JOURNAL ONKOLOGIE – STUDIE

H3.3K27M Peptide Vaccine With Nivolumab for Children With Newly Diagnosed DIPG and Other Gliomas

Studien-Informationen Einschlusskriterien Studien-Rationale Studien-Arme Geprüfte Regime

Rekrutierend

NCT-Nummer:
NCT02960230

Studienbeginn:
November 2016

Letztes Update:
22.12.2020

Wirkstoff:
K27M peptide, Nivolumab

Indikation (Clinical Trials):
Glioma

Geschlecht:
Alle

Altersgruppe:
Alle

Phase:
-

Sponsor:
Sabine Mueller, MD, PhD

Collaborator:
The V Foundation for Cancer Research, Pacific Pediatric Neuro-Oncology Consortium, Bristol-Myers Squibb,

Studienleiter

Sabine Mueller, MD, PhD, MAS
Study Chair
University of California, San Francisco

Hideho Okada, MD, PhD
Study Chair
University of California, San Francisco

Kontakt

Sabine Mueller, MD, PhD, MAS
Kontakt:
Phone: 877-827-3222
E-Mail: cancertrials@ucsf.edu» Kontaktdaten anzeigen

Rosemarie Dehesa
Kontakt:
E-Mail: rosemarie.dehesa@ucsf.edu» Kontaktdaten anzeigen

Studienlocations (3 von 15)

Rady Children's Hospital-San Diego
92123 San Diego
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Jennifer Elster, MD
Phone: 858-576-1600
Phone (ext.): 220040
E-Mail: jelster@rchsd.org

John Crawford, MD
Phone: 858-966-4939
E-Mail: jcrawford@rchsd.org» Ansprechpartner anzeigen

UCSF Helen Diller Family Comprehensive Cancer Center
94158 San Francisco
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Sabine Mueller, MD
Phone: 415-476-3831
E-Mail: sabine.mueller@ucsf.edu» Ansprechpartner anzeigen

Children's National Medical Center
20010 Washington
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Lindsay Kilburn, MD
Phone: 202-476-3854
E-Mail: lkilburn@cnmc.org

Roger Packer, MD
Phone: 202-476-5973
E-Mail: rpacker@cnmc.org» Ansprechpartner anzeigen

Ann & Robert H. Lurie Children's Hospital of Chicago
60611 Chicago
United StatesSchwebend» Google-Maps

Dana-Farber Cancer Institute
02215 Boston
United StatesSchwebend» Google-Maps

Children's Hospitals and Clinics of Minnesota
55455 Minneapolis
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Anne Bendel, MD
Phone: 612-813-5940
E-Mail: anne.bendel@childrensmn.org

Maggie Skrypek, MD
Phone: 612-813-5940
E-Mail: maggie.skrypek@childrensmn.org» Ansprechpartner anzeigen

St. Louis Children's Hospital
63110 Saint Louis
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Karen Gauvain, MD
Phone: 314-454-2002
E-Mail: gauvain_k@kids.wustl.edu

Joshua Rubin, MD, PhD
Phone: 314-286-2790
E-Mail: rubin_j@kids.wustl.edu» Ansprechpartner anzeigen

Nationwide Children's Hospital
43205 Columbus
United StatesSchwebend» Google-Maps

Oregon Health & Science University
97239 Portland
United StatesSchwebend» Google-Maps

Children's Hospital of Philadelphia
19104 Philadelphia
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Jane Minturn, MD, PhD
Phone: 267-426-5026
E-Mail: MINTURN@email.chop.edu

Kristina Cole, MD
E-Mail: colek@email.chop.edu» Ansprechpartner anzeigen

St. Jude Children's Research Hospital
38105 Memphis
United StatesSchwebend» Google-Maps

Texas Children's Hospital
77030 Houston
United StatesSchwebend» Google-Maps

University of Utah
84112 Salt Lake City
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Nicholas Whipple, MD, MPH
Phone: 801-662-4700
E-Mail: nicholas.whipple@hsc.utah.edu

Carol Bruggers
Phone: 801-662-4700
E-Mail: Carol.bruggers@imail.org» Ansprechpartner anzeigen

Seattle Children's Hospital
98105 Seattle
United StatesRekrutierend» Google-Maps
Ansprechpartner:
Sarah Leary, MD
Phone: 206-987-2106
E-Mail: sarah.leary@seattlechildrens.org

Nicholas Vitanza, MD
Phone: 206-987-2106
E-Mail: nicholas.vitanza@seattlechildrens.org» Ansprechpartner anzeigen

The University Children's Hospital in Zurich
8032 Zürich
SwitzerlandRekrutierend» Google-Maps
Ansprechpartner:
Nicolas Gerber, MD
Phone: +41 44 266 31 17
E-Mail: PNOC_Regulatory@ucsf.edu

Stephanie Mathes, PhD
Phone: +41 44 266 3726» Ansprechpartner anzeigen

Alle anzeigen

Studien-Informationen

Detailed Description:

Subjects who are eligible will receive a specific peptide vaccine, along with a helper drug

called poly-ICLC, in combination with nivolumab, every 3 weeks for the first 6 months of

treatment. Subjects will be monitored routinely by laboratory assessments, physical

evaluation, vital signs, and MRI. Subjects who tolerate therapy well and have stable or

improved disease after 6 months of treatment can continue to receive treatment, nivolumab

continuing every 3 weeks but vaccine and poly-ICLC now every 6 weeks, for a total of 96 weeks

of treatment.

Ein-/Ausschlusskriterien

Inclusion Criteria:

- Stratum A:

• Newly diagnosed children (3-21 years old) with DIPG who are positive for the

H3.3K27M mutation (positive testing in CLIA laboratory) that underwent standard

radiation therapy.

- Stratum B:

- Newly diagnosed children (3-21 years old) with diagnosis of glioma other than

DIPG who are positive for the H3.3K27M mutation (positive testing in CLIA

laboratory) including spinal cord gliomas that underwent standard radiation

therapy.

- Stratum C • Newly diagnosed children 3-21 years of age with diagnosis of DIPG or

midline glioma other than DIPG (excluding spinal cord gliomas) who are positive for

the H3.3K27M mutation (positive testing from a CLIA or equivalent laboratory

required), that underwent standard radiation therapy.

The following eligibility criteria apply to strata A, B and C:

- The patient must test positive for HLA-A*02:01 (positive testing from a CLIA or

equivalent laboratory required; only the HLA A*02:01 subtype is eligible; other

subtypes are excluded)

- The patient must be either off systemic steroids or be on stable dose of dexamethasone

(max 0.1 mg/kg/day; maximum 4mg/day) at time of enrollment.

- Patients must not have received any prior chemotherapy, immunotherapy or bone marrow

transplant for the treatment of their tumor. Prior use of temozolomide during

radiation at maximum of the standard pediatric dosing (defined as 90 mg/m^2/dose

continuously during radiation therapy for 42 days) or dexamethasone is allowed.

- Patients must have undergone radiation therapy and surgery as part of their standard

of care.

o Stratum A: Radiation therapy must have started within 4 weeks of diagnosis by

imaging or surgery, whichever is later.

o Stratum B: For subjects undergoing surgery for more extensive resection, radiation

therapy should be started within 4-6 weeks from surgery.

o Stratum C: Radiation therapy must have started within 4 weeks of diagnosis by

imaging or surgery, whichever is later. For subjects undergoing surgery for more

extensive resection, radiation therapy should be started within 4-6 weeks from

surgery.

- H3.3K27 mutation must have been confirmed in the tumor tissue in a CLIA or equivalent

approved laboratory.

- Karnofsky ≥ 50 for patients ≥ 16 years of age, and Lansky ≥ 50 for patients < 16 years

of age (See Appendix A). Patients who are unable to walk because of paralysis, but who

are up in a wheelchair, will be considered ambulatory for the purpose of assessing the

performance score.

- The patient must have adequate organ function defined as

Adequate Bone Marrow Function Defined as:

- Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 and

- Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving

platelet transfusions for at least 7 days prior to enrollment).

Adequate Renal Function Defined as:

- Creatinine clearance or radioisotope glomerular filtration rate (GFR) ≥ 70mL/min/1.73

m2 or

- A serum creatinine based on age/gender as follows:

Age Maximum Serum Creatinine (mg/dL) Male Female 3 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 The threshold creatinine values in this

table were derived from the Schwartz formula for estimating GFR utilizing child length and

stature data published by the CDC.

Adequate Liver Function Defined as:

- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN) for

age and

- SGPT (ALT) ≤ 110 U/L and

- Serum albumin ≥ 2 g/dL.

Adequate Pancreatic Function Defined as:

• Serum lipase ≤ ULN at baseline.

Adequate Pulmonary Function Defined as:

• No evidence of dyspnea at rest, no exercise intolerance due to pulmonary insufficiency,

and a pulse oximetry of > 92% while breathing room air.

Adequate Neurologic Function Defined as:

- Patients with seizure disorder may be enrolled if seizure disorder is well controlled.

- The effects of the H3.3K27M vaccine and nivolumab on the developing human fetus are

unknown. For this reason, females of child-bearing potential and males must agree to

use adequate contraception. Adequate methods include: hormonal or barrier method of

birth control; or abstinence prior to study entry and for the duration of study

participation. 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. Males treated or enrolled on this protocol must also agree to use

adequate contraception prior to the study and for the duration of study participation.

- Ability to understand a written informed consent document, and the willingness to sign

it. Assent will be obtained when appropriate based on the subjects age.

Exclusion Criteria:

- Investigational Drugs

- Patients who are currently receiving another investigational drug are not

eligible.

- Prior treatment with another investigational drug.

- Anti-cancer Agents

- Patients who are currently receiving other anti-cancer agents are not eligible.

- Prior treatment with other anti-cancer agents.

- Patients who have received a live / attenuated vaccine within 30 days of first

treatment.

- Patients with a known disorder that affects their immune system, such as HIV or

Hepatitis B or C, or an auto-immune disorder requiring systemic cytotoxic or

immunosuppressive therapy are not eligible. Note: Patients that are currently using

inhaled, intranasal, ocular, topical or other non-oral or non-IV steroids are not

necessarily excluded from the study but need to be discussed with the study chair.

- Patients with a ≥ Grade 2 hypothyroidism due to history of autoimmunity are not

eligible. (Note: Hypothyroidism due to previous irradiation or thyroidectomy will not

impact eligibility).

- Patients who have received prior solid organ or bone marrow transplantation are not

eligible.

- Patients with uncontrolled infection.

- Female patients of childbearing potential must not be pregnant or breast-feeding.

Female patients of childbearing potential must have a negative serum or urine

pregnancy test prior to the start of therapy (as clinically indicated).

Studien-Rationale

Primary outcome:

1. Number of Participants with Adverse Events related to treatment (Time Frame - 24 months):
Safety of the vaccine (Strata A and B) or vaccine in combination with nivolumab (Stratum C) will be assessed by monitoring for adverse events (AEs), scheduled laboratory assessments, vital signs, & physical examinations for subjects who receive the vaccination. The severity of toxicities will be graded according to the NCI CTCAE v5.0. AEs & clinically significant lab abnormalities (meeting Grade 3, 4, or 5 criteria according to CTCAE) will be summarized by maximum intensity & relationship to study drug(s). Grade 1 & 2 AEs will be summarized if related to study therapy. Descriptive statistics will be utilized to display the data on toxicity seen.

2. Overall survival (OS) at 12 months (OS12) (Time Frame - 36 months):
OS12 will be the clinical efficacy primary endpoint for Stratum A. Any eligible subject that receives at least one dose of the K27M/TT vaccine will be considered evaluable for clinical efficacy. For subjects who are still alive at 12 months, OS12 will be censored at the last contact date. OS will be estimated using the Kaplan-Meier method.

Studien-Arme

Experimental: Stratum A: Newly Diagnosed DIPG
Newly diagnosed children with diffuse intrinsic pontine glioma who are positive for HLA-A2 and the H3.3K27M mutation that underwent radiation therapy will receive the specific H3.3K27M peptide vaccine, combined with the tetanus toxoid (TT) peptide, emulsified in Montanide. Poly-ICLC, which is a synthetic nucleic acid, will be given concurrently to improve the therapeutic effects of the vaccine. Vaccine will be given every 3 weeks for the first 24 weeks, then if there is stable or improved disease, will be given every 6 weeks for a total treatment period of 96 weeks.
Experimental: Stratum B: Newly Diagnosed Glioma (non-DIPG)
Newly diagnosed children with gliomas other than DIPG who are positive for HLA-A2 and the H3.3K27M mutation that underwent radiation therapy will receive the specific H3.3K27M peptide vaccine, combined with the tetanus toxoid peptide, emulsified in Montanide. Poly-ICLC, which is a synthetic nucleic acid, will be given concurrently to improve the therapeutic effects of the vaccine. Vaccine will be given every 3 weeks for the first 24 weeks, then if there is stable or improved disease, will be given every 6 weeks for a total treatment period of 96 weeks.
Experimental: Stratum C: Newly Diagnosed DIPG or other Midline Glioma
Newly diagnosed children with DIPG or other midline gliomas (excluding spinal cord tumors) who are positive for HLA-A2 (02:01) and the H3.3K27M mutation that underwent radiation therapy will receive the specific H3.3K27M peptide vaccine, combined with the tetanus toxoid peptide, emulsified in Montanide. Poly-ICLC, which is a synthetic nucleic acid, will be given concurrently to improve the therapeutic effects of the vaccine. Nivolumab will also be given via IV. Vaccine will be given every 3 weeks for the first 24 weeks, then if there is stable or improved disease, will be given every 6 weeks for a total treatment period of 96 weeks. Nivolumab will continue to be given every 3 weeks throughout all of treatment.

Geprüfte Regime

K27M peptide:
K27M peptide vaccine, combined with Tetanus Toxoid peptide, emulsified in montanide. Poly-ICLC will be given concurrently
Nivolumab:
anti-PD1 monoclonal antibody

Quelle: ClinicalTrials.gov