A Phase 1, First-in-Human, Open Label Study Evaluating Safety, Tolerability, Pharmacokinetics and Preliminary Efficacy of ABBV-438 in Adult Subjects With Relapsed or Refractory Multiple Myeloma

Study Identifier:
M25-025
CT.gov Identifier:
NCT07409246
EudraCT Identifier:
202552351729
EU Trial (CTIS) Number:
N/A
Study Contact Information:
(210) 593-5651 or [email protected]
Recruiting

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Study Summary

Multiple myeloma (MM) is a plasma cell disease characterized by the growth of clonal plasma cells in the bone marrow. The purpose of this study is to assess the safety, tolerability, and how ABBV-438 moves through the body, in adult participants with relapsed/refractory (R/R) MM. Adverse events, tolerability, how ABBV-438 moves through the body will be assessed.

ABBV-438 is an investigational drug being developed for the treatment of R/R MM. Study doctors put the participants in groups called treatment arms broken into 2 parts. ABBV-438 will be given alone and multiple doses will be explored. This study will include a dose escalation phase (Part 1) to determine the best dose of ABBV-438, followed by a dose expansion phase (Part 2) to confirm the dose. Approximately 127 adult participants with R/R MM will be enrolled in the study in approximately 24 sites worldwide.

Participants will receive intravenous (IV) ABBV-438 alone first in multiple doses in the dose escalation phase (Part 1); then in 1 of 2 doses from Part 1 in the dose expansion phase (Part 2). The overall study duration will be approximately 69.5 months.

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at an approved institution (hospital or clinic). The effect of the treatment will be frequently checked by medical assessments, blood tests, questionnaires and side effects.

Medical Condition
The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.
Multiple Myeloma
Phase
The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
Phase I
Sex
Female & Male
Age
18+ years
Study Drug
N/A
Study Status
Indicates the current recruitment status or the expanded access status
Recruiting

Requirements information
Inclusion criteria
  • * Has relapsed or refractory Multiple Myeloma (MM) with documented evidence of progression during or after the participant's last treatment regimen based on the investigator's determination of the standard International Myeloma Working Group (IMWG) (2016) response criteria:
  • * Relapsed defined as previously treated myeloma that progresses and requires initiation of salvage therapy;
  • * Refractory defined as disease that is nonresponsive (failure to achieve minimal response) while on last therapy, or progresses within 60 days of last therapy.
  • * Has measurable disease at screening, defined by at least 1 of the following within 28 days prior to enrollment:
  • * Serum M-protein >= 0.5 g/dL (>=5 g/L); OR;
  • * Urine M-protein >= 200 mg/24 hours; OR;
  • * Involved serum free light chain (sFLC) >= 10 mg/dL (100mg/L), provided serum FLC ratio is abnormal;
  • * Must have had 3 or more prior lines of therapy with exposure to a proteasome inhibitor (PI), an immunomodulatory imide drugs (IMiD), and an anti-CD38 therapy and are intolerant to, or unable to access, available therapies that are known to confer clinical benefit to participants with relapsed or refractory (R/R) MM. Note: A line of therapy consists of relapsed or refractory 1 complete cycle of a single agent, a regimen consisting of a combination of several drugs, or a planned sequential therapy of various regimens. Before commencing any screening or research-specific procedure, participants must voluntarily sign and date an informed consent form approved by an Independent Ethics Committee (IEC)/Institutional Review Board (IRB).
  • Participants must not be imprisoned and must be willing and able to provide informed consent. Participants who are unable to freely provide informed consent include: adults under certain legal protection measures (such as those in guardianship/management) or who are unable to express consent, and some adults receiving psychiatric treatment. Specific circumstances should be determined at the researcher's discretion.
  • Adults who are 18 years of age or older.
  • Participants had relapsed or refractory multiple myeloma (MM) and had documented evidence that, according to the 2016 International Myeloma Working Group (IMWG) (2016) criteria for remission, the participants experienced disease progression during or after treatment with their most recent treatment regimen: relapse was defined as progression of previously treated myeloma requiring salvage therapy; refractory was defined as no remission during the most recent treatment (failure to achieve minimum remission) or disease progression within 60 days of the most recent treatment.
  • Participants must have a measurable disease defined as meeting at least one of the following criteria within 28 days prior to enrollment: serum M protein ≥ 0.5 g/dL (≥ 5 g/L); or urinary M protein ≥ 200 mg/24 hours; or affected serum free light chain ≥ 10 mg/dL (100 mg/L), provided that the sFLC ratio is abnormal.
  • Participants must have received three or more lines of prior therapy (including prior treatment with a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and an anti-CD38 therapy) and be intolerant to or unable to access existing therapies known to provide clinical benefit to participants with relapsed/refractory (R/R) MM. Note: A line of therapy refers to ≥ 1 complete cycle of a single drug, a combination regimen containing multiple drugs, or a planned sequential therapy containing multiple regimens. For guidance on determining the number of prior lines of therapy, please refer to the protocol.
  • Willing and able to comply with the procedures stipulated in this research protocol.
  • Eastern Cooperative Oncology Group (ECOG) Performance Status Score ≤ 1.
  • Participants agreed to undergo a bone marrow aspiration and core needle biopsy for fresh sample collection prior to treatment. A bone marrow aspiration is required at screening; however, if archived bone marrow tumor tissue was collected within 12 weeks prior to screening, has not undergone interventional treatment, and is in sufficient quantity, a core needle biopsy may be omitted at screening. Note: Participants enrolled in the fill-in cohort should agree to a bone marrow aspiration during treatment.
  • Laboratory values at screening must meet the following criteria and be confirmed prior to C1D1 administration: Absolute neutrophil count ≥ 1,000/mm³ (no growth factor support therapy within 7 days); Platelet count ≥ 75,000/mm³ (no transfusion support within 7 days); Hemoglobin ≥ 8.0 g/dL (no transfusion support within 7 days); Total bilirubin ≤ 1.5 × Upper Limit of Normal (ULN). Note: For participants with documented Gilbert's syndrome, enrollment is permitted if total bilirubin ≤ 3.0 × ULN and direct bilirubin ≤ 1.5 × ULN. Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤ 2.5 × ULN. The estimated glomerular filtration rate (eGFR) calculated using the Chronic Kidney Disease Epidemiology Collaborative Study (CKD-EPI) formula (2021) or the actual measured creatinine clearance (24-hour urine collection) ≥ 50 mL/min; if CKD-EPI is unavailable, the Kidney Disease Diet Improvement Study (MDRD) formula may be used. The estimated glomerular filtration rate (eGFR) estimated using the CKD-EPI formula ≥ 50 mL/min is calculated as follows: [eGFR (mL/min/1.73 m^2) = 142 × min(serum creatinine/K, 1)^α × maximum value(serum creatinine/K, 1)^-1.200 × (0.9938)^ Age × 1.012 (if female)]. Please note that this is for serum creatinine in mg/dL. K: 0.7 (female), 0.9 (male) α: -0.241 (female), -0.302 (male) eGFR estimated using the MDRD formula ≥ 50 mL/min, which is: [GFR (mL/min/1.73m^3 ) = 175 × (serum creatinine)^-1.154 × (Age)^-0.203 × (if female × 0.742) × (if African American × 1.212)]. Please note that this is for serum creatinine in mg/dL. International Normalized Ratio (INR) or prothrombin time (PT) ≤ 1.5 × ULN and activated partial thromboplastin time (aPTT) ≤ 1.5 × ULN, unless the participant is receiving anticoagulation therapy, in which case PT and/or PTT should be within the therapeutic range for the intended use of the anticoagulant. Albumin-corrected serum calcium ≤ 14.0 mg/dL (≤ 3.5 mmol/L).
  • Female participants of childbearing potential will undergo pregnancy testing: Participants must have a negative serum pregnancy test result at the screening visit and a negative urine pregnancy test result at baseline prior to the first dose of study treatment. Participants with borderline serum pregnancy test results at screening must have clinically ruled out pregnancy or have no other pathological cause for a borderline result, and must undergo a serum pregnancy test ≥ 3 days later to demonstrate a persistently negative result (unless local regulations prohibit this). Participants with borderline or indeterminate urine pregnancy test results at baseline must undergo serum pregnancy testing. In this case, if the serum pregnancy result is positive, the subject must be excluded. In addition to baseline pregnancy testing, investigators should confirm through interviews that subjects are indeed following the contraceptive and barrier method contraception guidelines outlined in the informed consent form (ICF) before the first dose of study treatment (C1D1). If a subject may be at risk of pregnancy, the investigator may decide not to administer the medication at their discretion. Japan only: If a physician's interview indicates a possibility of pregnancy, the patient will be excluded from this study.
  • Female participants of childbearing potential must use at least one method of contraception as specified in the study protocol from day 1 of the study until at least 50 days after the last dose of study treatment. Women of childbearing potential do not need to use contraception.
  • Female participants who are not pregnant or breastfeeding and are not considered to be pregnant or donating eggs during the study or within approximately 50 days after the last dose of study treatment.
  • Male participants who have sexual relations with fertile female partners must agree to use the contraceptive methods specified in the study protocol from Day 1 of the study until approximately 50 days after the last dose of study treatment.
  • Male participants who impregnated another person or donated sperm during the study or within approximately 50 days after the last dose of study treatment were excluded.
Exclusion criteria
  • Known history of Central Nervous System involvement by MM.
  • * History of idiopathic pulmonary fibrosis, organizing pneumonia (e.g., bronchiolitis obliterans), drug-induced pneumonitis, or idiopathic pneumonitis. Active non-secreting multiple myeloma (MM), plasma cell leukemia (i.e., plasma cells reaching 5% of peripheral blood leukocytes or an absolute circulating plasma cell count > 0.5 × 10^9 L by standard classification), Waldenström macroglobulinemia, light chain amyloidosis or polyneuropathy, organ enlargement, endocrine disorders, monoclonal protein, and skin alterations (POEMS) syndrome are all considered contraindications for MM.
  • The patient has a known history of multiple myeloma (MM) affecting the central nervous system.
  • Anti-CD38 therapy was used in the immediate first-line treatment. Exception: This Exclusion criteria does not apply to participants in the enrolled filler cohort.
  • According to the researchers' assessment, the combined hemolysis test (total bilirubin, direct bilirubin and unconjugated serum bilirubin, hemoglobin, hematocrit, lactate dehydrogenase (LDH), reticulocyte count and serum haptoglobin) showed evidence of persistent hemolysis.
  • A history of idiopathic pulmonary fibrosis, organizing pneumonia (such as bronchiolitis obliterans), drug-induced pulmonary inflammation, or idiopathic pulmonary inflammation.
  • Participants were known to have chronic obstructive pulmonary disease (COPD) and their forced expiratory volume in one second (FEV1) was less than 50% of the predicted normal value.
  • Participants must have had moderate or persistent chronic asthma within the past two years, or any category of uncontrolled asthma. Note: Participants currently with controllable intermittent asthma or controllable mild persistent asthma are eligible to participate in the study.
  • A clinically significant and uncontrollable history of medical conditions (including but not limited to the following): uncontrollable diabetes; uncontrollable hypertension; uncontrollable active infection; symptomatic congestive heart failure; unstable angina or uncontrollable arrhythmia, including atrial fibrillation; recent (within 6 months prior to enrollment) myocardial infarction, New York Heart Association class III/IV congestive heart failure; or mental illness/social conditions that limit participant compliance with the study.
  • At the time of screening, the glycated hemoglobin (HbA1c) value was ≥ 8.0%.
  • A history of coagulation disorders or platelet disease, and a significant clinical risk of thromboembolic events as determined by the investigator; or a major thromboembolic event (such as stroke, pulmonary embolism, deep vein thrombosis [DVT]) that occurred within 6 months prior to the first treatment received in the study.
  • Blood tests at screening showed active hepatitis B (HBV) infection (HBsAg positive) (according to the Japanese Society for Liver Diseases HBV Infection Management Guidelines). For participants whose infection has regressed (HBsAg negative, but HBc or HBsAg positive), screening using real-time HBV DNA PCR is mandatory. PCR-positive subjects will be excluded. - Exception: For participants with serological results indicating HBV vaccination (HBsAg positive as the sole serological marker) and a known history of HBV vaccination, HBV DNA testing by polymerase chain reaction (PCR) is not required.
  • Known positive serological response to hepatitis C (HCV). - Exception: Participants with a positive serological response to hepatitis C are eligible if they have a sustained virological response (defined as being free from viremia for at least 12 weeks after completion of antiviral therapy).
  • A known history of human immunodeficiency virus (HIV) or active HIV. HIV testing is not required during screening unless required by local guidelines or institutional standards.
  • Students who have undergone major surgery within 4 weeks prior to the first dose of the study treatment, or who plan to undergo major surgery during the study period.
  • A recent infection requiring systemic treatment that was completed within ≤ 7 days prior to the first dose of study treatment, and/or an uncontrollable active systemic infection (including grade 3 or higher viral, bacterial, or fungal [including Aspergillus] infection) occurring within 2 weeks prior to the first dose of study treatment. - Note: Routine antimicrobial prophylaxis is permitted.
  • Participants with a history of malignancy or concurrent malignancy whose natural history or treatment may interfere with the assessment of the safety or efficacy of the study treatment regimen should not be enrolled, except in the following circumstances: - No known active disease within 3 years prior to the first dose of study treatment, and the attending investigator considers the risk of recurrence to be low. - Well-treated cervical carcinoma in situ, breast carcinoma in situ, or other non-invasive lesions, which the investigator considers cured, and the risk of recurrence within 3 years is minimal. - Localized prostate cancer, having undergone radical prostatectomy or having no known active disease, Gleason grade ≤ 6 or lower, and stable prostate-specific antigen (PSA) levels during or after treatment. - Basal cell carcinoma or localized squamous cell carcinoma of the skin, with no evidence of disease.
  • Currently participating in any other interventional clinical study, except for survival follow-up.
  • A history of clinically significant (in the investigator’s judgment) drug or alcohol abuse within the past 6 months.
  • The participant has a history of clinically significant medical conditions, or any other reason that the investigator believes would interfere with the participant's participation in the study or make the participant unsuitable for the study treatment.
  • Clinically relevant or significant ECG abnormalities include ECG results with QTcF > 450 ms (male) or > 470 ms (female). - The single ECG value obtained during screening will be used as the clinical safety measurement result to determine eligibility, according to the following rules: - If an abnormal ECG value of QTcF > 500 ms is measured, the subject will be excluded. - If QTcF > 450/470 ms but < 500 ms, the measurement will be repeated as a single ECG; if the remeasured QTcF value is > 450/470 ms, the subject will be excluded.
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  • twenty one Active infection caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is known. If participants do not meet the eligibility criteria for SARS-CoV-2 infection, screening may proceed, but participants must have a negative test result at least 24 hours prior to enrollment and administration.
  • 21
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  • twenty two Participants must have received anti-myeloma treatment (including chemotherapy, radiotherapy, biotherapy, immunotherapy, or any experimental treatment [e.g., small molecule targeted drugs]) within 14 days or 5 half-lives (whichever is shorter) prior to the first dose of the study treatment, or be currently receiving treatment in another interventional clinical study, or have been previously enrolled in this study.
  • 22
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  • twenty three Those who have received peripheral autologous stem cell transplantation (SCT) within 12 weeks prior to the first dose of study treatment, or allogeneic SCT within 1 year prior to the first dose of study treatment, or have active graft-versus-host disease.
  • 23
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  • twenty four Within 14 days prior to the first treatment received in the study, the patient was using or had previously used immunosuppressive drugs, including systemic corticosteroids. Exceptions: Intranasal, inhaled, topical, or local steroid injections (such as intra-articular injections), anti-inflammatory drugs, and antihistamines are permitted.
  • Participants must have used known potent or intermediate inhibitors or potent inducers of cytochrome P450 (CYP) 3A within 7 days or 5 half-lives (whichever is shorter) prior to the first administration of the study drug; such drugs are prohibited during dose-limiting toxicity (DLT) periods.
  • Participants must have used a known CYP3A-sensitive substrate or a CYP3A substrate with a narrow therapeutic index within 7 days or 5 half-lives (whichever is shorter) prior to the first administration of the study drug; such drugs are prohibited during DLT.
  • Anyone who has received any live vaccine within 4 weeks prior to the first dose of the study treatment, or who is expected to receive a live vaccine during the study period (including at least 4 weeks after the last dose of the study treatment).
  • Adverse events (AEs) of grade ≥ 2 (according to the National Cancer Institute [NCI] Common Terminology Criteria for Adverse Events [CTCAE] version 5.0) that have not resolved due to prior anticancer treatment, excluding alopecia (not an Exclusion criteria) and peripheral neuropathy (grade ≥ 3 is an Exclusion criteria).
  • A history of allergic reactions or significant sensitivity to the research therapeutic ingredient (and its excipients) and/or other similar products.
  • It is known that there have been previous cases of grade ≥ 3 immunogenicity, hypersensitivity or infusion-related reactions in response to anti-CD38 therapy.

Clinical Study Information for Healthcare Providers

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Study Locations

Location
Investigator
Status
Condition(s) Treated at Site
Location
START Midwest
Grand Rapids, MI, United States, 49546
Investigator
Andrew Sochacki
Status
Recruiting
Condition(s) Treated at Site
Multiple Myeloma