Clinical trial NCT06179888: Iberdomide Versus Observation Off Therapy After Idecabtagene Vicleucel CAR-T for Multiple Myeloma
Official title: Randomized Phase 2 Study of Iberdomide Maintenance Therapy Following Idecabtagene Vicleucel CAR-T in Multiple Myeloma Patients
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE2
Conditions: Multiple Myeloma
Lead sponsor: National Cancer Institute (NCI)
Sponsor class: NIH
First posted: 2023-12-22
Enrollment: 78
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

Brief summary: This phase II trial compares iberdomide maintenance therapy to disease monitoring for improving survival in patients who have received idecabtagene vicleucel (a type of chimeric antigen receptor T-cell \[CAR-T\] therapy) for multiple myeloma. The usual approach after treatment with idecabtagene vicleucel is to monitor the multiple myeloma without giving myeloma medications. There is currently no medication approved specifically for use after idecabtagene vicleucel treatment. Upon administration, iberdomide modifies the immune system and activates immune cells called T-cells, which could enhance the effectiveness of idecabtagene vicleucel. Iberdomide may keep multiple myeloma under control for longer than the usual approach (disease monitoring) after idecabtagene vicleucel, and may help multiple myeloma patients live longer.

Detailed description: PRIMARY OBJECTIVES:

I. To establish and confirm the safety and dose of iberdomide as maintenance after idecabtagene vicleucel (ide-cel) CAR-T. (Safety run-in) II. To assess whether iberdomide maintenance therapy after idecabtagene vicleucel CAR-T cell therapy increases progression-free survival (PFS) relative to observation without additional therapy. (Randomized phase II)

SECONDARY OBJECTIVES:

I. To demonstrate anti-tumor activity, defined as conversion from non-minimal residual disease (MRD) complete response (CR)/stringent CR (sCR) status to MRD-negative CR/sCR, as well as improvement in PFS in the safety run-in cohort. (Safety run-in) II. To estimate the rate of conversion from MRD-positive at baseline to MRD-negative at any time point post-initiation of iberdomide maintenance or observation without additional therapy. (Key secondary objective; Randomized phase II) III. To estimate overall survival (OS) distribution post-initiation of iberdomide maintenance or observation without additional therapy. (Key secondary objective; Randomized phase II) IV. To estimate the minimal residual disease (MRD)-negativity rate at pre-registration and at one year post-initiation of iberdomide maintenance or observation without additional therapy. (Randomized phase II) V. To estimate rate of deepening hematological response among patients with measurable multiple myeloma (MM) post-initiation of iberdomide maintenance or observation without additional therapy. (Randomized phase II) VI. To evaluate the safety profile of iberdomide maintenance. (Randomized phase II) VII. To evaluate the peripheral blood immunophenotype before and during iberdomide maintenance or observation without additional therapy. (Randomized phase II) VIII. To evaluate persistence of CAR-T cells with iberdomide maintenance or observation without additional therapy. (Randomized phase II)

CORRELATIVE SCIENCE OBJECTIVES:

I. To estimate the minimal residual disease (MRD)-negativity rate at start of maintenance and at one year post-initiation of maintenance or observation.

II. To estimate the sustained MRD-negativity rate. III. To estimate the rate of conversion from MRD-positive to MRD-negative. (Key objective) IV. To evaluate the peripheral blood immunophenotype before and during maintenance therapy or observation.

V. To evaluate the persistence of CAR-T cells. VI. To evaluate B-cell maturation antigen (BCMA) protein expression by immunohistochemistry on myeloma cells from patients that have relapsed/recurrent disease.

OUTLINE: Patients are randomized to 1 of 2 groups.

GROUP 1: Patients undergo disease monitoring at monthly clinic visits until disease progression. Patients also undergo bone marrow aspiration and biopsy throughout the trial, undergo collection of blood samples at screening and on study, and undergo positron emission tomography (PET)/computed tomography (CT) and/or skeletal survey x-ray, CT, or magnetic resonance imaging (MRI) at screening and then as clinically indicated.

GROUP 2: Patients receive iberdomide orally (PO) once daily (QD) on days 1-21 of each cycle. Cycles repeat every 28 days in the absence of disease progression or unacceptable toxicity. Patients also undergo bone marrow aspiration and biopsy throughout the trial, undergo collection of blood samples at screening and on study, and undergo PET/CT and/or skeletal survey x-ray, CT, or MRI at screening and then as clinically indicated.

After completion of study treatment, patients are followed up within 30 days, then every 3-6 months until 4 years following registration.

Eligibility criteria: Inclusion Criteria:

* PRE-REGISTRATION ELIGIBILITY CRITERIA (STEP 0):
* All patients must be pre-registered. For patients who consent to biobanking, submit the bone marrow and blood specimens

  * Note: Patients who do not consent to the optional biobanking must be pre-registered, but specimens should not be submitted for these patients
  * Please ensure patient has suspected diagnosis of multiple myeloma and meets on study guidelines prior to informed consent and biospecimen collection
  * In cases where the bone marrow aspiration may be inadequate at Step 0 registration, the patient may still register on study
* ELIGIBILITY CRITERIA (STEP 1):
* Patients must have diagnostically confirmed MM in response status of stable disease or better by International Myeloma Working Group (IMWG) criteria at day 80-110 post-infusion of ide-cel. Patients in deep remission (e.g., CR, MRD-negative, etc.), are eligible
* All patients are required to have received ide-cel CAR-T within 80-110 days of registration
* Adverse events related to ide-cel are required to have resolved to grade =\< 1 except fatigue, alopecia, and other events that are unlikely to interfere with study assessments or pose a safety risk to participants
* Patients must have had ≥ 4 lines of therapy for MM (this includes proteasome inhibitor, immunomodulatory agent, and anti-CD38 monoclonal antibody)
* Prior therapy with iberdomide is permitted but prior iberdomide refractoriness is prohibited. Refractoriness is defined as per published IMWG criteria; progression while on iberdomide or within 60 days of stopping iberdomide
* Patients who have received MM-directed therapy since ide-cel infusion are not eligible, with the exception of short-course steroids for managing ide-cel toxicity as described below
* Age ≥ 18 years
* Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2
* Absolute neutrophil count (ANC) ≥ 1,500/mm\^3

  * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
* Platelet count ≥ 75,000/mm\^3

  * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
* Calculated (calc.) creatinine clearance \>= 30 mL/min by Modification of Diet in Renal Disease (MDRD)

  * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
* Total bilirubin ≤ 1.5 x upper limit of normal (ULN)

  * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
* Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase \[SGOT\])/alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase \[SGPT\]) ≤ 3 x upper limit of normal (ULN)

  * Platelet transfusions or use of growth factors for neutropenia (e.g., filgrastim, tbo-filgrastim, sagramostim) are not permitted to meet enrollment criteria
* Not pregnant and not nursing, because this study involves an investigational agent whose genotoxic, mutagenic and teratogenic effect on the developing fetus and newborn are unknown.

  * FCBP (female of childbearing potential) is a female who: 1) has achieved menarche (first menstrual cycle) at some point, 2) has not undergone a hysterectomy (the surgical removal of the uterus) or bilateral oophorectomy (the surgical removal of both ovaries) or 3) has not been naturally postmenopausal (amenorrhea following cancer therapy does not rule out childbearing potential) for at least 24 consecutive months (ie, has had menses at any time during the preceding 24 consecutive months).
  * Females of childbearing potential (FCBP):

    * Must use a contraceptive method that is highly effective (with a failure rate of \< 1% per year), preferably with low user dependency during the intervention period and for at least 28 days after the last dose of study intervention and agrees not to donate eggs (ova, oocytes) for the purpose of reproduction during this period. The investigator should evaluate the effectiveness of the contraceptive method in relationship to the first dose of study intervention.
    * The effects of iberdomide on the developing human fetus are unknown. Immunodulatory derivative (IMiD) agents as well as other therapeutic agents used in this trial are known to be teratogenic. Females of child-bearing potential (FCBP) must have a negative serum or urine pregnancy test with a sensitivity of at least 25 mIU/mL within 10-14 days prior to, and again within 24 hours of starting iberdomide, and must either commit to continued abstinence from heterosexual intercourse or begin two acceptable methods of birth control, one highly effective method and one additional effective method at the same time, at least 28 days before she starts taking iberdomide. Examples of highly effective methods are intrauterine device, hormonal contraceptives, tubal ligation, or partner's vasectomy. Examples of barrier method are male condom, diaphragm, or cervical cap. FCBP must also agree to ongoing pregnancy testing. Men must agree to use a latex condom during sexual contact with a FCBP even if they have had a successful vasectomy. All patients must be counseled at a minimum of every 28 days about pregnancy precautions and risk of fetal exposure.
    * Should a woman become pregnant or suspect she is pregnant while she or her partner are participating in this study, she should inform her treating physician immediately. FCBP must use adequate contraception for at least 28 days after discontinuation from study. Because of the potential for serious adverse reactions in a breastfed child, women are advised not to breastfeed during treatment and for at least 28 days after the last dose.
    * The investigator is responsible for review of medical history, menstrual history, and recent sexual activity to decrease the risk for inclusion of a woman with a nearly undetected pregnancy.
  * Non-childbearing potential is defined as follows (by other than medical reasons):

    * ≥ 45 years of age and has not had menses for \> 1 year
    * Patients who have been amenorrhoeic for \< 2 years without history of a hysterectomy and oophorectomy must have a follicle stimulating hormone value in the postmenopausal range upon screening evaluation
    * Post-hysterectomy, post-bilateral oophorectomy, or post-tubal ligation. Documented hysterectomy or oophorectomy must be confirmed with medical records of the actual procedure or confirmed by an ultrasound. Tubal ligation must be confirmed with medical records of the actual procedure
* Male patients must agree to use an adequate method of contraception for the duration of the study and for 28 days afterwards.

  * Male participants: contraceptive use should be consistent with local regulations regarding the methods of contraception for those participating in clinical studies:

    * Male participants are eligible to participate if they agree to the following during the intervention period and for 28 days after the last dose of study treatment to allow for clearance of any altered sperm:

      * Refrain from donating sperm

PLUS, either:

* Be abstinent from heterosexual intercourse as their preferred and usual lifestyle (abstinent on a long term and persistent basis) and agree to remain abstinent OR
* Must agree to use contraception/barrier as detailed below:

  * Agree to use a male condom, even if they have undergone a successful vasectomy, and female partner to use an additional highly effective contraceptive method with a failure rate of \< 1% per year as when having sexual intercourse with a woman of childbearing potential (including pregnant females)

    * Patients may not have polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes (POEMS) syndrome or amyloidosis involving any vital organ; amyloidosis found in skin or lymph nodes ("non-vital organs"), or incidental observation of amyloidosis on bone marrow biopsy, are both permissible. Plasma cell leukemia is permissible for study enrollment
    * Patients with a prior or concurrent malignancy whose natural history or treatment does not have the potential to interfere with the safety or efficacy assessment of the investigational regimen are eligible for this trial
    * Human immunodeficiency virus (HIV)-infected patients on effective anti-retroviral therapy with undetectable viral load within 6 months prior to registration are eligible for this trial
    * For patients with evidence of chronic hepatitis B virus (HBV) infection, the HBV viral load must be undetectable on suppressive therapy, if indicated
    * Patients with a history of hepatitis C virus (HCV) infection must have been treated and cured. Patients with HCV infection who are currently on treatment are eligible if they have an undetectable HCV viral load
    * Patients may not have other, active infections at time of study registration. Recent infections are not exclusionary if antibiotics have been completed and infection is considered to be resolved / controlled. (Chronic maintenance antibiotics for prior infections, such as fungal, are permissible.)
    * No known allergy to iberdomide
    * No known medical condition causing an inability to swallow oral formulations of agents
    * Patients receiving other active therapies for MM since ide-cel infusion are prohibited from participating in the study
    * Corticosteroids used for the purpose of managing ide-cel toxicity (often neurotoxicity) soon after ide-cel administration are acceptable, provided that the participant will have been off corticosteroids for \> 30 days by cycle 1 day 1. Physiologically dosed chronic steroids are permitted
    * Given the potential for interaction with iberdomide, patients who take strong CYP3A4 inducers or inhibitors may enroll after switching to a different agent and after an appropriate washout period for that particular medication, ideally three half-lives, prior to cycle 1 day 1

Primary outcomes:
measure: Incidence of dose-limiting toxicities (safety run-in)
timeFrame: The first 3 months of therapy
measure: Progression-free survival (PFS) (randomized phase II)
timeFrame: From randomization to the time of progression and/or death, assessed up to 4 years
Secondary outcomes:
measure: Incidence of adverse events
timeFrame: Up to 4 years
measure: Number of treatment cycles received (tolerability)
timeFrame: Up to 4 years
measure: Proportion of patients with dose modifications, omissions, and/or delays (tolerability)
timeFrame: Up to 4 years
measure: Proportion of patients who go off treatment due to adverse events
timeFrame: Up to 4 years
measure: Overall survival (OS)
timeFrame: From randomization until death from any cause, assessed up to 4 years
measure: Best response achieved while on study
timeFrame: Up to 4 years
measure: Proportion of patients who improve their status
timeFrame: After randomization, up to 4 years
Other outcomes:
measure: MRD-negativity rate
timeFrame: At start of maintenance and at one year post-initiation of maintenance or observation
measure: Sustained MRD-negativity rate
timeFrame: Up to 4 years
measure: Rate of conversion from MRD-positive to MRD-negative
timeFrame: Up to 4 years
measure: Peripheral blood immunophenotype
timeFrame: Before and during maintenance therapy or observation
measure: Persistence of chimeric antigen receptor T-cells
timeFrame: At cycle 12
measure: B-cell maturation antigen (BCMA) protein expression
timeFrame: Up to 4 years
Locations:
city: Los Angeles
country: United States
facility: Cedars Sinai Medical Center
state: California
city: Orange
country: United States
facility: UC Irvine Health/Chao Family Comprehensive Cancer Center
state: California
city: Sacramento
country: United States
facility: University of California Davis Comprehensive Cancer Center
state: California
city: Chicago
country: United States
facility: University of Illinois
state: Illinois
city: Ankeny
country: United States
facility: UI Health Care Mission Cancer and Blood - Ankeny Clinic
state: Iowa
city: Clive
country: United States
facility: UI Health Care Mission Cancer and Blood - West Des Moines Clinic
state: Iowa
city: Des Moines
country: United States
facility: Iowa Methodist Medical Center
state: Iowa
city: Des Moines
country: United States
facility: UI Health Care Mission Cancer and Blood - Des Moines Clinic
state: Iowa
city: Des Moines
country: United States
facility: Mercy Medical Center - Des Moines
state: Iowa
city: Des Moines
country: United States
facility: UI Health Care Mission Cancer and Blood - Laurel Clinic
state: Iowa
city: Southhaven
country: United States
facility: Baptist Memorial Hospital and Cancer Center-Desoto
state: Mississippi
city: Creve Coeur
country: United States
facility: Siteman Cancer Center at West County Hospital
state: Missouri
city: Saint Louis
country: United States
facility: Washington University School of Medicine
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center-South County
state: Missouri
city: Saint Louis
country: United States
facility: Siteman Cancer Center at Christian Hospital
state: Missouri
city: Saint Peters
country: United States
facility: Siteman Cancer Center at Saint Peters Hospital
state: Missouri
city: Bellevue
country: United States
facility: Nebraska Medicine-Bellevue
state: Nebraska
city: Omaha
country: United States
facility: Nebraska Medicine-Village Pointe
state: Nebraska
city: Omaha
country: United States
facility: University of Nebraska Medical Center
state: Nebraska
city: Middletown
country: United States
facility: Memorial Sloan Kettering Monmouth
state: New Jersey
city: Montvale
country: United States
facility: Memorial Sloan Kettering Bergen
state: New Jersey
city: Commack
country: United States
facility: Memorial Sloan Kettering Commack
state: New York
city: Harrison
country: United States
facility: Memorial Sloan Kettering Westchester
state: New York
city: New York
country: United States
facility: Memorial Sloan Kettering Cancer Center
state: New York
city: Chapel Hill
country: United States
facility: UNC Lineberger Comprehensive Cancer Center
state: North Carolina
city: Fargo
country: United States
facility: Sanford Broadway Medical Center
state: North Dakota
city: Fargo
country: United States
facility: Sanford Roger Maris Cancer Center
state: North Dakota
city: Oklahoma City
country: United States
facility: University of Oklahoma Health Sciences Center
state: Oklahoma
city: Portland
country: United States
facility: Providence Portland Medical Center
state: Oregon
city: Portland
country: United States
facility: Providence Saint Vincent Medical Center
state: Oregon
city: Greenville
country: United States
facility: Prisma Health Cancer Institute - Eastside
state: South Carolina
city: Memphis
country: United States
facility: Baptist Memorial Hospital and Cancer Center-Memphis
state: Tennessee
city: Baytown
country: United States
facility: Houston Methodist San Jacinto Hospital
state: Texas
city: Houston
country: United States
facility: Houston Methodist Hospital
state: Texas
city: Houston
country: United States
facility: Methodist Willowbrook Hospital
state: Texas
city: Houston
country: United States
facility: Houston Methodist West Hospital
state: Texas
city: Nassau Bay
country: United States
facility: Houston Methodist Saint John Hospital
state: Texas
city: Sugar Land
country: United States
facility: Houston Methodist Sugar Land Hospital
state: Texas
city: The Woodlands
country: United States
facility: Houston Methodist The Woodlands Hospital
state: Texas
city: Edmonds
country: United States
facility: Swedish Cancer Institute-Edmonds
state: Washington
city: Issaquah
country: United States
facility: Swedish Cancer Institute-Issaquah
state: Washington
city: Seattle
country: United States
facility: Swedish Medical Center-First Hill
state: Washington
city: Burlington
country: United States
facility: Aurora Cancer Care-Southern Lakes VLCC
state: Wisconsin
city: Cudahy
country: United States
facility: Aurora Saint Luke's South Shore
state: Wisconsin
city: Germantown
country: United States
facility: Aurora Health Care Germantown Health Center
state: Wisconsin
city: Grafton
country: United States
facility: Aurora Cancer Care-Grafton
state: Wisconsin
city: Green Bay
country: United States
facility: Aurora BayCare Medical Center
state: Wisconsin
city: Kenosha
country: United States
facility: Aurora Cancer Care-Kenosha South
state: Wisconsin
city: Marinette
country: United States
facility: Aurora Bay Area Medical Group-Marinette
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Cancer Care-Milwaukee
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Saint Luke's Medical Center
state: Wisconsin
city: Milwaukee
country: United States
facility: Aurora Sinai Medical Center
state: Wisconsin
city: Oshkosh
country: United States
facility: Vince Lombardi Cancer Clinic - Oshkosh
state: Wisconsin
city: Racine
country: United States
facility: Aurora Cancer Care-Racine
state: Wisconsin
city: Sheboygan
country: United States
facility: Vince Lombardi Cancer Clinic-Sheboygan
state: Wisconsin
city: Summit
country: United States
facility: Aurora Medical Center in Summit
state: Wisconsin
city: Two Rivers
country: United States
facility: Vince Lombardi Cancer Clinic-Two Rivers
state: Wisconsin
city: Wauwatosa
country: United States
facility: Aurora Cancer Care-Milwaukee West
state: Wisconsin
city: West Allis
country: United States
facility: Aurora West Allis Medical Center
state: Wisconsin
Study officials:
affiliation: Alliance for Clinical Trials in Oncology
name: Sascha A Tuchman
role: PRINCIPAL_INVESTIGATOR
References: