A Study of Varlilumab and IMA950 Vaccine Plus Poly-ICLC in Patients With WHO Grade II Low-Grade Glioma (LGG)

NCT02924038 | Terminated Phase 1 Results DMC FDA Drug

• 3 other identifiers: 15108NCI-2017-013695R21CA233856-02
• Study Type: interventional
• Target: 14
• Locations: 1 country
• Sites: 1

Brief Summary

This is a pilot, randomized, two arm neoadjuvant vaccine study in human leukocyte antigen-A2 positive (HLA-A2+) adults with World Health Organization (WHO) grade II glioma, for which surgical resection of the tumor is clinically indicated. Co-primary objectives are to determine: 1) the safety of the novel combination of subcutaneously administered IMA950 peptides and poly-ICLC (Hiltonol) and i.v. administered CDX-1127 (Varlilumab) in the neoadjuvant approach; and 2) whether addition of i.v. CDX-1127 (Varlilumab) increases the response rate and magnitude of CD4+ and CD8+ T-cell responses against the IMA950 peptides in post-vaccine peripheral blood mononuclear cell (PBMC) samples obtained from participating patients.

Conditions

Glioma; Malignant Glioma; Astrocytoma, Grade II; Oligodendroglioma; Glioma, Astrocytic; Oligoastrocytoma, Mixed

Keywords

low-grade glioma; glioma; immunotherapy; vaccine; WHO grade II

Outcome Measures

Primary Outcomes (3)

• Proportion of Participants Experiencing Regimen Limiting Toxicity (RLT)

  The proportion of participants experiencing and RLT defined as an adverse event judged to be possibly, probably or definitely associated with treatment that requires participants to be taken off study and no further injections will be given will be reported.

  up to 2 years

• Mean Percentage of CD8+ T-cell Responses in Pre- and Post-vaccine Peripheral Blood Mononuclear Cells (PBMC)

  The expansion of IMA950-reactive CD8+ T cell frequencies over post-vaccine periods was assessed by calculating the mean percentage of total IMA950 tetramer-positive CD8+ T cell per available post-vaccine time point. CD8+ T-cell response to the IMA950-epitope is defined to be positive when the percentage of tetramer-positive CD8+ T cells showed a four-fold or higher increase within at least one-time point in the post-vaccine phase relative to the corresponding percentage at the pre-vaccine.

  Up to 2 years

• Mean Percentage of CD4+ T-cell Responses in Pre- and Post-vaccine PBMC

  The expansion of IMA950-reactive CD4+ T cell frequencies over post-vaccine periods was assessed by calculating the mean percentage of total IMA950 tetramer-positive CD4+ T cell per available post-vaccine time point. CD4+ T-cell response to the IMA950-epitope is defined to be positive when the percentage of tetramer-positive CD4+ T cells showed a four-fold or higher increase within at least one-time point in the post-vaccine phase relative to the corresponding percentage at the pre-vaccine.

  Up to 2 years

Study Arms (2)

IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV

EXPERIMENTAL

IMA950 4.96mg and poly-ICLC 1.4mg administered as one formulation subcutaneously followed immediately by a Varlilumab 3mg/kg infusion (intravenously) -23±2 days (about 3 weeks) before the date of scheduled standard-of-care surgery to remove the WHO grade II glioma. Patients will continue receiving IMA950/poly-ICLC subcutaneous injections every week leading up to surgery (Days -16±2, -9±2 and 24-48 hours prior to scheduled surgery) and every 3 weeks after surgery (Weeks A1, A4, A7, A10, A13, A16, A19, A22; defining Week A1 as the first post-surgery vaccine). After surgery, patients will continue receiving a Varlilumab infusion every 6 weeks immediately following the IMA950/poly-ICLC injection (Weeks A1, A7, A13, and A19).

Biological: IMA950; Biological: poly-ICLC; Biological: Varlilumab

IMA950/poly-ICLC subQ only

EXPERIMENTAL

IMA950 4.96mg and poly-ICLC 1.4mg administered as one formulation subcutaneously every week leading up to standard-of-care surgery to remove the WHO grade II glioma (Days -23±2, -16±2, -9±2 and 24-48 hours prior to scheduled surgery) and every three weeks after surgery (Weeks A1, A4, A7, A10, A13, A16, A19, A22; defining Week A1 as the first post-surgery vaccine). Patients will not receive Varlilumab.

Biological: IMA950; Biological: poly-ICLC

Interventions

IMA950 BIOLOGICAL

IMA950 vaccine

Also known as: IMA950 peptides

IMA950/poly-ICLC subQ only; IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV

poly-ICLC BIOLOGICAL

poly-ICLC vaccine

Also known as: Hiltonol

IMA950/poly-ICLC subQ only; IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV

Varlilumab BIOLOGICAL

Intravenous solution

Also known as: CDX-1127

IMA950/poly-ICLC subcutaneous (subQ) + Varlilumab IV

Eligibility Criteria

• Age: 18 Years+
• Sex: all
• Healthy Volunteers: No
• Age Groups: Adult (18-64), Older Adult (65+)

You may qualify if:

• Patients must be \>= 18 years old.
• Pathological criteria - Participants must have a newly diagnosed or recurrent WHO grade II astrocytoma, oligoastrocytoma or oligodendroglioma that has been histologically confirmed by prior biopsy or surgical resection. If the pathological diagnosis ws made outside of University of California, San Francisco (UCSF), the pathology must be reviewed and confirmed at UCSF.
• Patients must be positive for HLA-A2 based on flow-cytometry or genotyping
• Before enrollment, patients must show non-enhancing T2-FLAIR lesions lesions that are amenable to surgical resection. Surgical resection of at least 0.3 grams of tumor is expected to ensure adequate evaluation of the study endpoints
• Prior radiation therapy (RT) after the initial diagnosis will be allowed but there must be at least 6 months from the completion of RT (or radiosurgery) to signed informed consent.
• Prior chemotherapy and any systemic molecularly targeted anti-tumor therapy will be allowed, and there must be at least 28 days from the last temodar chemotherapy, 42 days for nitrosourea; at least 14 days from the last dose for chemotherapy regimens given continuously or on a weekly basis with limited potential for delayed toxicity.
• Patients must have a Karnofsky performance status (KPS) of \>= 70%.
• Off or low dose (\<= 4 mg/day by Decadron) corticosteroid at least two weeks before the first pre-surgical vaccine
• Adequate organ function within 28 days of study registration including: 1) Adequate bone marrow reserve: absolute neutrophil (segmented and bands) count (ANC) \>=1.0 x 10\^9/L, absolute lymphocyte count \>=4.0 x 10\^8/L, platelets \>=100 x 10\^9/L; hemoglobin \>=8 g/dL; 2) Hepatic: - Total bilirubin \<= 1.5 x upper limit of normal (ULN) and Serum glutamic pyruvic transaminase(SGPT)/ (alanine aminotransferase (ALT)) \<=2.5 x upper limit of normal (ULN), and 3) Renal: Normal serum creatinine or creatinine clearance \>=60 ml/min/1.73 m\^2
• Must be free of systemic infection. Subjects with active infections (whether or not they require antibiotic therapy) may be eligible after complete resolution of the infection. Subjects on antibiotic therapy must be off antibiotics for at least 7 days before beginning treatment.
• Sexually active females of child bearing potential must agree to use adequate contraception (diaphragm, birth control pills, injections, intrauterine device (IUD), surgical sterilization, subcutaneous implants, or abstinence, etc.) for the duration of the vaccination period. Sexually active males must agree to use barrier contraceptive for the duration of the vaccination period.
• Women of child-bearing potential and men must agree to use adequate contraception (ex. Hormonal or barrier method of birth control or abstinence) prior to study entry and for the duration of study participation (until one month after the last vaccine) since the effects of the current regimen on the developing human fetus are unknown. Should a woman become pregnant or suspect she is pregnant while she or her partner is participating in this study, she should inform her treating physician immediately
• Patient must sign an informed consent document indicating that they are aware of the investigational nature of this study, which includes an authorization for the release of their protected health information

You may not qualify if:

• Presence of gliomatosis cerebri, cranial or spinal leptomeningeal metastatic disease
• Presence of T1 Gadolinium (Gd)-enhancing lesions (on MRI) suggestive of high-grade glioma
• Pathological diagnosis for the resected tumor demonstrates transformation to higher grade (i.e. WHO grade III or IV) gliomas. If a patient is diagnosed as HGG upon resection after receiving the pre-surgical treatment, the patient will be withdrawn from the study and considered for therapeutic options for HGG (trials for HGG or standard of care). The tumor tissue of such a case would be brought to the lab before the pathological diagnosis is made; and thus would be processed before the lab is informed of the final HGG diagnosis. Because HGG tissue may still reflect the vaccine effects, we will evaluate the tumor tissue to help us develop future approaches for HGG.
• Pregnant women are excluded from this study because IMA950 and poly-ICLC are drugs with the potential for teratogenic or abortifacient effects. Because there is an unknown but potential risk for adverse events in nursing infants secondary to treatment of the mother with IMA950 plus poly-ICLC (IMA950-poly-ICLC hereafter) vaccine, breastfeeding should be discontinued if the mother is treated with IMA950- poly-ICLC vaccine
• Uncontrolled intercurrent illness including, but not limited to ongoing or active infection (e.g. active or chronic hepatitis B and C), symptomatic congestive heart failure, unstable angina pectoris, or psychiatric illness/social situations that would limit compliance with study requirements
• History or current status of immune system abnormalities such as hyperimmunity (e.g., autoimmune diseases) that needed to be treated by systemic therapy, such as immuno-suppressants and hypoimmunity (e.g., myelodysplastic disorders, marrow failures, AIDS, transplant immunosuppression).
• Any isolated laboratory abnormality suggestive of a serious autoimmune disease (e.g. hypothyroidism): Antinuclear antibody, thyroid-stimulating hormone (TSH), free thyroxine (FT4), rheumatoid factor
• Any condition that could potentially alter immune function (AIDS, multiple sclerosis, diabetes, renal failure)
• Receiving ongoing treatment with immunosuppressive drugs or dexamethasone \> 4mg
• Use of any of the following concurrent treatment or medications:
• radiation therapy
• chemotherapy
• interferon (e.g. Intron-A)
• allergy desensitization injections
• growth factors (e.g. Procrit, Aranesp, Neulasta)

Sponsors & Collaborators

• Nicholas Butowski: lead
• Celldex Therapeutics: collaborator
• National Cancer Institute (NCI): collaborator

Study Sites (1)

University of California

San Francisco, California, 94143, United States

Location

Related Publications (1)

• Saijo A, Ogino H, Butowski NA, Tedesco MR, Gibson D, Watchmaker PB, Okada K, Wang AS, Shai A, Salazar AM, Molinaro AM, Rabbitt JE, Shahin M, Perry A, Clarke JL, Taylor JW, Daras M, Oberheim Bush NA, Hervey-Jumper SL, Phillips JJ, Chang SM, Hilf N, Mayer-Mokler A, Keler T, Berger MS, Okada H. A combinatory vaccine with IMA950 plus varlilumab promotes effector memory T-cell differentiation in the peripheral blood of patients with low-grade gliomas. Neuro Oncol. 2024 Feb 2;26(2):335-347. doi: 10.1093/neuonc/noad185.

  PMID: 37758193 BACKGROUND

MeSH Terms

Conditions

Glioma; Astrocytoma; Oligodendroglioma; Lymphoma, Follicular

Interventions

IMA950; poly ICLC; varlilumab

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Lymphoma, Non-Hodgkin; Lymphoma; Lymphoproliferative Disorders; Lymphatic Diseases; Hemic and Lymphatic Diseases; Immunoproliferative Disorders; Immune System Diseases

Limitations and Caveats

Enrollment was closed earlier than expected due to industry sponsor's prioritization of other programs, the termination of Varliumab development, and Coronavirus disease of 2019 (COVID-19) related challenges during the period of enrollment. Appropriate reagents were not available for the CD4+ outcome measure. Due to the small number of participants, the biological/immunological evaluations are insufficiently powered to provide meaningful statistical significance.

Results Point of Contact

• Title: Dr. Nicholas Butowski, MD
• Organization: University of California, San Francisco

Nicholas.Butowski@ucsf.edu

415-353-7500

Study Officials

• Hideho Okada, MD, PhD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

• Nicholas Butowski, MD

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: RANDOMIZED
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: PARALLEL
• Sponsor Type: OTHER
• Responsible Party: SPONSOR INVESTIGATOR
• PI Title: MD

Study Record Dates

• First Submitted: May 12, 2016
• First Posted: October 5, 2016
• Study Start: April 3, 2017
• Primary Completion: December 31, 2022
• Study Completion: December 31, 2022
• Last Updated: June 14, 2024
• Results First Posted: June 14, 2024

Record last verified: 2024-06

Data Sharing

• IPD Sharing: Will not share

Locations

US (1)