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

NCT03139331 | Completed Phase 1 DMC FDA Drug

• 2 other identifiers: 160821NCI-2017-01929
• Study Type: interventional
• Target: 16
• Locations: 1 country
• Sites: 3

Brief Summary

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.

Conditions

Sarcoma; Refractory Sarcoma

Outcome Measures

Primary Outcomes (3)

• Maximum Tolerated Dose

  Maximum tolerated dose or recommended phase 2 dose of pazopanib administered in combination with irinotecan and temozolomide

  3 weeks

• Number of Patients with Dose-Limiting Toxicities (DLTs) Using the National Cancer Institute (NCI) Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0

  Toxicity will be graded using the CTCAE criteria, version 4.0. DLT will be defined as any of the events as defined per the protocol that are at least possibly, probably, or definitely attributable to the combination of pazopanib, irinotecan, and temozolomide. DLTs are generally grade 3 or greater in severity. Dose limiting hematological and non-hematological toxicities are defined differently, per the protocol.

  3 weeks

• Describing toxicities of PAZIT drug combination using NCI CTCAE Version 4.0

  To describe any toxicities associated with the combination of pazopanib, irinotecan and temozolomide (PAZIT).

  3 weeks

Secondary Outcomes (3)

• Objective Response Rate Using Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1

  From treatment initiation until disease progression, an average of about 6 months

• Progression-Free Survival (PFS) Using RECIST Version 1.1

  From treatment initiation until disease progression, an average of about 6 months

• Overall Survival (OS)

  From treatment initiation until death, an average of about 1 year

Study Arms (1)

Pazopanib, irinotecan, temozolomide (PAZIT)

EXPERIMENTAL

Patients 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.

Drug: Pazopanib; Drug: Irinotecan; Drug: Temozolomide

Interventions

Pazopanib DRUG

Pazopanib will be administered orally as a tablet according to an assigned dose level per protocol. A cycle will be defined as 21 days. Drug dosing for the tablet formulation will be determined using a study-specific nomogram.

Pazopanib, irinotecan, temozolomide (PAZIT)

Irinotecan DRUG

Patients will be given irinotecan at a dose of 25 mg/m2/dose IV on days 1-5 of a 21-day cycle during Cycle 1. In subsequent cycles, irinotecan may be given intravenously at a dose of 25 to 37.5 mg/m2/dose or orally at a dose of 45 to 67.5 mg/m2/dose on days 1-5 of a 21-day cycle. Note that some patients enrolled on an earlier protocol version received 50 mg/m2/dose IV on days 1-5 of the first 21-day cycle and then either 50 mg/m2/dose IV or 90 mg/m2/dose orally for subsequent 21-day cycles. This higher dose level is no longer being given to newly enrolled subjects.

Pazopanib, irinotecan, temozolomide (PAZIT)

Temozolomide DRUG

Temozolomide will be given at a dose of 100 mg/m2/dose orally on days 1-5 of each 21-day cycle.

Pazopanib, irinotecan, temozolomide (PAZIT)

Eligibility Criteria

• Age: 6 Years - 30 Years
• Sex: all
• Healthy Volunteers: No
• Age Groups: Child (0-17), Adult (18-64)

You may qualify if:

• Age: Patients must be 6-30 years of age at the time of study enrollment.
• 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.
• 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.
• Disease Status: Patients must have either measurable or evaluable disease
• 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.
• 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.
• 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).

You may not qualify if:

• 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.
• 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.
• Patients who are unable to swallow whole tablets are not eligible.
• Infection: Patients who have an active or uncontrolled infection are not eligible.
• Bleeding and Thrombosis: Patients will be excluded if any of the following are present:

Sponsors & Collaborators

• University of California, San Francisco: lead
• UCSF Benioff Children's Hospital Oakland: collaborator
• Dana-Farber Cancer Institute: collaborator
• Alex's Lemonade Stand Foundation: collaborator

Study Sites (3)

UCSF Benioff Children's Hospital, Oakland

Oakland, California, 94609, United States

Location

University of California, San Francisco

San Francisco, California, 94143, United States

Location

Dana-Farber Cancer Institute

Boston, Massachusetts, 02215, United States

Location

MeSH Terms

Conditions

Sarcoma

Interventions

pazopanib; Irinotecan; Temozolomide

Condition Hierarchy (Ancestors)

Neoplasms, Connective and Soft Tissue; Neoplasms by Histologic Type; Neoplasms

Intervention Hierarchy (Ancestors)

Camptothecin; Alkaloids; Heterocyclic Compounds; Dacarbazine; Triazenes; Organic Chemicals; Imidazoles; Azoles; Heterocyclic Compounds, 1-Ring

Study Officials

• Kieuhoa Vo, MD, MAS

  University of California, San Francisco

  PRINCIPAL INVESTIGATOR

Study Design

• Study Type: interventional
• Phase: phase 1
• Allocation: NA
• Masking: NONE
• Purpose: TREATMENT
• Intervention Model: SINGLE GROUP
• Sponsor Type: OTHER
• Responsible Party: SPONSOR

Study Record Dates

• First Submitted: April 28, 2017
• First Posted: May 3, 2017
• Study Start: June 6, 2017
• Primary Completion: October 15, 2019
• Study Completion: September 30, 2020
• Last Updated: January 5, 2021

Record last verified: 2020-12

Data Sharing

• IPD Sharing: Will not share

Locations

US (3)