Abatacept, Ixazomib Citrate, and Dexamethasone in Treating Patients With Multiple Myeloma Resistant to Chemotherapy

Phase II Study of Targeting CD28 in Multiple Myeloma With Abatacept (CTLA4-Ig) to Overcome Resistance to Chemotherapy

This phase II trial studies how well abatacept, ixazomib citrate, and dexamethasone work in treating patients with multiple myeloma that is resistant to chemotherapy. Abatacept may block certain proteins that are present on multiple myeloma cells that have been shown to protect against chemotherapy. Drugs used in chemotherapy, such as ixazomib citrate and dexamethasone, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving abatacept, ixazomib citrate, and dexamethasone may work better at treating patients with multiple myeloma resistant to chemotherapy.

Study Overview

• Status: Active, not recruiting
• Conditions: Refractory Plasma Cell Myeloma; Recurrent Plasma Cell Myeloma
• Intervention / Treatment: Other: Laboratory Biomarker Analysis; Drug: Dexamethasone; Drug: Ixazomib Citrate; Biological: Abatacept

Detailed Description

PRIMARY OBJECTIVES:

I. To determine the therapeutic efficacy (as measured by response rate) of abatacept + ixazomib citrate (ixazomib) + dexamethasone in multiple myeloma patients who have relapsed (or who are primary refractory) following treatment with their first proteasome inhibitor-containing regimen (excluding ixazomib), compared to historical controls of ixazomib + dexamethasone.

SECONDARY OBJECTIVES:

I. To assess the toxicity profile of abatacept + ixazomib + dexamethasone in multiple myeloma patients who have relapsed (or who are primary refractory) following treatment with their first proteasome inhibitor-containing regimen, compared to historical controls of ixazomib + dexamethasone.

II. To assess progression-free and overall survival profile of abatacept + ixazomib + dexamethasone in multiple myeloma patients who have relapsed (or who are primary refractory) following treatment with their proteasome inhibitor-containing regimen, compared to historical controls of ixazomib + dexamethasone.

TERTIARY OBJECTIVES:

I. Assess whether myeloma expression of CD28, CD86, serum kynurenine and/or IL-6 are correlated with specific clinical outcomes.

OUTLINE:

Patients receive abatacept intravenously (IV) over 30 minutes on day 1 of course 1, then subcutaneously (SC) on days 2, 8, 15, and 22 of course 1, and then on days 1, 8, 15, and 22 of subsequent courses. Patients also receive ixazomib citrate orally (PO) once daily (QD) on days 1, 8, and 15 and dexamethasone on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

After completion of study treatment, patients are followed up at 30 days and then every 3 months thereafter.

• Study Type: Interventional
• Enrollment (Actual): 15
• Phase: Phase 2

Contacts and Locations

Study Locations

• United States
  • New York
    • Buffalo, New York, United States, 14263
      • Roswell Park Cancer Institute
    • East Hills, New York, United States, 11548
      • St. Francis Hospital
    • West Islip, New York, United States, 11795
      • Good Samaritan Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Patients with multiple myeloma who have relapsed (or who are primary refractory) following treatment with a proteasome inhibitor-containing regimen (excluding ixazomib) and who have not been treated with a second proteasome inhibitor (ixazomib, bortezomib, carfilzomib or other proteasome inhibitor).
• Have an Eastern Cooperative Oncology Group (ECOG) performance status of =< 2 at study entry

• Must be free of systemic infection:

  • Subjects with active infections (whether or not they require antibiotic therapy) may be eligible after complete resolution of the infection
  • Subjects on antibiotic therapy must be off antibiotics for at least 7 days before beginning treatment
• Absolute neutrophil count >= 750/mm^3
• Platelet count >= 25,000/mm^3
• Creatinine clearance >= 30 mL/min
• Total bilirubin =< 3 x upper limit of normal (ULN)
• Aspartate aminotransferase (AST) (serum glutamic-oxaloacetic transaminase [SGOT]) and alanine aminotransferase (ALT) (serum glutamate pyruvate transaminase [SGPT]) =< 3 x ULN
• Patient's multiple myeloma cells are positive for CD28 or CD86 expression by flow cytometry or immunohistochemistry (in any proportion) CD28 or CD86 positivity can have been determined on previous bone marrow aspirates or biopsies
• Disease free of prior malignancies for > 2 years with exception of currently treated basal cell, squamous cell carcinoma of the skin, or carcinoma ?in situ? of the cervix or breast
• Participants of child-bearing potential must agree to use adequate contraceptive methods (e.g., hormonal or barrier method of birth control; abstinence) prior to study entry; should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Participant must understand the investigational nature of this study and sign an Independent Ethics Committee/Institutional Review Board approved written informed consent form prior to receiving any study related procedure

Exclusion Criteria:

• Prior treatment with ixazomib
• Inability to take ixazomib or abatacept
• Life expectancy less than 4 months
• Patients with a known diagnosis of plasma cell leukemia
• Known active tuberculosis or fungal infection
• Known seropositive for or active viral infection with, human immunodeficiency virus (HIV), hepatitis B virus (HBV) or hepatitis C virus (HCV)
• Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements
• Any condition, including the presence of laboratory abnormalities, which places the subject at unacceptable risk if he/she were to participate in the study or, which confounds the ability to interpret data from the study
• Pregnant or nursing female participants
• Unwilling or unable to follow protocol requirements
• Any condition which in the investigator?s opinion deems the participant an unsuitable candidate to receive study drug
• Received an investigational agent within 30 days prior to enrollment

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm

Intervention / Treatment

Experimental: Treatment (abatacept, ixazomib citrate, dexamethasone); Patients receive abatacept IV over 30 minutes on day 1 of course 1, then SC on days 2, 8, 15, and 22 of course 1, and then on days 1, 8, 15, and 22 of subsequent courses. Patients also receive ixazomib citrate PO QD on days 1, 8, and 15 and dexamethasone on days 1, 8, 15, and 22. Courses repeat every 28 days in the absence of disease progression or unacceptable toxicity.

Other: Laboratory Biomarker Analysis; Correlative studies; Drug: Dexamethasone; Given PO; Other Names: Decadron; Aacidexam; Adexone; Aknichthol Dexa; Alba-Dex; Alin; Alin Depot; Alin Oftalmico; Amplidermis; Anemul mono; Auricularum; Auxiloson; Baycuten; Baycuten N; Cortidexason; Cortisumman; Decacort; Decadrol; Decalix; Decameth; Decasone R.p.; Dectancyl; Dekacort; Deltafluorene; Deronil; Desamethasone; Desameton; Dexa-Mamallet; Dexa-Rhinosan; Dexa-Scheroson; Dexa-sine; Dexacortal; Dexacortin; Dexafarma; Dexafluorene; Dexalocal; Dexamecortin; Dexameth; Dexamethasonum; Dexamonozon; Dexapos; Dexinoral; Dexone; Dinormon; Fluorodelta; Fortecortin; Gammacorten; Hexadecadrol; Hexadrol; Lokalison-F; Loverine; Methylfluorprednisolone; Millicorten; Mymethasone; Orgadrone; Spersadex; Visumetazone; Drug: Ixazomib Citrate; Given PO; Other Names: Ninlaro; MLN-9708; MLN9708; Biological: Abatacept; Given IV and SC; Other Names: Orencia; CTLA4-Ig; BMS-188667; CTL A4-Ig B7 Inhibitor; cytotoxic T lymphocyte-associated antigen-4; RG2077

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Response rate of abatacept + ixazomib citrate + dexamethasone in multiple myeloma patients	Will be compared to historical controls of ixazomib citrate + dexamethasone. Responses to treatment will be measured by serum immunoglobulins, serum free kappa and lambda light chains, serum protein electrophoresis/immunofixation electrophoresis, and 24-hour urine protein electrophoresis/immunofixation. International uniform response criteria will be used. The anti-myeloma activity will be evaluated on an exploratory basis and will be summarized using descriptive statistics or graphical methods. No formal comparison will be carried forth.	Up to 1.5 years

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Incidence of adverse events assessed using National Cancer Institute Common Terminology Criteria for Adverse Events version 4.0	The adverse events and drug related toxicities will be summarized by grade using frequencies and relative frequencies. The rate of grade 3 or higher toxicities that are probably or definitely related to abatacept will be reported with 90% confidence intervals obtained using Jeffrey?s prior method.	Up to 30 days after last dose
Overall survival	Will be summarized using standard Kaplan-Meier methods; where estimates of median survival and survival rates will be obtained with 90% confidence intervals.	From the date of the first study treatment until initiation of a new therapy or until death, whichever occurs first, assessed up to 1.5 years
Progression-free survival	Will be summarized using standard Kaplan-Meier methods; where estimates of median survival and survival rates will be obtained with 90% confidence intervals.	From the date of the first study treatment to the date of first observed disease progression or death due to any cause, assessed up to 1.5 years

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
CD28 and CD86 expression assessed by flow cytometry	The expression/levels and response will be evaluated using logistic regression models.	Up to 1.5 years
Serum kynurenine and IL-6 levels	The association between CD28, CD86, serum kynurenine and IL-6 expression/levels and response will be evaluated using logistic regression models.	Up to 1.5 years

Collaborators and Investigators

• Sponsor: Roswell Park Cancer Institute
• Collaborators: Bristol-Myers Squibb
• Investigators: Principal Investigator: Jens Hillengass, MD, PhD, Roswell Park Cancer Institute

Study record dates

Study Major Dates

• Study Start (Actual): September 11, 2018
• Primary Completion (Actual): November 21, 2022
• Study Completion (Estimated): January 11, 2025

Study Registration Dates

• First Submitted: February 27, 2018
• First Submitted That Met QC Criteria: March 5, 2018
• First Posted (Actual): March 7, 2018

Study Record Updates

• Last Update Posted (Estimated): February 6, 2024
• Last Update Submitted That Met QC Criteria: February 4, 2024
• Last Verified: February 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Immune System Diseases; Neoplasms by Histologic Type; Neoplasms; Lymphoproliferative Disorders; Immunoproliferative Disorders; Hematologic Diseases; Hemorrhagic Disorders; Hemostatic Disorders; Paraproteinemias; Blood Protein Disorders; Multiple Myeloma; Neoplasms, Plasma Cell; Physiological Effects of Drugs; Neurotransmitter Agents; Molecular Mechanisms of Pharmacological Action; Autonomic Agents; Peripheral Nervous System Agents; Enzyme Inhibitors; Anti-Inflammatory Agents; Antirheumatic Agents; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antiemetics; Gastrointestinal Agents; Glucocorticoids; Hormones; Hormones, Hormone Substitutes, and Hormone Antagonists; Antineoplastic Agents, Hormonal; Protease Inhibitors; Antineoplastic Agents, Immunological; Dermatologic Agents; Immune Checkpoint Inhibitors; Glycine Agents; Dexamethasone; Dexamethasone acetate; BB 1101; Ixazomib; Abatacept; Glycine; Ichthammol
• Other Study ID Numbers: I 47217 (Other Identifier: Roswell Park Cancer Institute); NCI-2017-02430 (Registry Identifier: CTRP (Clinical Trial Reporting Program))

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes