Study to Find a Safe Dose and Show Early Clinical Activity of Weekly Nab-paclitaxel in Pediatric Patients With Recurrent/ Refractory Solid Tumors

Phase 2CompletedNCT01962103

Celgene107 enrolled

Overview

The purpose of this study is to find the safe dose of nab-paclitaxel in children with solid tumors, and to see if it works to treat these solid tumors in children and young adults (in Phase 1 ≤ 18 years old and in Phase 2 ≤ 24 years old). After the final dose has been chosen, patients will be enrolled according to the specific solid tumor type, (neuroblastoma, rhabdomyosarcoma, or Ewing's sarcoma), to see how nab-paclitaxel works in treating these tumors.

ABI-007-PST-001 is a Phase 1/2, multicenter, open-label, dose-finding study to assess the safety , tolerability, and preliminary efficacy of weekly nab-paclitaxel in pediatric patients with recurrent or refractory solid tumors (excluding brain tumors). The Phase 1 portion of the study, with a dose escalation design, ended and the recommended Phase 2 dose (RP2D) was determined as 240 mg/m\^2 intravenously (IV) in patients weighing \> 10 kg and 11.5 mg/kg in patients weighing ≤ 10 kg, on Days 1, 8 and 15 of a 28-day cycle. The Phase 2 portion of the study will enroll additional patients at the RP2D into 1 of 3 solid tumor groups \[neuroblastomas, rhabdomyosarcomas, Ewing's sarcomas\]. Both phases of the study are open-label and conducted at multiple centers. The Phase 2 is using a Simon 2-stage design to monitor patient enrollment for each group separately. The rhabdomyosarcoma group, neuroblastoma or Ewing's sarcoma groups did not reach the expected number of 2 responders out of 14 efficacy eligible patients. Consequently, the groups were stopped.

Study Type

INTERVENTIONAL

Allocation

NON_RANDOMIZED

Purpose

TREATMENT

Masking

NONE

Enrollment

107

Conditions

Eligibility

Sex: ALLMin age: 6 MonthsMax age: 24 Years

Medical Language ↔ Plain English

Inclusion Criteria: * Patients must meet all of the following criteria to be enrolled in the study: 1. Patient has a confirmed solid tumor diagnosis according to the following: 1. 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 2. Phase 2: patient has radiologically documented measurable disease by Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 (for neuroblastoma, evaluable disease by 123\^I-metaiodobenzylguanidine \[MIBG\]/Curie score is also acceptable) in 1 of the following tumor types and has failed up to 3 lines of treatment: Group 1: neuroblastoma, Group 2: rhabdomyosarcoma; Group 3: Ewing's sarcoma. 2. The patient has a Lansky/Karnofsky performance status score of ≥ 70%. 3. The patient has adequate serum chemistry levels, evidenced by the following laboratory values 1. aspartate aminotransferase (AST)/serum glutamic-oxaloacetric transaminase (SGOT), alanine aminotransferase (ALT)/serum glutamic pyruvate transaminase (SGPT) ≤ 2.5 × upper limit of normal range (ULN) 2. Total bilirubin ≤ 1.5 × ULN 3. Creatinine ≤ 1.5 × ULN 4. The patient has adequate bone marrow function, evidenced by the following: 1. Absolute neutrophil count ≥ 1.0 × 10\^9 cells/L 2. 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 × 10\^9 cells/L 3. Hemoglobin ≥ 8 g/dL (transfusion is permitted to fulfill this criterion). 5. 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. 6. 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. 7. 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 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 investigational product (if serum test occurred \> 72 hours from first dose); pregnancy test with sensitivity of at least 25 mIU/mL. Exclusion Criteria: * The presence of any of the following will exclude a patient from enrollment:  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 received therapeutic dose chemotherapy or radiotherapy ≤ 21 days prior to start of investigational product. 3. The patient has received maintenance dose chemotherapy (e.g., low dose cyclophosphamide) ≤ 7 days from the first dose of investigational product. 4. The patient has received any investigational therapy ≤ 28 days prior to start of investigational product. Investigational therapy is defined as any medicinal product that is not approved in the country of treatment for any indication, adult or pediatric. 5. The patient has received any biological therapy ≤ 7 days prior to the start of investigational product, or monoclonal antibody ≤ 3 half-lives or 28 days, whichever is shorter, prior to the first dose of investigational product. 6. The patient has received any hematopoietic stem cell transplantation (HSCT) ≤ 3 months prior to start of investigational product. 7. The patient has received allogeneic hematopoietic stem cell transplantation (HSCT) ≤ 3 months or autologous HSCT ≤ 21 days prior to start of investigational product. 8. The patient has not recovered from the acute toxic effects of prior chemotherapy, radiation, or major surgery/significant trauma. 9. The patient has had minor surgery ≤ 7 days from the start of study treatment (excluding the placement of central/peripheral lines, skin biopsy). 10. The patient has a known history of stroke, myocardial infarction, peripheral vascular disease, or recent (within 3 months) uncontrolled deep venous thrombosis. 11. The patient has a known history or current diagnosis of human immunodeficiency virus (HIV) infection, regardless of treatment status. 12. 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. 13. The patient has any significant medical condition, laboratory abnormality, or psychiatric illness that would prevent the patient from participating in the study. 14. The patient has any condition, including the presence of laboratory abnormalities, that places the patient at unacceptable risk if he/she were to participate in the study. 15. The patient has any condition that confounds the ability to interpret data from the study. 16. 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. 17. The patient has ≥ Grade 2 peripheral neuropathy by National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) at screening.

Locations (20)

Phoenix Childrens Hospital

Phoenix, Arizona, United States

Columbia University Medical Center

New York, New York, United States

The Hospital for Sick Children

Toronto, Ontario, Canada

Institute for Pediatric Hematology - Oncology, Leon Berard Cancer Center

Lyon, France

Hopital d'Enfants, CHU Nancy

Nancy, France

Institut Curie

Paris, France

Institut Gustave Roussy

Villejuif, France

Azienda Ospedaliera Universitaria Meyer

Florence, Italy

Children's Hospital Largo

Genova, Italy

Istituto Nazionale Tumori

Milan, Italy

...and 10 more locations

Outcomes

Primary Outcomes

Phase 1: Number of Participants With Dose Limiting Toxicities (DLTs)

A DLT was defined as investigational product (IP)-related adverse events occurring during the DLT assessment period that led to treatment discontinuation or met one of the following criteria: - Common Terminology Criteria for Adverse Events (CTCAE) Grade (Gr) 3 or 4 nonhematologic toxicity (excluding transient transaminitis) - CTCAE Gr 3 or 4 nausea or vomiting that persisted \> 5 days despite maximal anti-emetic treatment - CTCAE Gr 4 thrombocytopenia or anemia that persisted \> 7 days or required transfusion \> 7 days - CTCAE Gr 3 thrombocytopenia with bleeding - CTCAE Gr 4 uncomplicated neutropenia lasting \> 7 days - Febrile neutropenia with confirmed bacterial infection - CTCAE Gr 3 hematologic toxicity requiring treatment (tx) delay \> 21 days. Use of "..." in the table rows signifies the continuation of row title per the above list.

Time frame: DLT assessment period: For participants > 10 kg: the first 28-day cycle including Cycle 2 Day 1 predose evaluations; for participants ≤ 10 kg: the first two 28-day cycles including Cycle 3 Day 1 predose evaluations

Phase 1: Number of Participants With Treatment-Emergent Adverse Events (TEAEs)

An adverse event (AE) was defined as any noxious, unintended, or untoward medical occurrence that may appear or worsen in a participant during the course of a study. A serious AE (SAE) is any AE occurring at any dose that: results in death; is life-threatening; requires inpatient hospitalization or prolongation of existing hospitalization; results in persistent or significant disability/incapacity; is a congenital anomaly/birth defect; constitutes an important medical event. TEAEs were defined as AEs that began or worsened in severity on or after the date of the first dose of study drug and within 28 days of the date of the last dose of study drug. The severity of an AE was graded according to the CTCAE, Version 4.0.

Time frame: Median treatment duration in Phase 1 was 7.0 weeks, with minimum and maximum duration of 1 and 49 weeks, respectively. Participants were followed for 28 days after discontinuing treatment for safety and monitoring of AEs.

Phase 2: Overall Response Rate (ORR)

Overall response rate was defined as the percentage of participants who achieved a complete response (CR; disappearance of all target lesions) or partial response (PR; at least a 30% decrease in the sum of diameters of target lesions) confirmed no less than 4 weeks after the criteria for response were first met using Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 guidelines. (For Phase 2 neuroblastoma participants who had both RECIST and Curie Score tumor evaluations, both tumor response results were considered and an overall response was derived.) Confidence interval was obtained using the Clopper-Pearson method.

Time frame: Median treatment duration in Phase 2 per group: Ewings Sarcoma = 14 weeks (3-31), Neuroblastoma = 7 weeks (3-23), Rhabdomyosarcoma = 5 weeks (1-13).

Secondary Outcomes

Phase 1: ORR

Overall response rate was defined as the percentage of participants who achieved a complete response (CR; disappearance of all target lesions) or partial response (PR: at least a 30% decrease in the sum of diameters of target lesions) confirmed no less than 4 weeks after the criteria for response were first met) using RECIST version 1.1 guidelines over the total number of participants available for the analysis. Confidence interval was obtained using the Clopper-Pearson method.

Time frame: Median treatment duration in Phase 1 was 7.0 weeks, with minimum and maximum duration of 1 and 49 weeks, respectively.

Phase 1: Maximum Observed Concentration of Paclitaxel in Blood Plasma (Cmax)

Time frame: Cycle 1 Day 1 (Participants ≥ 6 years: 1-2 minutes prior to the end of infusion [EOI], and 15 minutes, 1, 3, 5, 8, 24, 48, and 72 hours after the EOI. Participants <6 years: 1-2 minutes prior to the EOI, and 15 minutes, 3, 5, and 24 hours after the EOI.)

Phase 1: Cmax - Dose-Normalized

Phase 1: Area Under the Plasma Concentration-Time Curve (AUC)

Measurements include: AUC from time zero to the last measurable concentration (AUCt), AUC from time zero to 24 hours (AUC24), and AUC from time zero to infinity (AUCinf).

Phase 1: AUC - Dose-Normalized

Measurements include: AUC24 and AUCinf.

Phase 1: Clearance (CL)

Measurement of renal clearance from the body.

Phase 1: CL - Body Surface Area (BSA)-Normalized

Measurement of renal clearance from the body.

Phase 1 and 2 Population PK: Volume of Distribution of the Central Compartment (V1)

Population PK analysis was performed using nonlinear mixed effect modeling. The estimated allometric function for V1 was 0.888.