Glucagon Receptor Inhibition to Enable Breast Cancer Patients to Benefit From PI3K Inhibitor Therapy (REMD-477)

A Pilot Study of Glucagon Receptor Inhibition to Enable Breast Cancer Patients to Benefit From PI3K Inhibitor Therapy (GRIP-IT PILOT)

REMD-477 (Volagidemab) is a human anti-glucagon receptor antibody. Its proposed mechanism of action in controlling hyperglycemia is by blocking glucagon receptor (GCGR) signaling. In this way, it increases hepatic glucose uptake, decreases hepatic glycogenolysis and gluconeogenesis, increases glycogen synthesis, and ultimately decreases blood glucose levels. This protocol will test the hypotheses that REMD-477 is safe and tolerable in patients with severe hyperglycemia on apelisib and prevent hyperglycemia associated with alpelisib in patients with advanced breast cancer who discontinue alpelisib due to severe hyperglycemia despite appropriate medical management.

Study Overview

• Status: Terminated
• Conditions: Hyperglycemia Drug Induced
• Intervention / Treatment: Biological: REMD-477

• Study Type: Interventional
• Enrollment (Actual): 1
• Phase: Phase 1

Contacts and Locations

Study Locations

• United States
  • North Carolina
    • Durham, North Carolina, United States, 27710
      • Duke University Medical Center

Participation Criteria

Eligibility Criteria

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

Description

Inclusion Criteria:

• Locally advanced (not amenable to curative surgery) or metastatic invasive breast cancer
• Age > 18 years
• Post-menopausal or pre/peri-menopausal women prescribed ovarian suppression or men prescribed Lupron are permitted to participate
• Histologically and/or cytologically confirmed diagnosis of ER+ and/or PgR+ breast cancer by local laboratory
• HER2-negative breast cancer defined as a negative in situ hybridization test or an IHC status of 0, 1+ or 2+. If IHC is 2+, a negative in situ hybridization test (FISH, CISH, or SISH) is required.
• Presence of one or more PIK3CA mutations in tumor tissue or plasma specimens
• Participant is eligible to receive alpelisib and fulvestrant as per current FDA labeling
• Participant has experienced grade 3 or 4 hyperglycemia during treatment with alpelisib (any cycle) despite standard of care measures (e.g metformin) leading to discontinuation of alpelisib.
• ECOG performance status 0, 1 or 2
• Ability to understand and the willingness to sign a written informed consent document

• Participants must have normal organ and marrow function as defined below:

  • Leukocytes > 3,000/mm3
  • Absolute neutrophil count > 1,500/mm3
  • Platelets > 100,000/mm3
  • Bilirubin ≤ 1.5 x institutional upper limit of normal (ULN
  • AST (SGOT)/ALT (SGPT) < 2.5 X institutional upper limit of normal; Creatinine ≤1.5 x institutional upper limit of normal OR creatinine clearance >L/min/1.73 m2 for subjects with creatinine levels above institutional normal.

Exclusion Criteria:

• Patient with symptomatic visceral disease or any disease burden that makes the patient ineligible for endocrine therapy per the investigator's best judgment
• Patient has received radiotherapy ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to therapy, and who has not recovered to grade 1 or better from related side effects of such therapy (with the exception of alopecia) and/or from whom ≥ 25% of the bone marrow was irradiated
• Established diagnosis of diabetes mellitus type 1 or uncontrolled type 2 diabetes (fasting plasma glucose level,>140 mg per deciliter or a glycosylated hemoglobin level of >6.4%)
• Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the absorption of alpelisib
• Known brain metastases.
• History of allergic reactions attributed to compounds of similar chemical or biologic composition to alpelisib or other agents used in this study.
• Receiving any medications or substances that are strong CYP3A4 inducers.
• A history or family history of pancreatic neuroendocrine tumors, multiple endocrine neoplasia or pheochromocytoma
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
• Pregnant women are excluded from this study. Because there is an unknown but potential risk of adverse events in nursing infants secondary to treatment of the mother with these agents, breastfeeding should be discontinued if the mother is treated on study.
• Individuals with a history of a different malignancy are ineligible except for the following circumstances. Individuals with a history of other malignancies are eligible if they have been disease-free for at least 3 years and are deemed by the investigator to be at low risk for recurrence of that malignancy. Individuals with the following cancers are eligible if diagnosed and treated within the past 3 years: cervical cancer in situ, and basal cell or squamous cell carcinoma of the skin. Patient has received prior treatment with chemotherapy (except for neoadjuvant/ adjuvant chemotherapy)

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: REMD-477; REMD-477 (human IgG2 anti-glucagon receptor antibody Volagidemab) will be administered as a subcutaneous injection for four weekly doses	Biological: REMD-477; REMD-477 will be administered as a subcutaneous injection for four weekly doses; Other Names: Volagidemab

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Adverse Events	Evaluate the safety of REMD-477 in patients with hyperglycemia due to a PI3 kinase inhibitor	28 days
Serious Adverse Events	Evaluate the safety of REMD-477 in patients with hyperglycemia due to a PI3 kinase inhibitor	28 days

Collaborators and Investigators

• Sponsor: Duke University
• Investigators: Principal Investigator: Susan Dent, MD, Duke University

Study record dates

Study Major Dates

• Study Start (Actual): November 13, 2020
• Primary Completion (Actual): May 5, 2021
• Study Completion (Actual): May 5, 2021

Study Registration Dates

• First Submitted: March 31, 2020
• First Submitted That Met QC Criteria: March 31, 2020
• First Posted (Actual): April 1, 2020

Study Record Updates

• Last Update Posted (Actual): November 8, 2022
• Last Update Submitted That Met QC Criteria: November 4, 2022
• Last Verified: November 1, 2022

More Information

Terms related to this study

• Keywords: breast cancer; hyperglycemia; anti-glucagon receptor antibody; PI3 Kinase; Volagidemab
• Additional Relevant MeSH Terms: Glucose Metabolism Disorders; Metabolic Diseases; Hyperglycemia; Hypoglycemic Agents; Physiological Effects of Drugs; Volagidemab
• Other Study ID Numbers: Pro00105104

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