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Trial details imported from ClinicalTrials.gov

For full trial details, please see the original record at https://clinicaltrials.gov/study/NCT06161974




Registration number
NCT06161974
Ethics application status
Date submitted
22/11/2023
Date registered
8/12/2023

Titles & IDs
Public title
Study of Olutasidenib and Temozolomide in HGG
Scientific title
Phase 2 Study of Olutasidenib With Temozolomide as Maintenance Therapy in Pediatric and Young Adult Patients Newly Diagnosed With High-Grade Glioma (HGG), Including Diffuse Intrinsic Pontine Glioma (DIPG), Which Harbor IDH1 Mutations
Secondary ID [1] 0 0
TarGeT-D
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
High Grade Glioma 0 0
Astrocytoma 0 0
Astrocytoma, Grade III 0 0
Astrocytoma, Grade IV 0 0
Diffuse Intrinsic Pontine Glioma 0 0
WHO Grade III Glioma 0 0
WHO Grade IV Glioma 0 0
Metastatic Brain Tumor 0 0
Diffuse Midline Glioma, H3 K27M-Mutant 0 0
Thalamus Tumor 0 0
Spinal Tumor 0 0
IDH1 Mutation 0 0
IDH1 R132 0 0
IDH1 R132C 0 0
IDH1 R132H 0 0
IDH1 R132S 0 0
IDH1 R132G 0 0
IDH1 R132L 0 0
Oligodendroglioma 0 0
Condition category
Condition code
Cancer 0 0 0 0
Brain
Cancer 0 0 0 0
Children's - Brain

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Treatment: Drugs - Olutasidenib + TMZ

Experimental: Stratum A - Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1 mutant Astrocytoma, CNS WHO Grade 3.

Experimental: Stratum B - Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1 mutant Astrocytoma, CNS WHO Grade 4.

Experimental: Stratum C - Patients with IDH-1 mutant DIPG, primary thalamic and spinal cord IDH-1 mutant HGG.


Treatment: Drugs: Olutasidenib + TMZ
Olutasidenib 150 mg PO BID + Temozolomide 200 mg/m2 PO QD
Intervention code [1] 0 0
Treatment: Drugs
Comparator / control treatment
Control group

Outcomes
Primary outcome [1] 0 0
Establish the RP2D of Olutasidenib and Temozolomide (Feasibility cohort)
Timepoint [1] 0 0
Completion of cycle 1 (28 days) for 6-24 patients
Primary outcome [2] 0 0
Assess Progression-Free Survival (PFS) in Grade 3 IDH1-mutant Astrocytoma (Stratum A)
Timepoint [2] 0 0
From date of diagnosis until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up 24 months
Primary outcome [3] 0 0
Maximum plasma concentration [Cmax] of Olutasidenib
Timepoint [3] 0 0
From Day 1 of treatment until date of first documented progression or date of death from any cause, whichever comes first, assessed up to 24 months
Secondary outcome [1] 0 0
Evaluate objective response rate (ORR) in HGG (All Strata)
Timepoint [1] 0 0
From day 1 of protocol treatment through 30 days following end of protocol treatment
Secondary outcome [2] 0 0
Evaluate Health-Related Quality of Life Outcomes (All Strata)
Timepoint [2] 0 0
From pre-maintenance (2 weeks before the first cycle), and at the start of even numbered cycles (each cycle is 28 days) and at the End of Treatment visit (can have up to 26 cycles)
Secondary outcome [3] 0 0
Evaluate Overall Survival in IDH1-mutant Grade 3 Astrocytoma (Stratum A)
Timepoint [3] 0 0
From date of diagnosis until date of death due to any cause or date of last follow-up, assessed up to 60 months
Secondary outcome [4] 0 0
Assess Progression-Free Survival in IDH1-mutant Grade 4 Astrocytoma (Stratum B)
Timepoint [4] 0 0
From date of diagnosis until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up 24 months

Eligibility
Key inclusion criteria
Criteria TarGeT-D study strata definitions

* Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1 mutant Astrocytoma, CNS WHO Grade 3.
* Stratum B: Patients with localized, intracranial, non-pontine, and non-thalamic IDH 1 mutant Astrocytoma, CNS WHO Grade 4.
* Stratum C: Patients with IDH-1 mutant DIPG, primary thalamic and spinal cord IDH-1 mutant HGG.



1. Inclusion criteria already met to enroll on TarGeT-SCR (central molecular and histopathologic screening) based on:

1.1) Age: patients must be =12 years and =39 years of age at the time of enrollment on TarGeT-SCR

1.2) Diagnosis:
* Patients with a newly-diagnosed IDH1-mutant HGG including DIPG are eligible. All patients must have tumor tissue from diagnostic biopsy or resection, without exceptions. The diagnosis of HGG, including DIPG, must have been confirmed through TarGeT-SCR.
* For the diagnosis of DIPG, patients must have a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, and histopathology consistent with diffuse WHO Grade 2-4 glioma.
* All other HGG must be WHO Grade 3 or 4.

1.3) Disease status: There are no disease status requirements for enrollment
* Measurable disease is not required. Patients without measurable disease are eligible.
* Primary spinal tumor: Patients with a primary spinal HGG are eligible.
* Patient must not have metastatic disease.
2. Inclusion criteria for assignment to TarGeT-D, for all strata:

2.1 Presence of at Least One Relevant Actionable Somatic Mutation in IDH1 Gene, Detailed Here:

* R132H, R132C, R132S, R132G or R132L.
* Patients whose tumors harbor other alterations in addition to IDH1 mutation will potentially be eligible following consensus recommendation by the international multidisciplinary molecular screening committee.
* Patients with IDH2 mutations are not eligible.
* Patients with oligodendroglioma, IDH-mutant and 1p/19q-codeleted are not eligible.

2.2 Performance Level: Karnofsky = 50% for patients > 16 years of age and Lansky = 50 for patients = 16 years of age. 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.

2.3 Prior Therapy

2.3.1 Surgery, radiation, and/or dexamethasone are permissible. Temozolomide administered concurrently with radiotherapy is permissible. No other prior anticancer therapy for HGG will be allowed.

2.3.2 Radiation therapy requirements: RT, delivered via photon or proton beam, must have been administered at a standard dose including 54 Gy in 30 fractions for DIPG, 59.4 Gy in 33 fractions or 54-60 Gy in 30 fractions for other HGG or 45-50.4 Gy for primary spinal disease. Any variances in the radiotherapy dose within 10% of the standard doses outlined above will be discussed with the Study Chair to confirm eligibility prior to study enrollment.

2.3.3 Timing between diagnosis and start of RT: Patients must have started RT within 31 calendar days of initial diagnosis defined as the date of diagnostic biopsy or resection; if a patient underwent two upfront surgeries (e.g., biopsy then resection or debulking), this is the date of the second surgery.

2.3.4 Timing post-RT

* Patients in pre-maintenance phase must enroll and start treatment no later than 21 calendar days post-completion of RT.
* Patients not in pre-maintenance phase must enroll and start treatment no later than 35 calendar days post-completion of RT.

2.4 Organ Function Requirements

2.4.1 Adequate Bone Marrow Function Defined as:

* Peripheral absolute neutrophil count (ANC) = 1000/mm3.
* Platelet count = 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment).
* Hemoglobin > 8 g/dL (may be transfused).

2.4.2 Adequate Renal Function Defined as

* Creatinine clearance or radioisotope GFR = 70ml/min/1.73 m2 OR
* Maximum serum creatinine based on age/gender as follows: 10 to < 13 yrs=1.2 mg/dL for males and females. 13 to < 16 yrs=1.5 mg/dL for males and 1.4 mg/dL for females.

2.4.3 Adequate Liver Function Defined as:

* Total bilirubin must be = 1.5 × institutional ULN.
* AST(SGOT)/ALT(SGPT) < 3 × institutional ULN.
* Alkaline Phosphatase < 3 × institutional ULN. 2.4.4 Informed consent: All patients and/or their parents or legally authorized representatives must sign a written informed consent. Assent, when appropriate, will be obtained according to institutional guidelines.
Minimum age
12 Years
Maximum age
39 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Pregnancy or Breast-Feeding: Pregnant or breast-feeding women will not be entered on this study due to unknown potential risks of fetal and teratogenic adverse events as seen in animal studies. Pregnancy tests must be obtained in girls who are post-menarchal. Patients of childbearing or child fathering potential must agree to use one highly effective method of contraception while being treated on this study and for 3 months after completing therapy. A woman is considered of childbearing potential if she is fertile, following menarche and until becoming post-menopausal unless permanently sterile. A postmenopausal state is defined as no menses for 12 months without an alternative medical cause. A high follicle stimulating hormone (FSH) level in the postmenopausal range may be used to confirm a post-menopausal state in women not using hormonal contraception or hormonal replacement therapy. However, in the absence of 12 months of amenorrhea, a single FSH measurement is insufficient. A man is considered fertile after puberty unless permanently sterile by bilateral orchidectomy. Male participants should refrain from sperm donation throughout the duration of treatment and for 3 months after completion of therapy.

A highly effective contraception method is defined as one that results in a low failure rate (<1% per year) when used consistently and correctly. The following are considered highly effective contraception methods:
* Combined estrogen and progesterone containing hormonal contraception associated with inhibition of ovulation.
* Progesterone-only hormonal contraception associated with inhibition of ovulation.
* Intra Uterine Device (IUD).
* Intra uterine hormone releasing system.
* Bilateral tubal occlusion.
* Vasectomized partner.
* Sexual abstinence (avoiding heterosexual intercourse).
* The following contraceptive measures are NOT considered effective:

* Progesterone-only hormonal contraception (birth control pill) that that does NOT stop ovulation.
* Male or female condom with or without spermicide.
* Cap, diaphragm, or sponge with spermicide.
2. Using the following types of concomitant medications:

* Corticosteroids: Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported.
* Investigational Drugs: Patients who are currently receiving another investigational drug are not eligible.
* Anti-cancer Agents: Concurrent anti-cancer agents are not allowed with the exception of temozolomide given concurrently with RT and as post RT maintenance therapy.
* Anticonvulsants: Patients who are receiving enzyme inducing anticonvulsants that are strong inducers of CYP3A4/5 are not eligible.
* Strong CYP3A4/5 inducers: Patients who are receiving strong inducers of CYP3A4/5 are not eligible. Strong inducers of CYP3A4/5 should be avoided from 14 days prior to or 5 half-lives (whichever is longer) enrollment to the end of the study.
* Patients who are receiving medications known to prolong QTc interval are not eligible
* Selective serotonin reuptake inhibitors (SSRIs) such as citalopram (Celexa), escitalopram (Lexapro), fluoxetine (Prozac), fluvoxamine (Luvox), paroxetine (Paxil), sertraline (Zoloft) should be used with caution but are not contraindicated.
* Anticoagulants: patients who are receiving therapeutic anticoagulation with warfarin are not eligible.
3. Other Criteria

* Infection: Patients who have an uncontrolled infection are not eligible.
* Patients who, in the opinion of the investigator, may not be able to comply with the safety monitoring requirements of the study are not eligible.
* Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible.
* Patients with malignancy related to HIV or solid organ transplant: known history of HIV, HBV surface antigen positivity or positive HCV antibody are not eligible. Viral testing is not required unless clinically indicated in patients without a known history.
* Patients with prior or ongoing clinically significant illness, medical or psychiatric condition, that, in the investigator's opinion, could affect the safety of the subject, or could impair the assessment of study results are not eligible.
* Patients with any prior solid organ transplant are not eligible.
* Patients with secondary/radiation-related HGG are not eligible.
* Patients with metastatic/disseminated HGG who have received CSI are not eligible.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Phase 2
Type of endpoint/s
Statistical methods / analysis

Recruitment
Recruitment status
Not yet recruiting
Data analysis
Reason for early stopping/withdrawal
Other reasons
Date of first participant enrolment
Anticipated
1/06/2024
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
1/06/2035
Actual
Sample size
Target
60
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW,QLD,WA
Recruitment hospital [1] 0 0
Sydney Children's Hospital - Randwick
Recruitment hospital [2] 0 0
Queensland Children's Hospital - South Brisbane
Recruitment hospital [3] 0 0
Perth Children's Hospital - Perth
Recruitment postcode(s) [1] 0 0
2031 - Randwick
Recruitment postcode(s) [2] 0 0
4101 - South Brisbane
Recruitment postcode(s) [3] 0 0
6000 - Perth
Recruitment outside Australia
Country [1] 0 0
United States of America
State/province [1] 0 0
Colorado
Country [2] 0 0
United States of America
State/province [2] 0 0
District of Columbia
Country [3] 0 0
United States of America
State/province [3] 0 0
Illinois
Country [4] 0 0
United States of America
State/province [4] 0 0
Massachusetts
Country [5] 0 0
United States of America
State/province [5] 0 0
North Carolina
Country [6] 0 0
United States of America
State/province [6] 0 0
Ohio
Country [7] 0 0
United States of America
State/province [7] 0 0
Pennsylvania
Country [8] 0 0
United States of America
State/province [8] 0 0
Texas
Country [9] 0 0
United States of America
State/province [9] 0 0
Washington
Country [10] 0 0
Canada
State/province [10] 0 0
Ontario
Country [11] 0 0
Canada
State/province [11] 0 0
Quebec
Country [12] 0 0
Germany
State/province [12] 0 0
Baden-Württemberg
Country [13] 0 0
Netherlands
State/province [13] 0 0
Utrecht
Country [14] 0 0
United Kingdom
State/province [14] 0 0
London

Funding & Sponsors
Primary sponsor type
Commercial sector/industry
Name
Rigel Pharmaceuticals
Address
Country
Other collaborator category [1] 0 0
Other
Name [1] 0 0
Nationwide Children's Hospital
Address [1] 0 0
Country [1] 0 0

Ethics approval
Ethics application status

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 0 0
Santosh Valvi, FRACP, MSc
Address 0 0
Perth Children's Hospital
Country 0 0
Phone 0 0
Fax 0 0
Email 0 0
Contact person for public queries
Name 0 0
Elizabeth Franklin
Address 0 0
Country 0 0
Phone 0 0
650-624-1100
Fax 0 0
Email 0 0
[email protected]
Contact person for scientific queries

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

No documents have been uploaded by study researchers.


Results not provided in https://clinicaltrials.gov/study/NCT06161974