| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
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| E.1.1.1 | Medical condition in easily understood language |
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| 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 | 10015562 |
| E.1.2 | Term | Ewing's sarcoma metastatic |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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) |
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| 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 | 10015564 |
| E.1.2 | Term | Ewing's sarcoma recurrent |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| E.1.2 Medical condition or disease under investigation |
| E.1.2 | Version | 21.1 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065143 |
| E.1.2 | Term | Malignant solid tumour |
| E.1.2 | System Organ Class | 10029104 - Neoplasms benign, malignant and unspecified (incl cysts and polyps) |
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| 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 |
Phase I
To determine the RP2Ds of onivyde combined with talazoparib (Arm A) and onivyde combined with temozolomide (Arm B) administered to children, adolescents and young adults with refractory or recurrent solid malignancies.
Phase II
To compare the PFS of onivyde plus talazoparib and onivyde plus temozolomide in patients with refractory or recurrent (RR) Ewing sarcoma. |
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| E.2.2 | Secondary objectives of the trial |
Phase I:
To characterize the safety profile of the drug regimens, onivyde plus talazoparib (Arm A) and onivyde plus temozolomide (Arm B).
To characterize the plasma pharmacokinetics of onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent solid malignancies.
To estimate the antitumor activity of onivyde plus talazoparib and onivyde plus temozolomide.
Phase II:
To describe the toxicity of the treatment regimens.
To describe the ORR, DCR after cycle 4, DoR, EFS and OS for patients receiving onivdye plus talazoparib and onivyde plus temozolomide.
To characterize the plasma pharmacokinetics of onivyde and talazoparib in children, adolescents and young adults with refractory or recurrent Ewing sarcoma |
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| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
• Patients> 12 months and ≤ 30 years at the time of enrollment
• Phase I: Patients with refractory or recurrent non-central nervous system (CNS) solid tumors not amenable to curative treatment; must have had histologic verification of malignancy at original diagnosis or at the time of relapse. Expansion cohort will include non-ES patients with refractory or recurrent non-CNS solid tumors with a deleterious alteration in germline or somatic genes involved in HR repair and DSBs signaling, germline or somatic assessed by prior comprehensive sequencing performed in a CLIA-approved (or equivalent) facility
• Phase II: Patients with refractory or recurrent Ewing sarcoma (during or after completion of first-line therapy). Patients must have a histologic diagnosis of Ewing sarcoma with EWSR1- FLI1 translocation or other EWS rearrangement at the time of initial diagnosis. Repeat biopsy at the time of disease recurrence is strongly encouraged but it is not required/mandated.
• Disease status: Patients must have either measurable or evaluable disease.Patients with bone disease without a measurable soft tissue component or bone marrow disease only are eligible for the phase 1 and phase 2 study but will not be included in the OR endpoint
• Performance level: Karnofsky ≥ 50% for patients ≥ 16 years of age and Lansky ≥ 50% for patients < 16 years of age Prior therapy
• Phase I: Patients who have received prior therapy with an irinotecan-based or temozolomide-based regimen are eligible. Patients who have received prior therapy with a PARP inhibitor other than talazoparib are eligible
• Phase II: Patients should have received first line therapy and developed either refractory or recurrent disease (first relapse)
• Organ function: Must have adequate organ and bone marrow function as defined by the following parameters:
- Patients with solid tumors not metastatic to bone marrow:Peripheral absolute neutrophil count (ANC) ≥1,000/mm3; Platelet count ≥ 75,000/mm3 (no transfusion within 7 days of enrollment); Hemoglobin ≥ 9 g/dL (with or without support)
- In the phase I study, patients with solid tumors metastatic to bone marrow or with bone marrow hypocellularity defined as <30% cellularity in at least one bone marrow site will be eligible for study, but they will not be evaluable for hematologic toxicity. These patients must not be refractory to red cell or platelet transfusions. At least 2 of every cohort of 3 patients (in the phase I study) must be evaluable for hematologic toxicity. If dose limiting hematologic toxicity is observed at any dose level, all subsequent patients enrolled at that dose level must be evaluable for hematologic toxicity
- Adequate renal function defined as: Creatinine clearance or radioisotope GFR ≥ 60ml/min/1.73m2 or a serum creatinine maximum(mg/dL) based on age/sex: 1 to < 2 years, creatinine 0.6; 2 < 6 years, creatinine 0.8; 6 < 10 years, creatinine 1; 10 to <13 years, creatinine 1.2; 13 to < 16 years creatinine 1.5 (males) or 1.4 (females); ≥ 16 years, creatinine 1.7 (males) 1.4 (females)
- Adequate liver function defined as: normal liver function as defined by SGPT (ALT) concentration ≤5x the institutional ULN, a total bilirubin concentration ≤2x the institutional ULN for age, and serum albumin ≥ 2g/dL
- Adequate pulmonary function defined as no evidence of dyspnea at rest and a pulse oximetry > 94% if there is a clinical indication for determination. Pulmonary function tests are not required.
• Patients must have fully recovered from the acute toxic effects of chemotherapy, immunotherapy, surgery, or radiotherapy prior to entering this study:
- Myelosuppressive chemotherapy: Patient has not received myelosuppressive chemotherapy within 3 weeks of enrollment onto this study (8 weeks if received prior myeloablative therapy)
- Hematopoietic growth factors: At least 7 days must have elapsed since the completion of therapy with a growth factor. At least 14 days must have elapsed after receiving pegfilgrastim
- Biologic (anti-neoplastic agent): At least 7 days must have elapsed since completion of therapy with a biologic agent
- Monoclonal antibodies: At least 3 half-lives must have elapsed since prior therapy that included a monoclonal antibody or 28 days have elapsed since last dose of the monoclonal antibody with complete resolution of symptoms related to treatment
- Radiotherapy: At least 2 weeks must have elapsed since any irradiation; at least 6 weeks must have elapsed since craniospinal RT, 131I-mIBG therapy or substantial bone marrow irradiation (e.g., >50% pelvis irradiation)
• Female participant who is post-menarchal must have a negative urine or serum pregnancy test and must be willing to have additional serum and urine pregnancy tests during the study
• Participant of reproductive potential must agree to use effective contraceptive methods at screening and throughout duration of study treatment
• Informed consent |
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| E.4 | Principal exclusion criteria |
• Pregnant or breast-feeding women will not be entered on this study. Pregnancy tests must be obtained in girls who are post-menarchal. Males or females of reproductive potential may not participate unless they have agreed to use two methods of birth control: a medically accepted barrier of contraceptive method (e.g., male or female condom) and a second method of birth control during protocol therapy. Two highly effective methods of contraception are required for female patients during treatment and for at least 7 months after completing therapy. Male patients with female partners of reproductive potential and/or pregnant partners are advised to use two highly effective methods of contraception during treatment and for at least 4 months after the final dose.
• Male and female participants must agree not to donate sperm or eggs, respectively, after the first dose of study drug through 105 days and 45 days after the last dose of study drug. Females considered not of childbearing potential include those who are surgically sterile (bilateral salpingectomy, bilateral oophorectomy, or hysterectomy).
• Concomitant medications
- Corticosteroids: Patients receiving corticosteroids that have not been on a stable or decreasing dose for at least 7 days prior to enrollment are not eligible.
- Investigational drugs: Patients cannot receive other investigational drugs while on this study.
- Anti-GVHD drugs post-transplant: Patients receiving cyclosporine, tacrolimus or other GVHD agents are not eligible.
- Patients treated within the last 7 days prior to enrollment with strong UGT1A1 inhibitors.
- Patients treated within the last 7 days prior to enrollment with food or drugs that are known to be strong CYP3A4 inhibitors (e.g., boceprevir, clarithromycin, conivaptan, delavirdine, indinavir, itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, telaprevir, telithromycin, voriconazole, and grapefruit or grapefruit juice);
- Patients treated within the last 7 days prior to enrollment with drugs that are known to be strong CYP3A4 inducers (i.e., carbamazepine, phenytoin, rifampin, rifapentine, rifabutin, phenobarbital, and St. John’s wort);
- Patients treated within the last 7 days prior to enrollment with drugs that are known to be potent P-gp inhibitors (i.e., amiodarone, carvedilol, clarithromycin, cobicistat, dronedarone, erythromycin, glecaprevir/pibrentasvir, indinavir, itraconazole, ketoconazole, lapatinib,
lopinavir, propafenone, quinidine, ranolazine, ritonavir, saquinavir, sofosbuvir/velpatasvir/voxilaprevir, telaprevir, tipranavir, valspodar, and verapamil);
• In the phase I study, patients who have previously received talazoparib or onivyde are NOT eligible. Additionally patients who have progressed on a PARP inhibitor plus irinotecan containing regimen are NOT eligible.
• In the phase II study, patients who have previously received talazoparib, onivyde, or temozolomide are NOT eligible.
• Active, uncontrolled infection.
• Prior solid organ transplant.
• Prior total body irradiation (TBI).
• Unwilling or unable to comply with the safety monitoring requirements of this protocol.
• History of a severe hypersensitivity reaction to irinotecan.
• Clinically significant gastrointestinal disorders including hepatic disorders, colitis, or diarrhea > grade 1 at baseline.
• Ongoing or history of non-infectious interstitial lung disease requiring significant medical intervention.
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| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I Primary Endpoint: First cycle dose limiting toxicities (DLTs)
Phase II Primary Endpoint: PFS based on central review assessment
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| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I (DLT): end of Cycle I
Phase II (PFS): after 65 events observed
Tumor disease evaluation:
- Before and during therapy: at screening, end of cycle 2, 4, 6, then every 4 cycles, at the end of treatment
- After therapy: every 3 months during 6 months, then every 6 months until 2 years, then annually
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| E.5.2 | Secondary end point(s) |
Phase I Secondary Endpoints:
- AEs characterized by type, frequency, severity (as graded by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) version 5), timing, seriousness, and relationship to study therapy.
- Talazoparib: Cmax, Tmax, CL on Day 1: AUCtau (AUC24), Ctrough (predose), Tmax and Cmax on Day 6; Onivyde: Cmax, Tmax, AUCinf, t½, CL, Vd, on Day 1.
- Objective response rate (ORR), disease control rate (DCR) at cycle 4, duration of response (DoR), event-free survival (EFS), overall survival (OS).
Phase II Secondary Endpoints:
- AEs as characterised by type, frequency, severity (as graded by NCI CTCAE version 5), timing, seriousness, and relationship to study therapy.
- ORR, DCR at cycle 4, DoR, EFS, OS.
- Talazoparib: Cmax and Tmax on Day 1: AUCtau (AUC24), Ctrough (predose), Tmax and Cmax on Day 6; Onivyde: Cmax, Tmax, AUCinf, t½, CL, Vd, on Day 1 |
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| E.5.2.1 | Timepoint(s) of evaluation of this end point |
• AEs evaluation: Weekly during Cycle 1, each subsequent cycle, at the end of treatment, post-treatment
• PK samples: will be collected pre-dose and then during Cycle 1 at various prespecified timepoints
• Tumor disease evaluation:
- Before and during therapy: at screening, end of cycle 2, 4, 6, then every 4 cycles, at the end of treatment
- After therapy: every 3 months during 6 months, then every 6 months until 2 years, then annually
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| 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 | Yes |
| 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 | Yes |
| 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) | Yes |
| 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 |
Will this trial be conducted at a single site globally?
| No |
| E.8.4 | Will this trial be conducted at multiple sites globally? | Yes |
| 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 |
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| 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
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LSLV
The study duration for the phase I accrual will be approximately 1.5 years. The study duration for the phase II study accrual will be approximately 3 years. In the phase II study, patients will be followed for EFS and OS for 5 years following the date the last patient was randomized. |
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| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.2 | In all countries concerned by the trial years | 10 |
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