatitis B surface antibody
(anti-HBs)) must be screened using real-time polymerase chain reaction (PCR)
measurement of hepatitis B virus (HBV) DNA levels. Those who are PCR positive
will be excluded. However, patients with serologic findings suggestive of HBV
vaccination (anti-HBs positivity as the only serologic marker) AND a known
history of HBV vaccination, do not need to be testing for HBV DNA by PCR, and
will not be excluded.
3. Seropositive for hepatitis C (except in the setting of a sustained virologic
response (SVR), defined as aviremia at least 12 weeks after completion of
antiviral therapy).
13. Concurrent medical condition or disease (e.g., active systemic infection) that is
likely to interfere with study procedures or results, or that in the opinion of the
investigator would constitute a hazard for participating in this study.
14. Has not recovered from adverse events due to prior anti-cancer therapy to <= grade 1
or baseline (other than alopecia).
15. Systemic treatment with any of the following within 7 days prior to the first dose
of study drug:
- Steroid therapy for anti-neoplastic intent
- Known moderate or strong cytochrome P450 3A (CYP3A) inhibitors
- Known moderate or strong CYP3A inducers ** Note: Patients who are taking strong
CYP3A4 inducers must discontinue their use at least 5 half-lives prior to the
first dose of study treatment
16. Administration or consumption of any of the following within 3 days prior to the
first dose of study drug:
- Grapefruit or grapefruit products
- Seville oranges (including marmalade containing Seville oranges)
- Starfruit
17. Patient anticipates use of prohibited medications or foods during study
participation.
18. Major surgery within 2 weeks before Cycle 1 Day 1, or will not have fully recovered
from surgery, or has surgery planned during the time the subject is expected to
participate in the study or within 2 weeks after the last dose of study treatment
administration.
* Note: Patients with planned surgical procedures to be conducted under local
anesthesia may participate.
19. Known or suspected of not being able to comply with the study protocol or the
patient has any condition for which, in the opinion of the investigator,
participation would not be in the best interest of the patient (e.g., compromise
their well-being) or that could prevent, limit, or confound the protocol-specified
assessments.
20. Woman who is pregnant or breastfeeding or planning to become pregnant while enrolled
in this study or within 3 months following discontinuation of daratumumab or
venetoclax.
21. Have received vaccination with live attenuated vaccines within 4 weeks of first
study agent administration.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
University of California, San Francisco
Address:
City:
San Francisco
Zip:
94143
Country:
United States
Status:
Recruiting
Contact:
Last name:
Kenya Gomez
Phone:
877-827-3222
Email:
Kenya.Gomez@ucsf.edu
Contact backup:
Phone:
877-827-3222
Email:
cancertrials@ucsf.edu
Investigator:
Last name:
Alfred Chung, MD
Email:
Principal Investigator
Start date:
January 8, 2024
Completion date:
December 31, 2027
Lead sponsor:
Agency:
Alfred Chung, MD
Agency class:
Other
Collaborator:
Agency:
Janssen Pharmaceuticals
Agency class:
Industry
Collaborator:
Agency:
AbbVie
Agency class:
Industry
Source:
University of California, San Francisco
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT05486481
