Study of Ribociclib and Everolimus in HGG and DIPG
Study Details
Study Description
Brief Summary
The goal of this study is to determine the efficacy of the study drugs ribociclib and everolimus to treat pediatric and young adult patients newly diagnosed with a high-grade glioma (HGG), including DIPG, that have genetic changes in pathways (cell cycle, PI3K/mTOR) that these drugs target.
The main question the study aims to answer is whether the combination of ribociclib and everolimus can prolong the life of patients diagnosed with HGG, including DIPG.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
| Phase 2 |
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. Efficacy is 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).
Study Design
Arms and Interventions
| Arm | Intervention/Treatment |
|---|---|
| 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). |
Drug: Ribociclib
Ribociclib PO qd on days 1-21
Other Names:
Drug: Everolimus
Everolimus PO qd on days 1-28
Other Names:
|
| 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). |
Drug: Ribociclib
Ribociclib PO qd on days 1-21
Other Names:
Drug: Everolimus
Everolimus PO qd on days 1-28
Other Names:
|
| Experimental: Stratum C (n=6-12) Patients with primary thalamic, spinal cord, and/or secondary (radiation-related) HGG. |
Drug: Ribociclib
Ribociclib PO qd on days 1-21
Other Names:
Drug: Everolimus
Everolimus PO qd on days 1-28
Other Names:
|
| Experimental: Stratum D (n=6-12) Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received craniospinal irradiation. |
Drug: Ribociclib
Ribociclib PO qd on days 1-21
Other Names:
Drug: Everolimus
Everolimus PO qd on days 1-28
Other Names:
|
Outcome Measures
Primary Outcome Measures
- Progression-Free Survival (PFS) in HGG [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 (Stratum A) by estimating the distribution of PFS compared to molecularly-stratified and matched historical controls.
- Overall Survival (OS) in DIPG [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 (Stratum B) by estimating the distribution of OS compared to molecularly-stratified and matched historical controls.
- Establish MTD and RP2D of ribociclib and everolimus [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 (stratum D).
Secondary Outcome Measures
- Overall Survival in HGG [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.
- Objective Response Rate (ORR) in HGG [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.
- Objective Response Rate (ORR) in DIPG [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.
- Number of participants with ribociclib and everolimus-related adverse events as assessed by CTCAE v5.0 [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.
- Evaluate Health-Related Quality of Life Outcomes [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.
Eligibility Criteria
Criteria
TarGeT-A study strata definitions
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Stratum A: Patients with localized, intracranial, non-pontine, and non-thalamic HGG (who do not meet criteria for strata C-D)
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Stratum B: Patients with DIPG
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Stratum C: Patients with primary thalamic, spinal cord, and/or secondary/radiation-related HGG.
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Stratum D: Patients with metastatic/disseminated HGG, multifocal HGG, and/or gliomatosis cerebri who received CSI.
Inclusion Criteria:
- 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 ≤30 years of age at the time of enrollment on TarGeT-SCR
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 (e.g., diffuse astrocytoma, anaplastic astrocytoma, glioblastoma, H3K27-altered diffuse midline glioma).
-
For all other tumors, histologic grade must be WHO grade 3-4.
1.3) Disease status: There are no disease status requirements for enrollment
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Patients without measurable disease are eligible.
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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.
- Inclusion criteria for assignment to TarGeT-A, for all strata:
2.1) BSA ≥0.45m2 at the time of study entry.
2.2) Presence of at least one relevant actionable somatic alteration, detailed here:
-
Pathogenic alterations presumed to cause activation of cell cycle:
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Amplification of CDK4 or CDK6
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Deletion of CDKN2A, CDKN2B, or CDKN2C
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Amplification of CCND1 or CCND2
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Pathogenic alterations presumed to cause activation of the PI3K/mTOR pathway:
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Deletion or mutation of PTEN
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Mutation or amplification of PIK3CA
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Mutation of PIK3R1
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Patients with evidence of homozygous (biallelic) RB1 loss by sequencing are excluded from this treatment protocol (TarGeT-A).
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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.
2.3) 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.
2.4) 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.
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Patients must have received photon or proton RT.
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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.
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RT delivered via photon or proton beam, must have been administered to a dose of within 10% of standard dosing (54 Gy for DIPG, 59.4 Gy for other HGG, XX for primary spinal disease, and/or XX Gy craniospinal for patients with spinal or leptomeningeal metastatic disease).
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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.
2.5) Organ Function Requirements
2.5.1) Adequate Bone Marrow Function Defined as:
-
Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3
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Platelet count ≥ 100,000/mm3 (transfusion independent, defined as not receiving platelet transfusions for at least 7 days prior to enrollment)
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Hemoglobin >8 g/dL (may be transfused)
2.5.2) 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.
2.5.3) Adequate Liver Function Defined as:
-
Total bilirubin must be ≤ 1.5 times institutional upper limit of normal for age
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AST(SGOT)/ALT(SGPT) ≤ 3 times institutional upper limit of normal
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Serum albumin ≥ 2g/dL
2.5.4) Adequate Cardiac Function Defined as:
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Ejection fraction of ≥ 50% by echocardiogram
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QTc ≤ 450 msec
2.5.5) 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. (Patients receiving enzyme inducing anti-epileptic drugs that are known strong inducers or inhibitors of CYP3A4/5 are not eligible)
2.5.6) 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.
2.6) 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 for All Strata:
-
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 adequate contraceptive methods (hormonal or barrier method of birth control; abstinence) while being treated on this study and for 3 months after completing therapy.
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Concomitant Medications
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Patients receiving corticosteroids are eligible. The use of corticosteroids must be reported.
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Patients who are currently receiving another investigational drug are not eligible.
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Patients who are currently receiving other anti-cancer agents are not eligible, with the exception of temozolomide given concurrently with RT only.
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Patients who are receiving enzyme inducing anticonvulsants that are strong inducers or inhibitors of CYP3A4/5 are not eligible.
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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.
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Patients who are receiving medications known to prolong QTc interval are not eligible.
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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.
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Patients who have an uncontrolled infection are not eligible.
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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.
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Patients with known clinically significant active malabsorption syndrome or other condition that could affect absorption are not eligible.
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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.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Children's Hospital Colorado | Aurora | Colorado | United States | 80045 |
| 2 | Children's National Medical Center | Washington | District of Columbia | United States | 20010 |
| 3 | Ann & Robert H. Lurie Children's Hospital of Chicago | Chicago | Illinois | United States | 60611 |
| 4 | Dana-Farber Cancer Institute | Boston | Massachusetts | United States | 02215 |
| 5 | Duke University Health System | Durham | North Carolina | United States | 27708 |
| 6 | Cincinnati Children's Hospital Medical Center | Cincinnati | Ohio | United States | 45229 |
| 7 | Nationwide Children's Hospital | Columbus | Ohio | United States | 43235 |
| 8 | Children's Hospital of Philadelphia | Philadelphia | Pennsylvania | United States | 19104 |
| 9 | Texas Children's Hospital | Houston | Texas | United States | 77030 |
| 10 | Seattle Children's Hospital | Seattle | Washington | United States | 98105 |
| 11 | Sydney Children's Hospital | Randwick | New South Wales | Australia | 2031 |
| 12 | Queensland Children's Hospital | South Brisbane | Queensland | Australia | 4101 |
| 13 | Perth Children's Hospital | Perth | Western Australia | Australia | 6000 |
| 14 | The Hospital for Sick Children (SickKids) | Toronto | Ontario | Canada | M5G1X8 |
| 15 | Montreal Children's Hospital | Montréal | Quebec | Canada | H4A3J1 |
| 16 | Hopp Children's Cancer Center at NCT Heidelberg (KiTZ) | Heidelberg | Baden-Württemberg | Germany | 69120 |
| 17 | Princess Máxima Center | Utrecht | Netherlands | 3720 | |
| 18 | Great Ormond Street Hospital | London | United Kingdom | WC1N 3JH |
Sponsors and Collaborators
- Nationwide Children's Hospital
- Novartis
Investigators
- Study Chair: Margot Lazow, MD, Nationwide Children's Hospital
- Principal Investigator: Maryam Fouladi, MD, Nationwide Children's Hospital
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- TarGeT-A