Radioimmunotherapy (211At-OKT10-B10) and Chemotherapy (Melphalan) Before Stem Cell Transplantation for the Treatment of Multiple Myeloma

A Phase I Trial Evaluating Escalating Doses of 211At-Labeled Anti-CD38 Monoclonal Antibody (211At-OKT10-B10) Combined With Melphalan as Conditioning Prior to Autologous Hematopoietic Cell Transplantation for Patients With Multiple Myeloma

This phase I trial studies the side effects and best dose of 211At-OKT10-B10 when given together with melphalan before a stem cell transplantation in treating patients with multiple myeloma. The radioimmunotherapy drug 211At-OKT10-B10 is a monoclonal antibody, called OKT10-B10, linked to a radioactive substance called 211At. OKT10-B10 attaches to CD38 positive cancer cells in a targeted way and delivers 211At to kill them. Drugs used in chemotherapy, such as melphalan, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving 211At-OKT10-B10 with melphalan before a stem cell transplant may kill more cancer cells.

Study Overview

• Status: Withdrawn
• Conditions: Plasma Cell Myeloma
• Intervention / Treatment: Biological: Astatine At 211 Anti-CD38 Monoclonal Antibody OKT10-B10; Drug: Melphalan; Procedure: Peripheral Blood Stem Cell Transplantation

Detailed Description

OUTLINE: This is a dose-escalation study of 211At-OKT10-B10.

Patients receive 211At-OKT10-B10 intravenously (IV) continuously on day -10 to day - 4 (approximately day -7) and melphalan via infusion on day -2. Patients then undergo hematopoietic cell transplantation (HCT) on day 0.

After completion of study treatment, patients are followed for 30 days, between 80 and 90 days, at 6, 9, 12, 18, and 24 months, and then annually thereafter.

• Study Type: Interventional
• Phase: Phase 1

Contacts and Locations

• Study Contact: Name: Damian J. Green; Phone Number: 206-667-5398; Email: dgreen@fredhutch.org

Study Locations

• United States
  • Washington
    • Seattle, Washington, United States, 98109
      • Fred Hutch/University of Washington Cancer Consortium

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Patients with a diagnosis of multiple myeloma
• Patients must have autologous hematopoietic stem cells collected with a minimum CD34+ stem cell yield of >= 4 x 10^6 CD34+ cells/kg of body weight
• Subjects must have disease meeting criteria for clinical relapse or progressive disease (International Myeloma Working Group [IMWG] consensus criteria) and a history of >= 1 prior autologous stem cell transplant(s)

• Subjects must have received at least 3 prior lines of therapy: an immunomodulatory drug, a proteasome inhibitor, and a CD38-targeting antibody

  * Aline of therapy is defined as one or more cycles of a planned treatment program. This may consist of one or more planned cycles of a single-agent therapy or combination therapy, as well as a sequence of treatments administered in a planned manner. For example, a planned treatment approach of induction therapy followed by autologous stem cell transplantation, followed by maintenance is considered one line of therapy. A new line of therapy starts when a planned course of therapy is modified to include other treatment agents (alone or in combination) as a results of disease progression, relapse, or toxicity. A new line of therapy also starts when a planned period of observation off therapy is interrupted by a need for additional treatment for the disease

• Subjects must have an estimated creatinine clearance greater than 60 ml per minute by the following formula (Cockcroft-Gault). Serum creatinine value must be within 28 +/- days prior to registration
• Subjects must have an Eastern Cooperative Oncology Group (ECOG) score =< 2 or Karnofsky score >= 70%
• Ability to provide informed consent
• Subjects 18 years of age

Exclusion Criteria:

• Subjects with a history of plasma cell leukemia
• History of central nervous system involvement by multiple myeloma
• Prior radioimmunotherapy or radiation of > 20 Gy to pelvis or at maximally tolerated levels to any critical normal organ
• Prior allogeneic hematopoietic cell transplant
• More than 2 prior autologous hematopoietic cell transplants
• Subjects with medullary or extramedullary plasmacytoma/s measuring > 3 cm by magnetic resonance imaging (MRI) or positron emission tomography (PET)-computed tomography (CT) (radiated lesions are exempt from this criterion)
• Subjects with a history of any one of the following cardiovascular conditions within the past 6 months: Class III or IV heart failure as defined by the New York Heart Association (NYHA), cardiac angioplasty or stenting, myocardial infarction, unstable angina, or other clinically significant cardiac disease as determined by the principal investigator (PI) or designee
• Subjects with corrected QT (QTc) prolongation at baseline
• Subjects with a history of cardiac arrhythmia and a heart rate > 100 beats per minute (BPM) (oral beta-blocker [excluding sotalol] and/or calcium channel blocker therapy are acceptable to achieve rate control)
• History of reactive airway disease and clinically significant asthma requiring any form of medical treatment in the prior three months
• Left ventricular ejection fraction < 40%
• Corrected diffusing capacity of the lungs for carbon monoxide (DLCO) < 50% or receiving supplemental continuous oxygen
• Liver abnormalities: fulminant liver failure, cirrhosis of the liver with evidence of portal hypertension, alcoholic hepatitis, esophageal varices, hepatic encephalopathy, uncorrectable hepatic synthetic dysfunction as evidenced by prolongation of the prothrombin time, ascites related to portal hypertension, bacterial or fungal liver abscess, biliary obstruction, chronic viral hepatitis, or symptomatic biliary disease.
• Bilirubin > 2 times the upper limit of normal
• Aspartate aminotransferase [AST] and alanine aminotransferase [ALT] > 2 times the upper limit of normal
• Subjects who are known to be seropositive for human immunodeficiency virus (HIV)
• Women of childbearing potential who are pregnant (beta-human chorionic gonadotropin [HCG]+) or breast feeding
• Fertile subjects unwilling to use contraceptives during and for 12 months post-transplant
• Subjects with untreated and uncontrolled infection at time of enrollment
• Subjects with known amyloid light-chain (AL) subtype amyloidosis
• Known allergy to murine-based monoclonal antibodies
• Known contraindications to radiotherapy
• History of another primary malignancy that has not been in remission for at least 2 years (the following are exempt from the 2-year limit: non-melanoma skin cancer, curatively treated localized prostate cancer, and cervical carcinoma in situ on biopsy or a squamous intraepithelial lesion on Papanicolaou [PAP] smear)
• Any anti-CD38 monoclonal antibody within 30 days of anticipated date of infusion of 211At-OKT10-B10
• Individuals with a history of CTCAE grade 4 gastrointestinal toxicity associated with prior high-dose melphalan conditioning therapy (previous autologous stem cell transplant)

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 (211At-OKT10-B10, melphalan, PBSC transplantation); Patients receive 211At-OKT10-B10 IV continuously on day -10 to day - 4 (approximately day -7) and melphalan via infusion on day -2. Patients then undergo HCT on day 0.

Biological: Astatine At 211 Anti-CD38 Monoclonal Antibody OKT10-B10; Given IV; Other Names: 211At-OKT10-B10; [211At]OKT10-B10; Astatine 211-labeled Anti-CD38 Monoclonal Antibody OKT10-B10; Astatine At 211 Anti-CD38 MoAb OKT10-B10; Astatine-211-OKT10-B10; At211-OKT10-B10; Drug: Melphalan; Given via infusion; Other Names: CB-3025; L-PAM; L-Sarcolysin; Alanine Nitrogen Mustard; L-Phenylalanine Mustard; L-Sarcolysin Phenylalanine mustard; L-Sarcolysine; Melphalanum; Phenylalanine Mustard; Phenylalanine Nitrogen Mustard; Sarcoclorin; Sarkolysin; WR-19813; Procedure: Peripheral Blood Stem Cell Transplantation; Undergo PBSC transplantation; Other Names: PBPC transplantation; Peripheral Blood Progenitor Cell Transplantation; Peripheral Stem Cell Support; Peripheral Stem Cell Transplantation; PBSCT; Peripheral Stem Cell Transplant

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Maximum tolerated dose	Defined a true dose limiting toxicity (DLT) probability of 25% of subjects, where a DLT is defined as any grade 3-5 nonhematologic regimen-related toxicity within the first 30 days following autologous hematopoietic cell transplantation.	Up to 30 days post-transplant

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Achievement of response	Measured per the International Myeloma Working Group criteria. The response rates (partial response [PR] or better) will be estimated along with the exact 95% confidence interval.	Between days +80 to +90 post-transplant
Duration of response	Duration of response will be estimated using Kaplan-Meier methodology.	From response (PR or better) to disease relapse or death, assessed up to 5 years
Overall survival	Kaplan-Meier methodology will be used to estimate the 2-year overall survival.	From transplantation to death, assessed up to 2 years post-transplant
Progression-free survival	Kaplan-Meier methodology will be used to estimate the 2-year progression-free survival.	From transplantation to disease relapse or death, assessed up to 2 years post-transplant
Rates of minimal residual disease (MRD)	MRD will be assessed using multi-color flow cytometry and next generation sequencing in conjunction with functional imaging (i.e., positron emission tomography-computed tomography). The proportion who achieve MRD will be estimated along with an exact 95% confidence interval.	At days 28, and +80 to +90 post-transplant

Collaborators and Investigators

• Sponsor: Fred Hutchinson Cancer Center
• Collaborators: National Cancer Institute (NCI); National Institutes of Health (NIH)
• Investigators: Principal Investigator: Damian J. Green, Fred Hutch/University of Washington Cancer Consortium

Study record dates

Study Major Dates

• Study Start (Estimated): January 27, 2024
• Primary Completion (Estimated): October 1, 2025
• Study Completion (Estimated): September 30, 2027

Study Registration Dates

• First Submitted: July 8, 2020
• First Submitted That Met QC Criteria: July 8, 2020
• First Posted (Actual): July 10, 2020

Study Record Updates

• Last Update Posted (Estimated): January 31, 2024
• Last Update Submitted That Met QC Criteria: January 30, 2024
• Last Verified: September 1, 2023

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; Molecular Mechanisms of Pharmacological Action; Antineoplastic Agents; Immunosuppressive Agents; Immunologic Factors; Antineoplastic Agents, Alkylating; Alkylating Agents; Myeloablative Agonists; Antibodies; Immunoglobulins; Daratumumab; Melphalan; Antibodies, Monoclonal; Antineoplastic Agents, Immunological; Mechlorethamine; Nitrogen Mustard Compounds
• Other Study ID Numbers: RG1006317; NCI-2019-06979 (Registry Identifier: CTRP (Clinical Trial Reporting Program)); 10306 (Other Identifier: Fred Hutch/University of Washington Cancer Consortium); R01CA205248 (U.S. NIH Grant/Contract)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No