Cancer
Conditions
Keywords
erlotinib, celecoxib, radiation, progression-free survival
Brief summary
Cancer is the second leading cause of death in the United States, with approximately 90% of deaths resulting from patients with metastatic spread. Save for notable exceptions such as testicular cancer, chemotherapy alone cannot cure patients with metastases. Some patients with limited metastatic deposits (most commonly colon cancer spread to the liver) can be cured with surgery followed by chemotherapy. Therefore, some patients with metastases should be considered for aggressive local therapy (surgery and/or radiation). Even though chemotherapy has improved significantly, patients treated with conventional chemotherapy and/or biologically targeted therapy are not cured of their disease. For the most common types of cancer, chemotherapy alone can shrink or stabilize tumors for an average of 6 months before the tumors regrow. Both chemotherapy and biologically targeted therapy have major limitations preventing cure of these patients. Radiation therapy is an effective modality of treating cancer. Until recently, radiation for metastases was used only to relieve symptoms resulting from local tumor growth. Technological advances, including stereotactic radiotherapy, allow for radiation to be more precisely delivered to the tumor while sparing nearby normal organs. Stereotactic radiotherapy can completely eradicate local tumors with minimal side effects. Stereotactic radiotherapy has never been combined with drug therapy. Sutent is a new F.D.A. approved cancer therapy that targets tumor blood vessels. It is effective against two types of cancer that rarely respond to chemotherapy (GI stromal tumors and kidney cancer). We propose combining biologically targeted drug therapy with physically targeted stereotactic radiotherapy. Our goal is to determine if this is a safe regimen and the best method of combining these treatments. Ultimately, our goal is to cure some patients with previously incurable metastatic cancer with this combination.
Interventions
Sutent administered PO QD from days 1 to 28 Two weeks after completion of any chemotherapy, maintenance Sutent in 6 week cycles (consisting of Sutent 50 mg PO QD weeks 1-4 followed by no treatment weeks 5-6) until progression or death If no chemotherapy is planned, maintenance Sutent (as described above) will start on day 43.
PROCEDUREradiotherapy
Radiation is to be delivered to each site over 10 fractions separated by at least 16 hours. Up to 5 sites may be treated
Sponsors
Pfizer
Icahn School of Medicine at Mount Sinai
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
TREATMENT
Masking
NONE
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Zubrod Performance Scale 0-1 * Metastatic disease confirmed by biopsy or imaging * 5 or fewer sites of metastatic disease on tumor staging (either CT chest/abdomen/pelvis plus bone scan or whole body FDG-PET) * All tumors measure \< 6 cm * Age \> 18 * Chemotherapy must be completed at least 2 weeks prior to radiation * Signed informed consent * Adequate bone marrow function, defined as follows; 1. Platelets \> 100,000 cells/mm3 based upon CBC/differential obtained within 2 weeks prior to registration on study 2. Absolute neutrophil count (ANC) \> 1,800 cells/mm3 based on CBC/differential obtained within 2 weeks prior to registration on study 3. Hemoglobin \> 8.0 g/dl based upon CBC/differential obtained within 2 weeks prior to registration on study (Note: The use of transfusion or other intervention to achieve Hgb \> 8.0 g/dt is acceptable.)
Exclusion criteria
* Other coexisting malignancies or malignancies diagnosed within the previous 3 years with the exception of basal cell carcinoma, cervical carcinoma in situ, and other treated malignancies with no evidence of disease for at least 3 years * Uncontrolled intercurrent illness including, but not limited to, ongoing active infection, symptomatic congestive heart failure (CHF), unstable angina pectoris, cardiac arrhythmia, or psychiatric illness/social situations that would limit compliance with the study requirements * Patients with clinically significant pulmonary dysfunction, cardiomyopathy, or any history of clinically significant CHF are excluded. The exclusion of patients with active coronary heart disease will be at the discretion of the attending physician. * Patients with exudative, bloody, or cytologically malignant effusions are not eligible. * Pregnancy or breast feeding (Women of child-bearing potential are eligible, but must consent to using effective contraception during therapy and for at least 3 months after completing therapy) * Patients must have no uncontrolled active infection other than that not curable without treatment of their cancer. * Prior radiation to target area * Patient may not be receiving any other investigational agents during radiotherapy. * Prior history of non-inducible bleeding (12/16/09). * Requirement for continuation of anticoagulation (defined as Coumadin, lovenox, heparin, plavix, aspirin, NSAIDs or similar drugs) during treatment (12/16/09) * Under 18 years of age
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Number of Participants With Dose Limiting Toxicity (DLT) | 2 years | Sunitinib (SU) and radiation (IGRT) doses were sequentially escalated using a ping-pong strategy according to a 3 + 3 design phase 1 study. The starting dose was sunitinib 25 mg and IGRT 40 Gy. MTD reflects the highest dose that did not cause a dose limiting toxicity. Toxicity was in assessed in patients at regular intervals by using the Common Terminology Criteria for Adverse Events criteria (version 3.0). Dose limiting events were defined as any grade 4 or 5 toxicity and unexpected grade 3 toxicity. Expected grade 3 toxicities from radiation include mucositis or esophagitis lasting ≤7 days. Grade 3 metabolic and hematologic toxicities are considered expected events with sunitinib and therefore were not considered DLTs |
| Number of Participants With Particular Disease Status | 5 years | Number of participants who have no evidence of disease and number of participants with distant metastases. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Percentage of Patients With Distant Control | 4 weeks | Distant control defined as distant metastasis contained outside of the radiation field within months of treatment. |
| Percentage of Patients With Toxicity Grade 3 or Higher | 5 years | % of patients experienced one or more grade ≥ 3 toxicities. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4),and death (Grade 5). |
| Number of Participants According Failure and Survival | 4 years | — |
| Quality of Life | 4-6 weeks after radiation therapy | — |
| Percentage of Patients With Local Control | 4 years | Local control was defined as a tumor volume equal to or less than the tumor volume at start of radiotherapy. |
Countries
United States
Participant flow
Recruitment details
Recruitment period began January 2007 and was open for recruitment through July 2014 with 47 patients enrolled in the study between February 2007 and September 2010.
Pre-assignment details
One patient withdrew prior to starting treatment and was excluded from analysis. Phase 1: 21 patients in Phase 1 in dose-escalating study to find maximum-tolerated dose Phase 2: 25 patients on the recommended phase II dose, 37.5mg
Participants by arm
| Arm | Count |
|---|---|
| Phase I N=21 participants Patients enrolled between Feb 2007 and May 2008 | 21 |
| Phase II Advanced Solid Tumor Malignancy Patients were eligible if they had histologically or cytological documented advanced solid tumor malignancy with radiographic evidence of 1 to 5 sites of active metastatic disease.
N=26 participants Patients enrolled between February 2008 and September 2010 | 25 |
| Total | 46 |
Withdrawals & dropouts
| Period | Reason | FG000 |
|---|---|---|
| Phase 1-Radiation 50Gy +Sunitinib 50mg | acute toxicity | 5 |
| Phase 2-Radiation 50Gy +Sunitinib 37.5mg | Withdrawal by Subject | 1 |
Baseline characteristics
| Characteristic | Phase II Advanced Solid Tumor Malignancy | Total | Phase I |
|---|---|---|---|
| Age, Continuous | 63 years | 64 years | 65 years |
| ECOG Performance status 0 | 4 participants | 11 participants | 7 participants |
| ECOG Performance status 1 | 13 participants | 22 participants | 9 participants |
| ECOG Performance status 2 | 8 participants | 13 participants | 5 participants |
| Largest Tumor size <=3cm | 15 participants | 26 participants | 11 participants |
| Largest Tumor size >=3cm | 10 participants | 20 participants | 10 participants |
| Number of involved organs 1 | 14 participants | 31 participants | 17 participants |
| Number of involved organs >=2 | 11 participants | 15 participants | 4 participants |
| Number of metastases 1 | 13 participants | 26 participants | 13 participants |
| Number of metastases 2 | 5 participants | 8 participants | 3 participants |
| Number of metastases >=3 | 7 participants | 12 participants | 5 participants |
| Prior radiation therapy No | 15 participants | 25 participants | 10 participants |
| Prior radiation therapy Yes | 10 participants | 21 participants | 11 participants |
| Prior systemic chemotherapy No | 14 participants | 22 participants | 8 participants |
| Prior systemic chemotherapy Yes | 11 participants | 24 participants | 13 participants |
| Sex: Female, Male Female | 7 Participants | 14 Participants | 7 Participants |
| Sex: Female, Male Male | 18 Participants | 32 Participants | 14 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 13 / 21 | 18 / 26 |
| other Total, other adverse events | 21 / 21 | 26 / 26 |
| serious Total, serious adverse events | 13 / 21 | 13 / 26 |
Outcome results
Primary
Number of Participants With Dose Limiting Toxicity (DLT)
Sunitinib (SU) and radiation (IGRT) doses were sequentially escalated using a ping-pong strategy according to a 3 + 3 design phase 1 study. The starting dose was sunitinib 25 mg and IGRT 40 Gy. MTD reflects the highest dose that did not cause a dose limiting toxicity. Toxicity was in assessed in patients at regular intervals by using the Common Terminology Criteria for Adverse Events criteria (version 3.0). Dose limiting events were defined as any grade 4 or 5 toxicity and unexpected grade 3 toxicity. Expected grade 3 toxicities from radiation include mucositis or esophagitis lasting ≤7 days. Grade 3 metabolic and hematologic toxicities are considered expected events with sunitinib and therefore were not considered DLTs
Time frame: 2 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
| Phase 1 - Radiation 40Gy + Suniitnib 37.5 mg | Number of Participants With Dose Limiting Toxicity (DLT) | 0 Participants |
| Phase 1 - Radiation 50Gy + Sunitinib 37.5mg | Number of Participants With Dose Limiting Toxicity (DLT) | 1 Participants |
| Phase 1 - Radiation 50Gy + Sunitinib 50mg | Number of Participants With Dose Limiting Toxicity (DLT) | 2 Participants |
Primary
Number of Participants With Particular Disease Status
Number of participants who have no evidence of disease and number of participants with distant metastases.
Time frame: 5 years
Population: Phase 2 only
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants With Particular Disease Status | No evidence of disease | 12 participants |
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants With Particular Disease Status | distant metastases | 3 participants |
Secondary
Number of Participants According Failure and Survival
Time frame: 4 years
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants According Failure and Survival | alive without evidence of disease | 12 Participants |
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants According Failure and Survival | alive with distant metastases | 3 Participants |
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants According Failure and Survival | dead from distant metasteses | 22 Participants |
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants According Failure and Survival | dead from local progression | 1 Participants |
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants According Failure and Survival | dead from comorbid illness | 6 Participants |
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Number of Participants According Failure and Survival | dead from treatment-related toxicities | 2 Participants |
Secondary
Percentage of Patients With Distant Control
Distant control defined as distant metastasis contained outside of the radiation field within months of treatment.
Time frame: 4 weeks
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Percentage of Patients With Distant Control | 40 percentage of participants |
Secondary
Percentage of Patients With Local Control
Local control was defined as a tumor volume equal to or less than the tumor volume at start of radiotherapy.
Time frame: 4 years
Population: the 4-year estimates for local control
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Percentage of Patients With Local Control | 75 percentage of participants |
Secondary
Percentage of Patients With Toxicity Grade 3 or Higher
% of patients experienced one or more grade ≥ 3 toxicities. Toxicity is graded as mild (Grade 1), moderate (Grade 2), severe (Grade 3), or life-threatening (Grade 4),and death (Grade 5).
Time frame: 5 years
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Phase 1 - Radiation 40Gy + Sunitinib 25 mg | Percentage of Patients With Toxicity Grade 3 or Higher | 15 Participants |
Secondary
Quality of Life
Time frame: 4-6 weeks after radiation therapy
Population: data not collected