Trial Title:
ATRA and Carfilzomib in Plasma Cell Myeloma Patients
NCT ID:
NCT06536413
Condition:
Multiple Myeloma
Conditions: Official terms:
Multiple Myeloma
Neoplasms, Plasma Cell
Tretinoin
Study type:
Interventional
Study phase:
Phase 1/Phase 2
Overall status:
Recruiting
Study design:
Allocation:
N/A
Intervention model:
Sequential Assignment
Primary purpose:
Treatment
Masking:
None (Open Label)
Intervention:
Intervention type:
Drug
Intervention name:
All-Trans Retinoic Acid (ATRA) Dose 0
Description:
Patients will receive oral ATRA 25 mg/m2 per day in two divided doses with
carfilzomib-based regimens.
Eligible patients will enter the study in cohorts of two with the first cohort treated at
Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation
according to the the trials Bayesian Optimal Interval (BOIN) Design is conducted. In
patients who respond and do not have any dose limiting toxicity (DLT), treatment will
continue for a total of 6 cycles in the phase II expansion cohort and subsequently
transitioned to standard -of-care options. Each cycle will be 28 days. In phase 1b, a
minimum of 16 evaluable patients will be recruited and in the second phase a minimum of
26 evaluable patients will be recruited. A minimum of 42 evaluable patients will be
recruited in the study.
If a dose limiting toxicity occurs at 25 mg/m2, then the dose will be reduced by 50% to
15 mg/sq m daily in two divided doses.
Arm group label:
All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone
Intervention type:
Drug
Intervention name:
All-Trans Retinoic Acid (ATRA) Dose -1
Description:
Patients will receive oral ATRA 15 mg/m2 per day in two divided doses with
carfilzomib-based regimens.
Eligible patients will enter the study in cohorts of two with the first cohort treated at
Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation
according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients
who respond and do not have any dose limiting toxicity (DLT), treatment will continue for
a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to
standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16
evaluable patients will be recruited and in the second phase a minimum of 26 evaluable
patients will be recruited. A minimum of 42 evaluable patients will be recruited in the
study.
Arm group label:
All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone
Intervention type:
Drug
Intervention name:
All-Trans Retinoic Acid (ATRA) Dose 1
Description:
Patients will receive oral ATRA 45 mg/m2 per day in two divided doses with
carfilzomib-based regimens.
Eligible patients will enter the study in cohorts of two with the first cohort treated at
Dose 0. To assign a dose to the next cohort of patients, dose escalation/de-escalation
according to the trials Bayesian Optimal Interval (BOIN) Design is conducted. In patients
who respond and do not have any dose limiting toxicity (DLT), treatment will continue for
a total of 6 cycles in the phase II expansion cohort and subsequently transitioned to
standard -of-care options. Each cycle will be 28 days. In phase 1b, a minimum of 16
evaluable patients will be recruited and in the second phase a minimum of 26 evaluable
patients will be recruited. A minimum of 42 evaluable patients will be recruited in the
study.
Arm group label:
All-Trans Retinoic Acid (ATRA), Carfilzomib, and Dexamethasone
Summary:
This is a Phase IB/II trial that will investigate the safety, tolerability and efficacy
of combination therapy using All-Trans Retinoic Acid (ATRA) with Carfilzomib based
therapies in plasma cell myeloma also commonly referred as Multiple Myeloma (MM), in
patients considered refractory to proteasome inhibitors (PIs). Multiple myeloma is an
incurable clonal plasma cell disorder that comprises 10% of all hematologic malignancies.
Over the past 30 years the global prevalence of multiple myeloma has risen to 126%, with
85% of diagnoses occurring in patients >55 years of age. In the past 15 years, survival
has improved considerably, which is attributed to the development of multiple different
classes of medications, including proteasome inhibitors. Proteasome inhibitors are the
foundation of many multiple myeloma treatments in both transplant eligible and ineligible
patients for the past 2 decades. While proteasome inhibitors have improved both
progression free survival (PFS) and overall survival (OS), many patients eventually
develop disease progression arising from resistance to therapies. As a result, there is
an unmet need to overcome resistance and find ways to enhance multiple myeloma
sensitivity to proteasome inhibitor toxicity. Carfilzomib, a modified peptide epoxyketone
that selectively targets intracellular proteasome enzymes, is approved in combination
with dexamethasone in patients that have received ≥1 line of therapy or in combination.
There are few studies assessing ways to enhance carfilzomib-mediated multiple myeloma
toxicity. All-Trans Retinoic Acid (ATRA) is an oxidative metabolite of retinol (vitamin
A) and plays an important role in the regulation of cellular proliferation and
differentiation. In a recent pre-clinical study, ATRA was found to enhance sensitivity of
carfilzomib-mediated apoptosis in vitro via an interferon beta (IFN-β) response pathway.
In the clinical setting, ATRA is a well-tolerated drug that has shown little change in
the rate of adverse events in early clinical trials with multiple myeloma. The
investigators hypothesize that ATRA enhances sensitivity of multiple myeloma to
carfilzomib therapy.
Criteria for eligibility:
Criteria:
Inclusion Criteria:
1. Age ≥ 18 years with relapsed/refractory multiple myeloma documented according to
International Myeloma Working Group (IMWG) criteria.
2. Previously treated with three lines of carfilzomib-based therapy which would include
Immunomodulatory drugs (IMiDs), Proteosome inhibitors and anti-CD 38 antibodies. and
failed to achieve a minor response after completing 2 cycles of carfilzomib-based
therapy or are relapsed while on therapy.
3. Patient or legal guardian voluntarily can sign informed consent.
4. Eastern Cooperative Oncology Group (ECOG) Performance Status (PS) ≤ 2
5. Adequate organ function defined as:
1. Hemoglobin ≥8 g/dL (baseline or after Peripheral Red Blood Cell transfusion),
Platelet count >75,000 and Absolute Neutrophil Count >1000/ micro liter.
2. Left Ventricular Ejection fraction >50%
3. Creatinine Clearance ≥ 30 ml/min
4. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 3 × upper
limit of normal (ULN)
5. Total bilirubin ≤ 1.5 × ULN
6. Measurable disease requiring treatment defined as patients having one or more of the
criteria below:
1. Serum M protein ≥ 0.5 g/dL or
2. Urine M-protein ≥ 200 mg/24 hours or
3. Serum free light chain (SFLC) ≥ 100 mg/L (involved light chain) and an abnormal
serum
4. kappa lambda ratio.
7. If previous autologous stem cell transplantation, must have fully recovered from
transplant related toxicities and be >60 days from transplant and have had
hematologic recovery independent of growth factor support.
8. Willingness to undergo interim bone marrow biopsy as scheduled or if felt to be
medically indicated.
9. Life Expectancy ≥ 6 months
10. Women with childbearing potential and men should practice at least one of the
following methods of birth control:
1. Total abstinence from sexual intercourse (periodic abstinence not acceptable);
2. Surgically sterile partner(s) including vasectomy, bilateral tubal ligation,
bilateral oophorectomy, or hysterectomy;
3. Intrauterine device with an additional method of contraception to make two
effective methods of contraception during treatment with Vesanoid;
4. Double-barrier method (condom + diaphragm or cervical cap with spermicide,
contraceptive sponge, jellies, or cream);
5. Hormonal contraceptives (oral, parenteral, vaginal ring, or transdermal) for at
least 3 months prior to study drug administration. If hormonal contraceptives
are used, the specific contraceptive must have been used for at least 3 months
prior to study drug administration. If the patient is currently using a
hormonal contraceptive, she should also use a barrier method during this study
Women of child-bearing potential must have a negative results of a pregnancy
test performed at initial screening on a serum sample obtained within 21 days
prior to C1D1, and prior to dosing on a urine sample obtained within 72 hours
of the first study drug administration. Males must refrain from sperm donations
from date of C1D1 to 90 days after the last date of the study drug.
Exclusion Criteria:
1. Non-secretory or hyposecretory multiple myeloma, defined as <0.5 g/dL M-protein in
serum, <200 mg/24-hour urine M-protein, or disease only measured by serum free light
chain.
2. Plasma Cell Leukemia
3. Concurrent light chain amyloidosis
4. Central nervous system involvement (patients with known brain metastases have poor
prognosis and often develop progressive neurologic dysfunction that may confound the
evaluation of neurologic and other Adverse Events while on ATRA).
5. Pregnant or breast feeding
6. Severe, active, recurrent, or intercurrent infection (viral, bacterial, fungal), or
diagnosis of neutropenia and fever within one week of C1D1.
7. History of allergic reactions or intolerance to any of the Carfilzomib based
therapies.
8. History of Allogeneic hematopoietic cell transplantation or solid organ
transplantation.
9. Unstable angina pectoris, cardiac arrhythmia or > New York Heart Failure association
class II cardiac failure, defined as comfortable at rest but ordinary physical
activity results in fatigue, palpitations, dyspnea, or anginal pain.
10. Patient has a significant history of renal, neurologic (peripheral neuropathy),
psychiatric, endocrinologic (diabetes mellitus), metabolic, immunologic,
cardiovascular, pulmonary, hepatic disease, or significant social situation within
the past 6 months that, in the opinion of the investigator, would impede his/her
ability to fully participate in the study. For patients who have required an
intervention for the above diseases within the past 6 months, a case-by-case
discussion with the investigator must occur.
11. On investigational therapies within 12 weeks of enrollment.
12. Previous intolerance to a proteasome inhibitor, including carfilzomib, bortezomib,
or ixazomib.
13. Or deemed unfit for the study on evaluation by Investigator.
Gender:
All
Minimum age:
18 Years
Maximum age:
N/A
Healthy volunteers:
No
Locations:
Facility:
Name:
Houston Methodist Neal Cancer Center
Address:
City:
Houston
Zip:
77030
Country:
United States
Status:
Recruiting
Contact:
Last name:
Sai Ravi Pingali, MD
Start date:
July 29, 2024
Completion date:
July 2030
Lead sponsor:
Agency:
The Methodist Hospital Research Institute
Agency class:
Other
Collaborator:
Agency:
Cancer Prevention Research Institute of Texas
Agency class:
Other
Source:
The Methodist Hospital Research Institute
Record processing date:
ClinicalTrials.gov processed this data on November 12, 2024
Source: ClinicalTrials.gov page:
https://clinicaltrials.gov/ct2/show/NCT06536413
https://odin.mdacc.tmc.edu/~yyuan/Software/BOIN/paper.pdf
https://ash.confex.com/ash/2020/webprogram/Paper140388.html
