A Phase II Trial of Poly-ICLC for Low-Grade Gliomas (NF111)

A Phase II Trial of Poly-ICLC for Progressive, Previously Treated Low-Grade Gliomas in Children and Young Adults With Neurofibromatosis Type 1

This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®) treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first 48 weeks (12 cycles) of therapy. There will also be secondary and exploratory objectives listed in the detailed description below.

Study Overview

• Status: Recruiting
• Conditions: Low-grade Glioma; NF1
• Intervention / Treatment: Drug: Poly ICLC

Detailed Description

This is a phase II, prospective, longitudinal, multi-center trial of poly-ICLC (Hiltonol ®) treatment for progressive low-grade gliomas in pediatric patients with NF1. The primary objective is to evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR) within the first 48 weeks (12 cycles) of therapy.

The secondary objectives are to:

1. Determine 12, 24 and 60 month progression free survival (PFS) in pediatric NF1 patients with progressive LGG treated with poly-ICLC.
2. Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by best objective tumor response rate (CR+PR) within 24 cycles of therapy.
3. Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by clinical benefit response rate (CR+PR+MR+SD) after 12 and 24 cycles of therapy.
4. Assess the toxicity associated with poly-ICLC treatment in pediatric NF1 patients with LGG.

Exploratory objectives are to:

1. Evaluate the visual outcome measures in children with progressive optic pathway gliomas treated with poly-ICLC. Visual response is defined as 0.2 logMAR or greater in acuity improvement.
2. Evaluate patient reported outcomes and quality of life measures.
3. Evaluate biological correlates.

• Study Type: Interventional
• Enrollment (Estimated): 20
• Phase: Phase 2

Contacts and Locations

• Study Contact: Name: Bruce R Korf, MD, PhD; Phone Number: 205.934.9410; Email: bkorf@uabmc.edu
• Study Contact Backup: Name: Karen A Cole-Plourde, BS; Phone Number: 205.934.5140; Email: kplourde@uab.edu

Study Locations

• United States
  • Alabama
    • Birmingham, Alabama, United States, 35294
      • Recruiting
      • The University of Alabama at Birmingham (Site 700)
      • Principal Investigator: Bruce Korf, MD, PhD
      • Contact: Katie Metrock, MD; Phone Number: 205-638-6945; Email: lmetrock@uabmc.edu
      • Contact: Brian Roberts; Phone Number: 205-638-5449; Email: brianroberts@uabmc.edu
  • California
    • Los Angeles, California, United States, 90027
      • Recruiting
      • Children's Hospital of Los Angeles
      • Contact: Tena Rosser, MD; Phone Number: 323-361-2471; Email: trosser@chla.usc.edu
      • Contact: Patricia Diaz; Phone Number: 323-361-7319; Email: padiaz@chla.usc.edu
      • Principal Investigator: Tena Rosser, MD
  • District of Columbia
    • Washington, District of Columbia, United States, 20010
      • Recruiting
      • Children's National Medical Center (Site 775)
      • Contact: Roger Packer, MD; Phone Number: 202-476-5997; Email: RPacker@childrensnational.org
      • Contact: Elizabeth Krisanda; Phone Number: (202) 476-6551; Email: EKrisanda@childrensnational.org
  • Georgia
    • Atlanta, Georgia, United States, 30342
      • Recruiting
      • Children's Healthcare of Atlanta
      • Contact: Dolly Aguilera, MD; Phone Number: 404-785-3598; Email: dolly.aguilera@choa.org
      • Contact: Olivia Floyd; Phone Number: 404-785-0232; Email: Olivia.floyd@choa.org
  • Illinois
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Children's Lurie Hospital
      • Contact: Angela Waanders, MD; Phone Number: 312-227-4939; Email: awaanders@luriechildrens.org
    • Chicago, Illinois, United States, 60611
      • Recruiting
      • Lurie Children's Hospital of Chicago (Site 350)
      • Contact: Angela Waanders, MD; Phone Number: 312-227-4939; Email: awaanders@luriechildrens.org
    • Chicago, Illinois, United States, 60637
      • Recruiting
      • University of Chicago (Site 850)
      • Contact: James Tonsgard, MD; Phone Number: 773-203-2344; Email: jtonsgar@peds.bsd.uchicago.edu
      • Contact: Cynthia MacKenzie, RN, BSN; Phone Number: 773-203-2344; Email: cmackenzie@peds.bsd.uchicago.edu
  • Missouri
    • Saint Louis, Missouri, United States, 63110
      • Recruiting
      • Washington University - St. Louis (Site 900)
      • Contact: Amy Armstrong, MD; Phone Number: 314-454-6018; Email: armstrongae@wustl.edu
  • New York
    • New York, New York, United States, 10016
      • Not yet recruiting
      • New York University Medical Center (Site 200)
      • Contact: Anna Yaffe; Phone Number: 212-263-9945; Email: anna.yaffe@nyumc.org
      • Contact: Kaleb Yohay, MD; Phone Number: 212-263-7744; Email: kaleb.yohay@nyumc.org
  • Ohio
    • Cincinnati, Ohio, United States, 45229-3039
      • Recruiting
      • Cincinnati Children's Hospital Medical Center (Site 800)
      • Contact: Peter de Blank, MD; Phone Number: 513-517-2068; Email: Peter.deBlank@cchmc.org
      • Contact: Lori Backus, BA, CCRP; Phone Number: 513.636.2047; Email: Lori.backus@cchmc.org
  • Pennsylvania
    • Philadelphia, Pennsylvania, United States, 19096
      • Recruiting
      • Children's Hospital of Philadelphia (Site 750)
      • Contact: Michael Fisher, MD; Phone Number: 215-590-2800; Email: fisherm@email.chop.edu
      • Contact: Ratnakar Patti; Phone Number: 267.426.5503; Email: pattir@email.chop.edu
  • Texas
    • Dallas, Texas, United States, 75235
      • Recruiting
      • Childrens Medical Center - Univ. of Texas SW (Site 917)
      • Contact: Laura Klesse, MD, PhD; Phone Number: 214-456-3727; Email: Laura.Klesse@utsouthwestern.edu

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: No older than 22 years (Child, Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

1. Age: Patients must be less than 22 years at the time of enrollment; there is no lower age limit.
2. All participants must have an identified pathogenetic constitutional NF1 mutation OR the clinical diagnosis of NF1 using the NIH Consensus Conference criteria.
3. Diagnosis: LGG (WHO Grade 1 and 2) of the brain and spinal cord are eligible. Histologic confirmation of tumor is not necessary in the presence of consistent clinical and radiographic findings. Biopsy for histologic diagnosis is required if there is clinical suspicion for a high-grade tumor; special attention is recommended in older adolescents or young adults to the potential for malignant transformation. Patients with metastatic disease are eligible.

4. Patients must meet at least one of the following criteria for progression or recurrence of a previously treated target tumor:

   1. Progression or recurrence on MRI.
   2. New or worsening neurologic symptoms attributable to the target tumor.
   3. For patients with OPG: visual worsening, defined as worsening of visual acuity (VA) or visual fields (VF) documented within the past year by examination or history, attributable to tumor.
5. Measurable Disease: Patients must have two-dimensional measurable tumor >1cm2.
6. Prior Therapy: Patients must have had at least one prior medical treatment for the target LGG.
7. Performance Level: Patients must have a performance status of equal or > than 50 using Karnofsky for patients equal or ≥ 16 years of age and Lansky for patients < 16 years of age.

8. Patients must have recovered to grade ≤1 from any acute toxicities from all prior treatments. to enroll on this study and meet time restrictions from end of prior therapy as defined below:

   1. Myelosuppressive chemotherapy: must have received the last dose of myelosuppressive therapy at least 4 weeks prior to study registration, or at least 6 weeks if nitrosourea.
   2. Investigational/biological agent: Patient must have received the last dose of other investigational, immunotherapy, or biological agent > 14 days prior to study registration or at least 5 half-lives, whichever is greater. Bevacizumab last dose > 36 days prior to enrollment.
   3. Radiation therapy: Patients SHOULD NOT have received prior irradiation.
   4. Study specific limitations on prior therapy: There is no limit on the number of prior treatment regimens.
   5. Growth factor(s): Must not have received any hematopoietic growth factors within 7 days of study entry or > 14 days if pegylated GCSF is used.
   6. Prior surgery: At the time of enrollment, must be ≥ 3 weeks from prior major surgery such as craniotomy, orthopedic surgery, abdominal surgery or ≥1 week from minor surgery and completely recovered. Port or central line placement is not considered a major surgery.

9. Organ Function Requirements:

   All patients must have adequate organ function defined as:

   9.1 Hematologic Function:

   1. Hemoglobin: > 8.0 gm/dl (may transfuse PRBCs)
   2. ANC: > 750/mm3. Must be at least 7 days after last dose of growth factor or > 14 days since last dose of pegylated GCSF
   3. Platelet Count: > 75,000/mm3 (transfusion independent; ≥ 7 days from last transfusion)

   9.2 Renal Function: Serum creatinine which is less than 1.5 times ULN for age (as per the table below) or GFR > 70 ml/min/1.73m2

   Renal Function Normal for Age

   Age Maximum Serum Creatinine (mg/dL) Male Female 1 month to < 6 months 0.4 0.4 6 months to < 1 year 0.5 0.5 1 to < 2 years 0.6 0.6 2 to < 6 years 0.8 0.8 6 to < 10 years 1 1 10 to < 13 years 1.2 1.2 13 to < 16 years 1.5 1.4

   ≥ 16 years 1.7 1.4

   Liver Function:

   1. Total bilirubin < 1.5 x ULN (Children with diagnosis of Gilbert's Syndrome will be allowed on the study regardless of their total and indirect bilirubin levels as long as the direct bilirubin is less than 3.1 mg/dL.)
   2. SGPT (ALT) ≤ 5 x ULN
   3. SGOT (AST) ≤ 5 x ULN

   Pulmonary Function:

   No evidence of dyspnea at rest, and a pulse oximetry ≥ 92%.

   Reproductive Function:

   Female patients of childbearing potential must have negative serum or urine pregnancy test within 7 days prior to the first dose of poly-ICLC. Patient must not be pregnant or breast-feeding. Patients of childbearing or child-fathering potential must be willing to use a medically acceptable form of birth control, including abstinence, while being treated on this study and for 90 days following cessation of treatment.

10. Patient is able to start treatment within 7 days after enrollment.
11. Patients with neurological deficits must be stable for a minimum of 1 week prior to enrollment.
12. Patients are only eligible if complete resection of the LGG with acceptable morbidity is not feasible, or if a patient with a surgical option refuses surgery.
13. Parents/legal guardians must provide written informed consent and agree that they will comply with the study.

Exclusion Criteria:

1. Prior radiation treatment for the low-grade glioma.
2. Prior exposure to poly-ICLC.
3. Patients currently receiving other anti-tumor therapy or experimental therapy (targeted agents, chemotherapy radiation).
4. Patients with a current or prior diagnosis of malignant glioma (WHO grade III or IV).
5. Patients with a prior diagnosis of malignant peripheral nerve sheath tumor or other malignancy requiring treatment in the last 48 months.
6. Patients may not have fever (≥38.50 C) within 3 days of enrollment.
7. Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study.
8. Active auto-immune illness.
9. Pregnant or lactating females.
10. Sexually active patients of reproductive potential who have not agreed to use an effective contraceptive method for the duration of their study participation and for 90 days after stopping study therapy are not eligible.
11. Severe unresolved infection that requires systemic IV antibiotics.
12. Patients with any significant medical illnesses that in the investigator's opinion cannot be adequately controlled with appropriate therapy or would compromise the patient's ability to tolerate this therapy.
13. Uncontrolled intercurrent illness including, but not limited to, ongoing or active infection, symptomatic congestive heart failure, unstable angina pectoris, cardiac arrhythmia, impaired gastrointestinal function, or psychiatric illness/social situations that would limit compliance with study requirements.
14. Patients requiring high doses of steroids. Patients may not be on immunosuppressive therapy, including corticosteroids (with the exception of physiologic replacement, defined as ≤ 0.75 mg/m2/day dexamethasone or equivalent) at time of enrollment. However, patients who require intermittent use of bronchodilators or local steroid injections will not be excluded from the study.

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: Administer Poly-ICLC; Enrolled participants will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using Monday/Thursday or Tuesday/Friday schedule if possible).	Drug: Poly ICLC; Enrolled participants will receive poly-ICLC 20 mcg/kg/dose twice weekly IM (using Monday/Thursday or Tuesday/Friday schedule if possible).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Evaluate the efficacy of poly-ICLC	evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive low-grade glioma (LGG) as measured by objective tumor response rate (CR+PR)	First 48 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Determine progression free survival (PFS)	a) Determine progression free survival (PFS) in pediatric NF1 patients with progressive LGG treated with poly-ICLC.	12 Months
Determine progression free survival (PFS)	a) Determine progression free survival (PFS) in pediatric NF1 patients with progressive LGG treated with poly-ICLC.	24 Months
Determine progression free survival (PFS)	a) Determine progression free survival (PFS) in pediatric NF1 patients with progressive LGG treated with poly-ICLC.	60 Months
Evaluate efficacy by best objective tumor response rate (CR+PR)	b) Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by best objective tumor response rate (CR+PR).	24 Months
Evaluate efficacy by clinical benefit response rate (CR+PR+MR+SD)	c) Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by clinical benefit response rate (CR+PR+MR+SD).	12 Months
Evaluate efficacy by clinical benefit response rate (CR+PR+MR+SD)	c) Evaluate the efficacy of poly-ICLC in pediatric NF1 patients with progressive LGG as measured by clinical benefit response rate (CR+PR+MR+SD).	24 Months
Assess toxicity	d) Assess the toxicity associated with poly-ICLC treatment in pediatric NF1 patients with LGG.	Up to 60 months

Collaborators and Investigators

• Sponsor: University of Alabama at Birmingham
• Collaborators: Children's Healthcare of Atlanta; Children's Hospital Los Angeles
• Investigators: Study Director: Juliette Southworth, BS, CCRP, University of Alabama at Birmingham, NFCTC

Study record dates

Study Major Dates

• Study Start (Actual): December 15, 2021
• Primary Completion (Estimated): February 15, 2026
• Study Completion (Estimated): February 15, 2027

Study Registration Dates

• First Submitted: September 2, 2020
• First Submitted That Met QC Criteria: September 2, 2020
• First Posted (Actual): September 10, 2020

Study Record Updates

• Last Update Posted (Actual): March 15, 2024
• Last Update Submitted That Met QC Criteria: March 12, 2024
• Last Verified: March 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms, Nerve Tissue; Glioma; Physiological Effects of Drugs; Immunologic Factors; Interferon Inducers; Poly ICLC
• Other Study ID Numbers: W81XWH-17-2-0037 (CDMRP of the Dept. of Defense, US Army)

Drug and device information, study documents

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