Sarcoma
Conditions
Keywords
recurrent Ewing sarcoma/peripheral primitive neuroectodermal tumor, chondrosarcoma, recurrent osteosarcoma
Brief summary
RATIONALE: Drugs used in chemotherapy, such as gemcitabine and docetaxel, work in different ways to stop tumor cells from dividing so they stop growing or die. Combining gemcitabine with docetaxel may kill more tumor cells. PURPOSE: Phase II trial to study the effectiveness of combining gemcitabine with docetaxel in treating patients who have recurrent osteosarcoma, recurrent Ewing's sarcoma, or unresectable or locally recurrent chondrosarcoma.
Detailed description
OBJECTIVES: Primary * Determine the objective response rate in patients with recurrent osteosarcoma or Ewing's sarcoma or unresectable or locally recurrent chondrosarcoma treated with sequential gemcitabine and docetaxel. Secondary * Determine the time to progression in patients treated with this regimen. * Assess the toxicity of this regimen in these patients. * Compare the pharmacokinetics of this regimen vs gemcitabine alone in these patients. * Obtain tumor samples for cDNA microarray analysis of gene expression and development of cell lines and xenotransplantation models. OUTLINE: This is a nonrandomized, multicenter study. Patients are stratified according to diagnosis recurrent osteosarcoma vs recurrent Ewing's sarcoma vs unresectable or locally recurrent chondrosarcoma). Patients receive gemcitabine intravenously over 90 minutes on days 1 and 8 and docetaxel intravenously over 1 hour on day 8. Patients also receive filgrastim (G-CSF) subcutaneously (SC) beginning on day 9 and continuing until blood counts recover. Patients may receive pegfilgrastim SC on day 9 (once per course) as an alternative to G-CSF. Treatment repeats every 21 days in the absence of disease progression or unacceptable toxicity. Optional blood samples are collected at baseline and periodically during study for pharmacokinetics studies. Optional tumor tissue samples from biopsy or surgical resection are analysed for cDNA microarray analysis of gene expression. Patients are followed every 3 months for 1 year and then every 6 months for 1 year. PROJECTED ACCRUAL: A maximum of 120 patients (40 per stratum) will be accrued for this study within 17-24 months.
Interventions
BIOLOGICALfilgrastim
filgrastim
BIOLOGICALpegfilgrastim
pegfilgrastim
DRUGdocetaxel
docetaxel
DRUGgemcitabine hydrochloride
gemcitabine hydrochloride
GENETICmicroarray analysis
microarray analysis
OTHERlaboratory biomarker analysis
laboratory biomarker analysis
OTHERpharmacokinetic study
pharmacokinetic study
Sponsors
Sarcoma Alliance for Research through Collaboration
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
4 Years to No maximum
Healthy volunteers
No
Inclusion criteria
DISEASE CHARACTERISTICS: * Histologically confirmed\* diagnosis of 1 of the following: * Recurrent high-grade osteosarcoma (closed to accrual as of 12/21/06) or Ewing's sarcoma * Progressive disease after standard therapy * Received no more than 2 additional salvage regimens * Chondrosarcoma * Unresectable OR locally recurrent and unable to be completely resected NOTE: \*Biopsy required for isolated pulmonary recurrences * Measurable disease * At least 1 unidimensionally measurable lesion by medical imaging techniques * Ascites, pleural effusions, and bone marrow disease are not considered measurable disease PATIENT CHARACTERISTICS: Age * 4 and over Performance status * ECOG (Eastern Cooperative Oncology Group) 0-2 (≥ 18 years of age) * Karnofsky 50-100% (11-17 years of age) * Lansky 50-100% (≤ 10 years of age) Life expectancy * Not specified Hematopoietic * Absolute neutrophil count ≥ 1,500/mm\^3 * Platelet count ≥ 100,000/mm\^3 (transfusion independent) * Hemoglobin ≥ 8.0 g/dL (transfusion allowed) Hepatic * Bilirubin ≤ upper limit of normal (ULN) (except for patients with Gilbert's syndrome) * ALT ≤ 2.5 times ULN Renal * Creatinine clearance or radioisotope glomerular filtration rate \> 70 mL/min/1.73 m\^2 OR * Serum creatinine ≤ ULN for age: * Ages 5 and under ≤ 0.8 mg/dL * Ages 6 to 10 ≤ 1.0 mg/dL * Ages 11 to 15 ≤ 1.2 mg/dL * Ages 16 to 18 ≤ 1.5 mg/dL Other * Not pregnant or nursing * Negative pregnancy test * Fertile patients must use effective contraception during and for 3 months after study participation * Sensory or motor neuropathy due to prior chemotherapy ≤ grade 1 * Sensory or motor neuropathy due to prior surgery or tumor involvement ≤ grade 2 AND stable or improving * No active or uncontrolled infection * No known hypersensitivity reaction to docetaxel or other polysorbate 80-formulated agents PRIOR CONCURRENT THERAPY: Biologic therapy * At least 72 hours since prior filgrastim (G-CSF) * No prior allogeneic transplantation * No concurrent immunotherapy Chemotherapy * At least 2 weeks since prior myelosuppressive therapy * At least 6 months since prior myeloablative therapy * No prior gemcitabine * No prior taxanes * No other concurrent chemotherapy Endocrine therapy * Concurrent hormonal therapy allowed Radiotherapy * At least 6 weeks since prior local radiotherapy * At least 4 months since prior extensive radiotherapy to more than 50% of the pelvis * At least 4 months since prior cranial spinal radiotherapy * At least 6 months since prior total body irradiation * No concurrent radiotherapy Surgery * No concurrent surgery Other * Recovered from all prior therapy * No other concurrent investigational anticancer therapy
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Objective Response Rate | After 2, 4, 8 and 12 cycles of therapy, each cycle is 21 days | Patients will be evaluated up to 4 time points(after 2,4,8 and 12 cycles of therapy), each cycle is 21 days. Per RECIST 1.0 and assessed by CT/MRI disease status will be categorized as R=CR/PR(response), F=progressive disease or death(failure), or S(stable disease=neither R nor F) based on the change from baseline. A patient with outcome R or F at any stage is scored as having that overall outcome, a patient with outcome S is re-evaluated after subsequent cycles of therapy. Patients who receive more than 14 cycles of therapy will be scored as the outcome at completion of cycle 14. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Time to Progression | post-cycle 2, 4, 8 and 12 | Stable disease is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started. The clinical relevance of the duration of stable disease varies for different tumor types and grades. Bayesian statistical model is used. Timepoints for evaluation are post-cycle 2, 4, 8 and 12 using RECIST 1.0 criteria. |
| Toxicity as Assessed by NCI CTCAE v3.0 | Throughout the study | Toxicity was graded according to Common Terminology Criteria for Adverse Events v.3.0 (CTCAE v.3.0). For gemcitabine or docetaxel related grade 3 or 4 non-hematological toxicities or hematological toxicities (grade 3 or 4 neutropenia for ≥ 7 days, grade 4 thrombocytopenia, or any platelet transfusion), both agents were withheld until the toxicity was ≤ grade 1. If the toxicity recovered to ≤ grade 1 by cycle day 35, the dose of both agents was reduced for all subsequent cycles. If the toxicity did not resolve by day 35, protocol therapy was discontinued. |
| Pharmacokinetics of Gemcitabine Alone and Gemcitabine Followed by Docetaxel at Protocol Specified Timeframe in Participants Enrolled on Study | Gemcitibine: 0hr, 75, 85, 95, 105 and 120 min after the start of the 90 minute infusion; docetaxel: 0hr, 55 min, 30 min post infusion, 5hr and 24hr post infusion. | Blood samples for the determination of gemcitabine (and its metabolite dFdU) will be obtained prior to infusion, at 75 and 85 minutes (steady state), and 95 105 and 120 minutes, after the start of the 90 minute infusion on day 1 and day 8 of cycle 1. On day 8, docetaxel pharmacokinetics will be performed prior to infusion, 55 minutes (5 minutes prior to the end of infusion), 30 minutes post infusion, 5 hr and 24hr post infusion. |
Participant flow
Recruitment details
Recruitment period began October 4, 2006 and was completed May 12, 2009. There were 11 SARC (Sarcoma Alliance for Research through Collaboration) sites participating. SARC sites are primarily academic institutions with Sarcoma programs.
Participants by arm
| Arm | Count |
|---|---|
| Combination Chemotherapy Gemcitibine 675 mg/m\^2 given intravenous (IV) on day 1 and 8; docetaxel 75 mg/m\^2 given IV on day 8 after gemcitibine. Each cycle is 21 days. Cycles of chemotherapy administered until off study criteria met. | 54 |
| Total | 54 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Overall Study | not evaluable | 1 |
Baseline characteristics
| Characteristic | Combination Chemotherapy |
|---|---|
| Age, Categorical <=18 years | 3 Participants |
| Age, Categorical >=65 years | 9 Participants |
| Age, Categorical Between 18 and 65 years | 42 Participants |
| Age Continuous | 43 years STANDARD_DEVIATION 19 |
| Region of Enrollment United States | 54 participants |
| Sex: Female, Male Female | 21 Participants |
| Sex: Female, Male Male | 33 Participants |
Adverse events
| Event type | EG000 affected / at risk |
|---|---|
| deaths Total, all-cause mortality | — / — |
| other Total, other adverse events | 36 / 53 |
| serious Total, serious adverse events | 12 / 53 |
Outcome results
Primary
Objective Response Rate
Patients will be evaluated up to 4 time points(after 2,4,8 and 12 cycles of therapy), each cycle is 21 days. Per RECIST 1.0 and assessed by CT/MRI disease status will be categorized as R=CR/PR(response), F=progressive disease or death(failure), or S(stable disease=neither R nor F) based on the change from baseline. A patient with outcome R or F at any stage is scored as having that overall outcome, a patient with outcome S is re-evaluated after subsequent cycles of therapy. Patients who receive more than 14 cycles of therapy will be scored as the outcome at completion of cycle 14.
Time frame: After 2, 4, 8 and 12 cycles of therapy, each cycle is 21 days
Population: Analysis per protocol. One patient with chondrosarcoma was ineligible due to lack of measurable disease at enrollment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Ewing's Sarcoma | Objective Response Rate | 6 participants |
| Osteosarcoma | Objective Response Rate | 5 participants |
| Chondrosarcoma | Objective Response Rate | 14 participants |
Secondary
Pharmacokinetics of Gemcitabine Alone and Gemcitabine Followed by Docetaxel at Protocol Specified Timeframe in Participants Enrolled on Study
Blood samples for the determination of gemcitabine (and its metabolite dFdU) will be obtained prior to infusion, at 75 and 85 minutes (steady state), and 95 105 and 120 minutes, after the start of the 90 minute infusion on day 1 and day 8 of cycle 1. On day 8, docetaxel pharmacokinetics will be performed prior to infusion, 55 minutes (5 minutes prior to the end of infusion), 30 minutes post infusion, 5 hr and 24hr post infusion.
Time frame: Gemcitibine: 0hr, 75, 85, 95, 105 and 120 min after the start of the 90 minute infusion; docetaxel: 0hr, 55 min, 30 min post infusion, 5hr and 24hr post infusion.
Population: There were insufficent samples obtained to analyze pharmacokinetics.
Secondary
Time to Progression
Stable disease is measured from the start of the treatment until the criteria for disease progression are met, taking as reference the smallest measurements recorded since the treatment started. The clinical relevance of the duration of stable disease varies for different tumor types and grades. Bayesian statistical model is used. Timepoints for evaluation are post-cycle 2, 4, 8 and 12 using RECIST 1.0 criteria.
Time frame: post-cycle 2, 4, 8 and 12
Population: Analysis not completed. One patient with chondrosarcoma was ineligible due to lack of measurable disease at enrollment.
Secondary
Toxicity as Assessed by NCI CTCAE v3.0
Toxicity was graded according to Common Terminology Criteria for Adverse Events v.3.0 (CTCAE v.3.0). For gemcitabine or docetaxel related grade 3 or 4 non-hematological toxicities or hematological toxicities (grade 3 or 4 neutropenia for ≥ 7 days, grade 4 thrombocytopenia, or any platelet transfusion), both agents were withheld until the toxicity was ≤ grade 1. If the toxicity recovered to ≤ grade 1 by cycle day 35, the dose of both agents was reduced for all subsequent cycles. If the toxicity did not resolve by day 35, protocol therapy was discontinued.
Time frame: Throughout the study
Population: Analysis per protocol. One patient with chondrosarcoma was ineligible due to lack of measurable disease at enrollment.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Ewing's Sarcoma | Toxicity as Assessed by NCI CTCAE v3.0 | Toxicity | 4 participants |
| Ewing's Sarcoma | Toxicity as Assessed by NCI CTCAE v3.0 | No Toxicity | 10 participants |
| Osteosarcoma | Toxicity as Assessed by NCI CTCAE v3.0 | Toxicity | 3 participants |
| Osteosarcoma | Toxicity as Assessed by NCI CTCAE v3.0 | No Toxicity | 11 participants |
| Chondrosarcoma | Toxicity as Assessed by NCI CTCAE v3.0 | Toxicity | 5 participants |
| Chondrosarcoma | Toxicity as Assessed by NCI CTCAE v3.0 | No Toxicity | 20 participants |