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Duffy Null-Specific Dose Modifications for the Treatment of Duffy Null Phenotype Multiple Myeloma and Stage II and III Triple Negative Breast Cancer
Trial Status: active
This phase I trial tests the effect of using Duffy null specific dose modification guidelines in treating multiple myeloma and stage II and III triple negative breast cancer patients with the Duffy null (DN) phenotype. People with the DN phenotype, a blood subtype common in some populations, often have lower neutrophil counts (a white blood cell). Standard dosing guidelines for chemotherapy, including dexamethasone, bortezomib, lenalidomide, daratumumab (Dara-RVD), pembrolizumab, paclitaxel, carboplatin, doxorubicin, and cyclophosphamide (Keynote 522), may not account for these naturally lower counts and may lead to unnecessary dose reductions or treatment delays, which can worsen cancer outcomes. Bortezomib blocks several molecular pathways in a cell and may cause tumor cells to die. It is a type of proteasome inhibitor and a type of dipeptidyl boronic acid. Lenalidomide may help the immune system kill abnormal blood cells or tumor cells. It may also prevent the growth of new blood vessels that tumors need to grow. Lenalidomide is a type of antiangiogenesis agent and a type of immunomodulating agent. Daratumumab is in a class of medications called monoclonal antibodies. It binds to a protein called CD38, which is found on some types of immune cells and tumor cells, including myeloma cells. Daratumumab may block CD38 and help the immune system kill tumor cells. Immunotherapy with monoclonal antibodies, such as pembrolizumab, may help the body's immune system attack the tumor, and may interfere with the ability of tumor cells to grow and spread. Paclitaxel is in a class of medications called antimicrotubule agents. It stops tumor cells from growing and dividing and may kill them. Carboplatin is in a class of medications known as platinum-containing compounds. It works in a way similar to the anticancer drug cisplatin, but may be better tolerated than cisplatin. Carboplatin works by killing, stopping or slowing the growth of cancer cells. Doxorubicin comes from the bacterium Streptomyces peucetius. It damages deoxyribonucleic acid (DNA) and may kill tumor cells. It is a type of anthracycline antitumor antibiotic. Cyclophosphamide is in a class of medications called alkylating agents. It works by damaging the cell’s DNA and may kill tumor cells. It may also lower the body’s immune response. Dexamethasone is in a class of medications called corticosteroids. It is used to reduce inflammation and lower the body's immune response to help lessen the side effects of chemotherapy drugs. Giving planned chemotherapy with dose adjustments based on DN status and neutrophil counts may be safe and tolerable and may avoid dose reductions and neutropenic fever in patients with multiple myeloma or stage II/III triple negative breast cancer.
Inclusion Criteria
SCREENING: Diagnosis of either:
* Multiple myeloma (MM) based on International Myeloma Working Group (IMWG) criteria, and currently requires treatment
* American Joint Committee on Cancer (AJCC) 8 anatomic tumor clinical stage II or III, histologically confirmed estrogen receptor (ER)-negative, progesterone receptor (PR)-negative, and HER2-negative breast cancer (triple-negative breast cancer [TNBC]). ER-negative is defined as ER < 10%, PR-negative as PR < 10%, and HER2-negative as per 2020 American Society of Clinical Oncology (ASCO) College of American Pathologists (CAP) guidelines
SCREENING: Plan for treatment with, or currently receiving their first cycle of:
* Dara-RVD (for MM)
* Keynote 522 or a neoadjuvant chemotherapy regimen that begins with carboplatin, paclitaxel, and pembrolizumab (for TNBC)
** Patients who are not be planned to receive the pembrolizumab, doxorubicin, and cyclophosphamide portion of Keynote 522 are eligible as long as they are planned to receive the carboplatin, paclitaxel, and pembrolizumab
SCREENING: Pre-treatment absolute neutrophil count (ANC) ≤ 3500 cells/mm^3 (3.5 x 10^9/L). If growth factor has been used in the last 14 days, there is no upper limit
** ANC within 90 days prior to the date of screening is acceptable. Any one ANC measured at ≤ 3500 cells/mm^3 by a local laboratory is sufficient for screening eligibility, even if other ANC are > 3500 cells/mm^3 within this timeframe. ANC 3500 cells/mm^3 is the intersection boundary of the DN and Duffy non-null ANC distributions, maximizing inclusion of DN individuals and minimizing inclusion of Duffy non-null individuals OR
* Self-identified Black race OR
* Self-reported African and/or Middle Eastern ancestry OR
* Known Duffy null phenotype
Diagnosis of:
* Cohort 1: MM, based on IMWG criteria, and currently requires treatment
* Cohort 2: Stage II or III TNBC
Plan for treatment, per their treating physician, or currently receiving their first cycle of:
* Cohort 1: Dara-RVd for MM
* Cohort 2: A Keynote 522-based regimen of carboplatin, paclitaxel, and pembrolizumab given as the first phase of neoadjuvant treatment for TNBC
** Participants are eligible even if the duration of carboplatin and paclitaxel goes beyond 4 cycles, or if the use of pembrolizumab, doxorubicin, and cyclophosphamide is not planned or is not certain, as long as neoadjuvant treatment starts with carboplatin-paclitaxel-pembrolizumab. This cohort will be referred to as "Keynote 522" for the remainder of the protocol
Confirmed Duffy null phenotype
* Previous testing is acceptable if performed by a Clinical Laboratory Improvement Act (CLIA)-approved test
** Those that test Duffy non-null will be eligible only for the observational non-interventional cohort
CORRELATIVE STUDIES SURVEY 2: English, Spanish, or Haitian Creole speaking
OBSERVATIONAL STUDY: Meeting screening criteria
OBSERVATIONAL STUDY: Having Duffy non-null phenotype. These individuals ARE NOT eligible for interventional clinical trial but ARE eligible for the observational correlative study
Exclusion Criteria
Inability to understand and the willingness to sign a written informed consent document
ANC ≤ 500 within 7 days of planned start of cycle 1 day 1
Participants who have started treatment at the time of enrollment cannot have started cycle 2 of therapy
Participants in Cohort 2 (TNBC) cannot have received any of the pembrolizumab, doxorubicin, and cyclophosphamide portion of therapy
Participants receiving any other investigational agents for any indication
Another known condition or medicine with known impacts on neutrophil counts or neutrophil function
* AUTOIMMUNE DISEASE: Addison’s disease, Graves’ disease, Hashimoto thyroiditis, myasthenia gravis, Sjogren’s syndrome, pernicious anemia, autoimmune vasculitis, celiac disease, autoimmune hepatitis, vitiligo, immune thrombocytopenia, dermatomyositis
* IMMUNODEFICIENCY: History of any primary immunodeficiency including chronic granulomatous disease, common variable immunodeficiency, Chediak-Higashi syndrome, cyclic neutropenia, leukocyte adhesion defects, or congenital neutropenia
* INFECTIOUS: History of hepatitis C infection, hepatitis B infection, HIV
* MALIGNANCY: History of malignant neoplasm or hematological cancer requiring systemic anticancer treatment
* TRANSPLANT: History of receiving organ transplant or skin graft including history of allogenic or autologous hematopoietic stem cell transplant
MEDICATION: Use of carbimazole, clozapine, dapsone, dipyrone, methimazole, penicillin G, procainamide, propylthiouracil, rituximab, sulfasalazine, ticlopidine, hydroxychloroquine, infliximab, lamotrigine, oxacillin, quinine, infliximab within the 14 days prior to planned cycle 1 day 1
Infection requiring systemic antimicrobial therapy or other serious infection within 14 days before the planned start of trial-based treatment. Those receiving antimicrobials to complete treatment for a prior infection AND have resolution of active infection ≥ 14 days prior to therapy, as determined by per the treating physician, are eligible.
Antimicrobials for prophylaxis, including trimethoprim-sulfamethoxazole, are not an exclusion criterion
Any medical or psychiatric illness/social situation that in the investigator’s opinion, would impose excessive risk to the participant, would adversely affect their participating in this study, or would limit their ability to comply with study requirements
Study sponsor and potential other locations can be found on ClinicalTrials.gov for NCT07341867.
I. To determine avoided or reduced dose modifications using DN-specific dose modification parameters for the regimens combined.
II. To determine the cumulative incidence of neutropenic fever for the regimens combined.
SECONDARY OBJECTIVES:
I. To determine avoided or reduced dose modifications using DN-specific dose modification parameters for each regimen individually.
II. To determine the cumulative incidence of neutropenic fever for each regimen individually.
III. To determine overall dose intensity using DN-specific dose modification parameters.
IV. To determine the safety of using DN-specific dose modification parameters.
V. For myeloma participants, end of treatment response will be examined.
VI. For breast cancer participants, pathological response and complete response rate will be examined.
CORRELATIVE STUDY OBJECTIVES:
I. To characterize participants' social determinants of health, knowledge of DN phenotype, reasons for interest or non-interest in trial participation.
II. To characterize participant views related to having DN phenotype and preferences related to a future comparative effectiveness trial we plan to conduct based on the present trial.
III. To assess differences in neutrophil-based dose-modifications and adverse events between non-DN observational study participants and DN participants enrolled in the trial.
OUTLINE: Duffy null patients are assigned to 1 of 2 cohorts. Duffy non-null patients are assigned to observational study. Patients not interested in the treatment intervention are assigned to correlative study.
COHORT 1 (DARA-RVD): Patients receive dexamethasone orally (PO) on days 1, 2, 8, 9, 15, 16, 22 and 23 of cycles 1-6, bortezomib subcutaneously (SC) on days 1, 8, 15, and 22 of cycles 1-6, lenalidomide PO on days 1-21 of cycles 1-6, and daratumumab SC over 3-5 minutes on days 1, 8, 15, and 22 of cycles 1 and 2, then on days 1 and 15 of cycles 3-6. Cycles repeat every 28 days for up to 6 cycles in the absence of disease progression or unacceptable toxicity.
COHORT 2 (KEYNOTE 522): Patients receive pembrolizumab intravenously (IV) over 30 minutes on day 1, paclitaxel IV over 1 hour on days 1, 8, and 15, and carboplatin IV over 15-60 minutes on days 1, 8, and 15 or on day 1 of cycles 1-4. Cycles repeat every 21 days for up to 4 cycles in the absence of disease progression or unacceptable toxicity. Starting with cycle 5, patients receive pembrolizumab IV over 30 minutes on day 1 every 21 days for up to 4 cycles. Patients also receive doxorubicin IV over 15 minutes and cyclophosphamide IV over 60 minutes on day 1 of cycles 5-8. Cycles repeat every 14 or 21 days at clinician discretion for up to 4 cycles in the absence of disease progression or unacceptable toxicity.
OBSERVATIONAL STUDY: Patients undergo observation throughout the study.
CORRELATIVE STUDY: Patients complete a survey on study.
blood sample collection and positron emission tomography (PET)/computed tomography (CT), magnetic resonance imaging (MRI) or CT throughout the study.
After completion of study treatment, patients are followed up at 30 days and at 3 months.
Trial PhaseNo phase specified
Trial Typetreatment
Lead OrganizationDana-Farber Harvard Cancer Center