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

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.

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.

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.