Radioimmunotherapy (111Indium/225Actinium-DOTA-daratumumab) for the Treatment of Relapsed/Refractory Multiple Myeloma

Официальное название

Phase 1 Trial of 111Indium/225Actinium-DOTA-Daratumumab in Patients With Relapsed/Refractory Multiple Myeloma

Обзор

This phase I trial tests the safety, side effects, and best dose of actinium Ac 225-DOTA-daratumumab (225Ac-DOTA-daratumumab) in combination with daratumumab and indium In 111-DOTA-daratumumab (111In-DOTA-daratumumab) in treating patients with multiple myeloma that does not respond to treatment (refractory) or that has come back (recurrent). Daratumumab is a monoclonal antibody that may interfere with the ability of cancer cells to grow and spread. 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab are forms of radioimmunotherapy in which a monoclonal antibody, daratumumab, has been linked to a radiotracer to allow for targeted delivery of the treatment to cancer cells. Giving all three together may kill more cancer cells.

Подробное описание

PRIMARY OBJECTIVE:

I. To assess the safety and tolerability of 111In/225Ac-DOTA-daratumumab, at each dose level in order to establish the maximum tolerated dose (MTD), which will inform the recommended phase 2 dose (RP2D).

SECONDARY OBJECTIVES:

I. To describe the anti-myeloma activity of 225Ac-DOTA-daratumumab as assessed by overall response rate (ORR).

II. To evaluate the organ biodistribution, pharmacokinetics and organ dose estimates of 111In/225Ac-DOTA-daratumumab.

EXPLORATORY OBJECTIVE:

I. To assess the activity of 225Ac-DOTA-daratumumab against non-cancer immune cells using the peripheral blood and bone marrow (BM) samples.

OUTLINE: This is a dose-escalation trial of 225Ac-DOTA-daratumumab.

Patients receive daratumumab intravenously (IV) over 45 minutes. Two hours later, patients receive 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes.

After completion of study treatment, patients are followed up weekly for 8 weeks, every 2 weeks for 4 weeks, every 4 weeks for 16 weeks, and then periodically up to 12 months.

Вмешательства

• Биопрепарат Actinium Ac 225-DOTA-Daratumumab
  Given IV
• Биопрепарат Daratumumab
  Given IV
• Биопрепарат Indium In 111-DOTA-Daratumumab
  Given IV

Первичные конечные точки

• Incidence of dose-limiting toxicities (DLTs) [Срок оценки: During the first 6 weeks post administration of study drug]
• Maximum tolerated dose (MTD) [Срок оценки: During the first 6 weeks post administration of study drug]

Вторичные конечные точки (6)

• Overall response rate [Срок оценки: Up to 12 months]
• Complete response rate [Срок оценки: Up to 12 months]
• 12-month overall survival [Срок оценки: Time from first day of treatment to time of death due to any cause, assessed up to 12 months]
• Progression free survival [Срок оценки: Time from first day of treatment to the first observation of disease progression or death due to any cause, assessed up to 12 months]
• Time to progression [Срок оценки: Time from first day of treatment to the first observation of disease progression or death due to disease, assessed up to 12 months]
• Duration of response [Срок оценки: In patients with PR or better, time from first response documented until disease progression, assessed up to 12 months]

Критерии участия

Критерии включения

• Documented informed consent of the participant and/or legally authorized representative

• Assent, when appropriate, will be obtained per institutional guidelines
• Age >= 18 years
• Karnofsky performance status (KPS) > 60%
• Multiple myeloma according to International Myeloma Working Group (IMWG) criteria with measurable disease defined as one of the following:

• Serum monoclonal protein >= 1.0 g/dL (or 0.5 g/dL in patients with immunoglobulin A \[IgA\] multiple myeloma \[MM\])
• 24 hour urine monoclonal protein >= 200 mg/24 hour
• Serum free light chain (FLC) of > 10 mg/dL and an abnormal kappa:lambda ratio
• Minimum of two prior lines of therapy
• Previously received treatment with all of the following: a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody. Refractory (defined per IMWG Consensus Criteria) to daratumumab
• CD38 expression on multiple myeloma (MM) cells from bone marrow aspirate or biopsy as demonstrated by flow cytometry or immunohistochemistry
• Refractory (defined per IMWG Consensus Criteria) or intolerant to most recent therapy
• Fully recovered from the acute toxic effects (except alopecia) to =< grade 1 to prior anti-cancer therapy
• Prior antitumor therapy must have been completed prior to enrollment as follows:

• >= 21 days for investigational agents, cytotoxic chemotherapy
• >= 21 days for radiation therapy. Note: Patients must have measurable disease that has been untreated/unaffected by local radiation therapy
• >= 3 months for prior anti-CD38-targeted therapy, adoptive cell therapy
• >=14 days for proteasome inhibitor therapy
• >= 7 days for immunomodulatory agents
• Absolute neutrophil count (ANC) >= 1,000/mm\^3 (within 14 days prior to day 1 of protocol therapy)

• NOTE: Growth factor is not permitted within 7 days of ANC assessment unless cytopenia is secondary to disease involvement
• Platelets >= 75,000/mm\^3 (>= 50,000/mm\^3 if >= 50% marrow involvement) (within 14 days prior to day 1 of protocol therapy)

• NOTE: Platelet transfusions are not permitted within 14 days of platelet assessment unless cytopenia is secondary to disease involvement
• Total bilirubin =< 1.5 x upper limit of normal (ULN) (unless has Gilbert's disease) (within 14 days prior to day 1 of protocol therapy)
• Aspartate aminotransferase (AST) =< 3 x ULN (within 14 days prior to day 1 of protocol therapy)
• Alanine aminotransferase (ALT) =< 3 x ULN (within 14 days prior to day 1 of protocol therapy)
• Creatinine =< 1.5 mg/dl AND/OR creatinine clearance of >= 40 mL/min per 24 hour urine test or the Cockcroft-Gault formula (within 14 days prior to day 1 of protocol therapy)
• Women of childbearing potential (WOCBP): negative urine or serum pregnancy test

• If the urine test is positive or cannot be confirmed as negative, a serum pregnancy test will be required (within 14 days prior to day 1 of protocol therapy)
• Woman of childbearing potential must be practicing a highly effective method of birth control consistent with local regulations regarding the use of birth control methods for subjects participating in clinical studies: e.g., established use of oral, injected or implanted hormonal methods of contraception; placement of an intrauterine device or intrauterine system; barrier methods; condom with spermicidal foam/gel/film/cream/suppository or occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository; male partner sterilization; true abstinence (when this is in line with the preferred and usual lifestyle of the subject) during and after the study (6 months after the last dose of 225Ac-DOTA-Daratumumab for women).

A man who is sexually active with a woman of childbearing potential and has not had a vasectomy must agree to use a barrier method of birth control, e.g., either condom with spermicidal foam/gel/film/cream/suppository or partner with occlusive cap (diaphragm or cervical/vault caps) with spermicidal foam/gel/film/cream/suppository, and all men must also not donate sperm during the study and for 6 months after receiving the last dose of study drug

• Childbearing potential defined as not being surgically sterilized (men and women) or have not been free from menses for > 1 year (women only)

Критерии исключения

• Daratumumab or other anti CD38 antibody treatment < 3 months prior to study enrollment
• Prior radiopharmaceutical therapy
• Detectable antibodies directed against daratumumab
• Subject has received previous radiation to > 25% of their bone marrow
• Female patients who are lactating or have a positive pregnancy test during the screening period
• Major surgery within 14 days prior to start of study treatment
• Subject is receiving concurrent chemotherapy, radiation, or biologic for cancer treatment. Subject is receiving bone marrow stimulatory factors (e.g., granulocyte-macrophage colony-stimulating factor \[GM-CSF\]). Note: Hormonal therapy for someone with a history of cancer treated with curative intent is permitted if subject has been on hormonal therapy > 1 year
• Vaccination with live attenuated vaccines within 4 weeks of study agent administration
• A diagnosis of primary amyloidosis, plasma cell leukemia, Waldenstrom macroglobulinemia, or POEMS
• Severe persistent asthma (forced expiratory volume in 1 second \[FEV1\] < 60% and/or daily symptoms) or severe chronic obstructive pulmonary disease (COPD) defined clinically or by historical pulmonary function tests with an FEV1 < 50% predicted
• Subject has known allergies, hypersensitivity, or intolerance to monoclonal antibodies or human proteins, or their excipients (refer to respective package inserts or investigator's brochure). Patients with a history of infusion reactions to daratumumab with prior treatment that resolved with supportive measures and in whom daratumumab therapy was not previously discontinued because of infusion reactions are permitted
• Subject has uncontrolled human immunodeficiency virus (HIV-1), chronic or active hepatitis B, or active hepatitis A or C

• Patients with HIV are eligible unless their CD4+ T-cell counts are < 350 cells/mcL or they have a history of acquired immunodeficiency syndrome (AIDS)-defining opportunistic infection within the 12 months prior to registration. Concurrent treatment with effective antiretroviral therapy (ART) according to Department of Health and Human Services (DHHS) treatment guidelines is recommended
• Subject has any one of the following:

• Clinically significant abnormal electrocardiogram (ECG) finding at screening
• Congestive heart failure (New York Heart Association class III or IV)
• Myocardial infarction within 12 months prior to starting study treatment
• Unstable or poorly controlled angina pectoris, including Prinzmetal variant angina pectoris
• Subject has presence of other active malignancy \[see exceptions below\] (However, research participants with history of prior malignancy treated with curative intent and in complete remission are eligible). The following malignancies are exceptions to the active malignancy statement:

• Basal cell carcinoma of the skin
• Squamous cell carcinoma of the skin
• Non-muscle invasive bladder cancer
• Carcinoma in situ of the cervix
• Carcinoma in situ of the breast
• Incidental histologic finding of prostate cancer (T1a or T1b using the TNM clinical staging system) or prostate cancer that is curative
• Any other condition that would, in the investigator's judgment, contraindicate the patient's participation in the clinical study due to safety concerns with clinical study procedures
• Prospective participants who, in the opinion of the investigator, may not be able to comply with all study procedures (including compliance issues related to feasibility/logistics)

Критерии приведены из реестра в оригинале (на английском). Окончательную оценку соответствия проводит исследовательский центр.

Здоровые добровольцы: Нет

Дизайн исследования

Распределение

Не применимо

Модель

Одна группа

Маскирование

Открытое

Основная цель

Лечение

Центры проведения

США · 1 центр

• City of Hope Medical Center — Duarte

Публикации

• Adhikarla V, Awuah D, Caserta E, Minnix M, Kuznetsov M, Krishnan A, Wong JYC, Shively JE, Wang X, Pichiorri F, Rockne RC. Designing combination therapies for cancer treatment: application of a mathematical framework combining CAR T-cell immunotherapy and targeted radionuclide therapy. Front Immunol. 2024 Apr 18;15:1358478. doi: 10.3389/fimmu.2024.1358478. eCollection 2024. PMID 38698840

Идентификаторы

NCT: NCT05363111 · 21599 · NCI-2022-03039 · 21599 · P30CA033572

Первоисточники (государственные реестры)

• ClinicalTrials.gov (NIH, США)

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