Study to assess safety and identify dose of ribociclib in combination of temozolomide and topotecan (TOTEM) in patients (12 months – 21 years old) with relapsed or refractory solid tumors (Phase I), and further assess efficacy and safety in patients (12 months – 21 years old) with relapsed or refractory neuroblastoma (Phase II)

Korábbi kezelés

• Received prior treatment with a CDK4/6 inhibitor
• Received anticancer therapy (including experimental) within 4 weeks
• Received myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks
• Received allogeneic stem cell transplant within 3 months
• Has radiation within 4 weeks (or 2 weeks if radiation therapy is given for palliation), or within 6 weeks of MIBG treatment
• Major surgery within 2 weeks and not recovered fully from the side effects
• Concurrent severe and/or uncontrolled concurrent medical conditions that in the Investigator's judgement could compromise their ability to tolerate or absorb protocol therapy or would interfere with the study procedures or results
• Currently taking medications that are known strong inducers or inhibitors of CYP3A4/5 cannot be discontinued at least 7 days or 5 halflives
• Currently taking medications that are mainly metabolized by CYP3A4/5 with a narrow therapeutic index that cannot be discontinued at least 7 days or 5 half-lives
• Vaccinated with live, attenuated vaccines within 4 weeks

Más betegség

• Known hypersensitivity to any of the excipients of ribociclib or topotecan or temozolomide.
• Clinically significant, uncontrolled heart disease and/or cardiac repolarization abnormality
• History of QTcF prolongation (i.e. QTcF interval of > 450 ms) or QTcF > 450 ms on screening ECG

Laborértékek

• Not recovered from clinical and laboratory acute toxicities related to prior anti-cancer therapies
• Currently taking medications with a known risk to prolong the QT interval or induce TdP that cannot be discontinued or replaced by safe alternative medication

Egyéb

• Participated in a investigational study within 30 days or 5 half-lives

• Signed informed consent/assent must be obtained prior to participation in the study. Participants and/or guardian must have the ability to understand and the willingness to sign a written informed consent document.
• Age ≥ 12 months and ≤ 21 years at the time of signing consent form.
• Histologically or cytologically confirmed solid tumors listed below that have progressed despite standard therapy or for which no effective standard therapy exists. a. Neuroblastoma (NB) (Phase I and Phase II) b. Medulloblastoma (MB) (Phase I) regardless of genetic status (i.e. Groups 3 or 4 WNT-activated or non-WNT, SHH-activated or non-SHH). c. High-grade glioma (HGG) (Phase I): Note: excluding any low grades (grade I or grade II) such as astrocytoma, oligodendroglioma, or mixed glioneuronal tumors d. Malignant rhabdoid tumor (MRT) (Phase I): includes diagnoses of atypical teratoid/rhabdoid tumor (AT/RT), and rhabdoid tumor of the kidney (RTK), and other soft tissues as defined by 2 of the 3 following criteria; either (i)+(ii) or (i)+(iii): e. Rhabdomyosarcoma (RMS) (Phase I) independent of fusion status and subtype.
• Participants with central nervous system (CNS) disease who are on corticosteroids should take stable doses for at least 7 days prior to first dose of ribociclib with no plans for escalation. Note: participants with symptomatic CNS disease who are neurologically unstable or require local CNS-directed therapy to control their CNS disease are not eligible for the study
• Measurable disease per Revised Assessment in Neuro-Oncology (RANO) criteria for participants with HGG and per Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 for MB, MRT and RMS.
• Performance status: participants who are unable to walk because of paralysis, but who are able to sit upright unassisted in a wheelchair, will be considered ambulatory for the purpose of assessing performance score
• Life expectancy of ≥ 12 weeks at the time of enrollment.
• Adequate bone marrow function (bone marrow may be involved with tumor) and organ function defined as: a. Peripheral absolute neutrophil count (ANC) ≥ 1000/mm3 without growth factor support within 7 days of the test b. Platelet count ≥ 75,000/mm3 without support within 7 days of the test c. Hemoglobin ≥ 8.0 g/dL (transfusion allowed) d. Total bilirubin ≤ 1.5 x ULN for age (in case of Gilbert's syndrome, ≤ 3.0 x ULN or direct bilirubin ≤ 1.5 x ULN for age) e. Adequate liver function, defined as total serum bilirubin ≤ 1.5 x ULN AND alanine aminotransferase (ALT) / aspartate aminotransferase (AST) ≤ 2.5 x ULN (in case of liver metastases, AST / ALT ≤ 5 x ULN) f. Adequate renal function, defined as serum creatinine ≤ 1.5 x ULN based on age/gender normal. In participants with serum creatinine > 1.5 x ULN for age/gender normal, a calculated glomerular filtration rate (GFR) must be ≥ 60 mL/min/1.73 m2. g. Adequate cardiac function, defined as corrected QTc interval using Fridericia's correction (QTcF) ≤ 450 ms and shortening fraction (SF) > 29% (> 35% for participants < 3 years) and left ventricular ejection fraction (LVEF) ≥ 50% on echocardiogram h. The following laboratory values within normal limits or corrected to within normal limits with supplements before first dose of study medication: Potassium; Magnesium; Total calcium (corrected for serum albumin)