Nab-paclitaxel in Combination With Gemcitabine for Pediatric Relapsed and Refractory Solid Tumors

Relapsed and refractory non-central nervous system (non-CNS) solid tumors have poor outcomes,
and novel therapies are needed. Many relapsed/refractory solid tumor patients desire further
therapy; however, they often wish to also preserve a high quality of life. Thus therapeutic
strategies that offer relatively minimal treatment-related toxicities are also desirable. The
combination of gemcitabine, a pyrimidine analog, and docetaxel, an antimitotic taxane, is an
attractive combination because of non-overlapping toxicities. This combination has shown
activity and tolerability in adult Phase II trials for solid tumors. Favorable experiences
with this regimen in pediatrics have been described retrospectively by several institutions.
Nab-paclitaxel is an albumin-bound, solvent-free taxane that allows higher dosing and shorter
infusion duration than solvent-bound taxanes (docetaxel and paclitaxel) by removing exposure
to toxic solvent carriers. Albumin binding of the agent also increases drug delivery to
tumors through increased albumin-initiated transcytosis, and may also increase tumoral
accumulation of drug through binding of secreted protein acidic and rich in cysteine (SPARC).
The combination of gemcitabine and nab-paclitaxel has been studied extensively in adults with
pancreatic adenocarcinoma, with the combination providing superior outcomes to treatment with
gemcitabine alone. There is also preclinical evidence of potent anti-tumor activity of
nab-paclitaxel alone and in combination with gemcitabine in pediatric solid tumor models.
Therefore, the researchers hypothesize that the combination of nab-paclitaxel with
gemcitabine will improve the anti-tumor efficacy observed with gemcitabine/docetaxel in
relapsed/refractory solid tumors.

This is a Phase 1 study of nab-paclitaxel in combination with gemcitabine for children,
adolescents, and young adults with relapsed or refractory non-central nervous system (CNS)
solid tumors in which the researchers will define toxicity, pharmacokinetics, and evaluate
SPARC expression in pediatric tumors as a biomarker of disease response. Nab-paclitaxel will
be administered intravenously (IV) once weekly on days 1,8, and 15 of a 28 day cycle. The
starting dose of nab-paclitaxel will be 180 mg/m2/dose which is 75% of the pediatric, single
agent MTD of 240 mg/m2/dose. The researchers will then dose escalate up to 240 mg/m2/dose.
Participants will also receive gemcitabine 1000 mg/m2/dose IV once weekly on days 1, 8, and
15. Participants may continue on therapy until there is evidence of progressive disease or
toxicity that requires removal from therapy. Therapy may otherwise continue for up to 24
cycles.

Inclusion Criteria:

- Subjects must be ≥ than 6 months and ≤ 30 years of age at the time of study
enrollment.

- Subjects must have had histologic verification of a malignancy at original diagnosis
or relapse. All subjects with relapsed or refractory solid tumors are eligible,
excluding CNS tumors.

- Subjects must have either measurable or evaluable disease.

- Subject's current disease state must be one for which there is no known curative
therapy, or in the case of a new diagnosis there must be ≤15% chance of cure if given
standard-of-care chemotherapy. (Prognosis to be determined at the discretion of the
treating physician.)

- Karnofsky ≥ 60 for subjects > 16 years of age and Lansky ≥ 50 for subjects ≤ 16 years
of age. Subjects who are unable to walk because of paralysis, but who are up in a
wheelchair, will be considered ambulatory for the purpose of assessing the performance
score.

- Subjects must have fully recovered from the acute toxic effects of all prior
anti-cancer chemotherapy.

- At least 21 days after the last dose of myelosuppressive chemotherapy (42 days if
prior nitrosourea).

- At least 14 days after the last dose of a long-acting growth factor (e.g.
Pegfilgrastim) or 7 days for short acting growth factor. For agents that have
known adverse events occurring beyond 7 days after administration, this period
must be extended beyond the time during which adverse events are known to occur.
The duration of this interval must be discussed with the study chair.

- At least 7 days after the last dose of a biologic agent. For agents that have
known adverse events occurring beyond 7 days after administration, this period
must be extended beyond the time during which adverse events are known to occur.
The duration of this interval must be discussed with the study chair.

- ≥ 42 days must have elapsed from last dose of any type of cellular therapy (e.g.
modified T cells, natural killer (NK) cells, dendritic cells, etc.)

- ≥ 21 days must have elapsed from the last dose of interleukins, interferon or
cytokines (other than Hematopoietic Growth Factors).

- ≥ 21 days must have elapsed from infusion of last dose of antibody, and toxicity
related to prior antibody therapy must be recovered to Grade ≤ 1.

- At least 28 days after local palliative radiation therapy (XRT) (small port); 6
weeks must have elapsed since treatment with therapeutic doses of iodine-131
metaiodobenzylguanidine (131I-MIBG); At least 42 days must have elapsed if other
substantial bone marrow (BM) radiation.

- No evidence of active graft vs. host disease and at least 84 days must have
elapsed after transplant and 42 days for autologous stem cell infusion after
131I-MIBG therapy.

- Patients who have previously received a taxane, including nab-paclitaxel, or a
nucleoside analogue, including gemcitabine, are eligible as long as they have not
received gemcitabine in combination with nab-paclitaxel.

- ≥72 hours must have elapsed since the last administration of medical cannabis and
cannabidiol (CBD Oil).

- ≥30 days must have elapsed since the last dose of any agents not specified above.
For agents with an uncertain washout period or for any questions or uncertainty
the study PI should be notified.

- Adequate bone marrow function defined as:

- For subjects with solid tumors without known bone marrow involvement: Peripheral
absolute neutrophil count (ANC) ≥ 750/mm3. Platelet count ≥ 75,000/mm3
(transfusion independent, defined as not receiving platelet transfusions for at
least 7 days prior to enrollment)

- Subjects with known bone marrow metastatic disease will be eligible for study
provided they meet the blood counts of peripheral absolute neutrophil count (ANC)
≥ 750/mm3 and platelet count ≥ 75,000/mm3 (may receive transfusions provided they
are not known to be refractory to red cell or platelet transfusions). These
subjects will not be evaluable for hematologic toxicity. At least 5 of every
cohort of 6 patients must be evaluable for hematologic toxicity for the
dose-escalation part of the study. If dose-limiting hematologic toxicity is
observed, all subsequent subjects enrolled must be evaluable for hematologic
toxicity.

- Adequate renal function defined as:

- Creatinine clearance or radioisotope glomerular filtration rate (GFR)
70ml/min/1.73 m2 or

- A serum creatinine based on age/gender using threshold creatinine values derived
from the Schwartz formula for estimating GFR utilizing child length and stature
data published by the Centers for Disease Control and Prevention (CDC).

- Adequate liver function defined as:

- Bilirubin (sum of conjugated + unconjugated) ≤ 1.5 x upper limit of normal (ULN)
for age

- Serum glutamic pyruvic transaminase (SGPT) (ALT) ≤ 5 x the ULN. For the purpose
of this study, the ULN for SGPT is 45 U/L.

Exclusion Criteria:

- Female patients who are pregnant are ineligible for study. Lactating females are not
eligible unless they have agreed not to breastfeed their infants from the time of
informed consent through the duration and at least 1 month following the study. Female
patients of childbearing potential are not eligible unless a negative pregnancy test
result has been obtained. Sexually active patients of reproductive potential are not
eligible unless they have agreed to use an effective contraceptive method from the
time of informed consent through the duration and for 1 month following study
participation. The definition of an effective contraceptive method will be at the
discretion of the institutional investigator.

- Patients taking any the following concomitant medications are not eligible:

- Subjects who are currently receiving another investigational drug.

- Subjects who are currently receiving other anti-cancer agents.

- Subjects who are receiving cyclosporine, tacrolimus, or other agents to prevent
graft-versus-host disease post bone marrow transplant.

- Subjects using medications which interfere with CYP3A4 and CYP2C8 metabolism,
which metabolize nab-paclitaxel. Paclitaxel is metabolized by CYP3A4 and CYP2C8,
so strong inhibitors or inducers of these enzymes should be avoided.

- Patients with any of the following adverse events at the time of enrollment are not
eligible:

- Grade ≥ 2 Motor, sensory or peripheral neuropathy

- Grade ≥3 Hyponatremia (serum Na ≤ 130 mmol/L)

- Subjects who have an uncontrolled infection are not eligible.

- Subjects who have received prior solid organ transplantation are not eligible.

- Subjects who in the opinion of the investigator may not be able to comply with the
safety monitoring requirements of the study are not eligible.