Clinical Trials /

PAZIT Study for Children and Young Adults With Relapsed or Refractory Sarcoma

NCT03139331

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.

Related Conditions:
  • Desmoplastic Small Round Cell Tumor
  • Ewing Sarcoma/Peripheral Primitive Neuroectodermal Tumor of Bone
  • Osteosarcoma
  • Rhabdomyosarcoma
  • Soft Tissue Sarcoma
Recruiting Status:

Recruiting

Phase:

Phase 1

Trial Eligibility

Document

Title

  • Brief Title: PAZIT Study for Children and Young Adults With Relapsed or Refractory Sarcoma
  • Official Title: Phase 1 Study of Pazopanib in Combination With Irinotecan and Temozolomide (PAZIT) for Children and Young Adults With Relapsed or Refractory Sarcoma

Clinical Trial IDs

  • ORG STUDY ID: 160821
  • SECONDARY ID: NCI-2017-01929
  • NCT ID: NCT03139331

Conditions

  • Sarcoma

Interventions

DrugSynonymsArms
PazopanibPazopanib, irinotecan, temozolomide (PAZIT)
IrinotecanPazopanib, irinotecan, temozolomide (PAZIT)
TemozolomidePazopanib, irinotecan, temozolomide (PAZIT)

Purpose

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.

Detailed Description

      The combination of irinotecan and temozolomide is well-tolerated and provides an active
      therapy option for heavily pre-treated patients with sarcoma. The toxicity profile and
      activity level suggest that this combination will provide a useful platform onto which novel
      compounds may be added. Pazopanib has been shown to demonstrate single-agent activity in
      sarcomas in the preclinical and clinical settings. Pazopanib has also been shown to have
      additive or synergistic effects in preclinical models of sarcomas when combined with
      cytotoxic chemotherapy. Pharmacokinetic studies of pazopanib and irinotecan as well as
      pharmacodynamic studies of pazopanib to assess anti-angiogenesis will be performed.
      Exploratory studies to assess non-invasive methods of monitoring tumor response [circulating
      tumor DNA and functional imaging by positron emission tomography (PET)/magnetic resonance
      imaging (MRI) will be performed].
    

Trial Arms

NameTypeDescriptionInterventions
Pazopanib, irinotecan, temozolomide (PAZIT)ExperimentalPatients will receive daily oral pazopanib on days 1-21 in a 21-day cycle. This will be combined with intravenous or oral irinotecan and oral temozolomide on days 1-5. Dosing of irinotecan will be from 25 to 37.5 mg/m2/day for IV dosing or from 45 to 67.5 mg/m2/dose for oral dosing and oral temozolomide will be 100 mg/m2/day for dose levels at each assigned dose level. In the absence of disease progression or unacceptable toxicity, patients will receive cycles of therapy repeating every 21 days for a maximum of 12 months on study.
  • Pazopanib
  • Irinotecan
  • Temozolomide

Eligibility Criteria

        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 </= 16 years of age.

             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
             </= 1.

             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 </= 1.5 x upper limit of normal (ULN) for age

          -  Serum glutamate pyruvate transaminase (SGPT)/alanine aminotransferase (ALT) </= 3.0 x
             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
             antibody.

        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) </= 95% percentile for
        age, height, and gender. Patients on stable doses of no more than one anti-hypertensive
        medication, with a baseline BP </= 95% percentile for age, height, and gender will be
        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 </= Grade 2.

        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
        (PTT) </= 1.5 x ULN and an international normalized ratio (INR) </= 1.2.

        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
             allowed.

             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
             enrollment.

             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
             present:

               -  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
                  therapy.

             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.
      
Maximum Eligible Age:30 Years
Minimum Eligible Age:6 Years
Eligible Gender:All
Healthy Volunteers:No

Primary Outcome Measures

Measure:Maximum Tolerated Dose
Time Frame:3 weeks
Safety Issue:
Description:Maximum tolerated dose or recommended phase 2 dose of pazopanib administered in combination with irinotecan and temozolomide

Secondary Outcome Measures

Measure:Objective Response Rate Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
Time Frame:From treatment initiation until disease progression, an average of about 6 months
Safety Issue:
Description:The best overall response is the best response recorded from the start of the treatment until disease progression/recurrence (taking as reference for progressive disease the smallest measurements recorded since the treatment started). The patient's best response assignment will depend on the achievement of both measurement and confirmation criteria. Tumor response will be assessed using RECIST version 1.1.
Measure:Progression-Free Survival (PFS) Using RECIST Version 1.1
Time Frame:From treatment initiation until disease progression, an average of about 6 months
Safety Issue:
Description:PFS is defined as the duration of time from start of treatment to time of tumor progression. Tumor response will be assessed using RECIST version 1.1.
Measure:Overall Survival (OS)
Time Frame:From treatment initiation until death, an average of about 1 year
Safety Issue:
Description:OS is defined as the duration of time from start of treatment to time of death from any cause.

Details

Phase:Phase 1
Primary Purpose:Interventional
Overall Status:Recruiting
Lead Sponsor:University of California, San Francisco

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