| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
Acute Lymphoblastic Leukemia (ALL) and Lymphoblastic Lymphoma
(LLy) |
|
| E.1.1.1 | Medical condition in easily understood language |
|
| E.1.1.2 | Therapeutic area | Diseases [C] - Cancer [C04] |
| MedDRA Classification |
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10000845 |
| E.1.2 | Term | Acute lymphoblastic leukemia |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 20.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065923 |
| E.1.2 | Term | Lymphoblastic lymphoma |
| E.1.2 | System Organ Class | 100000004864 |
|
| E.1.3 | Condition being studied is a rare disease | Yes |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| The phase 1 study is to determine the maximum tolerated dose (MTD) of the PO formulation, followed by a screening phase 2 study to investigate the efficacy of ixazomib in combination with chemotherapy in children with relapsed/refractory Acute lymphoblastic leukemia (ALL) and lymphoblastic lymphoma (LLy). |
|
| E.2.2 | Secondary objectives of the trial |
Describe toxicities occurring in patients receiving PO ixazomib with block 2 re-induction chemotherapy after achieving CR with PO ixazomib
+ VXLD. Assess the palatability and acceptability of the liquid oral ixazomib in children with multiply relapsed/refractory ALL or LLy. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
•Age ≤21 years of age at the time of enrollment.
Phase 1 - Initial enrollment will be restricted to patients < 18 years of age until 9 such patients are enrolled
Phase 2 - Initial enrollment will be restricted to patients < 18 years of age until 6 such patients are enrolled
•Diagnosis Patients must have a diagnosis of relapsed/refractory ALL or LLy with or without extramedullary disease (including CNS2 and CNS3). Patient with mixed phenotype ALL or mature B (Burkitt-like) leukemia are not eligible.
Patients with ALL must have ≥ 5% blasts by morphology.
Patients with LLy must have measurable disease documented by clinical, radiologic or histologic criteria
•Performance Level Karnofsky ≥ 50% for patients > 16 years of age and Lansky ≥ 50% for patients ≤ 16 years of age.
•Prior Therapy A. Prior therapeutic attempts
◦Phase 1 - Any patients with relapsed/refractory ALL or LLy
Phase 2 B-cell ALL/LLy: all patients must have failed two or more therapeutic attempts.
T-cell ALL/LLy: all patients must have failed one or more therapeutic attempts. B. Recent prior chemotherapy Patients must have fully recovered from the acute toxic effects of all prior chemotherapy, immunotherapy, or radiotherapy prior to entering this study.
◦Cytoreduction with hydroxyurea Hydroxyurea can be initiated and continued for up to 24 hours prior to the start of protocol therapy.
◦Patients who relapsed while they are receiving cytotoxic therapy, at least 14 days must have elapsed since the completion of the last dose
There is no waiting period for those relapsing on maintenance therapy.
Hematopoietic stem cell transplant: Patients who have experienced their relapse after a HSCT are eligible, provided they have no evidence of acute or chronic Graft-versus-Host Disease (GVHD), are not receiving GVHD prophylaxis or treatment, and are at least 90 days post-transplant at the time of enrollment.
Hematopoietic growth factors: It must have been at least 7 days since the completion of therapy with G-CSF or other growth factors. It must have been at least 14 days since the completion of therapy with pegfilgrastim (Neulasta®).
Biologic (anti-neoplastic agent): At least 7 days since the last dose of biologic agent. For agents that have known adverse events occurring beyond 7 days after administration, this period must be extended beyond the time during which adverse events are known to occur. The duration of this interval must be discussed with the study chair
1.Monoclonal antibodies: At least 3 half-lives of the antibody must have elapsed after the last dose of monoclonal antibody. (i.e., blinatumomab = 6 hours,44 inotuzumab = 37 days, rituximab = 66 days)
2.Immunotherapy: At least 30 days after the completion of any type of immunotherapy, e.g., tumor vaccines, CAR T cells.
XRT: Craniospinal XRT is prohibited during protocol therapy. No washout period is necessary for radiation given to any extramedullary site other than CNS; ≥90 days must have elapsed if prior total body irradiation (TBI) or craniospinal XRT.
Anthracyclines: Patients must have had a lifetime exposure of <400 mg/m2 of doxorubicin equivalents of anthracyclines.
Proteasome inhibitors: Patients with a prior exposure to proteasome inhibitors (e.g., bortezomib, carfilzomib) are eligible as long as the patient demonstrated at least a partial response to a proteasome inhibitor with chemotherapy combination.
-Renal and hepatic function
Patients must have adequate renal and hepatic functions as indicated by the following laboratory values:
A. Adequate renal function defined as: Patient must have a calculated creatinine clearance or radioisotope GFR 70ml/min/1.73m2 OR a normal serum creatinine based on age/gender
B. Adequate Liver Function Defined as: Direct bilirubin ≤ 1.5 x upper limit of normal (ULN) for age or normal (except in the presence of Gilbert's syndrome), AND alanine transaminase (ALT) ≤ 5 x ULN for age. The hepatic requirements are waived for patients with known or suspected liver involvement by leukemia or lymphoma. This must be reviewed by and approved by the study chair or vice chair.
•Adequate Cardiac Function Defined as: Shortening fraction of more than or equal to 27% by echocardiogram, OR ejection fraction of equal to or more than 50% by radionuclide angiogram (MUGA).
•Reproductive Function A. Female patients of childbearing potential must have a negative urine or serum pregnancy test confirmed within 2 weeks prior to enrollment.
B. Female patients with infants must agree not to breastfeed their infants while on this study.
C. Male and female patients of child-bearing potential must agree to use an effective method of contraception during the study and for a minimum of 6 months after study treatment.
•Informed Consent Patients and/or their parents or legal guardians must be capable of understanding the investigational nature, potential risks and benefits of the study.
•All institutional, FDA, and OHRP requirements for human studies must be met. |
|
| E.4 | Principal exclusion criteria |
Patients will be excluded if they have isolated CNS or testicular disease.
Patients will be excluded if they have ≥grade 2 peripheral sensory or motor neuropathy (defined by the Modified "Balis" Pediatric Scale of Pediatric Neuropathies) at the time of enrollment (see section 4.7.1.1).
Patients will be excluded if they have a known allergy or intolerance to any of the drugs used in the study - except for PEG-asparaginase for which erwinia asparaginase may be substituted
Patients will be excluded if they have a systemic fungal, bacterial, viral or other infection that is exhibiting ongoing signs/symptoms related to the infection without improvement despite appropriate antibiotics or other treatment. The patient needs to be off pressors and have negative blood cultures for 48 hours.
Patients will be excluded if there is a plan to administer non-protocol chemotherapy, radiation therapy, or immunotherapy during the study period.
Patients will be excluded if they have significant concurrent disease, illness, psychiatric disorder or social issue that would compromise patient safety or compliance with the protocol treatment or procedures, interfere with consent, study participation, follow up, or interpretation of study results.
Patients with DNA fragility syndromes (such as Fanconi anemia, Bloom syndrome) are excluded.
Patients will be excluded if they have had a lifetime exposure of ≥400 mg/m2 doxorubicin equivolents of anthracyclines (anthracycline equivalence to doxorubicin conversion see appendix iv) .
Concomitant medications Investigational drugs: Patients currently receiving another investigational drug are not eligible.
Anti-GVHD agents post transplant: patients who are receiving cyclosporine, tacrolimus or other agents to prevent graft-versus-host disease post hematopoetic stem cell transplant are not eligible.
CYP3A4 agents: patients who are currently receiving drugs that are strong inducers of CYP3A4 are not eligible. Strong inducers of CYP3A4 should be avoided from 14 days prior to enrollment to the end of the study. See appendix ii for a list of agents which fall into this category.
Patients with Ph+ALL and Ph-like ALL who are currently receiving TKI therapy
Infants or Patients with Down Syndrome will be excluded in phase 2 of the study
|
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
o Phase 1: Dose limiting toxicity (DLT) during block 1 of chemotherapy
o Phase 1: PK parameters of ixazomib during block 1 of chemotherapy
o Phase 1: CTCAE toxicities during block 1 of chemotherapy
o Phase 2: Response (CR and CR+CRp) after block 1 chemotherapy |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Disease evaluation end block 1
+A bone marrow aspiration (biopsy is optional) and CT and PET (lymphoma patients only) to assess remission status should be performed >day 29.
+The bone marrow evaluation may be delayed no later than day 36 (±1 day) if ANC < 0.5 x 10x9/L and platelet < 50 x 10x9/L on day 29.
+If the marrow is hypoplastic and/or there is little or no evidence of normal hematopoiesis, a repeat marrow should be performed after every 7-21 days (based upon peripheral blood count recovery and the
clinician's judgment) and remission status assessed at this later time point.
+For lymphoma patients, if the bone marrow was M1 marrow with negative MRD at the beginning of the block 1, repeat bone marrow aspiration/biopsy is not necessary. |
|
| E.5.2 | Secondary end point(s) |
o CTCAE toxicities during block 2 chemotherapy
o Palatibility study of ixazomib |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Disease evaluation end block 2 (only applies to leukemia patients not in MRD negative CR, or lymphoma patients not in CR)
+A bone marrow aspiration (biopsy is optional) and CT and PET (lymphoma patients only) to assess remission status should be performed no earlier than day 29 (± 3 days). Gallium scan may be substituted for PET scan at sites where PET is not available. PET without CT should not be used as a substitute for CT with contrast. Combined PET/CT is acceptable.
+The evaluation may be delayed no later than day 36 (± 1 day) if ANC < 0.5 x 109/L and platelet < 50 x 109/L on day 29. |
|
| E.6 and E.7 Scope of the trial |
| E.6 | Scope of the trial |
| E.6.1 | Diagnosis | No |
| E.6.2 | Prophylaxis | No |
| E.6.3 | Therapy | Yes |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | Yes |
| E.6.8 | Bioequivalence | No |
| E.6.9 | Dose response | No |
| E.6.10 | Pharmacogenetic | No |
| E.6.11 | Pharmacogenomic | No |
| E.6.12 | Pharmacoeconomic | No |
| E.6.13 | Others | No |
| E.7 | Trial type and phase |
| E.7.1 | Human pharmacology (Phase I) | Yes |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | Yes |
| E.7.1.3.1 | Other trial type description |
|
| E.7.2 | Therapeutic exploratory (Phase II) | Yes |
| E.7.3 | Therapeutic confirmatory (Phase III) | No |
| E.7.4 | Therapeutic use (Phase IV) | No |
| E.8 Design of the trial |
| E.8.1 | Controlled | No |
| E.8.1.1 | Randomised | No |
| E.8.1.2 | Open | Yes |
| E.8.1.3 | Single blind | No |
| E.8.1.4 | Double blind | No |
| E.8.1.5 | Parallel group | No |
| E.8.1.6 | Cross over | No |
| E.8.1.7 | Other | No |
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | No |
| E.8.2.2 | Placebo | No |
| E.8.2.3 | Other | No |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| E.8.3 |
Will this trial be conducted at a single site globally?
| Yes |
| E.8.4 | Will this trial be conducted at multiple sites globally? | No |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.2 | Trial being conducted completely outside of the EEA | Yes |
| E.8.6.3 | Specify the countries outside of the EEA in which trial sites are planned |
|
| E.8.7 | Trial has a data monitoring committee | Yes |
| E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
|
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 5 |
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