Approval Probability 71%
TA Base Rate26%
Adjusted LOA41%
ML RiskLOW_RISK
| NCT ID | Title | Phase | Status | Enrollment | Velocity | Design | Start | Completion | Last Updated | Sites | Countries |
|---|---|---|---|---|---|---|---|---|---|---|---|
| NCT02114229 | Phase 2 Study of Alisertib Therapy for Rhabdoid Tumors | PHASE2 | ACTIVE NOT_RECRUITING | 125 | — | — | May 14, 2014 | Sep 1, 2027 | Mar 17, 2026 | 9 | United States |
Efficacy endpoint: Objective responses (partial response + complete response) that occur within the first 10 courses (approximately 30 weeks) of treatment which are sustained for an additional 2 courses (approximately 6 weeks) and/or 12-week disease stabilization as confirmed by MRI are considered a success in the statistical analysis of the efficacy endpoint.
Efficacy endpoint: Objective responses (partial response + complete response) that occur within the first 10 courses (approximately 30 weeks) of treatment which are sustained for an additional 2 courses (approximately 6 weeks) and/or 12-week disease stabilization as confirmed by MRI are considered a success in the statistical analysis of the efficacy endpoint.
Participants with AT/RT who are younger than 36 months of age at diagnosis with no metastatic disease treated with alisertib in sequence with induction and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up.
Participants with AT/RT who are younger than 36 months of age at diagnosis with metastatic disease treated with alisertib in sequence with induction and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up.
Participants with AT/RT who are 3 years of age or older at diagnosis with no metastatic disease and gross total resection or near total resection treated with alisertib in sequence with radiation therapy and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up.
Participants with AT/RT who are 3 years of age or older at diagnosis with metastatic or residual disease treated with alisertib in sequence with radiation therapy and consolidation chemotherapy will be included for this analysis. Progression free survival will be measured from the date of diagnosis to the earliest date of disease progression, death, second malignancy, or the date of last follow-up
Single dose pharmacokinetic studies will be performed on cycle 1 day 1 and serial plasma samples will be collected at: pre-dose and 0.5, 1, 1.5, 4, 6 (± 0.5), 24 (± 4), and 48 (± 6) hours after the first dose. Steady-state pharmacokinetic studies will be performed on cycle 1 day 7 and serial plasma samples will be collected at: pre-dose, and 1.5, 4, and 24 (±4) hours after the dose. The analysis for the pharmacokinetic primary objective of this study will be conducted using compartmental and noncompartmental approaches. The noncompartmental analysis will provide an estimate of the maximum concentration (Cmax), minimum concentration (Cmin), area under the concentration time curve (AUC), and apparent oral clearance (CL/F). Compartmental analysis will be performed using nonlinear mixed effects modeling and estimated pharmacokinetic parameters may include absorption rate constant (ka), apparent oral clearance (CL/F), and apparent volume of distribution (Vd/F).
| Arm | Type | Description |
|---|---|---|
| (A) Alisertib alone | EXPERIMENTAL | Stratum A: Patients with recurrent/progressive AT/RT or extra-CNS malignant rhabdoid tumors (MRT). Interventions: alisertib, 35 cycles of 3 weeks each (up to 105 weeks). Surgical resection, if indicated. |
| (B) Alisertib, chemotherapy, radiation therapy | EXPERIMENTAL | Stratum B: Children \< 36 months old with newly diagnosed AT/RT. AT/RT those with synchronous extraneural AT/RT (Stratum D1) may also be treated on this arm. Interventions: * B1 or D1: Induction chemotherapy using methotrexate, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by focal radiation therapy; followed by induction therapy using alisertib, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by maintenance alisertib. Those \<12 months who are not ready for focal radiation therapy will receive consolidation chemotherapy using alisertib, cyclophosphamide, carboplatin and etoposide while RT is delayed. Surgical resection, if indicated. * B2, B3, D2 or D3: Induction chemotherapy using alisertib, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by consolidation with topotecan and cyclophosphamide or optional craniospinal irradiation; followed by maintenance alisertib. Surgical resection, if indicated. |
| (C) Alisertib, chemotherapy, radiation therapy | EXPERIMENTAL | Stratum C: Children ≥36 months old with newly diagnosed AT/RT. Participants with synchronous extraneural AT/RT (Stratum D4) will also be treated as those assigned to Stratum C. Interventions: Craniospinal radiation therapy; followed by consolidation chemotherapy using alisertib, vincristine, cisplatin (or carboplatin), cyclophosphamide; followed by maintenance alisertib, surgical resection, if indicated. |
| Name | Type | Description |
|---|---|---|
| alisertib | DRUG | Alisertib will be administered orally at 80 mg/m\^2 per day for enteric coated tablet formulation and 60 mg/m\^2 per day for oral solution formulation. |
| methotrexate | DRUG | Methotrexate will be given at a dose of 5 g/m\^2/dose as an intravenous infusion over 24 hours on day 1 of each induction cycle except in patients ≤ 31 days of age at enrollment. These young infants will receive methotrexate at a reduced dose of 2.5g/m\^2/dose. |
| cisplatin | DRUG | Cisplatin will be given intravenously (IV): 75 mg/m\^2 IV infusion. |
| carboplatin | DRUG | Carboplatin may be substituted for cisplatin during induction for patients having Grade 4 ototoxicity or bi-lateral hearing loss after having prior cisplatin dose reduction. Route of administration is IV. |
| cyclophosphamide | DRUG | Cyclophosphamide will be given 1.5 g/m\^2 IV infusion during induction and consolidation. |
| etoposide | DRUG | Etoposide will be given 100 mg/m\^2 IV infusion. In case of etoposide reactions, etoposide phosphate will be given 40 mg/kg/day. |
| topotecan | DRUG | Topotecan will be administered by intravenous infusion over 4 hours on days 1-5 of each consolidation cycle for Stratum B2 and B3 patients not receiving craniospinal irradiation. The initial dose of Topotecan will be based on patient's age with subsequent doses adjusted, if necessary, to achieve a topotecan lactone area under the curve (AUC) of 140 ± 20 ng/mL\*hr. |
| vincristine | DRUG | Vincristine will be given 1 mg/m\^2 IV via 25 mL normal saline (NS) mini-bag (maximum 2 mg for all patients) or administration per local institutional standards for participating sites. |
| Surgical resection | PROCEDURE | For patients with localized AT/RT, gross total resection results in a significant survival benefit. Maximal resection that can be achieved without undue risk to the patient should be attempted prior to trial enrollment. Decisions about initial resectability will be at the discretion of the local neurosurgeon. In rare instances, the feasibility of completely resecting residual tumor may change as a result of induction chemotherapy; in these cases a "second-look" operation is encouraged if and may be performed prior to consolidation therapy. |
| Radiation therapy | RADIATION | The guidelines for this protocol were developed to maximize the curative potential of radiation therapy and minimize the risk of treatment complications for children with newly diagnosed CNS AT/RT. Focal irradiation is indicated for children \< 36 months with no evidence of metastatic disease. Craniospinal irradiation is indicated for children age \> 36 months. |
INCLUSION CRITERIA for Patients on All Strata EXCEPT Stratum P * Patients must be \< 22 years of age at time of diagnosis (e.g., eligible until 22nd birthday). * Histologic diagnosis of AT/RT or MRT as documented by the institutional pathologist with loss of INI1 or BRG1 expression in tumor cells c...