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JOURNAL ONKOLOGIE – STUDIE

Study of Olutasidenib and Temozolomide in HGG

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NCT-Nummer:
NCT06161974

Studienbeginn:
Juni 2024

Letztes Update:
02.04.2024

Wirkstoff:
Olutasidenib + TMZ

Indikation (Clinical Trials):
Glioma, Astrocytoma, Oligodendroglioma, Diffuse Intrinsic Pontine Glioma, Glioblastoma

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
Phase 2

Sponsor:
Rigel Pharmaceuticals

Collaborator:
Nationwide Children's Hospital

Studienleiter

Santosh Valvi, FRACP, MSc
Study Chair
Perth Children's Hospital
Nicholas G Gottardo, MB FRACP PhD
Study Chair
Perth Children's Hospital
Michael J Fisher, MD
Study Chair
Children's Hospital of Philadelphia
Maryam Fouladi, MD
Study Chair
Nationwide Children's Hospital

Kontakt

Studienlocations
(3 von 18)

Hopp Children's Cancer Center at NCT Heidelberg (KiTZ)
69120 Heidelberg
(Baden-Württemberg)
Germany» Google-Maps
Ansprechpartner:
Olaf Witt, MD
Phone: 0496221423570
E-Mail: o.witt@kitz-heidelberg.de» Ansprechpartner anzeigen
Alle anzeigen

Studien-Informationen

Detailed Description:

This is a multicenter, international, phase II study of post-radiotherapy (RT) administration

of olutasidenib to treat pediatric and young adult patients newly diagnosed with an

IDH1-mutant HGG. The trial will include a feasibility cohort to identify the dose of

olutasidenib that is feasible when given in combination with temozolomide as maintenance

therapy after completion of focal radiotherapy in this patient population.

Efficacy will be defined by progression-free survival (PFS) distribution of these patients

after completion of radiotherapy treated with maintenance olutasidenib and TMZ for 13 cycles

followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and

matched historical controls.

Objective radiographic response rates, agent-specific toxicities as well as the

pharmacokinetic and pharmacodynamic properties of olutasidenib will also be assessed.

Ein-/Ausschlusskriterien

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.

Inclusion Criteria:

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.

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.

Studien-Rationale

Primary outcome:

1. Establish the RP2D of Olutasidenib and Temozolomide (Feasibility cohort) (Time Frame - Completion of cycle 1 (28 days) for 6-24 patients):
To identify the dose of olutasidenib that is feasible when given post-RT in combination with temozolomide as maintenance therapy in pediatric and young adult patients newly diagnosed with IDH1-mutant high-grade glioma

2. Assess Progression-Free Survival (PFS) in Grade 3 IDH1-mutant Astrocytoma (Stratum A) (Time Frame - 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):
To assess the post-RT efficacy of olutasidenib in newly diagnosed patients with WHO Grade 3 IDH1-mutant Astrocytoma treated with maintenance olutasidenib and temozolomide for 13 cycles followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and matched historical controls

3. Maximum plasma concentration [Cmax] of Olutasidenib (Time Frame - 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):
To characterize the plasma pharmacokinetic (PK) properties of olutasidenib in pediatric patients (e.g., 12 to < 18 years of age), administered in combination with temozolomide (first year) and as single agent (second year) as maintenance chemotherapy by measuring the Maximum Concentration [Cmax] and Area Under the Curve (AUC) of olutasidenib in plasma (All strata).

Secondary outcome:

1. Evaluate objective response rate (ORR) in HGG (All Strata) (Time Frame - From day 1 of protocol treatment through 30 days following end of protocol treatment):
Evaluate the radiographic objective response rate (ORR) defined as complete response (CR) + partial response (PR) in pediatric and young adult patients newly diagnosed with IDH1-mutant HGG treated with post-RT olutasidenib with temozolomide.

2. Evaluate Health-Related Quality of Life Outcomes (All Strata) (Time Frame - 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)):
Evaluate health-related quality of life outcomes of pediatric and young adult patients newly-diagnosed with IDH1-mutant HGG treated with post-RT olutasidenib by patient and/or parent reporting at key timepoints in therapy using the patient reported outcomes measurement information system (PROMIS) survey. These survey systems report scores on a scale of 1(minimum) to 5 (maximum). The scores may reflect frequencies from "1-Never" to "5-Always" or levels of autonomy from "1-With no trouble" to "5-Not able to do". Scores are interpreted differently for the different outcome measures

3. Evaluate Overall Survival in IDH1-mutant Grade 3 Astrocytoma (Stratum A) (Time Frame - From date of diagnosis until date of death due to any cause or date of last follow-up, assessed up to 60 months):
Determine distribution of OS in pediatric and young adult patients newly-diagnosed with IDH1-mutant Grade 3 Astrocytoma treated with post-RT olutasidenib and temozolomide for 13 cycles followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and matched historical controls.(Stratum A)

4. Assess Progression-Free Survival in IDH1-mutant Grade 4 Astrocytoma (Stratum B) (Time Frame - 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):
To assess the post-RT efficacy of olutasidenib in newly diagnosed patients with WHO Grade 4 IDH1-mutant Astrocytoma treated with maintenance olutasidenib and temozolomide for 13 cycles followed by 13 cycles of single agent olutasidenib compared to molecularly-stratified and matched historical controls

Studien-Arme

  • 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.

Geprüfte Regime

  • Olutasidenib + TMZ:
    Olutasidenib 150 mg PO BID + Temozolomide 200 mg/m2 PO QD

Quelle: ClinicalTrials.gov


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