Ribociclib and Everolimus in Treating Children With Recurrent or Refractory Malignant Brain Tumors

NCT03387020 | Completed Phase 1 Results DMC FDA Drug

• 3 other identifiers: PBTC-050NCI-2017-02079UM1CA081457
• Study Type: interventional
• Target: 22
• Locations: 1 country
• Sites: 12

Brief Summary

This phase I trial studies the side effects and best dose of ribociclib and everolimus and to see how well they work in treating patients with malignant brain tumors that have come back or do not respond to treatment. Ribociclib may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth. Drugs used in chemotherapy, such as everolimus, work in different ways to stop the growth of tumor cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving ribociclib and everolimus may work better at treating malignant brain tumors.

Conditions

CNS Embryonal Tumor, Not Otherwise Specified; Malignant Glioma; Recurrent Atypical Teratoid/Rhabdoid Tumor; Recurrent Childhood Ependymoma; Recurrent Diffuse Intrinsic Pontine Glioma; Recurrent Medulloblastoma; Refractory Diffuse Intrinsic Pontine Glioma

Outcome Measures

Primary Outcomes (2)

• Maximum Tolerated Dose of Ribociclib and Everolimus

  Defined as the highest dose level at which six patients have been treated with at most one patient experiencing a dose limiting toxicity (DLT) and the next higher dose level has been determined to be too toxic. Will be estimated using a Rolling-6 phase I design. Only patients who are evaluable for DLT will be consider for estimating of Maximum Tolerated Dose. Patient who were enrolled under Surgical cohort but received sufficient study defined treatment would also be evaluable for DLT.

  4 weeks

• Average Tumor and Plasma Concentrations of Ribociclib for the Surgical Study

  Average tumor Ribociclib concentrations will be compared to plasma concentrations. The mean tumor-to-plasma ratio of Ribociclib at the time of surgery will be described.

  Surgical study: Prior to starting ribociclib (day -7 or -10), prior to ribociclib dose on days -5 & -2, day 0, and at the time of surgery

Secondary Outcomes (2)

• Objective Responses (Complete Response + Partial Response)

  Up to 2 years

• Percent Change in ki67 Between Archival and Post-treatment Tissue

  Up to 2 years

Other Outcomes (4)

• Ribociclib AUC (Area Under the Plasma Concentration Versus Time Curve) as Obtained From the Patients Who Received Phase I Defined Treatment

  Pre-dose, 1, 2, 4, 8, 24, 32 (day 1 course 1 only), & 48 (day 1 course 1 only) hours after dose on days 1 and 17 of course 1.

• Everolimus AUC (Area Under the Plasma Concentration Versus Time Curve) as Obtained From the Phase I Study

  Pre-dose, 0.5 (course 2 only), 1, 1.5 (course 2 only), 2, 4, 6 (course 2 only), 8, 24 hours after dose on day 17 of course 1, and day 1 of course 2.

• Ribociclib Half-Life as Obtained From the Phase 1 Study

  Pre-dose, 1, 2, 4, 8, 24, 32 (day 1 course 1 only), & 48 (day 1 course 1 only) hours after dose on days 1 and 17 of course 1.

Study Arms (1)

Treatment (ribociclib, everolimus)

EXPERIMENTAL

Patients receive ribociclib PO QD on days 1-21 of course 1 and subsequent courses and days 2-21 of course 2, and everolimus PO QD on days 3-28 of course 1 and days 1-28 of subsequent courses. Patients who are undergoing surgery also receive ribociclib PO QD on days 7-10 before surgery. Treatment repeats every 28 days for up to 13 courses in the absence of disease progression or unacceptable toxicity. Patients with stable disease after 13 courses may continue receiving ribociclib and everolimus every 28 days for up to 13 additional courses in the absence of disease progression or unacceptable toxicity.

Drug: Everolimus; Other: Laboratory Biomarker Analysis; Other: Pharmacological Study; Drug: Ribociclib

Interventions

Everolimus DRUG

Given PO

Also known as: 42-O-(2-Hydroxy)ethyl Rapamycin, Afinitor, Certican, RAD 001, RAD001, Votubia, Zortress

Treatment (ribociclib, everolimus)

Laboratory Biomarker Analysis OTHER

Correlative studies

Treatment (ribociclib, everolimus)

Pharmacological Study OTHER

Correlative studies

Treatment (ribociclib, everolimus)

Ribociclib DRUG

Given PO

Also known as: Kisqali, LEE-011, LEE011

Treatment (ribociclib, everolimus)

Eligibility Criteria

• Age: 1 Year - 21 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• ELIGIBILITY FOR SCREENING
• Patients with a histologically confirmed diagnosis of high-grade glioma (HGG), medulloblastoma, CNS embryonal tumor (not otherwise specified \[NOS\]), ependymoma, or atypical teratoid rhabdoid tumor (ATRT) that is recurrent, progressive or refractory
• Patients with recurrent diffuse intrinsic pontine glioma (DIPG) with typical radiographic appearance who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma World Health Organization (WHO) II-IV; Rb1 screening for these patients is required only if adequate tissue is available
• Patients with recurrent brainstem tumors with an atypical presentation who have undergone biopsy are eligible provided there is histologic confirmation of malignant glioma WHO II-IV; these patients must undergo Rb1 screening; these patients must have radiographic evidence of progression
• Patients with secondary malignant gliomas will be eligible for this study but should conform to all other eligibility requirements; patients with low-grade gliomas are excluded
• Formalin fixed paraffin embedded tumor tissue (preferably from the most recent recurrence) must be available to assess Rb1 protein status prior to enrollment on phase I or surgical study; if the subject has results from prior Rb1 IHC testing in a Clinical Laboratory Improvement Act (CLIA)-certified laboratory the requirement for screening to assess Rb1 protein status is waived
• Patients with recurrent diffuse intrinsic brain stem glioma (DIPG) that has an atypical presentation must also submit the tumor tissue for Rb1 protein status confirmation or provide previous testing results from a CLIA certified laboratory; patients who have been biopsied for atypical DIPG but do not have sufficient tissue for Rb1 screening are not eligible
• Body surface area (BSA)
• Patients enrolled on dose level -1 must have BSA \>= 0.55m\^2
• Patients enrolled on dose level -0.5 must have BSA \>= 0.75m\^2
• Patients enrolled on dose level 0 must have BSA \>= 0.55m\^2
• Patients enrolled on dose level 1 must have BSA \>= 0.75m\^2
• Patients enrolled on dose level 2 and 3 must have BSA \>= 0.45m\^2
• Patients who are candidates for enrollment for the phase I or surgical studies must sign a screening consent and provide pre-trial tumor material for Rb1 testing unless testing is not needed due to diagnosis or the availability of prior Rb1 IHC results; the screening consent is to be obtained according to institutional guidelines
• Patients screened for this trial should be expected to meet the criteria for treatment

You may not qualify if:

• Patients who are otherwise deemed clinically unsuitable for surgical resection (applicable for surgical study only)
• Patients who are breast feeding
• Patients with any clinically significant unrelated systemic illness (serious infections or significant cardiac, pulmonary, hepatic or other organ dysfunction), that would compromise the patient?s ability to tolerate protocol therapy, put them at additional risk for toxicity or would interfere with the study procedures or results
• Patients who are receiving any other anticancer or investigational or/and anti-neoplastic therapies, including chemotherapy, immunotherapy, target therapy, biological response modifiers
• Previous treatment with CDK4/6 inhibitors (such as PD-0332991, abemaciclib) and/or mTOR inhibitors (such as sirolimus, temsirolimus or everolimus)
• Patients who are currently receiving treatment with agents that are known to cause corrected QT (QTc) prolongation or induce Torsades de Pointes
• Known need for major surgery within 14 days of the first dose of ribociclib and everolimus; please note: gastrostomy, insertion of a gastrostomy (G) tube, ventriculo-peritoneal shunt, endoscopic ventriculostomy and central venous access are NOT considered major surgery
• Patient is currently receiving any of the following medications and cannot be discontinued 7 days prior to enrollment:
• Known strong and moderate inducers or inhibitors of CYP3A4/5, including enzyme inducing anti-convulsant drugs (EIACDs), grapefruit, grapefruit hybrids, pummelos, star-fruit, and Seville oranges
• Substrates of CYP3A4/5 with a narrow therapeutic index
• Herbal preparations/medications (except for vitamins) including, but not limited to: St. John?s wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, black cohosh and ginseng; patients should stop using all herbal medications and dietary supplements at least 7 days prior to enrollment
• Clinically significant active cardiac disease, uncontrolled heart disease and/or a history of cardiac dysfunction including any of the following:
• History of acute coronary syndromes (including myocardial infarction, unstable angina, coronary artery bypass grafting, coronary angioplasty, or stenting) or symptomatic pericarditis within 12 months prior to screening
• History of documented congestive heart failure (New York Heart Association functional classification III-IV)
• Documented cardiomyopathy

Sponsors & Collaborators

• Pediatric Brain Tumor Consortium: lead
• National Cancer Institute (NCI): collaborator

Study Sites (12)

Children's Hospital Los Angeles

Los Angeles, California, 90026, United States

Location

Lucile Packard Children Hospital Stanford University

Palo Alto, California, 94304, United States

Location

Children's Hospital Colorado

Aurora, Colorado, 80045, United States

Location

Children's National Medical Center

Washington D.C., District of Columbia, 20010, United States

Location

Children's Healthcare of Atlanta

Atlanta, Georgia, 30322, United States

Location

National Cancer Institute Pediatric Oncology Branch

Bethesda, Maryland, 20892, United States

Location

Memorial Sloan Kettering Cancer Center

New York, New York, 10065, United States

Location

Cincinnati Children Hospital Medical Center

Cincinnati, Ohio, 45229, United States

Location

Children Hospital of Pittsburgh of UPMC

Pittsburgh, Pennsylvania, 15224, United States

Location

Pediatric Brain Tumor Consortium

Memphis, Tennessee, 38105, United States

Location

St. Jude Children Research Hospital

Memphis, Tennessee, 38105, United States

Location

Texas Children's Cancer Center

Houston, Texas, 77030, United States

Location

MeSH Terms

Conditions

Glioma; Rhabdoid Tumor; Familial ependymoma; Diffuse Intrinsic Pontine Glioma; Medulloblastoma

Interventions

Everolimus; ribociclib

Condition Hierarchy (Ancestors)

Neoplasms, Neuroepithelial; Neuroectodermal Tumors; Neoplasms, Germ Cell and Embryonal; Neoplasms by Histologic Type; Neoplasms; Neoplasms, Glandular and Epithelial; Neoplasms, Nerve Tissue; Neoplasms, Complex and Mixed; Brain Stem Neoplasms; Infratentorial Neoplasms; Brain Neoplasms; Central Nervous System Neoplasms; Nervous System Neoplasms; Neoplasms by Site; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Neuroectodermal Tumors, Primitive

Intervention Hierarchy (Ancestors)

Sirolimus; Macrolides; Lactones; Organic Chemicals

Results Point of Contact

• Title: Dr. Arzu Onar-Thomas
• Organization: St. Jude Children's Research Hospital

arzu.onar@stjude.org

901-595-5499

Study Officials

• Mariko D. DeWire-Schottmiller, MD

  Pediatric Brain Tumor Consortium

  PRINCIPAL INVESTIGATOR

Publication Agreements

• PI is Sponsor Employee: No
• Restriction Type: OTHER
• Restrictive Agreement: Yes

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: NETWORK
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: December 5, 2017
• First Posted: December 29, 2017
• Study Start: January 13, 2018
• Primary Completion: April 1, 2020
• Study Completion: April 1, 2020
• Last Updated: August 27, 2021
• Results First Posted: August 27, 2021

Record last verified: 2021-08

Locations

US (12)