| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| recurrent/refractory Ewing sarcoma |
|
| E.1.1.1 | Medical condition in easily understood language |
| recurrent/refractory Ewing sarcoma |
|
| 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 | PT |
| E.1.2 | Classification code | 10015560 |
| E.1.2 | Term | Ewing's sarcoma |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
|
| E.1.3 | Condition being studied is a rare disease | No |
| E.2 Objective of the trial |
| E.2.1 | Main objective of the trial |
| - To compare the efficacy of palbociclib in combination with TMZ and IRN vs TMZ and IRN chemotherapy alone in the treatment of children, adolescents, and young adults with recurrent or refractory EWS. |
|
| E.2.2 | Secondary objectives of the trial |
- To further compare the efficacy of palbociclib in combination with TMZ and IRN vs TMZ and IRN chemotherapy alone.
- To characterize the toxicity and safety of the combination of TMZ and IRN plus or minus palbociclib.
- To describe the PK of palbociclib, TMZ, and IRN in children, adolescents, and young adults with recurrent or refractory EWS when given in combination.
- To assess the impact of the combination of palbociclib with TMZ and IRN treatment on the quality of life (QoL) of patients with
refractory and recurrent EWS. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
Patients must meet all the following inclusion criteria to be eligible for enrollment in the study:
1. Histologically confirmed relapsed or refractory solid tumor as follows:
•For dose escalation and dose determination parts: Histologically confirmed relapsed or refractory solid tumor (including CNS tumors but not lymphomas). Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
•For dose expansion cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
•For tumor-specific cohorts: Histologically confirmed relapsed or refractory solid tumor including but not limited to EWS, rhabdoid tumor, rhabdomyosarcoma, neuroblastoma, and medulloblastoma. Patients with Diffuse Intrinsic Pontine Glioma do not require histological only radiographic confirmed relapse to enroll.
• For randomized Phase 2 part: Histologically confirmed Ewing sarcoma at diagnosis or at relapse, with presence of EWSR1-ETS or FUS-ETS rearrangement. Histopathology confirmation of both EWSR1-ETS or FUSETS rearrangement partners is required OR availability of formalin fixed paraffin embedded (FFPE) tumor tissue sample for central testing. Patient must have relapsed or have refractory disease and at least evaluable disease in at least one site other than bone marrow that can be followed by imaging.
2. Age ≥2 and <21 years at the time of study entry. Refer to Section 4.3 for reproductive criteria for male and female participants.
3. Lansky performance status ≥50% for patients ≤16 years of age, or Eastern Cooperative Oncology Group (ECOG) 0, 1 or 2 for patients >16 years of age.
4. Adequate bone marrow function.
•Absolute neutrophil count ≥1000/mm3;
•Platelet count ≥75,000/mm3 (transfusion independent, no platelet transfusion in
past 7 days prior study entry);
• Hemoglobin ≥8.5 g/dL (transfusion allowed).
5. Adequate renal function: Serum creatinine level based on age/gender must be less than or equal to the following maximum upper limits as shown in Table 10:
Table 10. Maximum Allowed Creatinine Levels
Age Maximum Serum Creatinine (mg/dL)
Male Female
2 to <6 years 0.8 0.8
6 to <10 years 1.0 1.0
10 to <13 years 1.2 1.2
13 to <16 years 1.5 1.4
16 to <21 years 1.7 1.4
The threshold creatinine values in this table were derived from the Schwartz formula for estimating glomerular filtration rate utilizing child length and stature data published by the CDC.
6. Adequate liver function, including:
•Aspartate aminotransferase (AST) and alanine aminotransferase (ALT) ≤2.5 × upper limit of normal (ULN) or ≤5 × ULN for age, if attributable to disease involvement of the liver;
•Total bilirubin ≤1.5 × ULN for age unless the patient has documented Gilbert’s syndrome. Patients with documented Gilbert’s syndrome are eligible if direct bilirubin is within normal ranges (≤ULN).
7. Patients enrolled to Phase 1 portion of the study and tumor specific cohorts must have measurable disease as defined by RECIST version 1.1 or modified RANO criteria for CNS disease or at least evaluable disease by INRC for neuroblastoma.
The eligible patients with neuroblastoma must have at least one of the following at the time of study entry:
•Measurable tumor by CT or MRI that is avid on MIBG scan or demonstrates increased FDG uptake on PET scan;
•Avid lesion on MIBG scan with positive uptake at a minimum of one site;
•For disease that is not avid by MIBG-scan, at least one lesion that demonstrates increased FDG uptake on PET scan AND viable neuroblastoma confirmed by current or prior biopsy;
•bone marrow involvement with more than 5% neuroblastoma cells in at least one sample from bilateral bone marrow biopsies;
•In non MIBG-avid refractory soft tissue disease that does not demonstrate increased FDG uptake; lesion biopsy is required to document the presence of viable neuroblastoma, unless patient has a new soft tissue lesion (radiographic
evidence of disease progression). Patients with EWS enrolled to Phase 2 portion of the study are eligible with at least evaluable disease (eg, bone only disease with no soft tissue component).
8. Recovered to CTCAE Grade ≤1, or to baseline, from any non-hematological acute toxicities of prior surgery, chemotherapy, immunotherapy, radiotherapy, differentiation therapy or biologic therapy, with the exception of alopecia.
9. Serum/urine pregnancy test (for all girls ≥8 years of age) negative at screening and at the baseline visit. |
|
| E.4 | Principal exclusion criteria |
Patients with any of the following characteristics/conditions will not be included in the study:
1. Phase 1 portion and tumor specific cohorts: For palbociclib with IRN and TMZ combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing regimen that includes TMZ. Patients who have
received the combination of IRN and TMZ and did not progress while on these medications are eligible. For patients enrolling in the palbociclib with TOPO and CTX combination, prior treatment with a CDK4/6 inhibitor or progression while on treatment with a TOPO-containing regimen that includes CTX. Patients who have received the combination of TOPO and CTX and did not progress while on thesemedications are eligible. Phase 2 portion: prior treatment with a CDK4/6 inhibitor or progression while on treatment with an IRN-containing or TMZ-containing regimen. Patients who have received IRN and/or TMZ and did not progress while on these medications are eligible.
2. Prior intolerability to IRN and/or TMZ for IRN and TMZ plus/minus palbociclib combinations and prior intolerability to TOPO and/or CTX for TOPO and CTX combination. For patients enrolled in the UK, any contraindication for IRN and/or TMZ treatment, as per the local SmPC.
3. Use of strong cytochrome P450 (CYP) 3A inhibitors or inducers within 12 days of study entry. Patients who are receiving strong uridine diphosphate-glucuronosyl transferase 1A1 (UGT1A1) inhibitors within 12 days of C1D1 are not eligible for the palbociclib with IRN and TMZ combination. Patients who are receiving strong UGT1A1 inhibitors within 12 days of C1D1 are eligible for the palbociclib with TOPO and CTX combination
4. Systemic anticancer therapy within 2 weeks prior to study entry and 6 weeks for nitrosoureas.
5. Prior irradiation to >50% of the bone marrow
6. Participation in other studies involving investigational drug(s) within 2 weeks or 5 halflives, whichever is longer, prior to study entry
7. Major surgery within 4 weeks prior to study entry. Surgical biopsies or central line placement are not considered major surgeries.
8. For IRN and TMZ with/without palbociclib combinations: known or suspected hypersensitivity to palbociclib, dacarbazine, IRN and/or TMZ. For combination of palbociclib with TOPO and CTX: known or suspected hypersensitivity to palbociclib, TOPO and/or CTX.
9. Patients with known symptomatic brain tumors or brain metastases and require steroids, unless they have been on a stable or on a decreasing steroid dose for >14 days.
10. Patients with previously diagnosed brain metastases are eligible if they have completed their prior treatment and have recovered from the acute effects of radiation therapy or surgery prior to study entry for these metastases for at least 14 days postradiation and 4 weeks post-surgery and are neurologically stable.
11. Hereditary bone marrow failure disorder.
12. QTc >470 msec.
13. History of clinically significant or uncontrolled cardiac disease, including:
History of or active congestive heart failure; if patient had congestive heart failure
resolve and >1 year from resolution, patient will be considered eligible;
•Clinically significant ventricular arrhythmia (such as ventricular tachycardia,
ventricular fibrillation or Torsades de Pointes);
•Diagnosed or suspected congenital or acquired prolonged QT syndrome;
•Need for medications known to prolong the QT interval;
•Uncorrected hypomagnesemia or hypokalemia because of potential effects on the QT interval;
•Left ventricular ejection fraction <50% or shortening fraction <28%.
14. Recent or ongoing clinically significant gastrointestinal disorder that may interfere with absorption of orally administered drugs (eg, gastrectomy).
15. Evidence of serious active or uncontrolled bacterial, fungal or viral infection or known history of hepatitis B virus, hepatitis C virus, or human immunodeficiency virus infection or acquired immunodeficiency syndrome-related illness. Screening for viral hepatitis and HIV is under discretion of investigator unless required by local regulation.
16. Severe acute or chronic medical or laboratory test abnormality that may increase the risk associated with study participation or investigational product administration or may interfere with the interpretation of study results, and in the judgment of the Investigator, would make the patient inappropriate for entry into this study.
17. Investigator site staff members directly involved in the conduct of the study and their family members, site staff members otherwise supervised by the investigator, or patients who are Pfizer employees, including their family members, directly involved in the conduct of the study.
18. Fertile male patients or female patients of childbearing potential who are unwilling or unable to follow contraceptive requirements as detailed in Section 4.3.
19. Pregnant or breastfeeding women. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
| • Event-free survival (EFS) based on investigator assessment. |
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
| time from randomization until first event (ie, progression, recurrence following response, second malignancy or death without progression or recurrence). |
|
| E.5.2 | Secondary end point(s) |
• Event-free survival (EFS) assessed by an independent review committee.
• Objective response (OR), as assessed by investigator using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1.
• PET-CT response after cycle 4 compared to objective response on MRI/CT.
• Progression free survival (PFS) based on investigator assessment.
• Overall survival (OS).
• Adverse Events (AEs) as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse events (CTCAE) version 4.03.
• Pharmacokinetic parameters of palbociclib, TMZ, IRN:
• Palbociclib PK: MD (assuming steady state is achieved) - Css,max, Tmax, AUCss,, Css,trough, and CL/F, as data permit.
• TMZ PK: MD - Css,max, Tmax, AUCss,, Css,trough, and CL/F, as data permit.
• IRN (and active metabolite, SN-38) PK: MD - Css,max, Tmax, AUCss,, Css,trough, and CL/F, as data permit.
• QoL reported by patient at baseline and after 2 and 4 cycles using age-appropriate tools.
• Days of hospitalization. |
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
| at baseline and after 2 and 4 cycles |
|
| 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) | No |
| E.7.1.1 | First administration to humans | No |
| E.7.1.2 | Bioequivalence study | No |
| E.7.1.3 | Other | No |
| 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 | Yes |
| 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 | 2 |
| E.8.3 |
The trial involves single site in the Member State concerned
| No |
| E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
| E.8.4.1 | Number of sites anticipated in Member State concerned | 2 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 50 |
| E.8.6 Trial involving sites outside the EEA |
| E.8.6.1 | Trial being conducted both within and outside the EEA | Yes |
| E.8.6.2 | Trial being conducted completely outside of the EEA | No |
| E.8.6.3 | If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned |
| Argentina |
| Ukraine |
| Belgium |
| Brazil |
| Bulgaria |
| Canada |
| Czechia |
| France |
| Germany |
| Hungary |
| India |
| Israel |
| Italy |
| Korea, Republic of |
| Netherlands |
| Poland |
| Slovakia |
| Spain |
| Sweden |
| Turkey |
| United Kingdom |
| United States |
|
| 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
|
End of trial in all participating countries is defined as the last patient last visit (LPLV). Since patients in this clinical trial will be followed for survival, the LPLV is anticipated to be the last survival follow-up for the last patient in the follow-up phase (ie, date last known alive or
of death). |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 1 |
| E.8.9.1 | In the Member State concerned months | 9 |
| E.8.9.1 | In the Member State concerned days | 27 |
| E.8.9.2 | In all countries concerned by the trial years | 1 |
| E.8.9.2 | In all countries concerned by the trial months | 9 |
| E.8.9.2 | In all countries concerned by the trial days | 27 |
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