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JOURNAL ONKOLOGIE – STUDIE

Study of Ribociclib and Everolimus in HGG and DIPG

Noch nicht rekrutierend

NCT-Nummer:
NCT05843253

Studienbeginn:
Juli 2024

Letztes Update:
08.08.2024

Wirkstoff:
Ribociclib, Everolimus

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

Geschlecht:
Alle

Altersgruppe:
Kinder (0-17)

Phase:
Phase 2

Sponsor:
Nationwide Children's Hospital

Collaborator:
Novartis

Studienleiter

Margot Lazow, MD
Study Chair
Nationwide Children's Hospital
Maryam Fouladi, MD
Principal Investigator
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)

combination of ribociclib and everolimus to treat pediatric, adolescent, and young adult

patients newly diagnosed with HGG and DIPG that harbor alterations of the cell cycle

and/or PI3K/mTOR pathways to assess treatment efficacy (Part 2). The study will include a

feasibility cohort (Part 1) to identify the dose of ribociclib PfOS (Powder for Oral

Suspension) that is safe and tolerable in combination with everolimus. Efficacy for Part

2 study will be defined by progression-free survival (PFS; HGG [stratum A]) and Overall

Survival (OS; DIPG [stratum B]), with key longitudinal biomarker correlatives. Outcomes

among patients with primary thalamic, spinal cord, and/or secondary (radiation related)

HGG (strata C) will be descriptively analyzed. Objective radiographic response rates and

agent-specific toxicities will also be assessed, with a feasibility cohort to determine

the recommended phase II dose (RP2D) of the combination of ribociclib and everolimus in

patients with metastatic disease who received upfront craniospinal irradiation (stratum

D).

Protocol therapy with the maintenance combination of ribociclib and everolimus must begin

no later than 35 calendar days post-completion of RT. The earliest patients can begin

protocol treatment is 28 calendar days post-completion of RT. Each cycle will be 28 days

in duration and treatment can continue up to a total of 26 cycles. Ribociclib will be

given orally once daily for 3 weeks (days 1-21), with one week off. Everolimus will be

given orally daily continuously (days 1-28).

Ein-/Ausschlusskriterien

TarGeT-A study strata definitions Part1: Initial Feasibility Study for the combination of

ribociclib PfOS formulation with everolimus: Enrollment on this cohort will be limited to

patients aged <21 years with primary intracranial localized HGG and DIPG

Part 2

- Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic HGG

(who do not meet criteria for strata C-D)

- Stratum B: Patients with DIPG

- Stratum C: Patients with primary thalamic, spinal cord, and/or

secondary/radiation-related HGG.

- Stratum D: Patients with metastatic/disseminated HGG, multifocal HGG, and/or

gliomatosis cerebri who received CSI.

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 months and ≤39 years of age at the time of enrollment

on TarGeT-SCR. For the Part 1 Initial Feasibility Cohort only: patients must be <21

years of age at the time of enrollment on this protocol.

1.2) Diagnosis: patients with newly-diagnosed 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, with histopathology,

consistent with diffuse WHO grade 2-4 glioma

- All other HGGs must be WHO grade 3 or 4.

1.3) Disease status: There are no disease status requirements for enrollment

- Patients without measurable disease are eligible.

- Patients with metastatic or multifocal disease or gliomatosis cerebri who

received upfront CSI are eligible

- Patients with a primary spinal HGG are eligible

- Patients with secondary, radiation-related HGG are eligible.

2. Inclusion criteria for assignment to TarGeT-A, for all strata:

2.1) Presence of at least one relevant actionable somatic alteration, detailed here:

- Pathogenic alterations presumed to cause activation of cell cycle:

- Amplification of CDK4 or CDK6

- Deletion of CDKN2A, CDKN2B, or CDKN2C

- Amplification of CCND1 or CCND2

- Pathogenic alterations presumed to cause activation of the PI3K/mTOR pathway:

- Deletion or mutation of PTEN

- Mutation or amplification of PIK3CA

- Mutation of PIK3R1

- Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded

from this treatment protocol (TarGeT-A).

- Patients whose tumors harbor other alterations suspected to activate the cell cycle

and/or PI3K/mTOR pathway could potentially also be eligible, but only following

consensus recommendation by the international multidisciplinary molecular screening

committee.

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

for patients ≤ 16 years of ag. 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 for HGG:

- Surgery, RT, dexamethasone are permissible. Temozolomide administered concurrently

with RT is permissible but discouraged. No other prior anticancer therapy for HGG

will be allowed.

- Patients must have received photon or proton 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 2 upfront

surgeries (e.g., biopsy then resection or debulking), this is the date of the second

surgery.

- 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), 45 Gy-50.4 Gy for primary spinal disease, and/or 36

Gy-39.6 Gy craniospinal for patients with spinal or leptomeningeal metastatic

disease with supplemental boost to 45-54 Gy for metastasis within the thecal sac and

54 Gy-60 Gy for intracranial metastasis). Any variances in the radiotherapy dose

within 10% of the standard doses outlined above will be discussed with the

Sponsor-Investigator to confirm eligibility prior to study enrollment.

- Patients must enroll and start treatment No later than 35 calendar days

post-completion of RT. The earliest patients can begin protocol treatment is 28

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 (Schwartz et al. J. Peds, 106:522, 1985)

age/gender as follows: 1 to < 2 years=0.6 mg/dL for males and females; 2 to < 6

years=0.8 mg/dL for males and females; 6 to < 10 years= 1.0 mg/dL for males and

females; 10 to < 13 years=1.2 mg/dL for males and females. 13 to < 16 years=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 times institutional upper limit of normal for age

- AST(SGOT)/ALT(SGPT) ≤ 3 times institutional upper limit of normal

- Serum albumin ≥ 2g/dL

2.4.4) Adequate Cardiac Function Defined as:

- Ejection fraction of ≥ 50% by echocardiogram

- QTc ≤ 450 msec (by Bazett formula)

2.4.5) Adequate Neurologic Function Defined as: Patients with seizure disorder may be

enrolled if well-controlled on anticonvulsants that are not strong inducers or inhibitors

of CYP3A4/5.

2.4.6) Adequate Pulmonary Function Defined as: No evidence of dyspnea at rest, and a

pulse oximetry >94% on room air if there is clinical indication for determination.

2.5) 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

2.6) Contraception: Male and female patients of childbearing potential must be willing to

use a highly effective contraception method.

Exclusion Criteria

1. Pregnant or Breast-Feeding Pregnant or breast-feeding women will not be entered on

this study due to known potential risks of fetal and teratogenic adverse events as

seen in animal/human studies. Pregnancy tests must be obtained in girls who are

post-menarchal. Patients of childbearing or child fathering potential must agree to

use at least 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 having 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. Concomitant Medications

- Patients receiving corticosteroids are eligible. The use of corticosteroids

must be reported.

- Patients who are currently receiving another investigational drug are not

eligible.

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

with the exception of temozolomide given concurrently with RT only.

- Patients who are receiving enzyme inducing anticonvulsants that are strong

inducers or inhibitors of CYP3A4/5 are not eligible.

- Patients who are receiving strong inducers or inhibitors of CYP3A4/5 are not

eligible and should be avoided from 14 days prior to enrollment to the end of

the study.

- Patients who are receiving medications known to prolong QTc interval are not

eligible.

- Patients who are receiving therapeutic anticoagulation with warfarin or other

coumadin-derived anticoagulants are not eligible. Therapy with heparin, low

molecular weight heparin (LMWH), or fondaparinux is allowed as long as the

patient has adequate coagulation defined as aPTT < 1.5Xs ULN and INR < 1.5.

3. Patients who have an uncontrolled infection are not eligible.

4. 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.

5. Patients with known clinically significant active malabsorption syndrome or other

condition that could affect absorption are not eligible.

6. Patients with prior or ongoing clinically significant 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.

Studien-Rationale

Primary outcome:

1. Progression-Free Survival (PFS) in HGG (Part 2, Stratum A) (Time Frame - From date on treatment until date of Progressive Disease or death due to any cause or date of last follow-up, assessed up to 60 months):
To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG by estimating the distribution of PFS compared to molecularly-stratified and matched historical controls.

2. Overall Survival (OS) in DIPG (Part 2, Stratum B) (Time Frame - From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months):
To assess the efficacy of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with DIPG by estimating the distribution of OS compared to molecularly-stratified and matched historical controls.

3. Establish MTD and RP2D of ribociclib and everolimus (Part 2, Stratum D) (Time Frame - Completion of Cycle 1 (28 days)):
To identify the Maximum Tolerated Dose (MTD) and Recommended Phase 2 Dose (RP2D) of the combination of ribociclib and everolimus given to patients with metastatic HGG who have received craniospinal irradiation CSI.

4. Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0 (Part 1- initial feasibility study) (Time Frame - Completion of Cycle 1 (28 days)):
Identify the safe dose of ribociclib powder for oral solution (PfOS) formulation in combination with everolimus that is feasible in pediatric patients with newly-diagnosed HGG, including DIPG, with cell cycle and/or PI3K/mTOR pathway alterations. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0 in the first 6-12 patients enrolled

Secondary outcome:

1. Overall Survival in HGG (Time Frame - From date on treatment until date of death due to any cause or date of last follow-up, assessed up to 60 months):
Determine distribution of OS for pediatric and young adult patients newly-diagnosed with HGG which harbor cell cycle and/or PI3K/mTOR pathway alterations treated with post-RT ribociclib and everolimus.

2. Objective Response Rate (ORR) in HGG (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 HGG treated with the combination of ribociclib and everolimus.

3. Objective Response Rate (ORR) in DIPG (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 DIPG treated with the combination of ribociclib and everolimus.

4. Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0 (Time Frame - From Day 1 of protocol treatment through 30 days following end of protocol treatment):
Assess and further characterize the safety and toxicity of post-RT combination of ribociclib and everolimus in pediatric and young adult patients newly diagnosed with HGG, including DIPG. This will be achieved by calculating the number of participants with, as well as frequency and severity of, ribociclib and everolimus-related Adverse Events as assessed by CTCAE v5.0.

5. Evaluate Health-Related Quality of Life Outcomes (Time Frame - At the end of Cycles 1, 3, 5, 7, 9, 11, 13, 15, 17, 19, 21, 23, 25 (each cycle is 28 days)):
Evaluate health-related quality of life outcomes of pediatric and young adult patients newly-diagnosed with HGG, including DIPG, treated with combination of ribociclib and everolimus, by patient and/or parent reporting at key timepoints in therapy using the patient reported outcomes measurement information system (PROMIS) survey.

Studien-Arme

  • Experimental: Stratum A (n=40)
    Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata B, C, or D).
  • Experimental: Stratum B (n=40)
    Patients with DIPG, defined as a tumor with pontine epicenter and diffuse involvement of at least 2/3 of the pons, with histopathology consistent with diffuse WHO grade 2-4 glioma (e.g., diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma).
  • Experimental: Stratum C (n=6-12)
    Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG.
  • Experimental: Stratum D (n=6-12)
    Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation.

Geprüfte Regime

  • Ribociclib (Kisqali):
    Ribociclib PO qd on days 1-21
  • Everolimus (Afinitor):
    Everolimus PO qd on days 1-28

Quelle: ClinicalTrials.gov


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