Phase 1 Study of Pazopanib in Combination with Irinotecan and Temozolomide (PAZIT) for Children and Young Adults with Relapsed or Refractory Sarcoma

Protocol # :
Refractory Sarcoma
Disease Sites
Bones and Joints
Soft Tissue
Principal Investigator
Dubois, Steven

Trial Description

This is the first study to evaluate the safety and clinical activity of the combination of
oral pazopanib, intravenous or oral irinotecan, and oral temozolomide in pediatric and young
adult patients with relapsed or refractory sarcomas. This study will use a 3 + 3 design for
dose escalation (Part 1), followed by an expansion cohort (Part 2) at the recommended phase 2
dose level.

Eligibility Requirements

Inclusion Criteria:

1. Age: Patients must be 6-30 years of age at the time of study enrollment.

2. Body Surface Area: Eligible patients have a body surface area >/= 0.7 m2 AND be able
to swallow whole tablets at the time of study enrollment.

3. Diagnosis: Patients must have had histologic verification of one of the malignancies
listed below at original diagnosis or at time of relapse.

- Ewing sarcoma/peripheral primitive neuroectodermal tumor (PNET)

- Osteosarcoma

- Rhabdomyosarcoma

- Non-rhabdomyosarcoma soft tissue sarcoma

- Desmoplastic small round cell tumor

Note: Patients with known involvement of the central nervous system (CNS) by
malignancy will be included if there is no evidence of active bleeding or intratumoral
hemorrhage on radiographic imaging.

4. Disease Status: Patients must have either measurable or evaluable disease

5. Therapeutic Options: Patient's current disease state must be one for which there is
not known curative therapy or therapy proven to prolong survival with an acceptable
quality of life.

6. Performance Level: Karnofsky >/= 50% for patients > 16 years of age and Lansky >/= 50%
for patients

Note: Neurologic deficits in patients with metastatic CNS tumors must have been
relatively stable for a minimum of 1 week prior to study enrollment. Patients 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.

7. Prior Therapy: Patients must have fully recovered from the acute toxic effects of all
prior anti-cancer therapy.

Myelosuppressive chemotherapy: Patients must not have received myelosuppressive
therapy within 2 weeks of enrollment onto this study (6 weeks if prior nitrosourea).

Hematopoietic growth factors: At least 14 days after the last dose of a long-acting
growth factor (e.g. Neulasta) 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.

Biologic (anti-neoplastic agent): At least 7 days must have passed after the last
treatment with a biologic agent. For agents that have known adverse events occurring
beyond 7 days from 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.

Immunotherapy: At least 4 weeks since the completion of any type of immunotherapy,
e.g. tumor vaccines.

Monoclonal antibodies: >/= 21 days must have elapsed from infusion of last dose of
antibody, and toxicity related to prior antibody therapy must be recovered to Grade

External beam radiation therapy (XRT): >/= 2 weeks must have elapsed for local
palliative XRT (small port) and enrollment on study. At least 24 weeks must have
elapsed since prior Total Body Irradiation (TBI), radiation to ≥50% of pelvis, or
craniospinal radiation; >/= 6 weeks must have elapsed if the patient has received
other substantial bone marrow radiation.

Stem Cell Transplant (SCT): No evidence of active graft-versus-host disease (GVHD) and
>/= 2 months must have elapsed since transplant or rescue.

Prior treatment with pazopanib, irinotecan, temozolomide: Patients may not have
previously received pazopanib. However, patients may have received other vascular
endothelial growth factor (VEGF) blocking tyrosine kinase inhibitors. Patients must
have recovered from any VEGF blocking drug-related toxicity (e.g., proteinuria).

Patients previously treated with irinotecan and/or temozolomide will be eligible for
this study provided they did not progress while receiving one of these agents.

8. Organ Function Requirements:

Adequate Bone Marrow Function defined as:

- Peripheral absolute neutrophil count (ANC) >/= 750/μL

- Platelet count >/= 75,000/μl (transfusion independent, defined as not receiving
platelet transfusions within a 7 day period prior to enrollment)

- Hemoglobin >/= 8.0 g/dL; may receive red blood cell (RBC) transfusions

Adequate Renal and Metabolic Function defined as:

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

- A serum creatinine based on age/gender per protocol.

The threshold creatinine values in this Table were derived from the Schwartz formula for
estimating GFR utilizing child length and stature data published by the Centers for Disease
Control and Prevention (CDC).

- Urine protein to creatinine ratio of <1, a urinalysis that is negative for protein, or
a 24-hour urine protein level <1000 mg/dL

- No more than Grade 1 abnormalities of potassium, calcium (confirmed by ionized
calcium), magnesium, and phosphorus (supplementation allowed).

Adequate Liver Function defined as:

- Total bilirubin

- Serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) ULN (for the purpose of this study, the ULN for SGPT is 45 U/L)

- Serum albumin >/= 2 g/dL

- Must not have active liver or biliary disease (with the exception of Gilbert's
syndrome or asymptomatic gallstones, liver metastases or otherwise stable chronic
liver disease per investigator assessment).

- No known positivity of hepatitis B surface antigen (HBsAg), or of positive hepatitis C

Adequate Cardiac Function defined as:

- Shortening fraction of >/= 27% by echocardiogram (while not receiving medications for
cardiac function), or

- Ejection fraction of >/= 50% by gated radionuclide study (while not receiving
medications for cardiac function).

- Corrected QT interval (QTc) < 480 msec

- Must not have a history of myocardial infarction, severe or unstable angina,
peripheral vascular disease or familial QT prolongation.

Adequate Blood Pressure Control defined as: A blood pressure (BP) age, height, and gender. Patients on stable doses of no more than one anti-hypertensive
medication, with a baseline BP eligible.

Central Nervous System Function defined as:

- Patients with a known history of seizures must have well-controlled seizures and may
not be receiving enzyme-inducing anti-convulsants

- CNS toxicity

Adequate pulmonary function defined as:

- No evidence of dyspnea at rest

- No exercise intolerance

Adequate Coagulation defined as: prothrombin time (PT) and partial thromboplastin time

Exclusion Criteria:

1. Pregnancy or Breast-Feeding: Pregnant or breastfeeding women will not be entered on
this study due to risks of fetal and teratogenic adverse events as seen in
animal/human studies. Negative 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 an effective contraceptive method. The definition of adequate
contraception will be based on the judgment of the principal investigator or
designated associate. Study drug may also potentially be secreted in milk and
therefore breastfeeding women are excluded.

2. Concomitant Medications:

Corticosteroids: Patients requiring corticosteroids who have not been on a stable or
decreasing dose of corticosteroid for the 7 days prior to enrollment are not eligible.

Investigational Drugs: patients who are currently receiving another investigational
drug are not eligible.

Anti-cancer Agents or Radiation Therapy: Patients who are currently receiving other
anti-cancer agents or radiation therapy are not eligible.

Anti-hypertensive Medications: Patients who are currently receiving more than one
anti-hypertensive medication or whose blood pressure is not controlled as defined by
protocol are not eligible for study enrollment.

Anti-coagulation: Patients must not be on therapeutic anti-coagulation. Prophylactic
anti-coagulation (i.e., intraluminal heparin) of venous or arterial access devices is

Anti-inflammatory and Anti-platelet Agents: Patients currently receiving aspirin,
and/or ibuprofen, or other NSAIDs are not eligible.

Enzyme-inducing Anti-convulsants: Patients who are currently receiving enzyme-inducing
anti-convulsants are not eligible.

CYP3A4 Substrates and Drugs Causing QTc Prolongation: Patients receiving drugs with a
known risk of torsades de pointes are not eligible. A list of enzyme inducing, enzyme
inhibiting, and other prohibited drugs is provided by the protocol.

Note: This list includes the prohibition of grapefruit for 14 days prior to

Thyroid Replacement Therapy: Patients who require thyroid replacement therapy are not
eligible if they have not been receiving a stable replacement dose for at least 4
weeks prior to study enrollment.

3. Patients who are unable to swallow whole tablets are not eligible.

4. Infection: Patients who have an active or uncontrolled infection are not eligible.

5. Bleeding and Thrombosis: Patients will be excluded if any of the following are

- Evidence of active bleeding, intratumoral hemorrhage, or bleeding diathesis.

- History (within 6 months prior to study enrollment) of pulmonary embolism, deep
vein thrombosis (DVT), or other venous thromboembolic event.

- History of hemoptysis within 6 weeks prior to study enrollment.

6. Patients with known involvement of the CNS by malignancy will be included if there is
no evidence of active bleeding or intratumoral hemorrhage on radiographic imaging.

7. Surgery: Patients who have had or are planning to have the following invasive
procedures will be excluded:

- Major surgical procedures, laparoscopic procedure, open biopsy, or significant
traumatic injury within 28 days prior to Day 1 therapy. Subcutaneous port
placement or central line placement is not considered major surgery, but must be
placed greater than 48 hours from planned Day 1 of therapy.

- Core biopsy within 7 days prior to Day 1 therapy.

- Fine needle aspirate or central line placement within 48 hours prior to Day 1

Note: Routine bone marrow aspirate and biopsy for the purposes of disease staging are
not part of these exclusion guidelines.

8. Patients with serious or non-healing wound, ulcer, or bone fracture.

9. History of abdominal fistula, gastrointestinal perforation, pneumothorax, or
intra-abdominal abscess within 28 days of study enrollment.

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

11. Patients with history of allergic reactions attributed to compounds of similar
composition to pazopanib, irinotecan, or temozolomide are not eligible.