Phase 1 Trial of 111Indium/225Actinium-DOTA-Daratumumab in Patients With Relapsed/Refractory Multiple Myeloma
Overview
- Phase
- Phase 1
- Intervention
- Actinium Ac 225-DOTA-Daratumumab
- Conditions
- Recurrent Plasma Cell Myeloma
- Sponsor
- City of Hope Medical Center
- Enrollment
- 15
- Locations
- 1
- Primary Endpoint
- Incidence of dose-limiting toxicities (DLTs)
- Status
- Recruiting
- Last Updated
- 6 months ago
Overview
Brief Summary
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.
Detailed Description
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.
Investigators
Eligibility Criteria
Inclusion Criteria
- •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
Exclusion Criteria
- •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
Arms & Interventions
Treatment (daratumumab, 225Ac/111In-DOTA-daratumumab)
Patients receive daratumumab IV over 45 minutes. Two hours later, patients receive 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes.
Intervention: Actinium Ac 225-DOTA-Daratumumab
Treatment (daratumumab, 225Ac/111In-DOTA-daratumumab)
Patients receive daratumumab IV over 45 minutes. Two hours later, patients receive 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes.
Intervention: Daratumumab
Treatment (daratumumab, 225Ac/111In-DOTA-daratumumab)
Patients receive daratumumab IV over 45 minutes. Two hours later, patients receive 111In-DOTA-daratumumab and 225Ac-DOTA-daratumumab IV over 20-30 minutes.
Intervention: Indium In 111-DOTA-Daratumumab
Outcomes
Primary Outcomes
Incidence of dose-limiting toxicities (DLTs)
Time Frame: During the first 6 weeks post administration of study drug
Toxicity will be graded according to the National Cancer Institute (NCI)- Common Terminology Criteria for Adverse Events (CTCAE) version 5.0.
Maximum tolerated dose (MTD)
Time Frame: During the first 6 weeks post administration of study drug
Toxicity will be graded according to the NCI-CTCAE version 5.0. The MTD is defined as the dose for which the isotonic estimate of the toxicity rate is closest to the target toxicity rate. The MTD will be based on the assessment of DLT during the first 6 weeks.
Secondary Outcomes
- Overall response rate(Up to 12 months)
- Complete response rate(Up to 12 months)
- 12-month overall survival(Time from first day of treatment to time of death due to any cause, assessed up to 12 months)
- Progression free survival(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(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(In patients with PR or better, time from first response documented until disease progression, assessed up to 12 months)