A Phase 2 interventional study of celecoxib and cyclophosphamide in Sarcoma, sponsored by Children's Oncology Group. Completed at 101 sites in 4 countries. Open to participants aged Up to 50 Years. Per ClinicalTrials.gov, last updated 2019-02-15.
Sponsored by Children's Oncology Group · Phase 2, Interventional, and Treatment
RATIONALE: Drugs used in chemotherapy, such as vinblastine, work in different ways to stop tumor cells from dividing so they stop growing or die. Celecoxib may stop the growth of Ewing's sarcoma by stopping blood flow to the tumor. Combining more than one chemotherapy drug with celecoxib may kill more tumor cells.
PURPOSE: Phase II trial to study the effectiveness of combining low-dose vinblastine and celecoxib with standard regimens of combination chemotherapy in treating patients who have newly-diagnosed metastatic Ewing's sarcoma family of tumors.
OBJECTIVES:
OUTLINE: This is a pilot, multicenter study.
Induction therapy: Patients receive the following alternating regimens:
Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning 24-48 hours after the last dose of chemotherapy and continuing until blood counts recover.
Treatment repeats every 21 days for a total of 4 courses in the absence of disease progression or unacceptable toxicity.
Local control and consolidation therapy: Beginning on week 13, patients are assigned to 1 of 4 regimens based on disease status.
Regimen A (surgery only): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients then begin consolidation therapy on week 15 with the following alternating regimens:
Regimen B (radiotherapy only): Patients with unresectable lesions undergo radiotherapy once daily 5 days a week for up to approximately 6 weeks beginning on week 13. Patients also receive consolidation therapy beginning on week 13, with the following alternating regimens:
Regimen C (surgery and radiotherapy): Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy (as in regimen B) beginning on week 15. Patients also receive consolidation therapy, beginning on week 15, with the following alternating regimens:
Regimen D (preoperative radiotherapy): Patients with bulky lesions who do not have a good clinical and radiographic response to induction therapy begin consolidation therapy on week 13 with VAC (course 5) and undergo concurrent radiotherapy as in regimen B. Patients then receive IE on weeks 16 and 19 for courses 6 and 7. Patients undergo surgery on week 22. Patients continue consolidation therapy with the following alternating regimens:
Consolidation therapy continues for 10 courses in the absence of disease progression or unacceptable toxicity.
Patients are followed every 3 months for 3 years and then every 6 months for 2 years.
PROJECTED ACCRUAL: A total of 6-36 patients will be accrued for this study within 1.17 years.
1,667 studies on the registry are indexed under Sarcoma; 393 are open to participants now.
This study's enrollment of 38 is close to the median of 40 across 1,283 interventional studies indexed under Sarcoma.
Browse Sarcoma studies →Children's Oncology Group is the lead sponsor of 436 studies on the registry; 34 are open to participants now.
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DISEASE CHARACTERISTICS:
Newly diagnosed Ewing's sarcoma family of tumors of the bone or soft tissues
Metastatic disease, defined by the following criteria:
PATIENT CHARACTERISTICS:
Age
Performance status
Karnofsky 50-100% (age 17 and over)
Life expectancy
Hematopoietic
Hepatic
Renal
Creatinine adjusted according to age as follows*:
Cardiovascular
Other
PRIOR CONCURRENT THERAPY:
Biologic therapy
Chemotherapy
Endocrine therapy
Radiotherapy
Surgery
Other
Metastatic Ewing Sarcoma - 14-cycle study building on conventional tx (cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, ifosfamide, etoposide) and adding two antiangiogenic agents: the vinca alkaloid vinblastine and the cyclooxygenase-2 inhibitor celecoxib. Refer to the Interventions section for dosages, method of delivery and frequency of administration.
Drug: celecoxib · Drug: cyclophosphamide · Drug: doxorubicin hydrochloride · Drug: etoposide · Drug: ifosfamide · Drug: vinblastine sulfate · Drug: vincristine sulfate · Procedure: conventional surgery · Radiation: radiation therapy · Drug: MESNA · Drug: Filgrastim
Given orally, Celecoxib 250 mg/m2 PO BID (500mg/m2/day) from Day 1 of Cycle 1 through Day 21 of Cycle 14. The dose should be rounded off to the nearest 100 mg. If PK studies are being done, Celecoxib should be given 24 hours prior to the other drugs for Cycle 1 only. \[Celecoxib may be interrupted for up to 7 days around the time of surgical procedures.\] .
Given IV, 1200 mg/m2 IV infusion over 1 hour with MESNA uroprotection, on Day 1. For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.
Given IV, Doxorubicin 75 mg/ m2 /course continuous IV infusion over 48 hours, beginning Day 1. Note: The total doxorubicin dose per cycle is 75 mg/ m2, which will be given as 37.5 mg/m2/day x 2 days. Doxorubicin may be given as a continuous infusion or brief infusion.
Given IV, Vincristine 2 mg/m2 IV push, on Day 1. Maximum dose 2 mg. For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.
Given IV,Ifosfamide 1800 mg/m2 /day IV infusion over 1 hour, Days 1-5 of each cycle. (9,000 mg/m2 max total dose per cycle). Prehydrate for 6 hours, 1,000 ml/m2 total volume (165 ml/m2/hour for 6 hours). For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.
Given IV, Vinblastine 1 mg/m2/d IV push three times per week beginning Day 1 of Cycle 1 and continuing through Day 21 of Cycle 14. In weeks during which vincristine is given, hold one dose of vinblastine and administer only 2 doses of vinblastine during that week. If vinblastine is due the same day as vincristine, hold that dose of vinblastine. \[Vinblastine may be interrupted for up to 7 days around the time of surgical procedures.\]
Given IV, Vincristine 2 mg/m2 IV push, on Day 1. Maximum dose 2 mg. For children \< 1 year treat with 50% doses calculated on a m2 basis. If tolerated (no delay in administration of the next cycle due to delayed count recovery or delayed resolution of other toxicities and no serious toxicities), consider increasing to 75% and then to 100% of the calculated full dose.
Patients who respond to induction chemotherapy undergo surgery on week 13. Patients who have inadequate margins after surgery undergo radiotherapy beginning on week 15. (see Detailed Description for frequency of administration and groups evaluated)
Patients with unresectable lesions undergo radiotherapy 5 days a week for approximately 6 weeks beginning on week 13. (see Detailed Description for frequency of administration and groups evaluated)
The total daily MESNA dose is equal to at least 60% of the daily cyclophosphamide or ifosfamide dose, or by continuous infusion of the 60% dose. MESNA continuous infusion should be started at the same time as the cyclophosphamide/ifosfamide and be completed no sooner than 8 hours after the end of the cyclophosphamide or ifosfamide infusion. The oral dose of MESNA is 2x the IV dose. Patients able to tolerate oral MESNA may receive the final dose by mouth at 40% of the oxazaphosphorine (cyclophosphamide or ifosfamide) dose. The dose should be given two hours earlier than the IV dose would be given. Additionally, if the patient vomits within two hours after the oral dose, the dose should be repeated or IV MESNA given.
G-CSF (Filgrastim) 5 micrograms/kg/day subcutaneously beginning 24 to 48 hours after the last dose of chemotherapy, and continuing until the absolute neutrophil count is 2,000/µL or greater after nadir.
Also known as: G-CSF
Occurrence of Severe Toxicity
An incidence of severe toxicity is defined to be the occurrence of grade 3 or higher infection or grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy. If 12 or more patients experience grade 3 or higher infection or five or more patients experience grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy, the regimen will be flagged as being associated with an excessive rate of severe toxicity.
Time frame: The first two cycles (6 weeks) of protocol chemotherapy
Event Free Survival
Time frame: 24 months after start of protocol therapy
| Milestone | Combination Chemotherapy |
|---|---|
| Started | 38 |
| Completed | 20 |
| Not completed | 18 |
An incidence of severe toxicity is defined to be the occurrence of grade 3 or higher infection or grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy. If 12 or more patients experience grade 3 or higher infection or five or more patients experience grade 3 or higher sensory neuropathy during cycles 1-2 of protocol therapy, the regimen will be flagged as being associated with an excessive rate of severe toxicity.
| participants | Combination Chemotherapy |
|---|---|
| Grade 3 or Higher Infection | 1 |
| Grade 3 or Higher Sensory Neuropathy | 1 |
| percentage of participants | Combination Chemotherapy |
|---|---|
| Event Free Survival | 35 (19 to 51) |
Non-serious events are listed at a 0% frequency threshold.
| Group | Deaths | Serious | Other |
|---|---|---|---|
| Combination Chemotherapy | — | 33/35 (94.3%) | 34/35 (97.1%) |
| Event | Combination Chemotherapy |
|---|---|
| Neutrophil count decreasedInvestigations | 19/35 |
| Infections and infestations - Other, specifyInfections and infestations | 18/35 |
| Platelet count decreasedInvestigations | 16/35 |
| White blood cell decreasedInvestigations | 16/35 |
| Febrile neutropeniaBlood and lymphatic system disorders | 15/35 |
| HypokalemiaMetabolism and nutrition disorders | 14/35 |
| AnemiaBlood and lymphatic system disorders | 12/35 |
| AnorexiaMetabolism and nutrition disorders | 6/35 |
| HyponatremiaMetabolism and nutrition disorders | 6/35 |
| HypoxiaRespiratory, thoracic and mediastinal disorders | 6/35 |
| Event | Combination Chemotherapy |
|---|---|
| HypophosphatemiaMetabolism and nutrition disorders | 17/35 |
| ProteinuriaRenal and urinary disorders | 15/35 |
| HematuriaRenal and urinary disorders | 12/35 |
| Rash maculo-papularSkin and subcutaneous tissue disorders | 10/35 |
| AcidosisMetabolism and nutrition disorders | 9/35 |
| HypokalemiaMetabolism and nutrition disorders | 9/35 |
| GastritisGastrointestinal disorders | 8/35 |
| Peripheral sensory neuropathyNervous system disorders | 4/35 |
| Alanine aminotransferase increasedInvestigations | 3/35 |
| HypocalcemiaMetabolism and nutrition disorders | 3/35 |
| Age, Continuous(years) | Combination Chemotherapy |
|---|---|
| Mean | 12.97 ± 5.81 |
| Sex: Female, Male(Participants) | Combination Chemotherapy |
|---|---|
| Female | 15 |
| Male | 23 |
| Ethnicity (NIH/OMB)(Participants) | Combination Chemotherapy |
|---|---|
| Hispanic or Latino | 5 |
| Not Hispanic or Latino | 31 |
| Unknown or Not Reported | 2 |
| Race (NIH/OMB)(Participants) | Combination Chemotherapy |
|---|---|
| American Indian or Alaska Native | 1 |
| Asian | 1 |
| Native Hawaiian or Other Pacific Islander | 1 |
| Black or African American | 0 |
| White | 30 |
| More than one race | 0 |
| Unknown or Not Reported | 5 |
| Region of Enrollment(participants) | Combination Chemotherapy |
|---|---|
| United States | 34 |
| Canada | 4 |
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