| E.1 Medical condition or disease under investigation |
| E.1.1 | Medical condition(s) being investigated |
| recurrent or refractory solid tumor |
|
| E.1.1.1 | Medical condition in easily understood language |
| subjects with solid tumors that have come back after disappearing or that don’t respond to any treatment |
|
| 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 | 19.0 |
| E.1.2 | Level | LLT |
| E.1.2 | Classification code | 10065147 |
| E.1.2 | Term | Malignant solid tumor |
| E.1.2 | System Organ Class | 100000004864 |
|
| 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 |
Phase I:
determine the pediatric MTD/RP2D, safety and tolerability of nab-paclitaxel administered intravenously over 30min on Days 1, 8, and 15 of a 28-day cycle in patients ≥ 6 months and < 18 years old with recurrent or refractory solid tumors
Phase II:
assess the antitumor activity by the overall response rate (ORR) of nab-paclitaxel given at the RP2D in patients ≥ 6 months and ≤ 24 years old with several discrete recurrent or refractory solid tumor types including neuroblastoma, rhabdomyosarcoma and Ewing's sarcoma |
|
| E.2.2 | Secondary objectives of the trial |
Phase I:
- To evaluate pharmacokinetics (PK).
- To characterize the ORR
Phase II:
- To characterize duration of response (DOR).
- To characterize the disease control rate (DCR).
- To characterize progression-free survival (PFS).
- To characterize 1-year survival.
- To confirm safety.
- To evaluate PK. |
|
| E.2.3 | Trial contains a sub-study | No |
| E.3 | Principal inclusion criteria |
1. Patient is male or female, meeting the following age requirements at the time the
informed consent document (and assent form, if applicable) is signed.
a. Phase 1: patient is ≥ 6 months to < 18 years of age
b. Phase 2: patient is ≥ 6 months to ≤ 24 years of age
2. Patient has a confirmed solid tumor diagnosis according to the following:
a. Phase 1: patient has a recurrent or refractory solid tumor that has progressed or did not respond to standard therapy, or for which no standard anticancer therapy exists
b. Phase 2: patient has radiologically documented measurable disease by RECIST 1.1 (for neuroblastoma, evaluable disease by MIBG/Curie score is also
acceptable) in one of the following tumor types and has failed up to three lines of treatment
i. Group 1: neuroblastoma (patients with bone marrow disease only are not permitted)
ii. Group 2: rhabdomyosarcoma
iii. Group 3: Ewing's sarcoma
3. The patient has a Lansky/ Karnofsky performance status score of ≥ 70%
4. The patient has adequate serum chemistry levels, evidenced by the following laboratory values
a. AST (SGOT), ALT (SGPT) ≤ 2.5 × upper limit of normal range (ULN)
b. Total bilirubin ≤ 1.5 × ULN
c. Creatinine ≤ 1.5 × ULN
5. The patient has adequate bone marrow function, evidenced by the following:
a. Absolute neutrophil count ≥ 1.0 × 10^9 cells/L
b. Platelets ≥ 80 × 10^9 cells/L (transfusion independent, defined as not receiving platelet transfusions within 7 days prior to laboratory sample). In the Phase 2
portion, for patients with known bone marrow involvement, platelets ≥ 50 × 109 cells/L.
c. Hemoglobin ≥ 8 g/dL (transfusion is permitted to fulfill this criterion)
6. The patient (when applicable) or patient’s parent(s) or legal guardian(s) understand(s) and voluntarily signed an informed consent document prior to any study-related assessments/ procedures being conducted. Where locally applicable, the patient also understands and voluntarily provides his/her assent prior to any study-related assessments/procedures being conducted.
7. Male patients of childbearing potential must use a condom during sexual intercourse and shall not father a child during the study and for 6 months after the last dose of study medication.
8. Female patients of childbearing potential [defined as all female patients ≥ 12 years old or who have reached menarche, whichever occurs first] must have both of the following:
a. Agree to the use of two physician-approved contraceptive methods simultaneously or practice complete abstinence while on study medication or for a longer period if
required by local regulations
i. True abstinence: When this is in line with the preferred and usual lifestyle of the patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, postovulation methods) and withdrawal are not acceptable methods of contraception.
ii. Acceptable contraceptive methods include: oral, injectable, or implantable hormonal contraceptive; tubal ligation; intra-uterine device; barrier contraceptive with spermicide; or vasectomized partner) including at least one barrier method.
b. Have negative serum pregnancy test result at screening confirmed by negative urine pregnancy dipstick within 72 hours prior to first dose of IP (if serum test occurred > 72 hours from first dose); pregnancy test with sensitivity of at least 25
mIU/mL |
|
| E.4 | Principal exclusion criteria |
1. The patient has a primary brain tumor(s) or brain metastasis (unless metastasis is treated and stable for > 28 days). In patients who are symptomatic, a brain scan is required to exclude metastasis.
2. The patient has ≥ Grade 2 peripheral neuropathy by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) at screening.
3. The patient has received therapeutic dose chemotherapy or radiotherapy ≤ 21 days prior to start of IP.
4. The patient has received maintenance dose chemotherapy (e.g., low dose cyclophosphamide) ≤ 7 days from the first dose of IP.
5. The patient has received any investigational therapy ≤ 28 days prior to start of IP.
Investigational therapy is defined as any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric
6. The patient has received any biological therapy ≤ 7 days prior to the start of IP, or monoclonal antibody ≤ 3 half-lives or 28 days, whichever is shorter, prior to the first dose of IP.
7. The patient has received allogenic hematopoietic stem cell transplantation (HSCT) ≤ 3 months or autologous HSCT ≤ 21 days prior to start of IP.
8. The patient has had major surgery or significant trauma ≤ 14 days prior to start of IP.
9. The patient has not recovered from the acute toxic effects of prior chemotherapy, radiation, or major surgery/significant trauma.
10. The patient has had minor surgery ≤ 7 days from the start of study treatment (excluding the placement of central/
peripheral lines, skin biopsy).
11. The patient has a known history of stroke, myocardial infarction, peripheral vascular disease, or recent (within 3 months) uncontrolled deep venous thrombosis.
12. The patient has a known history or current diagnosis of HIV infection, regardless of treatment status.
13. The patient has an uncontrolled intercurrent illness including but not limited to ongoing or active infection requiring antibiotic, antifungal, or antiviral therapy, symptomatic heart failure, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with study requirements.
14. The patient has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study.
15. The patient has any condition, including the presence of laboratory abnormalities, that places him/her at unacceptable risk if he/she were to participate in the study.
16. The patient has any condition that confounds the ability to interpret data from the study.
17. The patient or parent(s)/guardian(s) is/are unable to comply with the study visit schedule and other protocol requirements, in the opinion of the investigator. |
|
| E.5 End points |
| E.5.1 | Primary end point(s) |
Phase I:
Incidence of DLTs and the incidence of treatment-emergent adverse events (TEAEs).
Phase II:
- ORR (CR + PR) confirmed no less than 4 weeks after the criteria for response are first met, based on RECIST version 1.1 criteria. In the neuroblastoma group the ORR will be determined by RECIST and/or the Curie scale (MIBG response).
|
|
| E.5.1.1 | Timepoint(s) of evaluation of this end point |
Phase I:
Initial 1-2 cycles of treatment
Phase II:
Expected 12-16 weeks after starting treatment; longer depending on the patient |
|
| E.5.2 | Secondary end point(s) |
Phase I:
1) PK parameters including the maximum observed concentration in blood (Cmax), area under the blood concentration-time curve (AUC), clearance and volume of distribution (Vss).
2) ORR
Phase II:
1) DoR in patients with a confirmed objective CR or partial response (PR)
DCR is the percentage of patients with a confirmed objective CR or PR, or stable disease for at least 16 weeks.
2) PFS based on investigator assessment of response using RECIST 1.1 guidelines. In the neuroblastoma group the PFS will be determined by RECIST and/or the Curie scale (MIBG response)
3) Survival at 1 year
4) The incidence of TEAEs
5) Population PK parameters
|
|
| E.5.2.1 | Timepoint(s) of evaluation of this end point |
Phase I:
1) and 2) Up to 4 days after the first treatment.
Phase II:
1)Until progression according to RECIST 1.
Expected 24 weeks after treatment starts; longer depending on the patient.
2)Until PFS event
3)1 Year after starting treatment
4)Up to 28 days after stopping study treatment
5)Up to 4 days after the first treatment.
|
|
| 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 | No |
| E.6.4 | Safety | Yes |
| E.6.5 | Efficacy | Yes |
| E.6.6 | Pharmacokinetic | Yes |
| E.6.7 | Pharmacodynamic | No |
| 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 | Information not present in EudraCT |
| 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 | Yes |
| E.8.1.7.1 | Other trial design description |
| phI: rolling-6 dose escalation; phII: treatment with MTD/RP2D |
|
| E.8.2 | Comparator of controlled trial |
| E.8.2.1 | Other medicinal product(s) | Information not present in EudraCT |
| E.8.2.2 | Placebo | Information not present in EudraCT |
| E.8.2.3 | Other | Information not present in EudraCT |
| E.8.2.4 | Number of treatment arms in the trial | 1 |
| 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 | 1 |
| E.8.5 | The trial involves multiple Member States | Yes |
| E.8.5.1 | Number of sites anticipated in the EEA | 6 |
| 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 |
| Canada |
| France |
| Italy |
| Spain |
| Switzerland |
| United Kingdom |
| United States |
|
| E.8.7 | Trial has a data monitoring committee | No |
| 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
|
After the EOT visit, all patients will be followed for survival until death, lost to follow-up, or one year after EOT, whichever occurs first.
The study will end when all patients have completed the posttreatment follow-up (max 1 year) or have died, whichever occurs first |
|
| E.8.9 Initial estimate of the duration of the trial |
| E.8.9.1 | In the Member State concerned years | 4 |
| E.8.9.1 | In the Member State concerned months | 7 |
| E.8.9.1 | In the Member State concerned days | 0 |
| E.8.9.2 | In all countries concerned by the trial years | 4 |
| E.8.9.2 | In all countries concerned by the trial months | 7 |
| E.8.9.2 | In all countries concerned by the trial days | 0 |
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