Efficacy of Montelukast in Reducing the Incidence and Severity of Monoclonal Antibodies Associated Infusion Reactions

A Phase II Study, Evaluating the Efficacy of Montelukast in Reducing the Incidence and Severity of Monoclonal Antibodies Associated Infusion Reactions

The use of monoclonal antibodies (MA) either alone or as part of chemoimmunotherapy in oncology, benign and malignant hematology is expanding. Of the 17 therapeutic MAs approved in 2017 by FDA, 50% of them are indicated for hematologic and oncologic condition. With increasing number of approved agents, therapeutic MAs have become one of the fastest growing areas in the management of benign and malignant hematologic condition. Advancement of recombinant technology allows development of partially or fully humanized new agents. Despite this, they still carry significant risk of immune and non-immune mediated adverse events. Most of the therapeutic monoclonal antibody related adverse events (MCAAE) The severity of reaction is variable, ranging from mild involvement of single organ to severe and life-threatening reactions requiring hospitalization or even resulting in death.

Even for mild infusion reactions, where re-initiation of infusion is possible, there is resultant delay in delivery of infusions, distress to patients, and additional utilization of health care resources.

Due to unpredictability of standard infusion reaction (SIR), efforts have been focused on premedication to decreasing the incidence and severity of infusion reaction. Most institutions have protocols using corticosteroid, acetaminophen and antihistamine as part of their premedication protocols. This has reduced but not eliminated standard infusion reactions. Most recently, mast cell stabilizers are being added to standard protocols to further reduce the incidence and severity of standard infusion reactions with variable anecdotal success without formal study. Of all the monoclonal antibodies, only Daratumumab has been evaluated using this strategy.

This study seeks to evaluate the efficacy of mast cell stabilizer Montelukast (SINGULAIR) 10 mg in decreasing the SIR in patients receiving therapeutic MAs either alone or as part of chemoimmunotherapy in hematologic condition. The MAs being studied includes: Blinatumomab (BLINCYTO, Amgen Inc.), Daratumumab (DARZALEX, Janssen Biotech, Inc.), Elotuzumab (EMPLICIT, Bristol-Myers Squibb Company), Gemtuzumab (MYLOTARG, Pfizer Inc.), Obinutuzumab (GAZYVA, Genentech USA, Inc.), and Rituximab (RITUXAN, Genentech US); The investigators postulate that 10 mg of Montelukast, when given in addition to standard premedication, will lead to decrease in incidence of MA associated SIR, shorter infusion time and decrease use of additional health care resources

Study Overview

• Status: Recruiting
• Conditions: Infusion Reaction; Monoclonal Antibody
• Intervention / Treatment: Drug: Montelukast 10 Mg Oral Tablet

Detailed Description

Study design:

This is a Phase II single arm open label study evaluating 10 mg Montelukast given at least 2 hours prior to infusion of monoclonal antibody in addition to standard premedication. Monoclonal antibodies being evaluated include those commonly used to treat hematologic and oncologic malignancies like (Blinatumomab, Daratumumab, Elotuzumab, Gemtuzumab, Obinutuzumab, and Rituximab).

Arms/Intervention; Study subjects will be given 10 mg of Montelukast to be orally self-administered at least 2 hours prior to beginning of chemotherapy section Standard premedication will be administered according to institution protocol

• Study Type: Interventional
• Enrollment (Estimated): 80
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Richard Ward; Phone Number: 41828 559.387.1828; Email: rward@fresno.ucsf.edu

Study Locations

• United States
  • California
    • Clovis, California, United States, 93611
      • Recruiting
      • Community Cancer Institute
      • Contact: RICHARD WARD; Phone Number: 41828 559-387-1828; Email: RWARD5@communitymedical.org
      • Contact: CYTHIA HO; Phone Number: 559.387.1850; Email: CHo@fresno.ucsf.edu

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

1. Patients must be at least 18 years.
2. Able to provide consent for study participation (English and Spanish).
3. Patients with hematologic disorders or malignancies starting on any of the following monoclonal antibodies alone or in combination with chemotherapy (Blinatumomab, Daratumumab, Elotuzumab, Gemtuzumab, Obinutuzumab, and Rituximab).
4. Able to tolerate leukotriene antagonist including Montelukast.
5. Able to tolerate oral intake.
6. Available for follow up by phone and on site.

Exclusion Criteria:

1. Patients undergoing treatment with above monoclonal antibodies for indications other than stated in above eligibility criteria.
2. Patients who cannot provide informed consent in English or Spanish.
3. Patients taking Montelukast or other leukotriene antagonists for other indications at the time of screening.
4. Known allergic reactions to Montelukast or other leukotriene inhibitors.
5. On monoclonal antibodies other than the ones being studied (Blinatumomab, Daratumumab, Elotuzumab, Gemtuzumab, Obinutuzumab, and Rituximab).
6. History of uncontrolled depression or suicidal ideation or psychiatric illness.
7. Known Severe Hepatic Impairment (AST>10x ULN; ALT>10x ULN; ALP>10x ULN; and/or Bilirubin >5x ULN).
8. Patient with eosinophilic vasculitis.
9. Unable to comply with phone or in person follow-up.
10. Patients participating in another clinical trial.
11. Pregnancy

Study Plan

How is the study designed?

Design Details

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

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Other: Montelukast (Singulair); Montelukast(Singulair) 10mg to be taken in addition to standard institutional premedication	Drug: Montelukast 10 Mg Oral Tablet; Montelukast(Singulair) 10mg to be taken at least 2 hours prior to initiation of monoclonal antibody infusion addition to institutional protocol premedication regiment; Other Names: Singulair

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The incidence rates of standard infusion reaction(SIR) at cycle 1 and during subsequent cycles of monoclonal antibody infusion in the study subjects	The incidence rate of infusion reaction includes all clinical sign and symptoms of reaction graded by CTCAE v5.0 in patients receiving each cycle monoclonal antibody infusions. The grade and rate of each grade will be measured and or calculated for each cycle of infusion up to 6 cycles or treatment discontinuation which ever comes first	Through study completion (average 6 months)

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Average infusion duration of each cycle the monoclonal antibody infusion in the study subject	The time from start to end of each cycle of infusion of monoclonal antibody will be measured in the study subject up to 6 cycles or treatment discontinuation which ever comes first. Average infusion time will then be calculated.	Through study completion (average 6 months)
Incidence rate of Grade 3 or more monoclonal antibody infusion with each cycle of infusion and through out the entire duration of infusion (up to 6 cycles or till discontinuation which ever comes first	The incidence rate of Grade 3 infusion reaction includes all clinical sign and symptoms of reaction graded by CTCAE v5.0 as grade 3 in patients receiving each cycle monoclonal antibody infusions and the entire duration of treatment(up to 6 cycles or till treatment is discontinue which ever comes first	Through study completion (average 6 months)
Discontinuation rate of monoclonal antibody infusion due to SIRs	Rate at which monoclonal antibody treatment is stopped and changed to new treatment due to adverse drug reaction attributed to monoclonal antibody infusion	Through study completion (average 6 months)

Collaborators and Investigators

• Sponsor: University of California, San Francisco
• Investigators: Principal Investigator: MOHAMMED BUKARI, MD, UCSF - Fresno

Study record dates

Study Major Dates

• Study Start (Actual): March 20, 2020
• Primary Completion (Estimated): May 31, 2024
• Study Completion (Estimated): May 31, 2024

Study Registration Dates

• First Submitted: December 10, 2019
• First Submitted That Met QC Criteria: December 11, 2019
• First Posted (Actual): December 13, 2019

Study Record Updates

• Last Update Posted (Estimated): November 17, 2023
• Last Update Submitted That Met QC Criteria: November 15, 2023
• Last Verified: November 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Physiological Effects of Drugs; Molecular Mechanisms of Pharmacological Action; Hormones, Hormone Substitutes, and Hormone Antagonists; Anti-Asthmatic Agents; Respiratory System Agents; Leukotriene Antagonists; Hormone Antagonists; Cytochrome P-450 CYP1A2 Inducers; Cytochrome P-450 Enzyme Inducers; Montelukast
• Other Study ID Numbers: IRB2019105; IND146287 (Other Identifier: US FDA)

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: YES
• IPD Plan Description: Incidence rate of Infusion reaction Tolerability of infusion reaction
• IPD Sharing Time Frame: Sept, 2022
• IPD Sharing Supporting Information Type: CSR

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.: No