pediatric cancer
Conditions
Interventions
Arm A. Ribociclib + Topotecan and Temozolomide
ARM C. AZD1775 + Carboplatin
ARM D. Olaparib + Irinotecan
ARM I: Enasidenib
ARM J: Lirilumab + Nivolumab
Sponsors
Institut Gustave Roussy
Eligibility
Age
2 Years to 99 Years
Inclusion criteria
Inclusion criteria: 1. Patients must be diagnosed with a haematologic or solid tumor malignancy that has progressed despite standard therapy, or for which no effective standard therapy exists. 2. Age 12 years of age) or Lansky Play score (for patients = 70%. Patients who are unable to walk because of paralysis or stable neurological disability, but who are up in a wheelchair, will be considered ambulatory for the purpose of assessing the performance score. 6. Life expectancy >= 3 months 7. Adequate organ function: Hematologic criteria (Leukemia patients are excluded from hematological criteria): - Peripheral absolute neutrophil count (ANC) >= 1000/µL (unsupported) - Platelet count >= 100,000/µL (unsupported) - Hemoglobin >= 8.0 g/dL (transfusion is allowed) Cardiac function: - Shortening fraction (SF) >29% (>35% for children =50% at baseline, as determined by echocardiography (mandatory only for patients who have received cardiotoxic therapy). - Absence of QTc prolongation (QTc > 450 msec on baseline ECG, using the Fridericia correction [QTcF formula]) or other clinically significant ventricular or atrial arrhythmia. Renal and hepatic function: - Serum creatinine <= 1.5 x upper limit of normal (ULN) for age - Total bilirubin <= 1.5 x ULN - Alanine aminotransferase (ALT)/serum glutamic pyruvic transaminase (SGPT) <= 2.5 x ULN; aspartate aminotransferase (AST)/serum glutamic oxaloacetic transaminase/SGOT <= 2.5 x ULN except in patients with documented tumor involvement of the liver who must have AST/SGOT and ALT/SGPT <= 5 x ULN. 8. Able to comply with scheduled follow-up and with management of toxicity. 9. Females of childbearing potential must have a negative serum or urine pregnancy test within 72 hours prior to initiation of treatment. Sexually active women of childbearing potential must agree to use acceptable and appropriate contraception during the study and for at least 6 months after the last study treatment administration. Sexually active males patients must agree to use condom during the study and for at least 6 months (7 months for arm J) after the last study treatment administration. Acceptable contraception is listed in Appendix 12. 10. For all oral medications patients must be able to comfortably swallow capsules (except for those for which an oral solution is available); nasogastric or gastrostomy feeding tube administration is allowed only if indicated. 11. Written informed consent from parents/legal representative, patient, and age-appropriate assent before any study-specific screening
Exclusion criteria
Exclusion criteria: 1. Patients with symptomatic central nervous system (CNS) metastases who are neurologically unstable or require increasing doses of corticosteroids or local CNS-directed therapy to control their CNS disease. Patients on stable doses of corticosteroids for at least 7 days prior to receiving study drug may be included. 2. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter drug absorption of oral drugs (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, or malabsorption syndrome). 3. Clinically significant, uncontrolled heart disease (including history of any cardiac arrhythmias, e.g., ventricular, supraventricular, nodal arrhythmias, or conduction abnormality, unstable ischemia, congestive heart failure within 12 months of screening) 4. Active viral hepatitis or known human immunodeficiency virus (HIV) infection or any other uncontrolled infection. 5. Presence of any >= CTCAE grade 2 treatment-related toxicity with the exception of alopecia, ototoxicity or peripheral neuropathy. 6. Systemic anticancer therapy within 21 days of the first study dose or 5 times its half-life, whichever is less. 7. Previous myeloablative therapy with autologous hematopoietic stem cell rescue within 8 weeks of the first study drug dose 8. Allogeneic stem cell transplant within 3 months prior to the first study drug dose. Patients receiving any agent to treat or prevent graft-versus host disease (GVHD) post bone marrow transplant are not eligible for this trial. 9. Radiotherapy (non-palliative) within 21 days prior to the first dose of drug (or within 6 weeks for therapeutic doses of MIBG or craniospinal irradiation). 10. Major surgery within 21 days of the first dose. Gastrostomy, ventriculo-peritoneal shunt, endoscopic ventriculostomy, tumor biopsy and insertion of central venous access devices are not considered major surgery, but for these procedures, a 48 hour interval must be maintained before the first dose of the investigational drug is administered. 11. Currently taking medications with a known risk of prolonging the QT interval or inducing Torsades de Pointes (Refer to Appendix 8). 12. Currently taking medications that are mainly metabolized by CYP3A4/5, CYP2C8, CYP2C9, CYP2C19, CYP2D6 or the drug transporters Pgp (MDR1), BCRP, OATP1B1, OATP1B3, OCT1 and OCT2 and have a low therapeutic index that cannot be discontinued at least 7 days or 5 x reported elimination half-life prior to start of treatment with any of the investigational drugs and for the duration of the study (Refer to Appendix 9). 13. Known hypersensitivity to any study drug or component of the formulation. 14. Pregnant or nursing (lactating) females. 15. Vaccinated with live, attenuated vaccines within 4 weeks of the first dose of study drug.
Design outcomes
Primary
| Measure | Time frame |
|---|---|
| Trial End-points 1. The recommended phase II dose (RP2D) will be defined as the adult recommended dose (adjusted for weight or BSA) if toxicity and PK profiling are similar in children and in adults, or a higher dose, providing it is below or equal to the maximum tolerated dose (MTD). 2. The maximum tolerate dose (MTD) will be defined as the dose associated with or closest to 25% of DLTs in cycle 1. 3. Dose Limiting Toxicities (DLT) will be defined using CTCAE v4.03. 4. Overall response rate (ORR); duration of response (DOR) will be defined as the time period between the first documented response (PR or CR) and the time of progression, according to RECIST v1.1, RANO criteria for patients with HGG, INRC criteria for patients with NB, etc. 5. Duration of response for patients free of progression at the cutoff date will be censored at the last Imaging response scan date; progression-free survival (PFS) will be defined as the time from treatment initiation until the date of first documented progression or death from any cause. Patients alive and free of progression at the cut-off date will be censored at the last assessment date. 6. Adverse events according to the NCI CTCAE V4.03 in all cycles of treatment. 7. PK parameters, including but not limited to plasma concentration time profiles, AUClast, AUCtau, Cmin, Cmax, Tmax, Clearance, Halflife time. 8. To explore relationship between the molecular profile of the tumor samples, circulating tumor DNA and tumor growth measured as modification of the sum of the diameters of the target lesions over time. | — |
Countries
Netherlands
Outcome results
None listed